AVAHO

The US Department of Veterans Affairs (VA) is home to the Veterans Health Administration (VHA), which delivers care at 1,255 health care facilities, including 170 medical centers. The VA serves 6 million veterans each year and is the largest integrated provider of cancer care in the US. The system uses a single, enterprise-wide electronic health record. The detailed curation of clinical outcomes, laboratory results, and radiology is used in VA efforts to improve oncology outcomes for veterans. The VA also has a National Precision Oncology Program (NPOP), which offers system-wide DNA sequencing for veterans with cancer. Given its size, integration, and capabilities, the VA is an ideal setting for rapid learning cycles of testing and implementing best practices at scale.

Prostate cancer is the most common malignancy affecting men in the US. It is the most commonly-diagnosed solid tumor in the VA, and in 2014, there were 11,376 prostate cancer diagnoses in the VA.¹ The clinical characteristics and treatment of veterans with prostate cancer largely parallel the broader population of men in the US.¹ Although the majority of men diagnosed with prostate cancer have disease localized to the prostate, an important minority develop metastatic disease, which represents a risk for substantial morbidity and is the lethal form of the disease. Research has yielded transformative advances in the care of men with metastatic prostate cancer, including drugs targeting the testosterone/androgen signaling axis, taxane chemotherapy, the radionuclide radium-223, and a dendritic cell vaccine. Unfortunately, the magnitude and duration of response to these therapies varies widely, and determining the biology relevant to an individual patient that would better inform their treatment decisions is a critical next step. As the ability to interrogate the cancer genome has improved, relevant drivers of tumorigenesis and predictive biomarkers are being identified rapidly, and oncology care has evolved from a one-size-fits-all approach to a precision approach, which uses these biomarkers to assist in therapeutic decision making.

Precision Oncology for Prostate Cancer

A series of studies interrogating the genomics of metastatic prostate cancer have been critical to defining the relevance of precision oncology for prostate cancer. Most of what is known about the genomics of prostate cancer has been derived from analysis of samples from the prostate itself. These samples may not reflect the biology of metastasis and genetic evolution in response to treatment pressure, so the genomic alterations in metastatic disease remained incompletely characterized. Two large research teams supported by grants from the American Association for Cancer Research, Stand Up 2 Cancer, and Prostate Cancer Foundation (PCF) focused their efforts on sampling and analyzing metastatic tissue to define the most relevant genomic alterations in advanced prostate cancer.

These efforts defined a broad range of relatively common alterations in the androgen receptor, as well as the tumor suppressors TP53 and PTEN.^2,3 Important subsets of less common alterations in pathways that were potentially targetable were also found, including new alterations in PIK3CA/B, BRAF/RAF1, and β-catenin. Most surprisingly, alterations of DNA repair pathways, including mismatch repair and homologous recombination were found in 20% of tumors, and half of these tumors contained germline alterations. The same groups performed a follow up analysis of germline DNA from men with metastatic prostate cancer, which confirmed that 12% of these patients carry a pathogenic germline alteration in a DNA repair pathway gene.⁴ These efforts immediately invigorated precision oncology clinical trials for prostate cancer and spurred an effort to find the molecular alterations that could be leveraged to improve care for men with advanced prostate cancer.

Targetable Alterations

Currently a number of genomic alterations are immediately actionable. There are several agents approved by the US Food and Drug Administration (FDA) that exploit these Achilles heels of prostate cancer. Mismatch repair deficiency occurs when any of a group of genes responsible for proofreading the fidelity of DNA replication is compromised by mutation or deletion. Imperfect reading and correction subsequently lead to many DNA mutations in a tissue (hypermutation), which then increases the risk of developing malignancy. If a defective gene in the mismatch repair pathway is inherited, a patient has a genetic predisposition to specific malignancies that are part of the Lynch syndrome.⁵ Prostate cancer is a relatively rare manifestation of Lynch syndrome, although it is considered one of the malignancies in the Lynch syndrome spectrum.⁶

Alteration of one of the mismatch repair genes also can occur spontaneously in a tumor, resulting in the same high frequency of spontaneous DNA mutations. Overall, between 3% and 5% of metastatic prostate cancers contain mismatch repair deficiency. The majority of these cases are a result of spontaneous loss or mutation of the relevant gene, but 1 in 5 of these tumors occurs as a component of Lynch syndrome.⁷ Identification of mismatch repair deficiency is critical because the resulting hypermutation makes these tumors particularly susceptible to intervention with immunotherapy. Up to half of patients with metastatic prostate cancer can have durable responses. This finding is consistent with the experience treating other malignancies with mismatch repair deficiency.⁸ Although screening for mismatch repair deficiency is standard of care for patients with malignancies such as colorectal cancer, few patients with prostate cancer may receive the mismatch repair deficiency screening (based on unpublished data). In contrast, screening is routine for patients with adenocarcinoma of the lung because their proportion of ROS1 and ALK alterations is similar to the frequency of mismatch repair deficiency when compared with patients with prostate cancer.⁹

Homologous recombination is another mechanism by which cells repair DNA damage and is responsible for repairing double strand breaks, the type of DNA damage most likely to lead to carcinogenesis. In advanced prostate cancer, BRCA2, ATM, BRCA1 and other members of the Fanconi Anemia/BRCA gene family are altered 20% of the time. These genes also are the most common germline alterations implicated in the development of prostate cancer.^2,10 Prostate cancer is considered a BRCA-related cancer much like breast, ovarian, and pancreatic cancers. Defects in homologous recombination repair make BRCA-altered prostate cancers susceptible to DNA damaging chemotherapy, such as platinum and to the use of poly–(adenosine diphosphate–ribose) polymerase (PARP) inhibitors because cancer cells then accumulate cytotoxic and apoptotic levels of DNA.¹¹

In May 2020, the FDA approved the use of PARP inhibitors for the treatment of prostate cancers that contain BRCA and other DNA repair alterations. Rucaparib received accelerated approval for the treatment of prostate cancers containing BRCA alterations and olaparib received full approval for treatment of prostate cancers containing an array of alterations in DNA repair genes.^12,13 Both approvals were the direct result of the cited landmark studies that demonstrated the frequency of these alterations in advanced prostate cancer.^2,3

Beyond mismatch and homologous recombination repair, there are a large number of potentially targetable alterations found in advanced prostate cancer. It is thus critical that we put systems into place both to find germline and somatic alterations that will inform a veteran’s clinical care and to provide veterans access to precision oncology clinical trials.

The POPCaP Network

Because prostate cancer is such a significant issue in the VA and best practices for precision oncology can be implemented broadly once defined as successful, the PCF and the VA formed a collaboration to support a network of centers that would focus on implementing a comprehensive strategy for precision oncology in prostate cancer. There are currently 11 centers in the Precision Oncology Program for Cancer of the Prostate (POPCaP) network (Figure). These centers are tasked with comprehensively sequencing germline and somatic tissue from veterans with metastatic prostate cancer to find alterations, which could provide access to treatments that would otherwise not be available or appropriate.

The network is collaborating with NPOP, which provides clinical grade tumor gene panel sequencing for veterans with prostate cancer from > 90% of VA medical centers. POPCaP also partners with the University of Washington to use its OncoPlex gene panel and University of Michigan to use the Oncomine panel to define the best platform for defining targetable alterations for veterans with prostate cancer. Investigators participate in a monthly molecular oncology tumor board continuing medical education-accredited program, which provides guidance and education across the VA about the evidence available to assist in decision making for veterans sequenced through NPOP and the academic platforms. These efforts leverage VA’s partnership with IBM Watson for Genomics to annotate DNA sequencing results to provide clinicians with potential therapeutic options for veterans.

A clinical trials mechanism is embedded in POPCaP to broaden treatment options, improve care for men with prostate cancer, and leverage the sequencing efforts in the network. The Prostate Cancer Analysis for Therapy Choice (PATCH) clinical trials network employs an umbrella study approach whereby alterations are identified through sequencing and veterans are given access to studies embedded at sites across the network. Graff and Huang provide a detailed description of the PATCH network and its potential as a multisite clinical trials mechanism.¹⁴ For studies within the network, funds can be provided to support travel to participate in clinical trials for veterans who would be eligible for study but do not live in a catchment for a network site. POPCaP also leverages both the resources of the National Cancer Institute (NCI)-designated cancer centers that are VA academic affiliates, as well as a VA/NCI partnership (NAVIGATE) to increase veteran access to NCI cutting-edge clinical trials.

The network has regular teleconference meetings of the investigators, coordinators, and stakeholders and face-to-face meetings, which are coordinated around other national meetings. These meetings enable investigators to work collaboratively to advance current knowledge in prostate cancer through the application of complementary and synergistic research approaches. Since research plays a critical role within the learning health care system, POPCaP investigators are working to optimize the transfer of knowledge from the clinic to the bench and back to the clinic. In this regard, investigators from network sites have organized themselves into working groups to focus on multiple critical aspects of research and care within the network, including sequencing, phenotyping, health services, health disparities, and a network biorepository.

VA Office of Research and Development

With support from the VA Office of Research and Development, there are research efforts focused on the development of data analytics to identify veterans with metastatic prostate cancer within the electronic health record to ensure access to appropriate testing, treatment, and clinical trials. This will optimize tracking and continuous quality improvement in precision oncology. The Office of Research and Development also supports the use of artificial intelligence to identify predictive markers for diagnosis, prognosis, therapeutic response and patient stratification. POPCaP investigators, along with other investigators from across the VA, conduct research that continually improves the care of veterans with prostate cancer. POPCaP has a special focus on prostate cancer among African Americans, who are disproportionately affected by the disease and well represented in VA. The efforts of the working groups, the research studies and the network as a whole also serve to recruit both junior and senior investigators to the VA in order to support the VA research enterprise.

Active collaborations between the network and other elements of VA include efforts to optimize germline testing and genetic counseling in prostate cancer through the Genomic Medicine Service, which provides telehealth genetic counseling throughout the VA. POPCaP pilots innovative approaches to increase access to clinical genetics and genetic counseling services to support the volume of genetic testing of veterans with cancer. Current National Comprehensive Cancer Network (NCCN) guidelines recommend germline testing for all men with metastatic prostate cancer, which can efficiently identify the roughly 10% of veterans with metastatic disease who carry a germline alteration and provide them with access to studies, FDA-approved treatments, while also offering critical health care information to family members who may also carry a pathogenic germline alteration.

Million Veteran Program

The Million Veteran Program (MVP) has collected > 825,000 germline DNA samples from an anticipated enrollment of > 1 million veterans in one of the most ambitious genetic research efforts to correlate how germline DNA interacts with lifestyle, medications and military exposure to affect health and illness (www.research.va.gov/mvp). MVP is a racially and ethnically diverse veteran cohort that is roughly 20% African American and 7% Hispanic. More than 40,000 of the participants have had prostate cancer, one third of whom are African Americans, giving researchers unprecedented ability to discover factors that impact the development and treatment of the disease in this population. In particular, MVP will provide unique insights into the genetic mutations that drive the development of aggressive prostate cancer in all male veterans, including African Americans. These discoveries will undoubtedly lead to improved screening of and treatment for prostate cancer.

In order to demonstrate clinical utility as well as the infrastructure needs to scale up within the VHA, MVP has launched a pilot project that offers to return clinically actionable genetic results to MVP participants with metastatic prostate cancer, opening the door to new therapies to improve the length and quality of these veterans’ lives. Importantly, the pilot includes cascade testing in family members of enrolled veterans. Given that the original MVP consent did not allow for return of results, and MVP genetic testing is research grade, veterans who volunteer will provide a second consent and undergo clinical genetic testing to confirm the variants. Results from this pilot study also will inform expansion of VA precision oncology efforts for patients with other cancers such as breast cancer or ovarian cancer, where the specific genetic mutations are known to play a role, (eg, BRCA2). In addition, through an interagency agreement with the US Department of Energy (DOE), MVP is leveraging DOE expertise and high-performance computing capabilities to identify clinical and genetic risk factors for prostate cancer that will progress to metastatic disease.

This active research collaboration between POPCaP, MVP, and the Genomic Medicine Service will identify germline BRCA alterations from MVP participants with metastatic prostate cancer and give them access to therapies that may provide better outcomes and access to genetic testing for their family members.

Future Directions

The POPCaP network and its partnership with VA clinical and research efforts is anticipated to provide important insights into barriers and solutions to the implementation of precision oncology for prostate cancer across the VA. These lessons learned may also be relevant for precision oncology care in other settings. As an example, the role of germline testing and genetic counseling is growing more relevant in precision oncology, yet it is clear that the number of men and women dealing with malignancy who actually receive counseling and testing is suboptimal in most health care systems.¹⁴ Optimizing the quality and efficiency of oncogenetics within the VA system in a manner that gives access to these services for every veteran in urban or rural environments is an important goal.

The VA has done extensive work in teleoncology and the Genomic Medicine Service provides telehealth genetic counseling service to 90 VA medical facilities nationwide. Expanding on this model to create a distributed network system across the country is an opportunity that will continue to raise VA profile as a leader in this area while providing increased access to genetic services.

Finally, the clinical trials network within POPCaP already has provided valuable insights into how research efforts that originate within the VA can leverage the VA’s strengths. The use of the NPOP centralized sequencing platform to identify potentially targetable alterations across medical centers provides the potential to bring critical access to research to veterans where they live through virtual clinical trials. The VA has a centralized institutional review board that can service large multisite study participation efficiently across the VA. The promise of virtual clinical trials to interrogate relatively rare biomarkers would benefit from institution of a virtual clinical trials workflow. In theory patients with a potentially targetable biomarker could be identified through the centralized DNA sequencing platform and a clinical trial team of virtual investigators and research coordinators would work with health care providers at sites for study startup and performance. Efforts to design and implement this approach are actively being pursued.

The goal of the VA/PCF POPCaP network is to make certain that every veteran has access to appropriate genetic and genomic testing and that the results are utilized so that veterans with targetable alterations receive the best clinical care and have access to clinical trials that could benefit them individually while advancing knowledge that benefits all.

The US Department of Veterans Affairs (VA) is home to the Veterans Health Administration (VHA), which delivers care at 1,255 health care facilities, including 170 medical centers. The VA serves 6 million veterans each year and is the largest integrated provider of cancer care in the US. The system uses a single, enterprise-wide electronic health record. The detailed curation of clinical outcomes, laboratory results, and radiology is used in VA efforts to improve oncology outcomes for veterans. The VA also has a National Precision Oncology Program (NPOP), which offers system-wide DNA sequencing for veterans with cancer. Given its size, integration, and capabilities, the VA is an ideal setting for rapid learning cycles of testing and implementing best practices at scale.

Prostate cancer is the most common malignancy affecting men in the US. It is the most commonly-diagnosed solid tumor in the VA, and in 2014, there were 11,376 prostate cancer diagnoses in the VA.¹ The clinical characteristics and treatment of veterans with prostate cancer largely parallel the broader population of men in the US.¹ Although the majority of men diagnosed with prostate cancer have disease localized to the prostate, an important minority develop metastatic disease, which represents a risk for substantial morbidity and is the lethal form of the disease. Research has yielded transformative advances in the care of men with metastatic prostate cancer, including drugs targeting the testosterone/androgen signaling axis, taxane chemotherapy, the radionuclide radium-223, and a dendritic cell vaccine. Unfortunately, the magnitude and duration of response to these therapies varies widely, and determining the biology relevant to an individual patient that would better inform their treatment decisions is a critical next step. As the ability to interrogate the cancer genome has improved, relevant drivers of tumorigenesis and predictive biomarkers are being identified rapidly, and oncology care has evolved from a one-size-fits-all approach to a precision approach, which uses these biomarkers to assist in therapeutic decision making.

Precision Oncology for Prostate Cancer

A series of studies interrogating the genomics of metastatic prostate cancer have been critical to defining the relevance of precision oncology for prostate cancer. Most of what is known about the genomics of prostate cancer has been derived from analysis of samples from the prostate itself. These samples may not reflect the biology of metastasis and genetic evolution in response to treatment pressure, so the genomic alterations in metastatic disease remained incompletely characterized. Two large research teams supported by grants from the American Association for Cancer Research, Stand Up 2 Cancer, and Prostate Cancer Foundation (PCF) focused their efforts on sampling and analyzing metastatic tissue to define the most relevant genomic alterations in advanced prostate cancer.

These efforts defined a broad range of relatively common alterations in the androgen receptor, as well as the tumor suppressors TP53 and PTEN.^2,3 Important subsets of less common alterations in pathways that were potentially targetable were also found, including new alterations in PIK3CA/B, BRAF/RAF1, and β-catenin. Most surprisingly, alterations of DNA repair pathways, including mismatch repair and homologous recombination were found in 20% of tumors, and half of these tumors contained germline alterations. The same groups performed a follow up analysis of germline DNA from men with metastatic prostate cancer, which confirmed that 12% of these patients carry a pathogenic germline alteration in a DNA repair pathway gene.⁴ These efforts immediately invigorated precision oncology clinical trials for prostate cancer and spurred an effort to find the molecular alterations that could be leveraged to improve care for men with advanced prostate cancer.

Targetable Alterations

Currently a number of genomic alterations are immediately actionable. There are several agents approved by the US Food and Drug Administration (FDA) that exploit these Achilles heels of prostate cancer. Mismatch repair deficiency occurs when any of a group of genes responsible for proofreading the fidelity of DNA replication is compromised by mutation or deletion. Imperfect reading and correction subsequently lead to many DNA mutations in a tissue (hypermutation), which then increases the risk of developing malignancy. If a defective gene in the mismatch repair pathway is inherited, a patient has a genetic predisposition to specific malignancies that are part of the Lynch syndrome.⁵ Prostate cancer is a relatively rare manifestation of Lynch syndrome, although it is considered one of the malignancies in the Lynch syndrome spectrum.⁶

Alteration of one of the mismatch repair genes also can occur spontaneously in a tumor, resulting in the same high frequency of spontaneous DNA mutations. Overall, between 3% and 5% of metastatic prostate cancers contain mismatch repair deficiency. The majority of these cases are a result of spontaneous loss or mutation of the relevant gene, but 1 in 5 of these tumors occurs as a component of Lynch syndrome.⁷ Identification of mismatch repair deficiency is critical because the resulting hypermutation makes these tumors particularly susceptible to intervention with immunotherapy. Up to half of patients with metastatic prostate cancer can have durable responses. This finding is consistent with the experience treating other malignancies with mismatch repair deficiency.⁸ Although screening for mismatch repair deficiency is standard of care for patients with malignancies such as colorectal cancer, few patients with prostate cancer may receive the mismatch repair deficiency screening (based on unpublished data). In contrast, screening is routine for patients with adenocarcinoma of the lung because their proportion of ROS1 and ALK alterations is similar to the frequency of mismatch repair deficiency when compared with patients with prostate cancer.⁹

Homologous recombination is another mechanism by which cells repair DNA damage and is responsible for repairing double strand breaks, the type of DNA damage most likely to lead to carcinogenesis. In advanced prostate cancer, BRCA2, ATM, BRCA1 and other members of the Fanconi Anemia/BRCA gene family are altered 20% of the time. These genes also are the most common germline alterations implicated in the development of prostate cancer.^2,10 Prostate cancer is considered a BRCA-related cancer much like breast, ovarian, and pancreatic cancers. Defects in homologous recombination repair make BRCA-altered prostate cancers susceptible to DNA damaging chemotherapy, such as platinum and to the use of poly–(adenosine diphosphate–ribose) polymerase (PARP) inhibitors because cancer cells then accumulate cytotoxic and apoptotic levels of DNA.¹¹

In May 2020, the FDA approved the use of PARP inhibitors for the treatment of prostate cancers that contain BRCA and other DNA repair alterations. Rucaparib received accelerated approval for the treatment of prostate cancers containing BRCA alterations and olaparib received full approval for treatment of prostate cancers containing an array of alterations in DNA repair genes.^12,13 Both approvals were the direct result of the cited landmark studies that demonstrated the frequency of these alterations in advanced prostate cancer.^2,3

Beyond mismatch and homologous recombination repair, there are a large number of potentially targetable alterations found in advanced prostate cancer. It is thus critical that we put systems into place both to find germline and somatic alterations that will inform a veteran’s clinical care and to provide veterans access to precision oncology clinical trials.

The POPCaP Network

Because prostate cancer is such a significant issue in the VA and best practices for precision oncology can be implemented broadly once defined as successful, the PCF and the VA formed a collaboration to support a network of centers that would focus on implementing a comprehensive strategy for precision oncology in prostate cancer. There are currently 11 centers in the Precision Oncology Program for Cancer of the Prostate (POPCaP) network (Figure). These centers are tasked with comprehensively sequencing germline and somatic tissue from veterans with metastatic prostate cancer to find alterations, which could provide access to treatments that would otherwise not be available or appropriate.

The network is collaborating with NPOP, which provides clinical grade tumor gene panel sequencing for veterans with prostate cancer from > 90% of VA medical centers. POPCaP also partners with the University of Washington to use its OncoPlex gene panel and University of Michigan to use the Oncomine panel to define the best platform for defining targetable alterations for veterans with prostate cancer. Investigators participate in a monthly molecular oncology tumor board continuing medical education-accredited program, which provides guidance and education across the VA about the evidence available to assist in decision making for veterans sequenced through NPOP and the academic platforms. These efforts leverage VA’s partnership with IBM Watson for Genomics to annotate DNA sequencing results to provide clinicians with potential therapeutic options for veterans.

A clinical trials mechanism is embedded in POPCaP to broaden treatment options, improve care for men with prostate cancer, and leverage the sequencing efforts in the network. The Prostate Cancer Analysis for Therapy Choice (PATCH) clinical trials network employs an umbrella study approach whereby alterations are identified through sequencing and veterans are given access to studies embedded at sites across the network. Graff and Huang provide a detailed description of the PATCH network and its potential as a multisite clinical trials mechanism.¹⁴ For studies within the network, funds can be provided to support travel to participate in clinical trials for veterans who would be eligible for study but do not live in a catchment for a network site. POPCaP also leverages both the resources of the National Cancer Institute (NCI)-designated cancer centers that are VA academic affiliates, as well as a VA/NCI partnership (NAVIGATE) to increase veteran access to NCI cutting-edge clinical trials.

The network has regular teleconference meetings of the investigators, coordinators, and stakeholders and face-to-face meetings, which are coordinated around other national meetings. These meetings enable investigators to work collaboratively to advance current knowledge in prostate cancer through the application of complementary and synergistic research approaches. Since research plays a critical role within the learning health care system, POPCaP investigators are working to optimize the transfer of knowledge from the clinic to the bench and back to the clinic. In this regard, investigators from network sites have organized themselves into working groups to focus on multiple critical aspects of research and care within the network, including sequencing, phenotyping, health services, health disparities, and a network biorepository.

VA Office of Research and Development

With support from the VA Office of Research and Development, there are research efforts focused on the development of data analytics to identify veterans with metastatic prostate cancer within the electronic health record to ensure access to appropriate testing, treatment, and clinical trials. This will optimize tracking and continuous quality improvement in precision oncology. The Office of Research and Development also supports the use of artificial intelligence to identify predictive markers for diagnosis, prognosis, therapeutic response and patient stratification. POPCaP investigators, along with other investigators from across the VA, conduct research that continually improves the care of veterans with prostate cancer. POPCaP has a special focus on prostate cancer among African Americans, who are disproportionately affected by the disease and well represented in VA. The efforts of the working groups, the research studies and the network as a whole also serve to recruit both junior and senior investigators to the VA in order to support the VA research enterprise.

Active collaborations between the network and other elements of VA include efforts to optimize germline testing and genetic counseling in prostate cancer through the Genomic Medicine Service, which provides telehealth genetic counseling throughout the VA. POPCaP pilots innovative approaches to increase access to clinical genetics and genetic counseling services to support the volume of genetic testing of veterans with cancer. Current National Comprehensive Cancer Network (NCCN) guidelines recommend germline testing for all men with metastatic prostate cancer, which can efficiently identify the roughly 10% of veterans with metastatic disease who carry a germline alteration and provide them with access to studies, FDA-approved treatments, while also offering critical health care information to family members who may also carry a pathogenic germline alteration.

Million Veteran Program

The Million Veteran Program (MVP) has collected > 825,000 germline DNA samples from an anticipated enrollment of > 1 million veterans in one of the most ambitious genetic research efforts to correlate how germline DNA interacts with lifestyle, medications and military exposure to affect health and illness (www.research.va.gov/mvp). MVP is a racially and ethnically diverse veteran cohort that is roughly 20% African American and 7% Hispanic. More than 40,000 of the participants have had prostate cancer, one third of whom are African Americans, giving researchers unprecedented ability to discover factors that impact the development and treatment of the disease in this population. In particular, MVP will provide unique insights into the genetic mutations that drive the development of aggressive prostate cancer in all male veterans, including African Americans. These discoveries will undoubtedly lead to improved screening of and treatment for prostate cancer.

In order to demonstrate clinical utility as well as the infrastructure needs to scale up within the VHA, MVP has launched a pilot project that offers to return clinically actionable genetic results to MVP participants with metastatic prostate cancer, opening the door to new therapies to improve the length and quality of these veterans’ lives. Importantly, the pilot includes cascade testing in family members of enrolled veterans. Given that the original MVP consent did not allow for return of results, and MVP genetic testing is research grade, veterans who volunteer will provide a second consent and undergo clinical genetic testing to confirm the variants. Results from this pilot study also will inform expansion of VA precision oncology efforts for patients with other cancers such as breast cancer or ovarian cancer, where the specific genetic mutations are known to play a role, (eg, BRCA2). In addition, through an interagency agreement with the US Department of Energy (DOE), MVP is leveraging DOE expertise and high-performance computing capabilities to identify clinical and genetic risk factors for prostate cancer that will progress to metastatic disease.

This active research collaboration between POPCaP, MVP, and the Genomic Medicine Service will identify germline BRCA alterations from MVP participants with metastatic prostate cancer and give them access to therapies that may provide better outcomes and access to genetic testing for their family members.

Future Directions

The POPCaP network and its partnership with VA clinical and research efforts is anticipated to provide important insights into barriers and solutions to the implementation of precision oncology for prostate cancer across the VA. These lessons learned may also be relevant for precision oncology care in other settings. As an example, the role of germline testing and genetic counseling is growing more relevant in precision oncology, yet it is clear that the number of men and women dealing with malignancy who actually receive counseling and testing is suboptimal in most health care systems.¹⁴ Optimizing the quality and efficiency of oncogenetics within the VA system in a manner that gives access to these services for every veteran in urban or rural environments is an important goal.

The VA has done extensive work in teleoncology and the Genomic Medicine Service provides telehealth genetic counseling service to 90 VA medical facilities nationwide. Expanding on this model to create a distributed network system across the country is an opportunity that will continue to raise VA profile as a leader in this area while providing increased access to genetic services.

Finally, the clinical trials network within POPCaP already has provided valuable insights into how research efforts that originate within the VA can leverage the VA’s strengths. The use of the NPOP centralized sequencing platform to identify potentially targetable alterations across medical centers provides the potential to bring critical access to research to veterans where they live through virtual clinical trials. The VA has a centralized institutional review board that can service large multisite study participation efficiently across the VA. The promise of virtual clinical trials to interrogate relatively rare biomarkers would benefit from institution of a virtual clinical trials workflow. In theory patients with a potentially targetable biomarker could be identified through the centralized DNA sequencing platform and a clinical trial team of virtual investigators and research coordinators would work with health care providers at sites for study startup and performance. Efforts to design and implement this approach are actively being pursued.

The goal of the VA/PCF POPCaP network is to make certain that every veteran has access to appropriate genetic and genomic testing and that the results are utilized so that veterans with targetable alterations receive the best clinical care and have access to clinical trials that could benefit them individually while advancing knowledge that benefits all.

The US Department of Veterans Affairs (VA) is home to the Veterans Health Administration (VHA), which delivers care at 1,255 health care facilities, including 170 medical centers. The VA serves 6 million veterans each year and is the largest integrated provider of cancer care in the US. The system uses a single, enterprise-wide electronic health record. The detailed curation of clinical outcomes, laboratory results, and radiology is used in VA efforts to improve oncology outcomes for veterans. The VA also has a National Precision Oncology Program (NPOP), which offers system-wide DNA sequencing for veterans with cancer. Given its size, integration, and capabilities, the VA is an ideal setting for rapid learning cycles of testing and implementing best practices at scale.

Prostate cancer is the most common malignancy affecting men in the US. It is the most commonly-diagnosed solid tumor in the VA, and in 2014, there were 11,376 prostate cancer diagnoses in the VA.¹ The clinical characteristics and treatment of veterans with prostate cancer largely parallel the broader population of men in the US.¹ Although the majority of men diagnosed with prostate cancer have disease localized to the prostate, an important minority develop metastatic disease, which represents a risk for substantial morbidity and is the lethal form of the disease. Research has yielded transformative advances in the care of men with metastatic prostate cancer, including drugs targeting the testosterone/androgen signaling axis, taxane chemotherapy, the radionuclide radium-223, and a dendritic cell vaccine. Unfortunately, the magnitude and duration of response to these therapies varies widely, and determining the biology relevant to an individual patient that would better inform their treatment decisions is a critical next step. As the ability to interrogate the cancer genome has improved, relevant drivers of tumorigenesis and predictive biomarkers are being identified rapidly, and oncology care has evolved from a one-size-fits-all approach to a precision approach, which uses these biomarkers to assist in therapeutic decision making.

Precision Oncology for Prostate Cancer

A series of studies interrogating the genomics of metastatic prostate cancer have been critical to defining the relevance of precision oncology for prostate cancer. Most of what is known about the genomics of prostate cancer has been derived from analysis of samples from the prostate itself. These samples may not reflect the biology of metastasis and genetic evolution in response to treatment pressure, so the genomic alterations in metastatic disease remained incompletely characterized. Two large research teams supported by grants from the American Association for Cancer Research, Stand Up 2 Cancer, and Prostate Cancer Foundation (PCF) focused their efforts on sampling and analyzing metastatic tissue to define the most relevant genomic alterations in advanced prostate cancer.

These efforts defined a broad range of relatively common alterations in the androgen receptor, as well as the tumor suppressors TP53 and PTEN.^2,3 Important subsets of less common alterations in pathways that were potentially targetable were also found, including new alterations in PIK3CA/B, BRAF/RAF1, and β-catenin. Most surprisingly, alterations of DNA repair pathways, including mismatch repair and homologous recombination were found in 20% of tumors, and half of these tumors contained germline alterations. The same groups performed a follow up analysis of germline DNA from men with metastatic prostate cancer, which confirmed that 12% of these patients carry a pathogenic germline alteration in a DNA repair pathway gene.⁴ These efforts immediately invigorated precision oncology clinical trials for prostate cancer and spurred an effort to find the molecular alterations that could be leveraged to improve care for men with advanced prostate cancer.

Targetable Alterations

Currently a number of genomic alterations are immediately actionable. There are several agents approved by the US Food and Drug Administration (FDA) that exploit these Achilles heels of prostate cancer. Mismatch repair deficiency occurs when any of a group of genes responsible for proofreading the fidelity of DNA replication is compromised by mutation or deletion. Imperfect reading and correction subsequently lead to many DNA mutations in a tissue (hypermutation), which then increases the risk of developing malignancy. If a defective gene in the mismatch repair pathway is inherited, a patient has a genetic predisposition to specific malignancies that are part of the Lynch syndrome.⁵ Prostate cancer is a relatively rare manifestation of Lynch syndrome, although it is considered one of the malignancies in the Lynch syndrome spectrum.⁶

Alteration of one of the mismatch repair genes also can occur spontaneously in a tumor, resulting in the same high frequency of spontaneous DNA mutations. Overall, between 3% and 5% of metastatic prostate cancers contain mismatch repair deficiency. The majority of these cases are a result of spontaneous loss or mutation of the relevant gene, but 1 in 5 of these tumors occurs as a component of Lynch syndrome.⁷ Identification of mismatch repair deficiency is critical because the resulting hypermutation makes these tumors particularly susceptible to intervention with immunotherapy. Up to half of patients with metastatic prostate cancer can have durable responses. This finding is consistent with the experience treating other malignancies with mismatch repair deficiency.⁸ Although screening for mismatch repair deficiency is standard of care for patients with malignancies such as colorectal cancer, few patients with prostate cancer may receive the mismatch repair deficiency screening (based on unpublished data). In contrast, screening is routine for patients with adenocarcinoma of the lung because their proportion of ROS1 and ALK alterations is similar to the frequency of mismatch repair deficiency when compared with patients with prostate cancer.⁹

Homologous recombination is another mechanism by which cells repair DNA damage and is responsible for repairing double strand breaks, the type of DNA damage most likely to lead to carcinogenesis. In advanced prostate cancer, BRCA2, ATM, BRCA1 and other members of the Fanconi Anemia/BRCA gene family are altered 20% of the time. These genes also are the most common germline alterations implicated in the development of prostate cancer.^2,10 Prostate cancer is considered a BRCA-related cancer much like breast, ovarian, and pancreatic cancers. Defects in homologous recombination repair make BRCA-altered prostate cancers susceptible to DNA damaging chemotherapy, such as platinum and to the use of poly–(adenosine diphosphate–ribose) polymerase (PARP) inhibitors because cancer cells then accumulate cytotoxic and apoptotic levels of DNA.¹¹

In May 2020, the FDA approved the use of PARP inhibitors for the treatment of prostate cancers that contain BRCA and other DNA repair alterations. Rucaparib received accelerated approval for the treatment of prostate cancers containing BRCA alterations and olaparib received full approval for treatment of prostate cancers containing an array of alterations in DNA repair genes.^12,13 Both approvals were the direct result of the cited landmark studies that demonstrated the frequency of these alterations in advanced prostate cancer.^2,3

Beyond mismatch and homologous recombination repair, there are a large number of potentially targetable alterations found in advanced prostate cancer. It is thus critical that we put systems into place both to find germline and somatic alterations that will inform a veteran’s clinical care and to provide veterans access to precision oncology clinical trials.

The POPCaP Network

Because prostate cancer is such a significant issue in the VA and best practices for precision oncology can be implemented broadly once defined as successful, the PCF and the VA formed a collaboration to support a network of centers that would focus on implementing a comprehensive strategy for precision oncology in prostate cancer. There are currently 11 centers in the Precision Oncology Program for Cancer of the Prostate (POPCaP) network (Figure). These centers are tasked with comprehensively sequencing germline and somatic tissue from veterans with metastatic prostate cancer to find alterations, which could provide access to treatments that would otherwise not be available or appropriate.

The network is collaborating with NPOP, which provides clinical grade tumor gene panel sequencing for veterans with prostate cancer from > 90% of VA medical centers. POPCaP also partners with the University of Washington to use its OncoPlex gene panel and University of Michigan to use the Oncomine panel to define the best platform for defining targetable alterations for veterans with prostate cancer. Investigators participate in a monthly molecular oncology tumor board continuing medical education-accredited program, which provides guidance and education across the VA about the evidence available to assist in decision making for veterans sequenced through NPOP and the academic platforms. These efforts leverage VA’s partnership with IBM Watson for Genomics to annotate DNA sequencing results to provide clinicians with potential therapeutic options for veterans.

A clinical trials mechanism is embedded in POPCaP to broaden treatment options, improve care for men with prostate cancer, and leverage the sequencing efforts in the network. The Prostate Cancer Analysis for Therapy Choice (PATCH) clinical trials network employs an umbrella study approach whereby alterations are identified through sequencing and veterans are given access to studies embedded at sites across the network. Graff and Huang provide a detailed description of the PATCH network and its potential as a multisite clinical trials mechanism.¹⁴ For studies within the network, funds can be provided to support travel to participate in clinical trials for veterans who would be eligible for study but do not live in a catchment for a network site. POPCaP also leverages both the resources of the National Cancer Institute (NCI)-designated cancer centers that are VA academic affiliates, as well as a VA/NCI partnership (NAVIGATE) to increase veteran access to NCI cutting-edge clinical trials.

The network has regular teleconference meetings of the investigators, coordinators, and stakeholders and face-to-face meetings, which are coordinated around other national meetings. These meetings enable investigators to work collaboratively to advance current knowledge in prostate cancer through the application of complementary and synergistic research approaches. Since research plays a critical role within the learning health care system, POPCaP investigators are working to optimize the transfer of knowledge from the clinic to the bench and back to the clinic. In this regard, investigators from network sites have organized themselves into working groups to focus on multiple critical aspects of research and care within the network, including sequencing, phenotyping, health services, health disparities, and a network biorepository.

VA Office of Research and Development

With support from the VA Office of Research and Development, there are research efforts focused on the development of data analytics to identify veterans with metastatic prostate cancer within the electronic health record to ensure access to appropriate testing, treatment, and clinical trials. This will optimize tracking and continuous quality improvement in precision oncology. The Office of Research and Development also supports the use of artificial intelligence to identify predictive markers for diagnosis, prognosis, therapeutic response and patient stratification. POPCaP investigators, along with other investigators from across the VA, conduct research that continually improves the care of veterans with prostate cancer. POPCaP has a special focus on prostate cancer among African Americans, who are disproportionately affected by the disease and well represented in VA. The efforts of the working groups, the research studies and the network as a whole also serve to recruit both junior and senior investigators to the VA in order to support the VA research enterprise.

Active collaborations between the network and other elements of VA include efforts to optimize germline testing and genetic counseling in prostate cancer through the Genomic Medicine Service, which provides telehealth genetic counseling throughout the VA. POPCaP pilots innovative approaches to increase access to clinical genetics and genetic counseling services to support the volume of genetic testing of veterans with cancer. Current National Comprehensive Cancer Network (NCCN) guidelines recommend germline testing for all men with metastatic prostate cancer, which can efficiently identify the roughly 10% of veterans with metastatic disease who carry a germline alteration and provide them with access to studies, FDA-approved treatments, while also offering critical health care information to family members who may also carry a pathogenic germline alteration.

Million Veteran Program

The Million Veteran Program (MVP) has collected > 825,000 germline DNA samples from an anticipated enrollment of > 1 million veterans in one of the most ambitious genetic research efforts to correlate how germline DNA interacts with lifestyle, medications and military exposure to affect health and illness (www.research.va.gov/mvp). MVP is a racially and ethnically diverse veteran cohort that is roughly 20% African American and 7% Hispanic. More than 40,000 of the participants have had prostate cancer, one third of whom are African Americans, giving researchers unprecedented ability to discover factors that impact the development and treatment of the disease in this population. In particular, MVP will provide unique insights into the genetic mutations that drive the development of aggressive prostate cancer in all male veterans, including African Americans. These discoveries will undoubtedly lead to improved screening of and treatment for prostate cancer.

In order to demonstrate clinical utility as well as the infrastructure needs to scale up within the VHA, MVP has launched a pilot project that offers to return clinically actionable genetic results to MVP participants with metastatic prostate cancer, opening the door to new therapies to improve the length and quality of these veterans’ lives. Importantly, the pilot includes cascade testing in family members of enrolled veterans. Given that the original MVP consent did not allow for return of results, and MVP genetic testing is research grade, veterans who volunteer will provide a second consent and undergo clinical genetic testing to confirm the variants. Results from this pilot study also will inform expansion of VA precision oncology efforts for patients with other cancers such as breast cancer or ovarian cancer, where the specific genetic mutations are known to play a role, (eg, BRCA2). In addition, through an interagency agreement with the US Department of Energy (DOE), MVP is leveraging DOE expertise and high-performance computing capabilities to identify clinical and genetic risk factors for prostate cancer that will progress to metastatic disease.

This active research collaboration between POPCaP, MVP, and the Genomic Medicine Service will identify germline BRCA alterations from MVP participants with metastatic prostate cancer and give them access to therapies that may provide better outcomes and access to genetic testing for their family members.

Future Directions

The POPCaP network and its partnership with VA clinical and research efforts is anticipated to provide important insights into barriers and solutions to the implementation of precision oncology for prostate cancer across the VA. These lessons learned may also be relevant for precision oncology care in other settings. As an example, the role of germline testing and genetic counseling is growing more relevant in precision oncology, yet it is clear that the number of men and women dealing with malignancy who actually receive counseling and testing is suboptimal in most health care systems.¹⁴ Optimizing the quality and efficiency of oncogenetics within the VA system in a manner that gives access to these services for every veteran in urban or rural environments is an important goal.

The VA has done extensive work in teleoncology and the Genomic Medicine Service provides telehealth genetic counseling service to 90 VA medical facilities nationwide. Expanding on this model to create a distributed network system across the country is an opportunity that will continue to raise VA profile as a leader in this area while providing increased access to genetic services.

Finally, the clinical trials network within POPCaP already has provided valuable insights into how research efforts that originate within the VA can leverage the VA’s strengths. The use of the NPOP centralized sequencing platform to identify potentially targetable alterations across medical centers provides the potential to bring critical access to research to veterans where they live through virtual clinical trials. The VA has a centralized institutional review board that can service large multisite study participation efficiently across the VA. The promise of virtual clinical trials to interrogate relatively rare biomarkers would benefit from institution of a virtual clinical trials workflow. In theory patients with a potentially targetable biomarker could be identified through the centralized DNA sequencing platform and a clinical trial team of virtual investigators and research coordinators would work with health care providers at sites for study startup and performance. Efforts to design and implement this approach are actively being pursued.

The goal of the VA/PCF POPCaP network is to make certain that every veteran has access to appropriate genetic and genomic testing and that the results are utilized so that veterans with targetable alterations receive the best clinical care and have access to clinical trials that could benefit them individually while advancing knowledge that benefits all.

The US Department of Veterans Affairs (VA) oversees the largest integrated health care system in the nation, administering care to 9 million veterans annually throughout its distributed network of 1,255 medical centers and outpatient facilities. Every year, about 50,000 veterans are diagnosed with and treated for cancer in the VA, representing about 3% of all cancer cases in the US.¹ After skin cancer, prostate, colon, and lung cancers are the most common among veterans.¹ One way that VA has sought to improve the care of its large cancer patient population is through the adoption of precision oncology, an ever-evolving practice of analyzing an individual patient’s cancer to inform clinical decision making. Most often, the analysis includes conducting genetic testing of the tumor itself. Here, we describe the opportunities and challenges of integrating germline genetics into precision oncology practice.

The Intersection of Precision Oncology and Germline Genetics

Precision oncology typically refers to genetic testing of tumor DNA to identify genetic variants with potential diagnostic, prognostic, or predictive therapeutic implications. It is enabled by a growing body of knowledge that identifies key drivers of cancer development, coupled with advances in tumor analysis by next-generation sequencing and other technologies and by the availability of new and repurposed therapeutic agents.² Precision oncology has transformed cancer care by targeting both common and rare malignancies with specific therapies that improve clinical outcomes in patients.³

Testing of tumor DNA can reveal both somatic (acquired) and germline (inherited) gene variants. Precision oncology testing strategies can include tumor-only testing with or without subtraction of suspected germline variants, or paired tumor-normal testing with explicit analysis and reporting of genes associated with germline predisposition.² With tumor-only testing, the germline status of variants may be inferred and follow-up germline testing in normal tissue such as blood or saliva can be considered. Paired tumor-normal testing provides distinct advantages over tumor-only testing, including improvement of the mutation detection rate in tumors and streamlining interpretation of results for both the tumor and germline tests.

Regardless of the strategy used, tumor testing has the potential to uncover clinically relevant germline variation associated with heritable cancer susceptibility and other conditions, as well as carrier status for autosomal recessive disorders (eAppendix

Germline Genetic Testing Challenges

Integrating germline genetic testing in precision oncology practice presents challenges at the patient, family, health care provider, and health system levels. Due to these challenges, implementation planning is obligatory, as germline testing has become a standard-of-care for certain tumor types and patients.²

On learning of a germline pathogenic variant or variant of uncertain significance, patients may experience distress and anxiety, especially in the short term.^16-18 In addition, it can be difficult for patients to share germline genetic test results with their family; parents may feel guilty about the possibility of passing on a predisposition to children, and unaffected siblings may experience survivor guilt. For some veterans, there can be concerns about losing service-connected benefits if a genetic factor is found to contribute to their cancer history. In addition, patients may have concerns about discrimination by employers or insurers, including commercial health insurance or long-term care, disability, and life insurance. Yet there are many state and federal laws that ensure some protection from employment and health insurance discrimination based on genetic information.

For cancer care clinicians, incorporating germline testing requires additional responsibilities that can complicate care. Prior to germline genetic testing, genetic counseling with patients is recommended to review the potential benefits, harms, and limitations of genetic testing. Further, posttest genetic counseling is recommended to help the patient understand how the results may influence future cancer risks, provide recommendations for cancer management and prevention, and discuss implications for family members.^9,10 While patients trust their health care providers to help them access and understand their genetic information, most health care providers are unprepared to integrate genetics into their practice; they lack adequate knowledge, skills, and confidence about genetics to effectively deliver genetic services.^19-26 This leads to failure to recognize patients with indications for genetic testing, which often is due to insufficient family history collection. Other errors can include offering germline genetic testing to patients without appropriate indications and with inadequate informed consent procedures. When genetic testing is pursued, lack of knowledge about genetic principles and testing methods can lead to misinterpretation and miscommunication of results, contributing to inappropriate management recommendations. These errors can contribute to under-use, overuse, or misuse of genetic testing that can compromise the quality of patient care.^27,28 With this in mind, thought must be given at the health care system level to develop effective strategies to deliver genetic services to patients. These strategies must address workforce capacity, organizational structure, and education.

Workforce Capacity

The VA clinical genetics workforce needs to expand to keep pace with increasing demand, which will be accelerated by the precision oncology programs for prostate and lung cancers and the VA Teleoncology initiative. In the US there are 10 to 15 genetics professionals per 1,000,000 residents.^29-31 Most genetics professionals work in academic and metropolitan settings, leaving suburban and rural areas underserved. For example, in California, some patients travel up to 386 miles for genetics care (mean, 76.6 miles).³² In the VA, there are only 1 to 2 genetics professionals per 1 million enrollees, about 10-fold fewer than in community care. Meeting clinical needs of patients at the VA is particularly challenging because more than one-third of veterans live in rural areas.³³

We recently surveyed genetics professionals in the VA about their practices and capacity to increase patient throughput (Table). Currently in the VA, there are 8 clinical geneticists, not all of whom practice clinical genetics, and 13 genetic counselors. Five VA programs provide clinical genetic services to local and nearby VA facilities near Boston, Massachusetts; Houston, Texas; Los Angeles and San Francisco, California; and Salt Lake City, Utah. These programs, first developed in 2008, typically are staffed by 1 or 2 genetics professionals. Most patients who are referred to the VA genetics programs are evaluated for hereditary cancer syndromes. Multiple modes of delivery may be used, including in-person, telehealth, telephone, and provider-to-provider e-consults in the EHR.

Genetic Health Care Organization in the VA

Understanding a patient’s genetic background increasingly has become more and more important in the clinic, which necessitates a major shift in health care. Unfortunately, on a national scale, the number of clinical genetics professionals has not kept pace with the need-limiting the ability to grow the traditional genetics workforce in the VA in the near term.^29-31 Thus, we must look to alternative genetic health care models in which other members of the health care team assume some of the genetic evaluation and counseling activities while caring for their cancer patients with referral to a clinical genetics team, as needed.³⁹

Two genetic health care models have been described.⁴⁰ Traditionally, clinical genetic services are coordinated between genetics professionals and other clinicians, organized as a regional genetics center and usually affiliated with an academic medical center. By contrast, the nontraditional genetic health care model integrates genetic services within primary and specialty care. Under the new approach, nongeneticists can be assisted by decision support tools in the EHR that help with assessing family history risk, identifying indications for genetic testing, and suggesting management options based on genetic test results.^41-43

The VA National Precision Oncology Program (NPOP) is shaped by a commitment to be a high reliability organization (HRO). As such, the goal is to create a system of excellence that integrates precision medicine, implementation science, and the learning health care system to improve the health and health care of veterans with cancer. This initiative is establishing the foundations for best-in-class cancer care to enable veterans access to life-saving therapies through a concerted effort that began with the Cancer Moonshot, development of the NPOP, and collaborations with the VA Office of Research and Development. One of the fundamental objectives of this initiative is to implement strategies that ensure clinical genetic services are available to veterans receiving cancer care at all VA facilities and to extend these services to veterans in remote geographic locations nationwide. The initiative aims to synergize VA Teleoncology services that seek to deliver best-in-class oncology care across the VA enterprise using cutting-edge technologies.

Conclusions

To accomplish the goal of delivering world-class clinical genetic services to veterans and meet the increasing needs of precision oncology and support quality genetic health care, the VA must develop an integrated system of genetic health care that will have a network of clinical genetics that interfaces with other clinical and operational programs, genomics researchers, and educational programs to support quality genetic health care. The VA has highly qualified and dedicated genetics professionals at many sites across the country. Connecting them could create powerful synergies that would benefit patients and strengthen the genetics workforce. The clinical genetics network will enable development and dissemination of evidence-based policies, protocols, and clinical pathways for genomic medicine. This will help to identify, benchmark, and promote best practices for clinical genetic services, and increase access, increase efficiencies, and reduce variability in the care delivered.

The VA is well positioned to achieve successful implementation of genetic services given its investment in genomic medicine and the commitment of the VA NPOP. However, there is a need for structured and targeted implementation strategies for genetic services in the VA, as uptake of this innovation will not occur by passive diffusion.^44,45 To keep pace with the demand for germline testing in veterans, VA may want to consider an outsized focus on training genetics professionals, given the high demand for this expertise. Perhaps most importantly, the VA will need to better prepare its frontline clinical workforce to integrate genetics into their practice. This could be facilitated by identifying implementation strategies and educational programs for genomic medicine that help clinicians to think genetically while caring for their patients, performing aspects of family history risk assessment and pre- and posttest genetic counseling as they are able, and referring complex cases to the clinical genetics network when needed.

Much is already known on how best to accomplish this through studies conducted by many talented VA health services researchers.⁴⁶ Crucially, clinical tools embedded within the VA EHR will be fundamental to these efforts by facilitating identification of patients who can benefit from genetic services and genetic testing at the point of care. Through integration of VA research with clinical genetic services, the VA will become more prepared to realize the promise of genomic medicine for veterans.

Acknowledgments

We thank the members of the Genomic Medicine Program Advisory Committee, Clinical Genetics Subcommittee for providing input and guidance on the topics included in this article.

The US Department of Veterans Affairs (VA) oversees the largest integrated health care system in the nation, administering care to 9 million veterans annually throughout its distributed network of 1,255 medical centers and outpatient facilities. Every year, about 50,000 veterans are diagnosed with and treated for cancer in the VA, representing about 3% of all cancer cases in the US.¹ After skin cancer, prostate, colon, and lung cancers are the most common among veterans.¹ One way that VA has sought to improve the care of its large cancer patient population is through the adoption of precision oncology, an ever-evolving practice of analyzing an individual patient’s cancer to inform clinical decision making. Most often, the analysis includes conducting genetic testing of the tumor itself. Here, we describe the opportunities and challenges of integrating germline genetics into precision oncology practice.

The Intersection of Precision Oncology and Germline Genetics

Precision oncology typically refers to genetic testing of tumor DNA to identify genetic variants with potential diagnostic, prognostic, or predictive therapeutic implications. It is enabled by a growing body of knowledge that identifies key drivers of cancer development, coupled with advances in tumor analysis by next-generation sequencing and other technologies and by the availability of new and repurposed therapeutic agents.² Precision oncology has transformed cancer care by targeting both common and rare malignancies with specific therapies that improve clinical outcomes in patients.³

Testing of tumor DNA can reveal both somatic (acquired) and germline (inherited) gene variants. Precision oncology testing strategies can include tumor-only testing with or without subtraction of suspected germline variants, or paired tumor-normal testing with explicit analysis and reporting of genes associated with germline predisposition.² With tumor-only testing, the germline status of variants may be inferred and follow-up germline testing in normal tissue such as blood or saliva can be considered. Paired tumor-normal testing provides distinct advantages over tumor-only testing, including improvement of the mutation detection rate in tumors and streamlining interpretation of results for both the tumor and germline tests.

Regardless of the strategy used, tumor testing has the potential to uncover clinically relevant germline variation associated with heritable cancer susceptibility and other conditions, as well as carrier status for autosomal recessive disorders (eAppendix

Germline Genetic Testing Challenges

Integrating germline genetic testing in precision oncology practice presents challenges at the patient, family, health care provider, and health system levels. Due to these challenges, implementation planning is obligatory, as germline testing has become a standard-of-care for certain tumor types and patients.²

On learning of a germline pathogenic variant or variant of uncertain significance, patients may experience distress and anxiety, especially in the short term.^16-18 In addition, it can be difficult for patients to share germline genetic test results with their family; parents may feel guilty about the possibility of passing on a predisposition to children, and unaffected siblings may experience survivor guilt. For some veterans, there can be concerns about losing service-connected benefits if a genetic factor is found to contribute to their cancer history. In addition, patients may have concerns about discrimination by employers or insurers, including commercial health insurance or long-term care, disability, and life insurance. Yet there are many state and federal laws that ensure some protection from employment and health insurance discrimination based on genetic information.

For cancer care clinicians, incorporating germline testing requires additional responsibilities that can complicate care. Prior to germline genetic testing, genetic counseling with patients is recommended to review the potential benefits, harms, and limitations of genetic testing. Further, posttest genetic counseling is recommended to help the patient understand how the results may influence future cancer risks, provide recommendations for cancer management and prevention, and discuss implications for family members.^9,10 While patients trust their health care providers to help them access and understand their genetic information, most health care providers are unprepared to integrate genetics into their practice; they lack adequate knowledge, skills, and confidence about genetics to effectively deliver genetic services.^19-26 This leads to failure to recognize patients with indications for genetic testing, which often is due to insufficient family history collection. Other errors can include offering germline genetic testing to patients without appropriate indications and with inadequate informed consent procedures. When genetic testing is pursued, lack of knowledge about genetic principles and testing methods can lead to misinterpretation and miscommunication of results, contributing to inappropriate management recommendations. These errors can contribute to under-use, overuse, or misuse of genetic testing that can compromise the quality of patient care.^27,28 With this in mind, thought must be given at the health care system level to develop effective strategies to deliver genetic services to patients. These strategies must address workforce capacity, organizational structure, and education.

Workforce Capacity

The VA clinical genetics workforce needs to expand to keep pace with increasing demand, which will be accelerated by the precision oncology programs for prostate and lung cancers and the VA Teleoncology initiative. In the US there are 10 to 15 genetics professionals per 1,000,000 residents.^29-31 Most genetics professionals work in academic and metropolitan settings, leaving suburban and rural areas underserved. For example, in California, some patients travel up to 386 miles for genetics care (mean, 76.6 miles).³² In the VA, there are only 1 to 2 genetics professionals per 1 million enrollees, about 10-fold fewer than in community care. Meeting clinical needs of patients at the VA is particularly challenging because more than one-third of veterans live in rural areas.³³

We recently surveyed genetics professionals in the VA about their practices and capacity to increase patient throughput (Table). Currently in the VA, there are 8 clinical geneticists, not all of whom practice clinical genetics, and 13 genetic counselors. Five VA programs provide clinical genetic services to local and nearby VA facilities near Boston, Massachusetts; Houston, Texas; Los Angeles and San Francisco, California; and Salt Lake City, Utah. These programs, first developed in 2008, typically are staffed by 1 or 2 genetics professionals. Most patients who are referred to the VA genetics programs are evaluated for hereditary cancer syndromes. Multiple modes of delivery may be used, including in-person, telehealth, telephone, and provider-to-provider e-consults in the EHR.

Genetic Health Care Organization in the VA

Understanding a patient’s genetic background increasingly has become more and more important in the clinic, which necessitates a major shift in health care. Unfortunately, on a national scale, the number of clinical genetics professionals has not kept pace with the need-limiting the ability to grow the traditional genetics workforce in the VA in the near term.^29-31 Thus, we must look to alternative genetic health care models in which other members of the health care team assume some of the genetic evaluation and counseling activities while caring for their cancer patients with referral to a clinical genetics team, as needed.³⁹

Two genetic health care models have been described.⁴⁰ Traditionally, clinical genetic services are coordinated between genetics professionals and other clinicians, organized as a regional genetics center and usually affiliated with an academic medical center. By contrast, the nontraditional genetic health care model integrates genetic services within primary and specialty care. Under the new approach, nongeneticists can be assisted by decision support tools in the EHR that help with assessing family history risk, identifying indications for genetic testing, and suggesting management options based on genetic test results.^41-43

The VA National Precision Oncology Program (NPOP) is shaped by a commitment to be a high reliability organization (HRO). As such, the goal is to create a system of excellence that integrates precision medicine, implementation science, and the learning health care system to improve the health and health care of veterans with cancer. This initiative is establishing the foundations for best-in-class cancer care to enable veterans access to life-saving therapies through a concerted effort that began with the Cancer Moonshot, development of the NPOP, and collaborations with the VA Office of Research and Development. One of the fundamental objectives of this initiative is to implement strategies that ensure clinical genetic services are available to veterans receiving cancer care at all VA facilities and to extend these services to veterans in remote geographic locations nationwide. The initiative aims to synergize VA Teleoncology services that seek to deliver best-in-class oncology care across the VA enterprise using cutting-edge technologies.

Conclusions

To accomplish the goal of delivering world-class clinical genetic services to veterans and meet the increasing needs of precision oncology and support quality genetic health care, the VA must develop an integrated system of genetic health care that will have a network of clinical genetics that interfaces with other clinical and operational programs, genomics researchers, and educational programs to support quality genetic health care. The VA has highly qualified and dedicated genetics professionals at many sites across the country. Connecting them could create powerful synergies that would benefit patients and strengthen the genetics workforce. The clinical genetics network will enable development and dissemination of evidence-based policies, protocols, and clinical pathways for genomic medicine. This will help to identify, benchmark, and promote best practices for clinical genetic services, and increase access, increase efficiencies, and reduce variability in the care delivered.

The VA is well positioned to achieve successful implementation of genetic services given its investment in genomic medicine and the commitment of the VA NPOP. However, there is a need for structured and targeted implementation strategies for genetic services in the VA, as uptake of this innovation will not occur by passive diffusion.^44,45 To keep pace with the demand for germline testing in veterans, VA may want to consider an outsized focus on training genetics professionals, given the high demand for this expertise. Perhaps most importantly, the VA will need to better prepare its frontline clinical workforce to integrate genetics into their practice. This could be facilitated by identifying implementation strategies and educational programs for genomic medicine that help clinicians to think genetically while caring for their patients, performing aspects of family history risk assessment and pre- and posttest genetic counseling as they are able, and referring complex cases to the clinical genetics network when needed.

Much is already known on how best to accomplish this through studies conducted by many talented VA health services researchers.⁴⁶ Crucially, clinical tools embedded within the VA EHR will be fundamental to these efforts by facilitating identification of patients who can benefit from genetic services and genetic testing at the point of care. Through integration of VA research with clinical genetic services, the VA will become more prepared to realize the promise of genomic medicine for veterans.

Acknowledgments

We thank the members of the Genomic Medicine Program Advisory Committee, Clinical Genetics Subcommittee for providing input and guidance on the topics included in this article.

The US Department of Veterans Affairs (VA) oversees the largest integrated health care system in the nation, administering care to 9 million veterans annually throughout its distributed network of 1,255 medical centers and outpatient facilities. Every year, about 50,000 veterans are diagnosed with and treated for cancer in the VA, representing about 3% of all cancer cases in the US.¹ After skin cancer, prostate, colon, and lung cancers are the most common among veterans.¹ One way that VA has sought to improve the care of its large cancer patient population is through the adoption of precision oncology, an ever-evolving practice of analyzing an individual patient’s cancer to inform clinical decision making. Most often, the analysis includes conducting genetic testing of the tumor itself. Here, we describe the opportunities and challenges of integrating germline genetics into precision oncology practice.

The Intersection of Precision Oncology and Germline Genetics

Precision oncology typically refers to genetic testing of tumor DNA to identify genetic variants with potential diagnostic, prognostic, or predictive therapeutic implications. It is enabled by a growing body of knowledge that identifies key drivers of cancer development, coupled with advances in tumor analysis by next-generation sequencing and other technologies and by the availability of new and repurposed therapeutic agents.² Precision oncology has transformed cancer care by targeting both common and rare malignancies with specific therapies that improve clinical outcomes in patients.³

Testing of tumor DNA can reveal both somatic (acquired) and germline (inherited) gene variants. Precision oncology testing strategies can include tumor-only testing with or without subtraction of suspected germline variants, or paired tumor-normal testing with explicit analysis and reporting of genes associated with germline predisposition.² With tumor-only testing, the germline status of variants may be inferred and follow-up germline testing in normal tissue such as blood or saliva can be considered. Paired tumor-normal testing provides distinct advantages over tumor-only testing, including improvement of the mutation detection rate in tumors and streamlining interpretation of results for both the tumor and germline tests.

Regardless of the strategy used, tumor testing has the potential to uncover clinically relevant germline variation associated with heritable cancer susceptibility and other conditions, as well as carrier status for autosomal recessive disorders (eAppendix

Germline Genetic Testing Challenges

Integrating germline genetic testing in precision oncology practice presents challenges at the patient, family, health care provider, and health system levels. Due to these challenges, implementation planning is obligatory, as germline testing has become a standard-of-care for certain tumor types and patients.²

On learning of a germline pathogenic variant or variant of uncertain significance, patients may experience distress and anxiety, especially in the short term.^16-18 In addition, it can be difficult for patients to share germline genetic test results with their family; parents may feel guilty about the possibility of passing on a predisposition to children, and unaffected siblings may experience survivor guilt. For some veterans, there can be concerns about losing service-connected benefits if a genetic factor is found to contribute to their cancer history. In addition, patients may have concerns about discrimination by employers or insurers, including commercial health insurance or long-term care, disability, and life insurance. Yet there are many state and federal laws that ensure some protection from employment and health insurance discrimination based on genetic information.

For cancer care clinicians, incorporating germline testing requires additional responsibilities that can complicate care. Prior to germline genetic testing, genetic counseling with patients is recommended to review the potential benefits, harms, and limitations of genetic testing. Further, posttest genetic counseling is recommended to help the patient understand how the results may influence future cancer risks, provide recommendations for cancer management and prevention, and discuss implications for family members.^9,10 While patients trust their health care providers to help them access and understand their genetic information, most health care providers are unprepared to integrate genetics into their practice; they lack adequate knowledge, skills, and confidence about genetics to effectively deliver genetic services.^19-26 This leads to failure to recognize patients with indications for genetic testing, which often is due to insufficient family history collection. Other errors can include offering germline genetic testing to patients without appropriate indications and with inadequate informed consent procedures. When genetic testing is pursued, lack of knowledge about genetic principles and testing methods can lead to misinterpretation and miscommunication of results, contributing to inappropriate management recommendations. These errors can contribute to under-use, overuse, or misuse of genetic testing that can compromise the quality of patient care.^27,28 With this in mind, thought must be given at the health care system level to develop effective strategies to deliver genetic services to patients. These strategies must address workforce capacity, organizational structure, and education.

Workforce Capacity

The VA clinical genetics workforce needs to expand to keep pace with increasing demand, which will be accelerated by the precision oncology programs for prostate and lung cancers and the VA Teleoncology initiative. In the US there are 10 to 15 genetics professionals per 1,000,000 residents.^29-31 Most genetics professionals work in academic and metropolitan settings, leaving suburban and rural areas underserved. For example, in California, some patients travel up to 386 miles for genetics care (mean, 76.6 miles).³² In the VA, there are only 1 to 2 genetics professionals per 1 million enrollees, about 10-fold fewer than in community care. Meeting clinical needs of patients at the VA is particularly challenging because more than one-third of veterans live in rural areas.³³

We recently surveyed genetics professionals in the VA about their practices and capacity to increase patient throughput (Table). Currently in the VA, there are 8 clinical geneticists, not all of whom practice clinical genetics, and 13 genetic counselors. Five VA programs provide clinical genetic services to local and nearby VA facilities near Boston, Massachusetts; Houston, Texas; Los Angeles and San Francisco, California; and Salt Lake City, Utah. These programs, first developed in 2008, typically are staffed by 1 or 2 genetics professionals. Most patients who are referred to the VA genetics programs are evaluated for hereditary cancer syndromes. Multiple modes of delivery may be used, including in-person, telehealth, telephone, and provider-to-provider e-consults in the EHR.

Genetic Health Care Organization in the VA

Understanding a patient’s genetic background increasingly has become more and more important in the clinic, which necessitates a major shift in health care. Unfortunately, on a national scale, the number of clinical genetics professionals has not kept pace with the need-limiting the ability to grow the traditional genetics workforce in the VA in the near term.^29-31 Thus, we must look to alternative genetic health care models in which other members of the health care team assume some of the genetic evaluation and counseling activities while caring for their cancer patients with referral to a clinical genetics team, as needed.³⁹

Two genetic health care models have been described.⁴⁰ Traditionally, clinical genetic services are coordinated between genetics professionals and other clinicians, organized as a regional genetics center and usually affiliated with an academic medical center. By contrast, the nontraditional genetic health care model integrates genetic services within primary and specialty care. Under the new approach, nongeneticists can be assisted by decision support tools in the EHR that help with assessing family history risk, identifying indications for genetic testing, and suggesting management options based on genetic test results.^41-43

The VA National Precision Oncology Program (NPOP) is shaped by a commitment to be a high reliability organization (HRO). As such, the goal is to create a system of excellence that integrates precision medicine, implementation science, and the learning health care system to improve the health and health care of veterans with cancer. This initiative is establishing the foundations for best-in-class cancer care to enable veterans access to life-saving therapies through a concerted effort that began with the Cancer Moonshot, development of the NPOP, and collaborations with the VA Office of Research and Development. One of the fundamental objectives of this initiative is to implement strategies that ensure clinical genetic services are available to veterans receiving cancer care at all VA facilities and to extend these services to veterans in remote geographic locations nationwide. The initiative aims to synergize VA Teleoncology services that seek to deliver best-in-class oncology care across the VA enterprise using cutting-edge technologies.

Conclusions

To accomplish the goal of delivering world-class clinical genetic services to veterans and meet the increasing needs of precision oncology and support quality genetic health care, the VA must develop an integrated system of genetic health care that will have a network of clinical genetics that interfaces with other clinical and operational programs, genomics researchers, and educational programs to support quality genetic health care. The VA has highly qualified and dedicated genetics professionals at many sites across the country. Connecting them could create powerful synergies that would benefit patients and strengthen the genetics workforce. The clinical genetics network will enable development and dissemination of evidence-based policies, protocols, and clinical pathways for genomic medicine. This will help to identify, benchmark, and promote best practices for clinical genetic services, and increase access, increase efficiencies, and reduce variability in the care delivered.

The VA is well positioned to achieve successful implementation of genetic services given its investment in genomic medicine and the commitment of the VA NPOP. However, there is a need for structured and targeted implementation strategies for genetic services in the VA, as uptake of this innovation will not occur by passive diffusion.^44,45 To keep pace with the demand for germline testing in veterans, VA may want to consider an outsized focus on training genetics professionals, given the high demand for this expertise. Perhaps most importantly, the VA will need to better prepare its frontline clinical workforce to integrate genetics into their practice. This could be facilitated by identifying implementation strategies and educational programs for genomic medicine that help clinicians to think genetically while caring for their patients, performing aspects of family history risk assessment and pre- and posttest genetic counseling as they are able, and referring complex cases to the clinical genetics network when needed.

Much is already known on how best to accomplish this through studies conducted by many talented VA health services researchers.⁴⁶ Crucially, clinical tools embedded within the VA EHR will be fundamental to these efforts by facilitating identification of patients who can benefit from genetic services and genetic testing at the point of care. Through integration of VA research with clinical genetic services, the VA will become more prepared to realize the promise of genomic medicine for veterans.

Acknowledgments

We thank the members of the Genomic Medicine Program Advisory Committee, Clinical Genetics Subcommittee for providing input and guidance on the topics included in this article.

For US Army veteran Tam Huynh, the US Department of Veterans Affairs (VA) precision oncology program has been the proverbial game changer. Diagnosed in 2016 with stage IV lung cancer and physically depleted by chemotherapy, Huynh learned that treatment based on the precise molecular makeup of his tumors held the potential for improving quality of life. Through the VA National Precision Oncology Program (NPOP), Huynh was matched to a medication shown to help patients whose tumors had the same genetic mutation as Huynh’s tumors. Today, Huynh is not only free of chemotherapy’s debilitating adverse effects, but able to enjoy time with his family and return to work.

Huynh is one of 400,000 veterans treated for cancer annually at the VA. The life-changing treatment he received is due to the legacy of research, integrated care, and collaboration that is the hallmark of the VA health care system. The NPOP is a natural outgrowth of this legacy, and, as Executive-in-Charge Richard Stone, MD, notes in his Foreword, part of the Veterans Health Administration’s (VHA) evolution as a learning health care system. The articles in this special issue represent a snapshot of the work underway under VHA NPOP as well as the dedication of VHA staff nationwide to provide patient-centric care to every veteran.

Leading off this special issue, NPOP director Michael J. Kelley, MD, provides context for understanding the paradigm shift represented by precision oncology.² He also discusses how, within 5 years, the program came together from its start as a regional effort to its use today by almost every VA oncology practice. Kelley also explains the complexity behind interpreting next-generation sequencing (NGS) gene panel test results and how VA medical centers can call upon NPOP for assistance with this interpretation. Further, he states the “obligation” for new medical technology to be accessible and notes how NPOP was “intentional” during implementation to ensure rural veterans would be offered testing.²

Following Kelley’s discussion is a series of articles focused on precision oncology for prostate cancer, which affects 15,000 veterans yearly. The first, an overview of the Prostate Cancer Foundation (PCF), provides a short history of the organization and how it came to partner with the VA.³ Written by several PCF staff, including President and CEO Jonathan Simons, MD, the paper notes how the commitment of early leaders like S. Ward Casscells, MD, and Larry Stupski led to PCF’s “no veteran left behind” philosophy; ie, ensuring veteran access to clinical trials and world class care regardless of location. As the first disease-specific national network for oncology trials serving veterans, PCF aims to provide a model for all of US health care in the delivery of precision oncology care.

A critical part of PCF is the Precision Oncology Program for Cancer of the Prostate (POPCaP), which focuses on genetics and genomic testing. Bruce Montgomery, MD, and Matthew Retting, MD—VHA’s leading experts in prostate cancer—shine the spotlight on VA’s research track record, specifically the genomics of metastatic prostate cancer.⁴ They also note the program’s focus on African American veteran patients who are disproportionately affected by the disease but well represented in the VA. In discussing future directions, the authors explain the importance of expanding genetic testing for those diagnosed with prostate cancer.

Prostate cancer Analysis for Therapy Choice (PATCH) is a clinical trials network that works hand-in-hand with POPCaP to use genetic data collected by POPCaP sites to find patients for trials. In their discussion, authors Julie N. Graff, MD, and Grant D. Huang, MD, who leads VA Research’s Cooperative Studies Program, focus on 3 key areas: (1) the challenges of precision oncology when working with relatively rare mutations; (2) 2 new drug trials at VA that will help clinicians know whether certain targeted therapies work for prostate cancer; and (3) how VA is emerging as a national partner in drug discovery and the approval of precision drugs.⁵

Turning to lung cancer–the second leading cause of cancer death among veterans–Drew Moghanaki, MD, MPH, and Michael Hagan, MD, discuss 3 multisite initiatives launched in 2016 and 2017.⁶ The first trial, VA Partnership to Increase Access to Lung Cancer Screening (VA-PALS), is a multisite project sponsored by the VA’s Office of Rural Health and Bristol-Myers Squibb Foundation. The trial’s goal is to reduce lung cancer mortality through a robust early detection program. The second trial, VA Lung Cancer Surgery OR Radiation therapy (VALOR) compares whether radiation or surgery is the best for early-stage lung cancer. Notably, VALOR may be one of the most difficult randomized trial ever attempted in lung cancer research (4 previous phase 3 trials outside the VA closed prematurely). By addressing the previous challenges associated with running such a trial, the VALOR study team already has enrolled more than all of the previous phase 3 efforts combined. The third trial is VA Radiation Oncology Quality Surveillance Program (VA-ROQS), which was created in 2016 to benchmark the treatment of veterans with lung cancer. VA-ROQS aims to create a national network of Lung Cancer Centers of Excellence that work with VISNs to ensure that treatment decisions for veterans with lung cancer are based on all available molecular information.

The final group of authors, led by Maren T. Scheuner, MD, discuss how the advent of germline testing as a standard-of-care practice for certain tumor types presents opportunities and challenges for precision oncology.⁷ One of the primary challenges they note is the shortage of genetics professionals, both within the VA system and health care generally. To help address this issue, they recommend leveraging VA’s longstanding partnership with its academic affiliates.

Precision oncology clearly demonstrates how applying knowledge regarding one of the smallest of living matter can make a tremendous difference in the matter of living. Tam Huynh’s story is proof positive. Speaking at last year’s AMSUS (Society for Federal Health Professionals) annual meeting about his experience, Huynh said that all veterans should have access to the same life-changing treatment he received. This is exactly where the VA NPOP is heading.

For US Army veteran Tam Huynh, the US Department of Veterans Affairs (VA) precision oncology program has been the proverbial game changer. Diagnosed in 2016 with stage IV lung cancer and physically depleted by chemotherapy, Huynh learned that treatment based on the precise molecular makeup of his tumors held the potential for improving quality of life. Through the VA National Precision Oncology Program (NPOP), Huynh was matched to a medication shown to help patients whose tumors had the same genetic mutation as Huynh’s tumors. Today, Huynh is not only free of chemotherapy’s debilitating adverse effects, but able to enjoy time with his family and return to work.

Huynh is one of 400,000 veterans treated for cancer annually at the VA. The life-changing treatment he received is due to the legacy of research, integrated care, and collaboration that is the hallmark of the VA health care system. The NPOP is a natural outgrowth of this legacy, and, as Executive-in-Charge Richard Stone, MD, notes in his Foreword, part of the Veterans Health Administration’s (VHA) evolution as a learning health care system. The articles in this special issue represent a snapshot of the work underway under VHA NPOP as well as the dedication of VHA staff nationwide to provide patient-centric care to every veteran.

Leading off this special issue, NPOP director Michael J. Kelley, MD, provides context for understanding the paradigm shift represented by precision oncology.² He also discusses how, within 5 years, the program came together from its start as a regional effort to its use today by almost every VA oncology practice. Kelley also explains the complexity behind interpreting next-generation sequencing (NGS) gene panel test results and how VA medical centers can call upon NPOP for assistance with this interpretation. Further, he states the “obligation” for new medical technology to be accessible and notes how NPOP was “intentional” during implementation to ensure rural veterans would be offered testing.²

Following Kelley’s discussion is a series of articles focused on precision oncology for prostate cancer, which affects 15,000 veterans yearly. The first, an overview of the Prostate Cancer Foundation (PCF), provides a short history of the organization and how it came to partner with the VA.³ Written by several PCF staff, including President and CEO Jonathan Simons, MD, the paper notes how the commitment of early leaders like S. Ward Casscells, MD, and Larry Stupski led to PCF’s “no veteran left behind” philosophy; ie, ensuring veteran access to clinical trials and world class care regardless of location. As the first disease-specific national network for oncology trials serving veterans, PCF aims to provide a model for all of US health care in the delivery of precision oncology care.

A critical part of PCF is the Precision Oncology Program for Cancer of the Prostate (POPCaP), which focuses on genetics and genomic testing. Bruce Montgomery, MD, and Matthew Retting, MD—VHA’s leading experts in prostate cancer—shine the spotlight on VA’s research track record, specifically the genomics of metastatic prostate cancer.⁴ They also note the program’s focus on African American veteran patients who are disproportionately affected by the disease but well represented in the VA. In discussing future directions, the authors explain the importance of expanding genetic testing for those diagnosed with prostate cancer.

Prostate cancer Analysis for Therapy Choice (PATCH) is a clinical trials network that works hand-in-hand with POPCaP to use genetic data collected by POPCaP sites to find patients for trials. In their discussion, authors Julie N. Graff, MD, and Grant D. Huang, MD, who leads VA Research’s Cooperative Studies Program, focus on 3 key areas: (1) the challenges of precision oncology when working with relatively rare mutations; (2) 2 new drug trials at VA that will help clinicians know whether certain targeted therapies work for prostate cancer; and (3) how VA is emerging as a national partner in drug discovery and the approval of precision drugs.⁵

Turning to lung cancer–the second leading cause of cancer death among veterans–Drew Moghanaki, MD, MPH, and Michael Hagan, MD, discuss 3 multisite initiatives launched in 2016 and 2017.⁶ The first trial, VA Partnership to Increase Access to Lung Cancer Screening (VA-PALS), is a multisite project sponsored by the VA’s Office of Rural Health and Bristol-Myers Squibb Foundation. The trial’s goal is to reduce lung cancer mortality through a robust early detection program. The second trial, VA Lung Cancer Surgery OR Radiation therapy (VALOR) compares whether radiation or surgery is the best for early-stage lung cancer. Notably, VALOR may be one of the most difficult randomized trial ever attempted in lung cancer research (4 previous phase 3 trials outside the VA closed prematurely). By addressing the previous challenges associated with running such a trial, the VALOR study team already has enrolled more than all of the previous phase 3 efforts combined. The third trial is VA Radiation Oncology Quality Surveillance Program (VA-ROQS), which was created in 2016 to benchmark the treatment of veterans with lung cancer. VA-ROQS aims to create a national network of Lung Cancer Centers of Excellence that work with VISNs to ensure that treatment decisions for veterans with lung cancer are based on all available molecular information.

The final group of authors, led by Maren T. Scheuner, MD, discuss how the advent of germline testing as a standard-of-care practice for certain tumor types presents opportunities and challenges for precision oncology.⁷ One of the primary challenges they note is the shortage of genetics professionals, both within the VA system and health care generally. To help address this issue, they recommend leveraging VA’s longstanding partnership with its academic affiliates.

Precision oncology clearly demonstrates how applying knowledge regarding one of the smallest of living matter can make a tremendous difference in the matter of living. Tam Huynh’s story is proof positive. Speaking at last year’s AMSUS (Society for Federal Health Professionals) annual meeting about his experience, Huynh said that all veterans should have access to the same life-changing treatment he received. This is exactly where the VA NPOP is heading.

For US Army veteran Tam Huynh, the US Department of Veterans Affairs (VA) precision oncology program has been the proverbial game changer. Diagnosed in 2016 with stage IV lung cancer and physically depleted by chemotherapy, Huynh learned that treatment based on the precise molecular makeup of his tumors held the potential for improving quality of life. Through the VA National Precision Oncology Program (NPOP), Huynh was matched to a medication shown to help patients whose tumors had the same genetic mutation as Huynh’s tumors. Today, Huynh is not only free of chemotherapy’s debilitating adverse effects, but able to enjoy time with his family and return to work.

Huynh is one of 400,000 veterans treated for cancer annually at the VA. The life-changing treatment he received is due to the legacy of research, integrated care, and collaboration that is the hallmark of the VA health care system. The NPOP is a natural outgrowth of this legacy, and, as Executive-in-Charge Richard Stone, MD, notes in his Foreword, part of the Veterans Health Administration’s (VHA) evolution as a learning health care system. The articles in this special issue represent a snapshot of the work underway under VHA NPOP as well as the dedication of VHA staff nationwide to provide patient-centric care to every veteran.

Leading off this special issue, NPOP director Michael J. Kelley, MD, provides context for understanding the paradigm shift represented by precision oncology.² He also discusses how, within 5 years, the program came together from its start as a regional effort to its use today by almost every VA oncology practice. Kelley also explains the complexity behind interpreting next-generation sequencing (NGS) gene panel test results and how VA medical centers can call upon NPOP for assistance with this interpretation. Further, he states the “obligation” for new medical technology to be accessible and notes how NPOP was “intentional” during implementation to ensure rural veterans would be offered testing.²

Following Kelley’s discussion is a series of articles focused on precision oncology for prostate cancer, which affects 15,000 veterans yearly. The first, an overview of the Prostate Cancer Foundation (PCF), provides a short history of the organization and how it came to partner with the VA.³ Written by several PCF staff, including President and CEO Jonathan Simons, MD, the paper notes how the commitment of early leaders like S. Ward Casscells, MD, and Larry Stupski led to PCF’s “no veteran left behind” philosophy; ie, ensuring veteran access to clinical trials and world class care regardless of location. As the first disease-specific national network for oncology trials serving veterans, PCF aims to provide a model for all of US health care in the delivery of precision oncology care.

A critical part of PCF is the Precision Oncology Program for Cancer of the Prostate (POPCaP), which focuses on genetics and genomic testing. Bruce Montgomery, MD, and Matthew Retting, MD—VHA’s leading experts in prostate cancer—shine the spotlight on VA’s research track record, specifically the genomics of metastatic prostate cancer.⁴ They also note the program’s focus on African American veteran patients who are disproportionately affected by the disease but well represented in the VA. In discussing future directions, the authors explain the importance of expanding genetic testing for those diagnosed with prostate cancer.

Prostate cancer Analysis for Therapy Choice (PATCH) is a clinical trials network that works hand-in-hand with POPCaP to use genetic data collected by POPCaP sites to find patients for trials. In their discussion, authors Julie N. Graff, MD, and Grant D. Huang, MD, who leads VA Research’s Cooperative Studies Program, focus on 3 key areas: (1) the challenges of precision oncology when working with relatively rare mutations; (2) 2 new drug trials at VA that will help clinicians know whether certain targeted therapies work for prostate cancer; and (3) how VA is emerging as a national partner in drug discovery and the approval of precision drugs.⁵

Turning to lung cancer–the second leading cause of cancer death among veterans–Drew Moghanaki, MD, MPH, and Michael Hagan, MD, discuss 3 multisite initiatives launched in 2016 and 2017.⁶ The first trial, VA Partnership to Increase Access to Lung Cancer Screening (VA-PALS), is a multisite project sponsored by the VA’s Office of Rural Health and Bristol-Myers Squibb Foundation. The trial’s goal is to reduce lung cancer mortality through a robust early detection program. The second trial, VA Lung Cancer Surgery OR Radiation therapy (VALOR) compares whether radiation or surgery is the best for early-stage lung cancer. Notably, VALOR may be one of the most difficult randomized trial ever attempted in lung cancer research (4 previous phase 3 trials outside the VA closed prematurely). By addressing the previous challenges associated with running such a trial, the VALOR study team already has enrolled more than all of the previous phase 3 efforts combined. The third trial is VA Radiation Oncology Quality Surveillance Program (VA-ROQS), which was created in 2016 to benchmark the treatment of veterans with lung cancer. VA-ROQS aims to create a national network of Lung Cancer Centers of Excellence that work with VISNs to ensure that treatment decisions for veterans with lung cancer are based on all available molecular information.

The final group of authors, led by Maren T. Scheuner, MD, discuss how the advent of germline testing as a standard-of-care practice for certain tumor types presents opportunities and challenges for precision oncology.⁷ One of the primary challenges they note is the shortage of genetics professionals, both within the VA system and health care generally. To help address this issue, they recommend leveraging VA’s longstanding partnership with its academic affiliates.

Precision oncology clearly demonstrates how applying knowledge regarding one of the smallest of living matter can make a tremendous difference in the matter of living. Tam Huynh’s story is proof positive. Speaking at last year’s AMSUS (Society for Federal Health Professionals) annual meeting about his experience, Huynh said that all veterans should have access to the same life-changing treatment he received. This is exactly where the VA NPOP is heading.

As the nation’s largest integrated health care system with about 50,000 new cancer diagnoses per year, providing care for over 400,000 veterans with cancer and a robust research portfolio, the US Department of Veterans Affairs (VA) is well positioned to be a leader in both clinical and research in oncology. The VA National Precision Oncology Program (NPOP), which provides tumor sequencing and consultative services, is a key component of VA oncology assets.

Case Presentation

As the mission of the VA is to “care for him who shall have borne the battle,” it is fitting to begin with the story of a US Army veteran in his 40s and the father of 2 young children who developed progressive shortness of breath, cough, and weight loss over a period of 8 months. He was diagnosed with metastatic lung adenocarcinoma in 2016, and standard testing of his tumor showed no alteration of the EGFR and ALK genes. He was treated with whole brain radiation and had begun treatment for carboplatin and pemetrexed chemotherapy with mixed tumor response.

Subsequently, his tumor was tested through NPOP, using a multigene next-generation sequencing (NGS) assay panel, which showed the presence of an abnormal fusion between the EML4 and ALK genes. The chemotherapy was discontinued and oral crizotinib precision therapy was started. The patient had an excellent response in all sites of disease (Figure 1). He was able to return to work and school.

In July 2017, his medication was switched to alectinib for asymptomatic progression in his brain, and there was further response. In September 2019, he was treated with precision intensity-modulated radiotherapy (IMRT), targeting a single brain metastasis as there were no other sites of cancer progression and no cancerrelated symptoms. He finished school and continues to work.

Precision Oncology

Oncology is a relatively young medical field. The early medical treatments for cancer were developed empirically against hematologic malignancies, particularly leukemias. Cytotoxic chemotherapeutic agents as a group have modest effects on most solid tumors, and even modern genomics has had limited ability to predict differential benefit in patients with advanced-stage carcinomas. As a result, the medications are used in a nonprecision manner in which all patients with the same cancer diagnosis and stage receive the same treatment. This is due in part to our limited understanding of both the pathophysiology of cancer and the mechanism of action of cytotoxic agents.

One of the first examples of precision oncology was tumor testing for the estrogen receptor in breast cancer, which distinguishes breast tumors sensitive to hormonal treatments from those that are resistant.³ In 2004, somatically acquired mutation of the EGFR gene was found to be associated with response to EGFR tyrosine kinase inhibitors such as gefitinib and erlotinib, and subsequently it was shown that patients without these mutations derived no benefit from use of these drugs.⁴ Thus, the precision oncology paradigm is using a molecular diagnostic as part of the indication for an antineoplastic agent, resulting in improved therapeutic efficacy and often reduced toxicity.

By 2015, multiple examples of DNA-based gene alterations that predict drug response were known, including at least 5 in non-small cell lung cancer (NSCLC). The heterogeneity of molecular testing practice patterns and methods of testing in VA along with the increasing number and complexity of molecular tests facilitated launch of a regional precision oncology program based primarily in Veterans Integrated Service Network 1, which provided tumor DNA sequencing through 2 vendors. Advances in DNA sequencing technology, particularly NGS, permit sequencing of multiple genes in clinical tumor samples, using a panel applicable for multiple tumor types. As part of VA contributions to the 2016 White House Cancer Moonshot initiative, the regional program became NPOP with expanded geographic scope, the addition of clinical consultative services, and robust informatics that supports associated research and a learning health care system. NPOP is a component of the VA National Oncology Program Office under the Office of Specialty Care.

Testing

With the launch of NPOP in mid-2016, there was rapid expansion of the number of VA facilities participating, and the number of tumor samples being submitted increased substantially. ⁵ The expansion was facilitated by both central funding for the tumor DNA sequencing and by NPOP-provided training of pathology laboratory staff and oncologists. Today, NPOP is utilized by almost every oncology practice in VA.

NPOP’s initial focus was on lung cancer, specifically advanced-stage nonsquamous NSCLC, which not only is very common in VA, but also has one of the highest number of mutated genes that result in sensitivity to antineoplastic drugs. Recently, metastatic prostate cancer was added as a second focus tumor type. Dashboards are available on the NPOP website to assist care teams in identifying veterans at their facility with either lung or prostate cancer who may be appropriate for testing. Other solid tumors can be sent for testing through NPOP if patients have advanced stage cancer and are medically appropriate for antineoplastic therapy. To date, NPOP has sequenced > 13,000 samples.

Testing options have been added to NPOP in addition to tumor DNA sequencing. The first addition was the so-called liquid biopsy, more properly known as the cell-free DNA (cfDNA) test, a plasma-based high-sensitivity DNA sequencing assay. cfDNA is shed from dying cells and can be captured and sequenced from a plasma sample obtained by standard venipuncture, using a special-purpose sample collection tube. The test is appropriate for patients who do not have an appropriate archival tumor sample or those who cannot have a new biopsy of tumor tissue. Tumor tissue remains the preferred test sample due to a higher sensitivity than that of cfDNA and less susceptibility to false positives, so consideration of a tumor biopsy is appropriate prior to requesting a cfDNA assay. Therapy can greatly impact the sensitivity of cfDNA testing, so patients should be having disease progression at the time of obtaining a blood sample for cfDNA.

Finally, myeloid leukocytic cells accumulate genetic alterations during aging similar to those found in myelodysplasia and acute myeloid leukemia. These myeloid-associated mutations can be detected in both tumor and cfDNA samples and are known as clonal hyperplasia of indeterminate potential (CHIP). CHIP is much more common in the cfDNA. For lung cancer, CHIP-associated gene variants are readily distinguished from lung cancer-associated variants, but that distinction is much more difficult in many other tumor types.

In partnership with the current DNA sequencing contractor, NPOP provides access to a second gene panel for hematologic malignancies or sarcomas, though neither of these classes of malignancies currently have clear indications for routine NGS multigene panel testing. Given the low rate of finding a gene mutation that would change therapy that could not be found with smaller, less expensive gene panels, NPOP requires prior approval for the use of this panel.

Finally, since early 2019, programmed deathligand 1 (PD-L1) immunohistochemistry analysis is available through NPOP in association with NGS testing of the same sample for those solid tumors with US Food and Drug Administration (FDA)-approved indications that include a PD-L1 companion diagnostic. This service was added to facilitate concurrent testing of PD-L1 and DNA sequencing, which speeds availability of molecular data to the health care provider and veteran.

Determining Clinical Significance

The complexity of tumor NGS gene panel test results is far greater than frequently ordered laboratory or molecular testing due to the near infinite number of possible results and varying degrees of consensus of the significance of the results for therapeutic decision making. That complexity is reflected in the length of the test reports, which are often ≥ 20 pages. Starting from the gene variants identified by the DNA sequencing variant-caller bioinformatics pipeline, there is a 2-step process, referred to as annotation, to interpret the clinical significance that is repeated for each variant.

The first step is to assign a pathogenicity value, also known as oncogenicity, using a 5-point Likert scale from pathogenic to benign with variant of unknown significance (VUS) in the middle of the scale. Only variants that are pathogenic or likely pathogenic are considered further. A VUS is usually communicated to the health care provider but should generally not be acted on, while benign and likely benign variants may or may not be included in the report and should never be acted on. NPOP examined the concordance of pathogenicity calls among 3 annotation services: N-of-One/QCI Precision Insights (qiagen.com), IBM Watson for Genomics (WfG), and OncoKB (www.oncokb.org).⁶ There was moderate-to-poor concordance, indicating lack of consensus about whether a significant fraction of observed gene variants contributes to the patient’s cancer. This variability likely arises due to differences in algorithms and criteria used to assess pathogenicity.

Another complexity in annotation for actionability is tumor type ontogeny—the classification system used for cancer types. WfG uses a subset of the National Cancer Institute Thesaurus (ncithesaurus.nci.nih.gov), OncoKB uses the unique OncoTree (oncotree.mskcc.org), and Foundation Medicine (www.foundationmed icine.com), and N-of-One use propriety classification systems. The WfG and OncoKB tumor types have evolved over time, while it is unclear what changes have been made in the FMI and N-of-One tumor type classification systems. Thus, a gene variant observed in a single patient may be annotated differently by these services because of how the tumor type is mapped onto the services’ tumor type ontogeny. NPOP has been assigning WfG diagnoses since 2017, including historic assignment for prior samples back to the pilot project in 2015. In early 2019, NPOP began requiring test requesters to include International Classification of Diseases for Oncology, 3rd Edition (ICD-O-3) diagnoses (histology and site codes) with the sample. ICD-O-3 codes are used in all cancer registry data in North America, including the VA Cancer Registry System. The approximately 50,000 possible diagnoses allow fine precision in diagnoses, which is important for less common and rare cancer types; however, the large number of diagnoses adds complexity. NPOP has created a partial translation table for ICD-O-3 to WfG diagnosis that includes all diagnoses seen to date; this table facilitates continuing provision of WfG diagnosis without manual review as was previously required.

NPOP-Provided Genetic Services

Given these complexities in interpretation of NGS multigene panel results, NPOP provides several services to assist health care providers and other members of the care team. First, the NPOP Interfacility Consult (IFC) is a virtual “phone-a-friend” service that provides asynchronous patient-specific expert recommendations in precision oncology. By far the most requested service is assistance with interpretation of a patient’s DNA sequence results. Other requests include advice on whether to perform NGS testing and what molecular testing to perform. The IFC is integral to the VA Computerized Patient Record System electronic health record. Additional requests have been submitted and answered by e-mail.

The Molecular Oncology Tumor Board is a monthly case-based educational conference supported by the VA Employee Education Service, which provides continuing education credits for attendees. NPOP staff coordinate the conference, and a panel of specialists from around the country provide expert commentary.

In 2016, IBM gifted the services of WfG to VA. WfG’s main functionality is annotation of NGS results. About 5,000 samples were processed from 2017 to 2019; sample processing is expected to resume shortly. The availability of WfG annotations early in NPOP operation was very useful to the implementation of NPOP in general and the NPOP consultation services in particular, resulting in improved thoroughness of opinions provided by NPOP staff.

Informatics

Informatics is an essential component of NPOP that facilitates both clinical care and research (Figure 3). Results of NGS gene panels are returned to the facility that submitted the sample for testing as a PDF document. NPOP receives the same PDF report in real time but also structured data of the results including a variant callformat file and XML file. The secondary sequence data in binary alignment map or FASTQ format is received in batches. NPOP program staff extract data from these files and then load it into SQL tables in the VA Corporate Data Warehouse. In partnership with the VA Pharmacy Benefits Management Service, NPOP has constructed user-friendly dashboards that allow users with no technical skills and who have the appropriate data access permissions to view various portions of the NPOP database. There are dashboards to display a list of NPOP samples by facility, find a patient by name or other identifying information, and display a list of patients who have received any antineoplastic drug, among other functions.

The NPOP database has been used to reannotate NGS results, such as when new drugs are approved. For example, when the first neurotrophic tropomyosin receptor kinase (NTRK) inhibitor was approved, NPOP rapidly identified all living patients with NTRK fusions and notified the health care providers of the availability a potential new treatment option for their patient. ⁷ NPOP is now building a method to allow NPOP dashboard users to similarly identify patients who have not received a corresponding drug for a user-selected LoE annotation. This will facilitate a systems approach to ensure that all patients with EGFR exon 19 deletions, for example, either have received an EGFR inhibitor or are reviewed to determine why they have not. Furthermore, the database will facilitate real-world data analysis in precision oncology. For example, prior to the recent FDA-approval of poly–(adenosine diphosphate–ribose) polymerase (PARP) inhibitors for prostate cancer, 50 veterans already had been treated with one of these agents. These data can help further inform which of the many variants of DNA damage repair genes benefit from PARP inhibitors.

Ensuring Access to Care for All Veterans

With any new medical technology comes an obligation to ensure appropriate equal access so as to not exacerbate health care disparities. Veterans enrolled in VA health care are much more likely to live in rural communities than does the US population as a whole, and there was concern that these veterans would not receive NGS testing at the same rate as urban veterans. NPOP therefore was intentional during implementation to ensure rural veterans were being offered testing. Indeed, there has been nearly equal utilization by rurality. No other disparities in NPOP utilization have been seen.

A majority of veterans who undergo testing in NPOP have at least 1 actionable gene variant reported.⁵ However, some of these are for lower LoE off-label use of FDA-approved medications, but many are for agents available only through clinical trials. Consideration of treatments available through a clinical trial is part of standard practice for patients with advanced malignancies. NPOP data have helped identify cohorts who are eligible for clinical trials on the basis of their tumor DNA sequencing results. The National Oncology Program Office has been working closely with the VA Office of Research and Development to expand access to cancer clinical trials in VA. Veterans also can be treated on trials outside VA as medically appropriate and with local VA approval.

Conclusions

The VA NPOP is one of the largest clinical DNA sequencing programs in the nation with integrated consultation services and health informatics resources to facilitate patient care, clinical trials, and health outcomes research. The clinical services of NPOP provide cuttingedge oncology services to veterans throughout VA without exacerbating disparities and will be a national resource for research.

Acknowledgments
NPOP was made possible and implemented through the efforts of a number of people in VHA, including the national and regional leaders who supported the program’s vision and implementation, especially Michael Mayo-Smith, David Shulkin, Jennifer S. Lee, and Laurence Meyer, the leaders and staff of the Massachusetts Veterans Epidemiology Research and Information Center who piloted regional NGS testing, and especially my current and former colleagues in the VA National Oncology Program Office, without whom NPOP would not be possible. The contributions of Neil L. Spector who served as inaugural Director of Precision Oncology and Jill E. Duffy in her role as Director of Oncology Operations are particularly noteworthy.

As the nation’s largest integrated health care system with about 50,000 new cancer diagnoses per year, providing care for over 400,000 veterans with cancer and a robust research portfolio, the US Department of Veterans Affairs (VA) is well positioned to be a leader in both clinical and research in oncology. The VA National Precision Oncology Program (NPOP), which provides tumor sequencing and consultative services, is a key component of VA oncology assets.

Case Presentation

As the mission of the VA is to “care for him who shall have borne the battle,” it is fitting to begin with the story of a US Army veteran in his 40s and the father of 2 young children who developed progressive shortness of breath, cough, and weight loss over a period of 8 months. He was diagnosed with metastatic lung adenocarcinoma in 2016, and standard testing of his tumor showed no alteration of the EGFR and ALK genes. He was treated with whole brain radiation and had begun treatment for carboplatin and pemetrexed chemotherapy with mixed tumor response.

Subsequently, his tumor was tested through NPOP, using a multigene next-generation sequencing (NGS) assay panel, which showed the presence of an abnormal fusion between the EML4 and ALK genes. The chemotherapy was discontinued and oral crizotinib precision therapy was started. The patient had an excellent response in all sites of disease (Figure 1). He was able to return to work and school.

In July 2017, his medication was switched to alectinib for asymptomatic progression in his brain, and there was further response. In September 2019, he was treated with precision intensity-modulated radiotherapy (IMRT), targeting a single brain metastasis as there were no other sites of cancer progression and no cancerrelated symptoms. He finished school and continues to work.

Precision Oncology

Oncology is a relatively young medical field. The early medical treatments for cancer were developed empirically against hematologic malignancies, particularly leukemias. Cytotoxic chemotherapeutic agents as a group have modest effects on most solid tumors, and even modern genomics has had limited ability to predict differential benefit in patients with advanced-stage carcinomas. As a result, the medications are used in a nonprecision manner in which all patients with the same cancer diagnosis and stage receive the same treatment. This is due in part to our limited understanding of both the pathophysiology of cancer and the mechanism of action of cytotoxic agents.

One of the first examples of precision oncology was tumor testing for the estrogen receptor in breast cancer, which distinguishes breast tumors sensitive to hormonal treatments from those that are resistant.³ In 2004, somatically acquired mutation of the EGFR gene was found to be associated with response to EGFR tyrosine kinase inhibitors such as gefitinib and erlotinib, and subsequently it was shown that patients without these mutations derived no benefit from use of these drugs.⁴ Thus, the precision oncology paradigm is using a molecular diagnostic as part of the indication for an antineoplastic agent, resulting in improved therapeutic efficacy and often reduced toxicity.

By 2015, multiple examples of DNA-based gene alterations that predict drug response were known, including at least 5 in non-small cell lung cancer (NSCLC). The heterogeneity of molecular testing practice patterns and methods of testing in VA along with the increasing number and complexity of molecular tests facilitated launch of a regional precision oncology program based primarily in Veterans Integrated Service Network 1, which provided tumor DNA sequencing through 2 vendors. Advances in DNA sequencing technology, particularly NGS, permit sequencing of multiple genes in clinical tumor samples, using a panel applicable for multiple tumor types. As part of VA contributions to the 2016 White House Cancer Moonshot initiative, the regional program became NPOP with expanded geographic scope, the addition of clinical consultative services, and robust informatics that supports associated research and a learning health care system. NPOP is a component of the VA National Oncology Program Office under the Office of Specialty Care.

Testing

With the launch of NPOP in mid-2016, there was rapid expansion of the number of VA facilities participating, and the number of tumor samples being submitted increased substantially. ⁵ The expansion was facilitated by both central funding for the tumor DNA sequencing and by NPOP-provided training of pathology laboratory staff and oncologists. Today, NPOP is utilized by almost every oncology practice in VA.

NPOP’s initial focus was on lung cancer, specifically advanced-stage nonsquamous NSCLC, which not only is very common in VA, but also has one of the highest number of mutated genes that result in sensitivity to antineoplastic drugs. Recently, metastatic prostate cancer was added as a second focus tumor type. Dashboards are available on the NPOP website to assist care teams in identifying veterans at their facility with either lung or prostate cancer who may be appropriate for testing. Other solid tumors can be sent for testing through NPOP if patients have advanced stage cancer and are medically appropriate for antineoplastic therapy. To date, NPOP has sequenced > 13,000 samples.

Testing options have been added to NPOP in addition to tumor DNA sequencing. The first addition was the so-called liquid biopsy, more properly known as the cell-free DNA (cfDNA) test, a plasma-based high-sensitivity DNA sequencing assay. cfDNA is shed from dying cells and can be captured and sequenced from a plasma sample obtained by standard venipuncture, using a special-purpose sample collection tube. The test is appropriate for patients who do not have an appropriate archival tumor sample or those who cannot have a new biopsy of tumor tissue. Tumor tissue remains the preferred test sample due to a higher sensitivity than that of cfDNA and less susceptibility to false positives, so consideration of a tumor biopsy is appropriate prior to requesting a cfDNA assay. Therapy can greatly impact the sensitivity of cfDNA testing, so patients should be having disease progression at the time of obtaining a blood sample for cfDNA.

Finally, myeloid leukocytic cells accumulate genetic alterations during aging similar to those found in myelodysplasia and acute myeloid leukemia. These myeloid-associated mutations can be detected in both tumor and cfDNA samples and are known as clonal hyperplasia of indeterminate potential (CHIP). CHIP is much more common in the cfDNA. For lung cancer, CHIP-associated gene variants are readily distinguished from lung cancer-associated variants, but that distinction is much more difficult in many other tumor types.

In partnership with the current DNA sequencing contractor, NPOP provides access to a second gene panel for hematologic malignancies or sarcomas, though neither of these classes of malignancies currently have clear indications for routine NGS multigene panel testing. Given the low rate of finding a gene mutation that would change therapy that could not be found with smaller, less expensive gene panels, NPOP requires prior approval for the use of this panel.

Finally, since early 2019, programmed deathligand 1 (PD-L1) immunohistochemistry analysis is available through NPOP in association with NGS testing of the same sample for those solid tumors with US Food and Drug Administration (FDA)-approved indications that include a PD-L1 companion diagnostic. This service was added to facilitate concurrent testing of PD-L1 and DNA sequencing, which speeds availability of molecular data to the health care provider and veteran.

Determining Clinical Significance

The complexity of tumor NGS gene panel test results is far greater than frequently ordered laboratory or molecular testing due to the near infinite number of possible results and varying degrees of consensus of the significance of the results for therapeutic decision making. That complexity is reflected in the length of the test reports, which are often ≥ 20 pages. Starting from the gene variants identified by the DNA sequencing variant-caller bioinformatics pipeline, there is a 2-step process, referred to as annotation, to interpret the clinical significance that is repeated for each variant.

The first step is to assign a pathogenicity value, also known as oncogenicity, using a 5-point Likert scale from pathogenic to benign with variant of unknown significance (VUS) in the middle of the scale. Only variants that are pathogenic or likely pathogenic are considered further. A VUS is usually communicated to the health care provider but should generally not be acted on, while benign and likely benign variants may or may not be included in the report and should never be acted on. NPOP examined the concordance of pathogenicity calls among 3 annotation services: N-of-One/QCI Precision Insights (qiagen.com), IBM Watson for Genomics (WfG), and OncoKB (www.oncokb.org).⁶ There was moderate-to-poor concordance, indicating lack of consensus about whether a significant fraction of observed gene variants contributes to the patient’s cancer. This variability likely arises due to differences in algorithms and criteria used to assess pathogenicity.

Another complexity in annotation for actionability is tumor type ontogeny—the classification system used for cancer types. WfG uses a subset of the National Cancer Institute Thesaurus (ncithesaurus.nci.nih.gov), OncoKB uses the unique OncoTree (oncotree.mskcc.org), and Foundation Medicine (www.foundationmed icine.com), and N-of-One use propriety classification systems. The WfG and OncoKB tumor types have evolved over time, while it is unclear what changes have been made in the FMI and N-of-One tumor type classification systems. Thus, a gene variant observed in a single patient may be annotated differently by these services because of how the tumor type is mapped onto the services’ tumor type ontogeny. NPOP has been assigning WfG diagnoses since 2017, including historic assignment for prior samples back to the pilot project in 2015. In early 2019, NPOP began requiring test requesters to include International Classification of Diseases for Oncology, 3rd Edition (ICD-O-3) diagnoses (histology and site codes) with the sample. ICD-O-3 codes are used in all cancer registry data in North America, including the VA Cancer Registry System. The approximately 50,000 possible diagnoses allow fine precision in diagnoses, which is important for less common and rare cancer types; however, the large number of diagnoses adds complexity. NPOP has created a partial translation table for ICD-O-3 to WfG diagnosis that includes all diagnoses seen to date; this table facilitates continuing provision of WfG diagnosis without manual review as was previously required.

NPOP-Provided Genetic Services

Given these complexities in interpretation of NGS multigene panel results, NPOP provides several services to assist health care providers and other members of the care team. First, the NPOP Interfacility Consult (IFC) is a virtual “phone-a-friend” service that provides asynchronous patient-specific expert recommendations in precision oncology. By far the most requested service is assistance with interpretation of a patient’s DNA sequence results. Other requests include advice on whether to perform NGS testing and what molecular testing to perform. The IFC is integral to the VA Computerized Patient Record System electronic health record. Additional requests have been submitted and answered by e-mail.

The Molecular Oncology Tumor Board is a monthly case-based educational conference supported by the VA Employee Education Service, which provides continuing education credits for attendees. NPOP staff coordinate the conference, and a panel of specialists from around the country provide expert commentary.

In 2016, IBM gifted the services of WfG to VA. WfG’s main functionality is annotation of NGS results. About 5,000 samples were processed from 2017 to 2019; sample processing is expected to resume shortly. The availability of WfG annotations early in NPOP operation was very useful to the implementation of NPOP in general and the NPOP consultation services in particular, resulting in improved thoroughness of opinions provided by NPOP staff.

Informatics

Informatics is an essential component of NPOP that facilitates both clinical care and research (Figure 3). Results of NGS gene panels are returned to the facility that submitted the sample for testing as a PDF document. NPOP receives the same PDF report in real time but also structured data of the results including a variant callformat file and XML file. The secondary sequence data in binary alignment map or FASTQ format is received in batches. NPOP program staff extract data from these files and then load it into SQL tables in the VA Corporate Data Warehouse. In partnership with the VA Pharmacy Benefits Management Service, NPOP has constructed user-friendly dashboards that allow users with no technical skills and who have the appropriate data access permissions to view various portions of the NPOP database. There are dashboards to display a list of NPOP samples by facility, find a patient by name or other identifying information, and display a list of patients who have received any antineoplastic drug, among other functions.

The NPOP database has been used to reannotate NGS results, such as when new drugs are approved. For example, when the first neurotrophic tropomyosin receptor kinase (NTRK) inhibitor was approved, NPOP rapidly identified all living patients with NTRK fusions and notified the health care providers of the availability a potential new treatment option for their patient. ⁷ NPOP is now building a method to allow NPOP dashboard users to similarly identify patients who have not received a corresponding drug for a user-selected LoE annotation. This will facilitate a systems approach to ensure that all patients with EGFR exon 19 deletions, for example, either have received an EGFR inhibitor or are reviewed to determine why they have not. Furthermore, the database will facilitate real-world data analysis in precision oncology. For example, prior to the recent FDA-approval of poly–(adenosine diphosphate–ribose) polymerase (PARP) inhibitors for prostate cancer, 50 veterans already had been treated with one of these agents. These data can help further inform which of the many variants of DNA damage repair genes benefit from PARP inhibitors.

Ensuring Access to Care for All Veterans

With any new medical technology comes an obligation to ensure appropriate equal access so as to not exacerbate health care disparities. Veterans enrolled in VA health care are much more likely to live in rural communities than does the US population as a whole, and there was concern that these veterans would not receive NGS testing at the same rate as urban veterans. NPOP therefore was intentional during implementation to ensure rural veterans were being offered testing. Indeed, there has been nearly equal utilization by rurality. No other disparities in NPOP utilization have been seen.

A majority of veterans who undergo testing in NPOP have at least 1 actionable gene variant reported.⁵ However, some of these are for lower LoE off-label use of FDA-approved medications, but many are for agents available only through clinical trials. Consideration of treatments available through a clinical trial is part of standard practice for patients with advanced malignancies. NPOP data have helped identify cohorts who are eligible for clinical trials on the basis of their tumor DNA sequencing results. The National Oncology Program Office has been working closely with the VA Office of Research and Development to expand access to cancer clinical trials in VA. Veterans also can be treated on trials outside VA as medically appropriate and with local VA approval.

Conclusions

The VA NPOP is one of the largest clinical DNA sequencing programs in the nation with integrated consultation services and health informatics resources to facilitate patient care, clinical trials, and health outcomes research. The clinical services of NPOP provide cuttingedge oncology services to veterans throughout VA without exacerbating disparities and will be a national resource for research.

Acknowledgments
NPOP was made possible and implemented through the efforts of a number of people in VHA, including the national and regional leaders who supported the program’s vision and implementation, especially Michael Mayo-Smith, David Shulkin, Jennifer S. Lee, and Laurence Meyer, the leaders and staff of the Massachusetts Veterans Epidemiology Research and Information Center who piloted regional NGS testing, and especially my current and former colleagues in the VA National Oncology Program Office, without whom NPOP would not be possible. The contributions of Neil L. Spector who served as inaugural Director of Precision Oncology and Jill E. Duffy in her role as Director of Oncology Operations are particularly noteworthy.

As the nation’s largest integrated health care system with about 50,000 new cancer diagnoses per year, providing care for over 400,000 veterans with cancer and a robust research portfolio, the US Department of Veterans Affairs (VA) is well positioned to be a leader in both clinical and research in oncology. The VA National Precision Oncology Program (NPOP), which provides tumor sequencing and consultative services, is a key component of VA oncology assets.

Case Presentation

As the mission of the VA is to “care for him who shall have borne the battle,” it is fitting to begin with the story of a US Army veteran in his 40s and the father of 2 young children who developed progressive shortness of breath, cough, and weight loss over a period of 8 months. He was diagnosed with metastatic lung adenocarcinoma in 2016, and standard testing of his tumor showed no alteration of the EGFR and ALK genes. He was treated with whole brain radiation and had begun treatment for carboplatin and pemetrexed chemotherapy with mixed tumor response.

Subsequently, his tumor was tested through NPOP, using a multigene next-generation sequencing (NGS) assay panel, which showed the presence of an abnormal fusion between the EML4 and ALK genes. The chemotherapy was discontinued and oral crizotinib precision therapy was started. The patient had an excellent response in all sites of disease (Figure 1). He was able to return to work and school.

In July 2017, his medication was switched to alectinib for asymptomatic progression in his brain, and there was further response. In September 2019, he was treated with precision intensity-modulated radiotherapy (IMRT), targeting a single brain metastasis as there were no other sites of cancer progression and no cancerrelated symptoms. He finished school and continues to work.

Precision Oncology

Oncology is a relatively young medical field. The early medical treatments for cancer were developed empirically against hematologic malignancies, particularly leukemias. Cytotoxic chemotherapeutic agents as a group have modest effects on most solid tumors, and even modern genomics has had limited ability to predict differential benefit in patients with advanced-stage carcinomas. As a result, the medications are used in a nonprecision manner in which all patients with the same cancer diagnosis and stage receive the same treatment. This is due in part to our limited understanding of both the pathophysiology of cancer and the mechanism of action of cytotoxic agents.

One of the first examples of precision oncology was tumor testing for the estrogen receptor in breast cancer, which distinguishes breast tumors sensitive to hormonal treatments from those that are resistant.³ In 2004, somatically acquired mutation of the EGFR gene was found to be associated with response to EGFR tyrosine kinase inhibitors such as gefitinib and erlotinib, and subsequently it was shown that patients without these mutations derived no benefit from use of these drugs.⁴ Thus, the precision oncology paradigm is using a molecular diagnostic as part of the indication for an antineoplastic agent, resulting in improved therapeutic efficacy and often reduced toxicity.

By 2015, multiple examples of DNA-based gene alterations that predict drug response were known, including at least 5 in non-small cell lung cancer (NSCLC). The heterogeneity of molecular testing practice patterns and methods of testing in VA along with the increasing number and complexity of molecular tests facilitated launch of a regional precision oncology program based primarily in Veterans Integrated Service Network 1, which provided tumor DNA sequencing through 2 vendors. Advances in DNA sequencing technology, particularly NGS, permit sequencing of multiple genes in clinical tumor samples, using a panel applicable for multiple tumor types. As part of VA contributions to the 2016 White House Cancer Moonshot initiative, the regional program became NPOP with expanded geographic scope, the addition of clinical consultative services, and robust informatics that supports associated research and a learning health care system. NPOP is a component of the VA National Oncology Program Office under the Office of Specialty Care.

Testing

With the launch of NPOP in mid-2016, there was rapid expansion of the number of VA facilities participating, and the number of tumor samples being submitted increased substantially. ⁵ The expansion was facilitated by both central funding for the tumor DNA sequencing and by NPOP-provided training of pathology laboratory staff and oncologists. Today, NPOP is utilized by almost every oncology practice in VA.

NPOP’s initial focus was on lung cancer, specifically advanced-stage nonsquamous NSCLC, which not only is very common in VA, but also has one of the highest number of mutated genes that result in sensitivity to antineoplastic drugs. Recently, metastatic prostate cancer was added as a second focus tumor type. Dashboards are available on the NPOP website to assist care teams in identifying veterans at their facility with either lung or prostate cancer who may be appropriate for testing. Other solid tumors can be sent for testing through NPOP if patients have advanced stage cancer and are medically appropriate for antineoplastic therapy. To date, NPOP has sequenced > 13,000 samples.

Testing options have been added to NPOP in addition to tumor DNA sequencing. The first addition was the so-called liquid biopsy, more properly known as the cell-free DNA (cfDNA) test, a plasma-based high-sensitivity DNA sequencing assay. cfDNA is shed from dying cells and can be captured and sequenced from a plasma sample obtained by standard venipuncture, using a special-purpose sample collection tube. The test is appropriate for patients who do not have an appropriate archival tumor sample or those who cannot have a new biopsy of tumor tissue. Tumor tissue remains the preferred test sample due to a higher sensitivity than that of cfDNA and less susceptibility to false positives, so consideration of a tumor biopsy is appropriate prior to requesting a cfDNA assay. Therapy can greatly impact the sensitivity of cfDNA testing, so patients should be having disease progression at the time of obtaining a blood sample for cfDNA.

Finally, myeloid leukocytic cells accumulate genetic alterations during aging similar to those found in myelodysplasia and acute myeloid leukemia. These myeloid-associated mutations can be detected in both tumor and cfDNA samples and are known as clonal hyperplasia of indeterminate potential (CHIP). CHIP is much more common in the cfDNA. For lung cancer, CHIP-associated gene variants are readily distinguished from lung cancer-associated variants, but that distinction is much more difficult in many other tumor types.

In partnership with the current DNA sequencing contractor, NPOP provides access to a second gene panel for hematologic malignancies or sarcomas, though neither of these classes of malignancies currently have clear indications for routine NGS multigene panel testing. Given the low rate of finding a gene mutation that would change therapy that could not be found with smaller, less expensive gene panels, NPOP requires prior approval for the use of this panel.

Finally, since early 2019, programmed deathligand 1 (PD-L1) immunohistochemistry analysis is available through NPOP in association with NGS testing of the same sample for those solid tumors with US Food and Drug Administration (FDA)-approved indications that include a PD-L1 companion diagnostic. This service was added to facilitate concurrent testing of PD-L1 and DNA sequencing, which speeds availability of molecular data to the health care provider and veteran.

Determining Clinical Significance

The complexity of tumor NGS gene panel test results is far greater than frequently ordered laboratory or molecular testing due to the near infinite number of possible results and varying degrees of consensus of the significance of the results for therapeutic decision making. That complexity is reflected in the length of the test reports, which are often ≥ 20 pages. Starting from the gene variants identified by the DNA sequencing variant-caller bioinformatics pipeline, there is a 2-step process, referred to as annotation, to interpret the clinical significance that is repeated for each variant.

The first step is to assign a pathogenicity value, also known as oncogenicity, using a 5-point Likert scale from pathogenic to benign with variant of unknown significance (VUS) in the middle of the scale. Only variants that are pathogenic or likely pathogenic are considered further. A VUS is usually communicated to the health care provider but should generally not be acted on, while benign and likely benign variants may or may not be included in the report and should never be acted on. NPOP examined the concordance of pathogenicity calls among 3 annotation services: N-of-One/QCI Precision Insights (qiagen.com), IBM Watson for Genomics (WfG), and OncoKB (www.oncokb.org).⁶ There was moderate-to-poor concordance, indicating lack of consensus about whether a significant fraction of observed gene variants contributes to the patient’s cancer. This variability likely arises due to differences in algorithms and criteria used to assess pathogenicity.

Another complexity in annotation for actionability is tumor type ontogeny—the classification system used for cancer types. WfG uses a subset of the National Cancer Institute Thesaurus (ncithesaurus.nci.nih.gov), OncoKB uses the unique OncoTree (oncotree.mskcc.org), and Foundation Medicine (www.foundationmed icine.com), and N-of-One use propriety classification systems. The WfG and OncoKB tumor types have evolved over time, while it is unclear what changes have been made in the FMI and N-of-One tumor type classification systems. Thus, a gene variant observed in a single patient may be annotated differently by these services because of how the tumor type is mapped onto the services’ tumor type ontogeny. NPOP has been assigning WfG diagnoses since 2017, including historic assignment for prior samples back to the pilot project in 2015. In early 2019, NPOP began requiring test requesters to include International Classification of Diseases for Oncology, 3rd Edition (ICD-O-3) diagnoses (histology and site codes) with the sample. ICD-O-3 codes are used in all cancer registry data in North America, including the VA Cancer Registry System. The approximately 50,000 possible diagnoses allow fine precision in diagnoses, which is important for less common and rare cancer types; however, the large number of diagnoses adds complexity. NPOP has created a partial translation table for ICD-O-3 to WfG diagnosis that includes all diagnoses seen to date; this table facilitates continuing provision of WfG diagnosis without manual review as was previously required.

NPOP-Provided Genetic Services

Given these complexities in interpretation of NGS multigene panel results, NPOP provides several services to assist health care providers and other members of the care team. First, the NPOP Interfacility Consult (IFC) is a virtual “phone-a-friend” service that provides asynchronous patient-specific expert recommendations in precision oncology. By far the most requested service is assistance with interpretation of a patient’s DNA sequence results. Other requests include advice on whether to perform NGS testing and what molecular testing to perform. The IFC is integral to the VA Computerized Patient Record System electronic health record. Additional requests have been submitted and answered by e-mail.

The Molecular Oncology Tumor Board is a monthly case-based educational conference supported by the VA Employee Education Service, which provides continuing education credits for attendees. NPOP staff coordinate the conference, and a panel of specialists from around the country provide expert commentary.

In 2016, IBM gifted the services of WfG to VA. WfG’s main functionality is annotation of NGS results. About 5,000 samples were processed from 2017 to 2019; sample processing is expected to resume shortly. The availability of WfG annotations early in NPOP operation was very useful to the implementation of NPOP in general and the NPOP consultation services in particular, resulting in improved thoroughness of opinions provided by NPOP staff.

Informatics

Informatics is an essential component of NPOP that facilitates both clinical care and research (Figure 3). Results of NGS gene panels are returned to the facility that submitted the sample for testing as a PDF document. NPOP receives the same PDF report in real time but also structured data of the results including a variant callformat file and XML file. The secondary sequence data in binary alignment map or FASTQ format is received in batches. NPOP program staff extract data from these files and then load it into SQL tables in the VA Corporate Data Warehouse. In partnership with the VA Pharmacy Benefits Management Service, NPOP has constructed user-friendly dashboards that allow users with no technical skills and who have the appropriate data access permissions to view various portions of the NPOP database. There are dashboards to display a list of NPOP samples by facility, find a patient by name or other identifying information, and display a list of patients who have received any antineoplastic drug, among other functions.

The NPOP database has been used to reannotate NGS results, such as when new drugs are approved. For example, when the first neurotrophic tropomyosin receptor kinase (NTRK) inhibitor was approved, NPOP rapidly identified all living patients with NTRK fusions and notified the health care providers of the availability a potential new treatment option for their patient. ⁷ NPOP is now building a method to allow NPOP dashboard users to similarly identify patients who have not received a corresponding drug for a user-selected LoE annotation. This will facilitate a systems approach to ensure that all patients with EGFR exon 19 deletions, for example, either have received an EGFR inhibitor or are reviewed to determine why they have not. Furthermore, the database will facilitate real-world data analysis in precision oncology. For example, prior to the recent FDA-approval of poly–(adenosine diphosphate–ribose) polymerase (PARP) inhibitors for prostate cancer, 50 veterans already had been treated with one of these agents. These data can help further inform which of the many variants of DNA damage repair genes benefit from PARP inhibitors.

Ensuring Access to Care for All Veterans

With any new medical technology comes an obligation to ensure appropriate equal access so as to not exacerbate health care disparities. Veterans enrolled in VA health care are much more likely to live in rural communities than does the US population as a whole, and there was concern that these veterans would not receive NGS testing at the same rate as urban veterans. NPOP therefore was intentional during implementation to ensure rural veterans were being offered testing. Indeed, there has been nearly equal utilization by rurality. No other disparities in NPOP utilization have been seen.

A majority of veterans who undergo testing in NPOP have at least 1 actionable gene variant reported.⁵ However, some of these are for lower LoE off-label use of FDA-approved medications, but many are for agents available only through clinical trials. Consideration of treatments available through a clinical trial is part of standard practice for patients with advanced malignancies. NPOP data have helped identify cohorts who are eligible for clinical trials on the basis of their tumor DNA sequencing results. The National Oncology Program Office has been working closely with the VA Office of Research and Development to expand access to cancer clinical trials in VA. Veterans also can be treated on trials outside VA as medically appropriate and with local VA approval.

Conclusions

The VA NPOP is one of the largest clinical DNA sequencing programs in the nation with integrated consultation services and health informatics resources to facilitate patient care, clinical trials, and health outcomes research. The clinical services of NPOP provide cuttingedge oncology services to veterans throughout VA without exacerbating disparities and will be a national resource for research.

Acknowledgments
NPOP was made possible and implemented through the efforts of a number of people in VHA, including the national and regional leaders who supported the program’s vision and implementation, especially Michael Mayo-Smith, David Shulkin, Jennifer S. Lee, and Laurence Meyer, the leaders and staff of the Massachusetts Veterans Epidemiology Research and Information Center who piloted regional NGS testing, and especially my current and former colleagues in the VA National Oncology Program Office, without whom NPOP would not be possible. The contributions of Neil L. Spector who served as inaugural Director of Precision Oncology and Jill E. Duffy in her role as Director of Oncology Operations are particularly noteworthy.

The Veterans Health Administration (VHA) facilitates care for > 7,700 veterans with newly diagnosed lung cancer each year.¹ This includes comprehensive clinical evaluations and management that are facilitated through interdisciplinary networks of pulmonologists, radiologists, thoracic surgeons, radiation oncologists, and medical oncologists. Veterans with lung cancer have access to advanced medical technologies at US Department of Veterans Affairs (VA) medical centers (VAMCs), including the latest US Food and Drug Administration (FDA)-approved targeted radiation delivery systems and novel immunotherapies, as well as precision oncology-driven clinical trials.²

Despite access to high-quality care, lung cancer remains the leading cause of cancer-related mortality among VHA enrollees as well as the US population.³ About 15 veterans die of lung cancer each day; most are diagnosed with advanced stage III or stage IV disease. To address this issue, VHA launched 3 new initiatives between 2016 and 2017 to improve outcomes for veterans impacted by lung cancer. The VA Partnership to increase Access to Lung Screening (VA-PALS) is a clinical implementation project to increase access to early detection lung screening scans at 10 VAMCs. The Veterans Affairs Lung cancer surgery Or stereotactic Radiotherapy (VALOR) is a phase 3 randomized trial that investigates the role of stereotactic body radiation therapy (SBRT) as a potential alternative to surgery for veterans with operable stage I non-small cell lung cancer (NSCLC). The VA Radiation Oncology Quality Surveillance program (VA-ROQS) established national expert-derived benchmarks for the quality assurance of lung cancer therapy.

VA-PALS

The central mission of VA-PALS is to reduce lung cancer mortality among veterans at risk by increasing access to low-dose computed tomography (LDCT) lung screening scans.^4,5 The program was developed as a public-private partnership to introduce structured lung cancer screening programs at 10 VAMCs to safely manage large cohorts of veterans undergoing annual screening scans. The VA-PALS project brings together pulmonologists, radiologists, thoracic surgeons, radiation oncologists, medical oncologists, and computer scientists who have experience developing open-source electronic health record systems for VHA networks. The project was launched in 2017 after an earlier clinical demonstration project identified substantial variability and challenges with efforts to implement new lung cancer screening programs in the VA.⁶

Each of the 10 VA-PALS-designated lung cancer screening programs (Atlanta, Georgia; Phoenix, Arizona; Indianapolis, Indiana; Chicago, Illinois; Nashville, Tennessee; Philadelphia, Pennsylvania; St. Louis, Missouri; Denver, Colorado; Milwaukee, Wisconsin; and Cleveland, Ohio) assumes a major responsibility for ordering and evaluating the results of LDCT scans to ensure appropriate follow-up care of veterans with abnormal radiographic findings. Lung cancer screening programs are supported with a full-time navigator (nurse practitioner or physician assistant) who has received training from the VA-PALS project team with direct supervision by a local site director who is a pulmonologist, thoracic surgeon, or medical oncologist. Lung cancer screening programs establish a centralized approach that aims to reduce the burden on primary care providers for remembering to order annual baseline and repeat LDCT scans. The lung screening programs also manage radiographic findings that usually are benign to facilitate appropriate decisions to minimize the risk of unnecessary tests and procedures. Program implementation across VA-PALS sites includes a strong connection among participants through meetings, newsletters, and attendance at conferences to create a collaborative learning network, which has been shown to improve dissemination of best practices across the VHA.^7,8

The International Early Lung Cancer Action Program (I-ELCAP), which pioneered the use of LDCT to reduce lung cancer mortality, is a leading partner for VA-PALS.⁹ This group has > 25 years of experience overcoming many of the obstacles and challenges that new lung cancer screening programs face.¹⁰ The I-ELCAP has successfully implemented new lung cancer screening programs at > 70 health care institutions worldwide. Their implementation processes provide continuous oversight for each center. As a result, the I-ELCAP team has developed a large and detailed lung cancer screening registry with > 75,000 patients enrolled globally, comprising a vast database of clinical data that has produced > 270 scientific publications focusing on improving the quality and safety of lung cancer screening.^11,12

These reports have helped guide evidence-based recommendations for lung cancer screening in several countries and include standardized processes for patient counseling and smoking cessation, data acquisition and interpretation of LDCT images, and clinical management of abnormal findings to facilitate timely transition from diagnosis to treatment.^13-15 The I-ELCAP management system detects 10% abnormal findings in the baseline screening study, which declines to 6% in subsequent years.¹² The scientific findings from this approach have provided additional insights into technical CT scanning errors that can affect tumor nodule measurements.¹⁶ The vast amount of clinical data and expertise have helped explore genetic markers.¹⁷ The I-ELCAP has facilitated cost-effectiveness investigations to determine the value of screening, and their research portfolio includes investigations into the longer-term outcomes after primary treatment for patients with screen-detected lung cancers.^18,19

I-ELCAP gifted its comprehensive clinical software management system that has been in use for the above contributions for use in the VHA through an open source agreement without licensing fees. The I-ELCAP software management system was rewritten in MUMPS, the software programming language that is used by the VA Computerized Patient Record System (CPRS). The newly adapted VA-PALS/I-ELCAP system underwent modifications with VHA clinicians’ input, and was successfully installed at the Phoenix VA Health Care System in Arizona, which has assumed a leading role for the VA-PALS project.

The VA-PALS/I-ELCAP clinical management system currently is under review by the VA Office of Information and Technology for broad distribution across the VHA through the VA Enterprise Cloud. Once in use across the VHA, the VA-PALS/I-ELCAP clinical management system will offer a longitudinal central database that can support numerous quality improvement and quality assurance initiatives, as well as innovative research projects. Research opportunities include: (1) large-scale examination of LDCT images with artificial intelligence and machine learning techniques; (2) epidemiologic investigations of environmental and genetic risk factors to better understand the high percentage of veterans diagnosed with lung cancer who were never smokers or had quit many years ago; and (3) multisite clinical trials that explore early detection blood screening tests that are under development.

The VA-PALS project is sponsored by the VHA Office of Rural Health as an enterprise-wide initiative that focuses on reaching rural veterans at risk. The project received additional support through the VA Secretary’s Center for Strategic Partnerships with a $5.8 million grant from the Bristol-Myers Squibb Foundation. The VistA (Veterans Health Information Systems and Technology Architecture) Expertise Network is an additional key partner that helped adapt the VAPALS-ELCAP system for use on VHA networks.

VALOR Trial

The VA Cooperative Studies Program (CSP) #2005 VALOR study is a randomized phase 3 clinical trial that evaluates optimal treatment for participants with operable early-stage NSCLC.²⁰ The trial is sponsored by the CSP, which is responsible for and provides resources for the planning and conduct of large multicenter surgical and clinical trials in VHA.²¹ The CSP #2005 VALOR study plans to enroll veterans with stage I NSCLC who will be treated with a surgical lobectomy or SBRT according to random assignment. An alternative surgical approach with a segmentectomy is acceptable, although patients in poor health who are only qualify for a wedge resection will not be enrolled. The CSP will follow each participant for at least 5 years to evaluate which treatment, if either, results in a higher overall survival rate. Secondary outcome measures are quality of life, pulmonary function, health state utilities, patterns of failure, and causes of death.

Although the study design of the VALOR trial is relatively straightforward, recruitment of participants to similar randomized trials of surgery vs SBRT for operable stage I NSCLC outside the VA has historically been very difficult. Three earlier phase 3 trials in the Netherlands and US closed prematurely after collectively enrolling only 4% of planned participants. Although a pooled analysis of 2 of these trials demonstrated a statistically significant difference of 95% vs 79% survival in favor of SBRT at a median follow-up of 40 months, the analysis was underpowered because only 58 of the planned 1,380 participants were enrolled.^22,23

The CSP #2005 VALOR study team was keenly aware of these past challenges and addressed many of the obstacles to enrollment by optimizing eligibility criteria and follow-up requirements. Enrollment sites were carefully selected after confirming equipoise between the 2 treatments, and study coordinators at each enrollment site were empowered to provide a leading role with recruitment. Multiple communication channels were established for constant contact to disseminate new best practices for recruitment as they were identified. Furthermore, a veteran-centric educational recruitment video, approved by the VA Central Institutional Review Board, was designed to help study participants better understand the purpose of participating in a clinical trial (www.vacsp.research.va.gov/CSP_2005/CSP_2005.asp).

After the first year of recruitment, researchers identified individual clinician and patient preferences as the predominant difficulty with recruitment, which was not easy to address. The CSP #2005 VALOR study team opted to partner directly with the Qualitative Research Integrated within Trials (QuinteT) team in the United Kingdom to adopt its methods to successfully support randomized clinical trials with serious recruitment challenges.^24,25 By working directly with the QuinteT director, the CSP #2005 VALOR team made a major revision to the informed consent forms by shifting focus away from disclosing potential harms of research to an informative document that emphasized the purpose of the study. The work with QuinteT also led to the creation of balanced narratives for study teams to use and for potential participants to read. These provide a more consistent message that describes why the study is important and why clinicians are no longer certain that surgery is the optimal treatment for all patients with operable stage I NSCLC.

The VALOR clinical trial, opened in 2017, remains open at only 9 VAMCs. As of early 2020, it has enrolled more participants than all previous phase 3 trials combined. Once completed, the results from CSP #2005 VALOR study will help clinicians and veterans with operable stage I NSCLC better understand the tradeoffs of surgery vs SBRT as an initial treatment option. Plans are under way to expand the scope of the trial and include investigations of pretreatment radiomic signatures and genetic markers from biopsy tissue and blood samples, to better predict when surgery or SBRT might be the best treatment option for an individual patient.

VA-ROQS

The VA-ROQS was created in 2016 to compare treatment of veterans with lung cancer in the VHA with quality standards recommended by nationally recognized experts in lung cancer care. Partnering with Washington University in St. Louis, Missouri and the American Society for Radiation Oncology, the VHA established a blue-ribbon panel of experts to review clinical trial data and medical literature to provide evidence-based quality metrics for lung cancer therapy. As a result, 26 metrics applicable to each patient’s case were developed, published, and used to assess lung cancer care in each VHA radiation oncology practice.²⁶

By 2019, the resulting data led to a report on 773 lung cancer cases accumulated from all VHA radiation oncology practices. Performance data for each quality metric were compared for each practice within the VHA, which found that VHA practices met > 80% of all 1,278 metrics scored. Quality metrics included those documented within each patient health record and the specific radiation delivery parameters that reflected each health care provider’s treatment. After team investigators visited each center and recorded treatment data, VA-ROQS is now maturing to permit continuous, electronic monitoring of all lung cancer treatment delivered within VHA. As each veteran’s case is planned, the quality of the therapy is monitored, assessed, and reported to the treating physician. Each VHA radiation oncologist will receive up-to-date evaluation of each case compared with these evidence-based quality standards. The quality standards are reviewed by the blue-ribbon panel to keep the process current and valid.

Future of VHA Lung Cancer Care

As VHA continues to prioritize resources to improve and assure optimal outcomes for veterans with lung cancer, it is now looking to create a national network of Lung Cancer Centers of Excellence (LCCE) as described in the VA Budget Submission for fiscal year 2021. If Congress approves funding, LCCEs will soon be developed within the VA regional Veteran Integrated Service Network system to ensure that treatment decisions for veterans with lung cancer are based on all available molecular information, including data on pharmacogenomic profiles. Such a network would create more opportunities to leverage public–private partnerships similar to the VA-PALS project. Creation of LCCEs would help the VA leverage an even stronger learning network to support more research so that all veterans who are impacted by lung cancer have access to personalized care that optimizes safety, quality of life, and overall survival. The lessons learned, networks developed, and partnerships established through VA-PALS, VALOR, and VA-ROQS are instrumental toward achieving these goals.

The Veterans Health Administration (VHA) facilitates care for > 7,700 veterans with newly diagnosed lung cancer each year.¹ This includes comprehensive clinical evaluations and management that are facilitated through interdisciplinary networks of pulmonologists, radiologists, thoracic surgeons, radiation oncologists, and medical oncologists. Veterans with lung cancer have access to advanced medical technologies at US Department of Veterans Affairs (VA) medical centers (VAMCs), including the latest US Food and Drug Administration (FDA)-approved targeted radiation delivery systems and novel immunotherapies, as well as precision oncology-driven clinical trials.²

Despite access to high-quality care, lung cancer remains the leading cause of cancer-related mortality among VHA enrollees as well as the US population.³ About 15 veterans die of lung cancer each day; most are diagnosed with advanced stage III or stage IV disease. To address this issue, VHA launched 3 new initiatives between 2016 and 2017 to improve outcomes for veterans impacted by lung cancer. The VA Partnership to increase Access to Lung Screening (VA-PALS) is a clinical implementation project to increase access to early detection lung screening scans at 10 VAMCs. The Veterans Affairs Lung cancer surgery Or stereotactic Radiotherapy (VALOR) is a phase 3 randomized trial that investigates the role of stereotactic body radiation therapy (SBRT) as a potential alternative to surgery for veterans with operable stage I non-small cell lung cancer (NSCLC). The VA Radiation Oncology Quality Surveillance program (VA-ROQS) established national expert-derived benchmarks for the quality assurance of lung cancer therapy.

VA-PALS

The central mission of VA-PALS is to reduce lung cancer mortality among veterans at risk by increasing access to low-dose computed tomography (LDCT) lung screening scans.^4,5 The program was developed as a public-private partnership to introduce structured lung cancer screening programs at 10 VAMCs to safely manage large cohorts of veterans undergoing annual screening scans. The VA-PALS project brings together pulmonologists, radiologists, thoracic surgeons, radiation oncologists, medical oncologists, and computer scientists who have experience developing open-source electronic health record systems for VHA networks. The project was launched in 2017 after an earlier clinical demonstration project identified substantial variability and challenges with efforts to implement new lung cancer screening programs in the VA.⁶

Each of the 10 VA-PALS-designated lung cancer screening programs (Atlanta, Georgia; Phoenix, Arizona; Indianapolis, Indiana; Chicago, Illinois; Nashville, Tennessee; Philadelphia, Pennsylvania; St. Louis, Missouri; Denver, Colorado; Milwaukee, Wisconsin; and Cleveland, Ohio) assumes a major responsibility for ordering and evaluating the results of LDCT scans to ensure appropriate follow-up care of veterans with abnormal radiographic findings. Lung cancer screening programs are supported with a full-time navigator (nurse practitioner or physician assistant) who has received training from the VA-PALS project team with direct supervision by a local site director who is a pulmonologist, thoracic surgeon, or medical oncologist. Lung cancer screening programs establish a centralized approach that aims to reduce the burden on primary care providers for remembering to order annual baseline and repeat LDCT scans. The lung screening programs also manage radiographic findings that usually are benign to facilitate appropriate decisions to minimize the risk of unnecessary tests and procedures. Program implementation across VA-PALS sites includes a strong connection among participants through meetings, newsletters, and attendance at conferences to create a collaborative learning network, which has been shown to improve dissemination of best practices across the VHA.^7,8

The International Early Lung Cancer Action Program (I-ELCAP), which pioneered the use of LDCT to reduce lung cancer mortality, is a leading partner for VA-PALS.⁹ This group has > 25 years of experience overcoming many of the obstacles and challenges that new lung cancer screening programs face.¹⁰ The I-ELCAP has successfully implemented new lung cancer screening programs at > 70 health care institutions worldwide. Their implementation processes provide continuous oversight for each center. As a result, the I-ELCAP team has developed a large and detailed lung cancer screening registry with > 75,000 patients enrolled globally, comprising a vast database of clinical data that has produced > 270 scientific publications focusing on improving the quality and safety of lung cancer screening.^11,12

These reports have helped guide evidence-based recommendations for lung cancer screening in several countries and include standardized processes for patient counseling and smoking cessation, data acquisition and interpretation of LDCT images, and clinical management of abnormal findings to facilitate timely transition from diagnosis to treatment.^13-15 The I-ELCAP management system detects 10% abnormal findings in the baseline screening study, which declines to 6% in subsequent years.¹² The scientific findings from this approach have provided additional insights into technical CT scanning errors that can affect tumor nodule measurements.¹⁶ The vast amount of clinical data and expertise have helped explore genetic markers.¹⁷ The I-ELCAP has facilitated cost-effectiveness investigations to determine the value of screening, and their research portfolio includes investigations into the longer-term outcomes after primary treatment for patients with screen-detected lung cancers.^18,19

I-ELCAP gifted its comprehensive clinical software management system that has been in use for the above contributions for use in the VHA through an open source agreement without licensing fees. The I-ELCAP software management system was rewritten in MUMPS, the software programming language that is used by the VA Computerized Patient Record System (CPRS). The newly adapted VA-PALS/I-ELCAP system underwent modifications with VHA clinicians’ input, and was successfully installed at the Phoenix VA Health Care System in Arizona, which has assumed a leading role for the VA-PALS project.

The VA-PALS/I-ELCAP clinical management system currently is under review by the VA Office of Information and Technology for broad distribution across the VHA through the VA Enterprise Cloud. Once in use across the VHA, the VA-PALS/I-ELCAP clinical management system will offer a longitudinal central database that can support numerous quality improvement and quality assurance initiatives, as well as innovative research projects. Research opportunities include: (1) large-scale examination of LDCT images with artificial intelligence and machine learning techniques; (2) epidemiologic investigations of environmental and genetic risk factors to better understand the high percentage of veterans diagnosed with lung cancer who were never smokers or had quit many years ago; and (3) multisite clinical trials that explore early detection blood screening tests that are under development.

The VA-PALS project is sponsored by the VHA Office of Rural Health as an enterprise-wide initiative that focuses on reaching rural veterans at risk. The project received additional support through the VA Secretary’s Center for Strategic Partnerships with a $5.8 million grant from the Bristol-Myers Squibb Foundation. The VistA (Veterans Health Information Systems and Technology Architecture) Expertise Network is an additional key partner that helped adapt the VAPALS-ELCAP system for use on VHA networks.

VALOR Trial

The VA Cooperative Studies Program (CSP) #2005 VALOR study is a randomized phase 3 clinical trial that evaluates optimal treatment for participants with operable early-stage NSCLC.²⁰ The trial is sponsored by the CSP, which is responsible for and provides resources for the planning and conduct of large multicenter surgical and clinical trials in VHA.²¹ The CSP #2005 VALOR study plans to enroll veterans with stage I NSCLC who will be treated with a surgical lobectomy or SBRT according to random assignment. An alternative surgical approach with a segmentectomy is acceptable, although patients in poor health who are only qualify for a wedge resection will not be enrolled. The CSP will follow each participant for at least 5 years to evaluate which treatment, if either, results in a higher overall survival rate. Secondary outcome measures are quality of life, pulmonary function, health state utilities, patterns of failure, and causes of death.

Although the study design of the VALOR trial is relatively straightforward, recruitment of participants to similar randomized trials of surgery vs SBRT for operable stage I NSCLC outside the VA has historically been very difficult. Three earlier phase 3 trials in the Netherlands and US closed prematurely after collectively enrolling only 4% of planned participants. Although a pooled analysis of 2 of these trials demonstrated a statistically significant difference of 95% vs 79% survival in favor of SBRT at a median follow-up of 40 months, the analysis was underpowered because only 58 of the planned 1,380 participants were enrolled.^22,23

The CSP #2005 VALOR study team was keenly aware of these past challenges and addressed many of the obstacles to enrollment by optimizing eligibility criteria and follow-up requirements. Enrollment sites were carefully selected after confirming equipoise between the 2 treatments, and study coordinators at each enrollment site were empowered to provide a leading role with recruitment. Multiple communication channels were established for constant contact to disseminate new best practices for recruitment as they were identified. Furthermore, a veteran-centric educational recruitment video, approved by the VA Central Institutional Review Board, was designed to help study participants better understand the purpose of participating in a clinical trial (www.vacsp.research.va.gov/CSP_2005/CSP_2005.asp).

After the first year of recruitment, researchers identified individual clinician and patient preferences as the predominant difficulty with recruitment, which was not easy to address. The CSP #2005 VALOR study team opted to partner directly with the Qualitative Research Integrated within Trials (QuinteT) team in the United Kingdom to adopt its methods to successfully support randomized clinical trials with serious recruitment challenges.^24,25 By working directly with the QuinteT director, the CSP #2005 VALOR team made a major revision to the informed consent forms by shifting focus away from disclosing potential harms of research to an informative document that emphasized the purpose of the study. The work with QuinteT also led to the creation of balanced narratives for study teams to use and for potential participants to read. These provide a more consistent message that describes why the study is important and why clinicians are no longer certain that surgery is the optimal treatment for all patients with operable stage I NSCLC.

The VALOR clinical trial, opened in 2017, remains open at only 9 VAMCs. As of early 2020, it has enrolled more participants than all previous phase 3 trials combined. Once completed, the results from CSP #2005 VALOR study will help clinicians and veterans with operable stage I NSCLC better understand the tradeoffs of surgery vs SBRT as an initial treatment option. Plans are under way to expand the scope of the trial and include investigations of pretreatment radiomic signatures and genetic markers from biopsy tissue and blood samples, to better predict when surgery or SBRT might be the best treatment option for an individual patient.

VA-ROQS

The VA-ROQS was created in 2016 to compare treatment of veterans with lung cancer in the VHA with quality standards recommended by nationally recognized experts in lung cancer care. Partnering with Washington University in St. Louis, Missouri and the American Society for Radiation Oncology, the VHA established a blue-ribbon panel of experts to review clinical trial data and medical literature to provide evidence-based quality metrics for lung cancer therapy. As a result, 26 metrics applicable to each patient’s case were developed, published, and used to assess lung cancer care in each VHA radiation oncology practice.²⁶

By 2019, the resulting data led to a report on 773 lung cancer cases accumulated from all VHA radiation oncology practices. Performance data for each quality metric were compared for each practice within the VHA, which found that VHA practices met > 80% of all 1,278 metrics scored. Quality metrics included those documented within each patient health record and the specific radiation delivery parameters that reflected each health care provider’s treatment. After team investigators visited each center and recorded treatment data, VA-ROQS is now maturing to permit continuous, electronic monitoring of all lung cancer treatment delivered within VHA. As each veteran’s case is planned, the quality of the therapy is monitored, assessed, and reported to the treating physician. Each VHA radiation oncologist will receive up-to-date evaluation of each case compared with these evidence-based quality standards. The quality standards are reviewed by the blue-ribbon panel to keep the process current and valid.

Future of VHA Lung Cancer Care

As VHA continues to prioritize resources to improve and assure optimal outcomes for veterans with lung cancer, it is now looking to create a national network of Lung Cancer Centers of Excellence (LCCE) as described in the VA Budget Submission for fiscal year 2021. If Congress approves funding, LCCEs will soon be developed within the VA regional Veteran Integrated Service Network system to ensure that treatment decisions for veterans with lung cancer are based on all available molecular information, including data on pharmacogenomic profiles. Such a network would create more opportunities to leverage public–private partnerships similar to the VA-PALS project. Creation of LCCEs would help the VA leverage an even stronger learning network to support more research so that all veterans who are impacted by lung cancer have access to personalized care that optimizes safety, quality of life, and overall survival. The lessons learned, networks developed, and partnerships established through VA-PALS, VALOR, and VA-ROQS are instrumental toward achieving these goals.

The Veterans Health Administration (VHA) facilitates care for > 7,700 veterans with newly diagnosed lung cancer each year.¹ This includes comprehensive clinical evaluations and management that are facilitated through interdisciplinary networks of pulmonologists, radiologists, thoracic surgeons, radiation oncologists, and medical oncologists. Veterans with lung cancer have access to advanced medical technologies at US Department of Veterans Affairs (VA) medical centers (VAMCs), including the latest US Food and Drug Administration (FDA)-approved targeted radiation delivery systems and novel immunotherapies, as well as precision oncology-driven clinical trials.²

Despite access to high-quality care, lung cancer remains the leading cause of cancer-related mortality among VHA enrollees as well as the US population.³ About 15 veterans die of lung cancer each day; most are diagnosed with advanced stage III or stage IV disease. To address this issue, VHA launched 3 new initiatives between 2016 and 2017 to improve outcomes for veterans impacted by lung cancer. The VA Partnership to increase Access to Lung Screening (VA-PALS) is a clinical implementation project to increase access to early detection lung screening scans at 10 VAMCs. The Veterans Affairs Lung cancer surgery Or stereotactic Radiotherapy (VALOR) is a phase 3 randomized trial that investigates the role of stereotactic body radiation therapy (SBRT) as a potential alternative to surgery for veterans with operable stage I non-small cell lung cancer (NSCLC). The VA Radiation Oncology Quality Surveillance program (VA-ROQS) established national expert-derived benchmarks for the quality assurance of lung cancer therapy.

VA-PALS

The central mission of VA-PALS is to reduce lung cancer mortality among veterans at risk by increasing access to low-dose computed tomography (LDCT) lung screening scans.^4,5 The program was developed as a public-private partnership to introduce structured lung cancer screening programs at 10 VAMCs to safely manage large cohorts of veterans undergoing annual screening scans. The VA-PALS project brings together pulmonologists, radiologists, thoracic surgeons, radiation oncologists, medical oncologists, and computer scientists who have experience developing open-source electronic health record systems for VHA networks. The project was launched in 2017 after an earlier clinical demonstration project identified substantial variability and challenges with efforts to implement new lung cancer screening programs in the VA.⁶

Each of the 10 VA-PALS-designated lung cancer screening programs (Atlanta, Georgia; Phoenix, Arizona; Indianapolis, Indiana; Chicago, Illinois; Nashville, Tennessee; Philadelphia, Pennsylvania; St. Louis, Missouri; Denver, Colorado; Milwaukee, Wisconsin; and Cleveland, Ohio) assumes a major responsibility for ordering and evaluating the results of LDCT scans to ensure appropriate follow-up care of veterans with abnormal radiographic findings. Lung cancer screening programs are supported with a full-time navigator (nurse practitioner or physician assistant) who has received training from the VA-PALS project team with direct supervision by a local site director who is a pulmonologist, thoracic surgeon, or medical oncologist. Lung cancer screening programs establish a centralized approach that aims to reduce the burden on primary care providers for remembering to order annual baseline and repeat LDCT scans. The lung screening programs also manage radiographic findings that usually are benign to facilitate appropriate decisions to minimize the risk of unnecessary tests and procedures. Program implementation across VA-PALS sites includes a strong connection among participants through meetings, newsletters, and attendance at conferences to create a collaborative learning network, which has been shown to improve dissemination of best practices across the VHA.^7,8

The International Early Lung Cancer Action Program (I-ELCAP), which pioneered the use of LDCT to reduce lung cancer mortality, is a leading partner for VA-PALS.⁹ This group has > 25 years of experience overcoming many of the obstacles and challenges that new lung cancer screening programs face.¹⁰ The I-ELCAP has successfully implemented new lung cancer screening programs at > 70 health care institutions worldwide. Their implementation processes provide continuous oversight for each center. As a result, the I-ELCAP team has developed a large and detailed lung cancer screening registry with > 75,000 patients enrolled globally, comprising a vast database of clinical data that has produced > 270 scientific publications focusing on improving the quality and safety of lung cancer screening.^11,12

These reports have helped guide evidence-based recommendations for lung cancer screening in several countries and include standardized processes for patient counseling and smoking cessation, data acquisition and interpretation of LDCT images, and clinical management of abnormal findings to facilitate timely transition from diagnosis to treatment.^13-15 The I-ELCAP management system detects 10% abnormal findings in the baseline screening study, which declines to 6% in subsequent years.¹² The scientific findings from this approach have provided additional insights into technical CT scanning errors that can affect tumor nodule measurements.¹⁶ The vast amount of clinical data and expertise have helped explore genetic markers.¹⁷ The I-ELCAP has facilitated cost-effectiveness investigations to determine the value of screening, and their research portfolio includes investigations into the longer-term outcomes after primary treatment for patients with screen-detected lung cancers.^18,19

I-ELCAP gifted its comprehensive clinical software management system that has been in use for the above contributions for use in the VHA through an open source agreement without licensing fees. The I-ELCAP software management system was rewritten in MUMPS, the software programming language that is used by the VA Computerized Patient Record System (CPRS). The newly adapted VA-PALS/I-ELCAP system underwent modifications with VHA clinicians’ input, and was successfully installed at the Phoenix VA Health Care System in Arizona, which has assumed a leading role for the VA-PALS project.

The VA-PALS/I-ELCAP clinical management system currently is under review by the VA Office of Information and Technology for broad distribution across the VHA through the VA Enterprise Cloud. Once in use across the VHA, the VA-PALS/I-ELCAP clinical management system will offer a longitudinal central database that can support numerous quality improvement and quality assurance initiatives, as well as innovative research projects. Research opportunities include: (1) large-scale examination of LDCT images with artificial intelligence and machine learning techniques; (2) epidemiologic investigations of environmental and genetic risk factors to better understand the high percentage of veterans diagnosed with lung cancer who were never smokers or had quit many years ago; and (3) multisite clinical trials that explore early detection blood screening tests that are under development.

The VA-PALS project is sponsored by the VHA Office of Rural Health as an enterprise-wide initiative that focuses on reaching rural veterans at risk. The project received additional support through the VA Secretary’s Center for Strategic Partnerships with a $5.8 million grant from the Bristol-Myers Squibb Foundation. The VistA (Veterans Health Information Systems and Technology Architecture) Expertise Network is an additional key partner that helped adapt the VAPALS-ELCAP system for use on VHA networks.

VALOR Trial

The VA Cooperative Studies Program (CSP) #2005 VALOR study is a randomized phase 3 clinical trial that evaluates optimal treatment for participants with operable early-stage NSCLC.²⁰ The trial is sponsored by the CSP, which is responsible for and provides resources for the planning and conduct of large multicenter surgical and clinical trials in VHA.²¹ The CSP #2005 VALOR study plans to enroll veterans with stage I NSCLC who will be treated with a surgical lobectomy or SBRT according to random assignment. An alternative surgical approach with a segmentectomy is acceptable, although patients in poor health who are only qualify for a wedge resection will not be enrolled. The CSP will follow each participant for at least 5 years to evaluate which treatment, if either, results in a higher overall survival rate. Secondary outcome measures are quality of life, pulmonary function, health state utilities, patterns of failure, and causes of death.

Although the study design of the VALOR trial is relatively straightforward, recruitment of participants to similar randomized trials of surgery vs SBRT for operable stage I NSCLC outside the VA has historically been very difficult. Three earlier phase 3 trials in the Netherlands and US closed prematurely after collectively enrolling only 4% of planned participants. Although a pooled analysis of 2 of these trials demonstrated a statistically significant difference of 95% vs 79% survival in favor of SBRT at a median follow-up of 40 months, the analysis was underpowered because only 58 of the planned 1,380 participants were enrolled.^22,23

The CSP #2005 VALOR study team was keenly aware of these past challenges and addressed many of the obstacles to enrollment by optimizing eligibility criteria and follow-up requirements. Enrollment sites were carefully selected after confirming equipoise between the 2 treatments, and study coordinators at each enrollment site were empowered to provide a leading role with recruitment. Multiple communication channels were established for constant contact to disseminate new best practices for recruitment as they were identified. Furthermore, a veteran-centric educational recruitment video, approved by the VA Central Institutional Review Board, was designed to help study participants better understand the purpose of participating in a clinical trial (www.vacsp.research.va.gov/CSP_2005/CSP_2005.asp).

After the first year of recruitment, researchers identified individual clinician and patient preferences as the predominant difficulty with recruitment, which was not easy to address. The CSP #2005 VALOR study team opted to partner directly with the Qualitative Research Integrated within Trials (QuinteT) team in the United Kingdom to adopt its methods to successfully support randomized clinical trials with serious recruitment challenges.^24,25 By working directly with the QuinteT director, the CSP #2005 VALOR team made a major revision to the informed consent forms by shifting focus away from disclosing potential harms of research to an informative document that emphasized the purpose of the study. The work with QuinteT also led to the creation of balanced narratives for study teams to use and for potential participants to read. These provide a more consistent message that describes why the study is important and why clinicians are no longer certain that surgery is the optimal treatment for all patients with operable stage I NSCLC.

The VALOR clinical trial, opened in 2017, remains open at only 9 VAMCs. As of early 2020, it has enrolled more participants than all previous phase 3 trials combined. Once completed, the results from CSP #2005 VALOR study will help clinicians and veterans with operable stage I NSCLC better understand the tradeoffs of surgery vs SBRT as an initial treatment option. Plans are under way to expand the scope of the trial and include investigations of pretreatment radiomic signatures and genetic markers from biopsy tissue and blood samples, to better predict when surgery or SBRT might be the best treatment option for an individual patient.

VA-ROQS

The VA-ROQS was created in 2016 to compare treatment of veterans with lung cancer in the VHA with quality standards recommended by nationally recognized experts in lung cancer care. Partnering with Washington University in St. Louis, Missouri and the American Society for Radiation Oncology, the VHA established a blue-ribbon panel of experts to review clinical trial data and medical literature to provide evidence-based quality metrics for lung cancer therapy. As a result, 26 metrics applicable to each patient’s case were developed, published, and used to assess lung cancer care in each VHA radiation oncology practice.²⁶

By 2019, the resulting data led to a report on 773 lung cancer cases accumulated from all VHA radiation oncology practices. Performance data for each quality metric were compared for each practice within the VHA, which found that VHA practices met > 80% of all 1,278 metrics scored. Quality metrics included those documented within each patient health record and the specific radiation delivery parameters that reflected each health care provider’s treatment. After team investigators visited each center and recorded treatment data, VA-ROQS is now maturing to permit continuous, electronic monitoring of all lung cancer treatment delivered within VHA. As each veteran’s case is planned, the quality of the therapy is monitored, assessed, and reported to the treating physician. Each VHA radiation oncologist will receive up-to-date evaluation of each case compared with these evidence-based quality standards. The quality standards are reviewed by the blue-ribbon panel to keep the process current and valid.

Future of VHA Lung Cancer Care

As VHA continues to prioritize resources to improve and assure optimal outcomes for veterans with lung cancer, it is now looking to create a national network of Lung Cancer Centers of Excellence (LCCE) as described in the VA Budget Submission for fiscal year 2021. If Congress approves funding, LCCEs will soon be developed within the VA regional Veteran Integrated Service Network system to ensure that treatment decisions for veterans with lung cancer are based on all available molecular information, including data on pharmacogenomic profiles. Such a network would create more opportunities to leverage public–private partnerships similar to the VA-PALS project. Creation of LCCEs would help the VA leverage an even stronger learning network to support more research so that all veterans who are impacted by lung cancer have access to personalized care that optimizes safety, quality of life, and overall survival. The lessons learned, networks developed, and partnerships established through VA-PALS, VALOR, and VA-ROQS are instrumental toward achieving these goals.

In May 2020, the US Food and Drug Administration (FDA) approved the first 2 targeted treatments for prostate cancer, specifically, the poly-(adenosine diphosphate-ribose) polymerase (PARP) inhibitors rucaparib and olaparib.^1,2 For these medications to work, the tumor must have a homologous recombination deficiency (HRD), which is a form of DNA repair deficiency. The PARP pathway is important for DNA repair, and PARP inhibition leads to “synthetic lethality” in cancer cells that already are deficient in DNA repair mechanisms.³ Now, there is evidence that patients with prostate cancer who have HRD tumors and receive PARP inhibitors live longer when compared with those who receive standard of care options.⁴ These findings offer hope for patients with prostate cancer. They also demonstrate the process and potential benefits of precision oncology efforts; namely, targeted treatments for specific tumor types in cancer patients.

This article discusses the challenges and opportunities of precision oncology for US Department of Veterans Affairs (VA) Veterans Health Administration (VHA). First, the article will discuss working with relatively rare mutations. Second, the article will examine how the trials of olaparib and rucaparib illuminate the VHA contribution to research on new therapies for patients with cancer. Finally, the article will explore the ways in which VHA is becoming a major national contributor in drug discovery and approval of precision medications.

Precision Oncology

Despite advances in screening and treatment, an estimated 600,000 people in the US will die of cancer in 2020.⁵ Meaningful advances in cancer care depend on both laboratory and clinical research. This combination, known as translational research, takes discoveries in the laboratory and applies them to patients and vice versa. Successful translational research requires many components. These include talented scientists to form hypotheses and perform the work; money for supplies and equipment; platforms for timely dissemination of knowledge; well-trained clinicians to treat patients and lead research teams; and patients to participate in clinical trials. In precision oncology, the ability to find patients for the trials can be daunting, particularly in cases where the frequency of the mutation of interest is low.

During the 20th century, with few exceptions, physicians caring for patients with cancer had blunt instruments at their disposal. Surgery and radiation could lead to survival if the cancer was caught early enough. Systemic therapies, such as chemotherapy, rarely cured but could prolong life in some patients. However, chemotherapy is imprecise and targets any cell growing rapidly, including blood, hair, and gastrointestinal tract cells, which often leads to adverse effects. Sometimes complications from chemotherapy may shorten a person’s life, and certainly the quality of life during and after these treatments could be diminished. The improvements in cancer care occurred more rapidly once scientists had the tools to learn about individual tumors.

In the summer of 2000, researchers announced that the human genome had been sequenced.⁶ The genome (ie, DNA) consists of introns and exons that form a map for human development. Exons can be converted to proteins that carry out specific actions, such as helping in cell growth, cell death, or DNA repair. Solving the human genome itself did not lead directly to cures, but it did represent a huge advance in medical research. As time passed, sequencing genomes became more affordable, and sequencing just the exome alone was even cheaper.⁷ Treatments for cancer began to expand with the help of these tools, but questions as to the true benefit of targeted therapy also grew.⁸

Physicians and scientists have amassed more information about cancer cells and have applied this knowledge to active drug development. In 2001, the FDA approved the first targeted therapy, imatinib, for the treatment of chronic myelogenous leukemia (CML). This rapidly improved patient survival through targeting the mutated protein that leads to CML, rather than just aiming for rapidly dividing cells.⁹ Those mutations for which there is a drug to target, such as the BCR-ABL translocation in CML, are called actionable mutations.

Precision Oncology Program for Prostate Cancer

In 2016, the VA and the Prostate Cancer Foundation (PCF) established the Precision Oncology Program for Prostate Cancer (POPCaP) Centers of Excellence (COE). This partnership was formed to accelerate treatment and cure for veterans with prostate cancer. The VA Greater Los Angeles Healthcare System in California and VA Puget Sound Health Care System in Washington led this effort, and their principal investigators continue to co-lead POPCaP. Since its inception, 9 additional funded POPCaP COEs have joined, each with a mandate to sequence the tumors of men with metastatic prostate cancer.

The more that is learned about a tumor, the more likely it is that researchers can find mutations that are that tumor’s Achilles heel and defeat it. In fact, many drugs that can target mutations are already available. For example, BRCA2 is an actionable mutation that can be exploited by knocking out another key DNA repair mechanism in the cell, PARP. Today, the effort of sequencing has led to a rich database of mutations present in men with metastatic prostate cancer.

Although there are many targeted therapies, most have not been studied formally in prostate cancer. Occasionally, clinicians treating patients will use these drugs in an unapproved way, hoping that there will be anticancer activity. It is difficult to estimate the likelihood of success with a drug in this situation, and the safety profile may not be well described in that setting. Treatment decisions for incurable cancers must be made knowing the risks and benefits. This helps in shared decision making between the clinician and patient and informs choices concerning which laboratory tests to order and how often to see the patient. However, treatment decisions are sometimes made with the hope of activity when a cancer is known to be incurable. Very little data, which are critical to determine whether this helps or hurts patients, support this approach.

Some data suggest that sequencing and giving a drug for an actionable mutation may lead to better outcomes for patients. Sequencing of pancreatic tumors by Pishvaian and colleagues revealed that 282 of 1,082 (26%) samples harbored actionable mutations.¹⁰ Those patients who received a drug that targeted their actionable mutation (n = 46; 24%) lived longer when compared with those who had an actionable mutation but did not receive a drug that targeted it (hazard ratio [HR] 0.42 [95% CI, 0.26-0.68; P = .0004]). Additionally, those who received therapy for an actionable mutation lived longer when compared with those who did not have an actionable mutation (HR 0.34 [95% CI, 0.22-0.53; P < .001]). While this finding is intriguing, it does not mean that treating actionable mutations outside of a clinical trial should be done. To this end, VA established Prostate cancer Analysis for Therapy CHoice (PATCH) as a clinical trials network within POPCaP.

Prostate Cancer Analysis

The overall PATCH vision is designed for clinical care and research work to together toward improved care for those with prostate cancer (Figure 1). The resources necessary for successful translational research are substantial, and PATCH aims to streamline those resources. PATCH will support innovative, precision-based clinical research at the POPCaP COEs through its 5 arms.

Arm 1. Dedicated personnel ensure veteran access to trials in PATCH by giving patients and providers accurate information about available trial options; aiding veterans in traveling from home VA to a POPCaP COE for participation on a study; and maintaining the Committee for Veteran Participation in PATCH, where veterans will be represented and asked to provide input into the PATCH process.

Arm 2. Coordinators at the coordinating COE in Portland, Orgeon, train investigators and study staff at the local POPCaP COEs to ensure research can be performed in a safe and responsible way.

Arm 3. Personnel experienced in conducting clinical trials liaise with investigators at VA Central Institutional Review Board, monitor trials, build databases for appropriate and efficient data collection, and manage high-risk studies conducted under an Investigational New Drug application. This group works closely with biostatisticians to choose appropriate trial designs, estimate numbers of patients needed, and interpret data once they are collected.

Arm 4. Protocol development and data dissemination is coordinated by a group to assist investigators in drafting protocols and reviewing abstracts and manuscripts.

Arm 5. A core group manages contracts and budgets, as well as relationships between VA and industry, where funding and drugs may be obtained.

Clinical Trials

There are currently 2 clinical trials in PATCH; 4 additional trials await funding decisions, and more trials are in the concept stage. BRACeD (NCT04038502) is a phase 2 trial examining platinum and taxane chemotherapy in tumors with HRD (specifically, BRCA1, BRCA2, and PALB2). About 15% to 20% of men with advanced prostate cancer will have a DNA repair defect in the tumor that could make them eligible for this study. The primary endpoint is progression-free survival.

A second study, CHOMP (NCT04104893), is a phase 2 trial examining the efficacy of immunotherapy (PD-1 inhibition) in tumors having mismatch repair deficiency or CDK12-/-. Each of those is found in about 7% of men with metastatic prostate cancer, and full accrual of a trial with rare mutations could take 5 to 10 years without a systematic approach of sequencing and identifying potential participants. The primary endpoint is a composite of radiographic response by iRECIST (immune response evaluation criteria in solid tumors), progression-free survival at 6 months and prostate specific antigen reduction by ≥ 50% in ≤ 12 weeks. With 11 POPCaP COEs sequencing the tumors of every man with metastatic prostate cancer, identifying men with the appropriate mutation is possible. PATCH will aid the sites in recruitment through outreach and coordination of travel.

Industry Partnerships

PATCH depends upon pharmaceutical industry partners, as clinical trials of even 40 patients can require significant funding and trial resources to operate. Furthermore, many drugs of interest are not available outside of a clinical trial, and partnerships enable VA researchers to access these medications. PATCH also benefits greatly from foundation partners, such as the PCF, which has made POPCaP possible and will continue to connect talented researchers with VA resources. Finally, access to other publicly available research funds, such as those from VA Office of Research and Development, National Institutes of Health, and US Department of Defense (DoD) Congressionally Directed Research Program are needed for trials.

Funding for these trials remains limited despite public health and broader interests in addressing important questions. Accelerated accrual through PATCH may be an attractive partnership opportunity for companies, foundations and government funding agencies to support the PATCH efforts.

Both POPCaP and PATCH highlight the potential promise of precision oncology within the nation’s largest integrated health care system. The VHA patient population enables prostate cancer researchers to serve an important early target. It also provides a foundational platform for a broader set of activities. These include a tailored approach to identifying tumor profiles and other patient characteristics that may help to elevate standard of care for other common cancers including ones affecting the lungs and/or head and neck.

To this end, VA has been working with the National Cancer Institute (NCI) and DoD to establish a national infrastructure for precision oncology across multiple cancer types.¹² In addition to clinical capabilities and the ability to run clinical trials that can accrue sufficient patients to answer key questions, we have developed capabilities for data collection and sharing, and analytical tools to support a learning health care system approach as a core element to precision oncology.

Besides having a research-specific context, such informatics and information technology systems enable clinicians to obtain and apply decision-making data rapidly for a specific patient and cancer type. These systems take particular advantage of the extensive electronic health record that underlies the VHA system, integrating real-world evidence into rigorous trials for precision oncology and other diseases. This is important for facilitating prerequisite activities for quality assessments for incorporation into databases (with appropriate permissions) to enhance treatment options. These activities are a key focus of the APOLLO initiative.¹³ While a more in-depth discussion of the importance of informatics is beyond the scope of this article, the field represents an important investment that is needed to achieve the goals of precision oncology.

In addition to informatics and data handling capabilities, VA has a longstanding tradition of designing and coordinating multisite clinical trials. This dates to the time of World War II when returning veterans had a high prevalence of tuberculosis. Since then, VA has contributed extensively to landmark findings in cardiovascular disease and surgery, mental health, infectious disease, and cancer. It was a VA study that helped establish colonoscopy as a standard for colorectal cancer screening by detecting colonic neoplasms in asymptomatic patients.¹⁴

From such investigations, the VA Cooperative Studies Program (CSP) has developed many strategies to conduct multisite clinical trials. But, CSP also has organized its sites methodically for operational efficiency and the ability to maintain institutional knowledge that crosses different types of studies and diseases. Using its Network of Dedicated Enrollment Sites (NODES) model, VA partnered with NCI to more effectively address administrative and regulatory requirements for initiating trials and recruiting veterans into cancer clinical trials.¹⁵ This partnership—the NCI And VA Interagency Group to Accelerate Trials Enrollment (NAVIGATE)—supports 12 sites with a central CSP Coordinating Center (CSPCC).

CSPCC provides support, shares best practices and provides organizational commitment at the senior levels of both agencies to overcome potential barriers. The goals and strategies are described by Schiller and colleagues.¹⁶ While still in its early stage as a cancer research network, NAVIGATE may be integrated with POPCaP and other parts of VA clinical research enterprise. This would allow us to specialize in advancing oncology care and to leverage capabilities more specifically to precision oncology. With an emphasis on recruitment, NAVIGATE has established capabilities with VA Informatics and Computing Infrastructure to quickly identify patients who may be eligible for particular clinical trials. We envision further refining these capabilities for precision oncology trials that incorporate genetic and other information for individual patients. VA also hopes to inform trial sponsors about design considerations. This is important since networked investigators will have direct insights into patient-level factors, which may help with more effectively identifying and enrolling them into trials for their particular cancers.

Conclusions

VA may have an opportunity to reach out to veterans who may not have immediate access to facilities running clinical trials. As it develops capabilities to bring the trial to the veteran, VA could have more virtual and/or centralized recruitment strategies. This would broaden opportunities for considering novel approaches that may not rely on a more traditional facility-based recruitment approach.

Ultimately, VA can be a critical part of a national effort to fight and, perhaps even, defeat cancers. With its extensive resources and capabilities, VA has the ability to advance a precision oncology agenda that provides veterans with the highest standard of care. It has built upon many key elements in clinical, technological and scientific fields of study that would challenge most health care systems given the extensive costs involved. In addition, creating strong partnerships with organizations such as PCF, NCI, and DoD that are complementary in resources and expertise will help VA to build a national network for cancer care. Putting this all together will support and facilitate a vision for more precise care for any veteran with cancer by more rapidly enabling the testing and approval of medications developed for this purpose.

Acknowledgments

The authors would like to thank Daphne Swancutt for comments and edits on drafts of this article.

In May 2020, the US Food and Drug Administration (FDA) approved the first 2 targeted treatments for prostate cancer, specifically, the poly-(adenosine diphosphate-ribose) polymerase (PARP) inhibitors rucaparib and olaparib.^1,2 For these medications to work, the tumor must have a homologous recombination deficiency (HRD), which is a form of DNA repair deficiency. The PARP pathway is important for DNA repair, and PARP inhibition leads to “synthetic lethality” in cancer cells that already are deficient in DNA repair mechanisms.³ Now, there is evidence that patients with prostate cancer who have HRD tumors and receive PARP inhibitors live longer when compared with those who receive standard of care options.⁴ These findings offer hope for patients with prostate cancer. They also demonstrate the process and potential benefits of precision oncology efforts; namely, targeted treatments for specific tumor types in cancer patients.

This article discusses the challenges and opportunities of precision oncology for US Department of Veterans Affairs (VA) Veterans Health Administration (VHA). First, the article will discuss working with relatively rare mutations. Second, the article will examine how the trials of olaparib and rucaparib illuminate the VHA contribution to research on new therapies for patients with cancer. Finally, the article will explore the ways in which VHA is becoming a major national contributor in drug discovery and approval of precision medications.

Precision Oncology

Despite advances in screening and treatment, an estimated 600,000 people in the US will die of cancer in 2020.⁵ Meaningful advances in cancer care depend on both laboratory and clinical research. This combination, known as translational research, takes discoveries in the laboratory and applies them to patients and vice versa. Successful translational research requires many components. These include talented scientists to form hypotheses and perform the work; money for supplies and equipment; platforms for timely dissemination of knowledge; well-trained clinicians to treat patients and lead research teams; and patients to participate in clinical trials. In precision oncology, the ability to find patients for the trials can be daunting, particularly in cases where the frequency of the mutation of interest is low.

During the 20th century, with few exceptions, physicians caring for patients with cancer had blunt instruments at their disposal. Surgery and radiation could lead to survival if the cancer was caught early enough. Systemic therapies, such as chemotherapy, rarely cured but could prolong life in some patients. However, chemotherapy is imprecise and targets any cell growing rapidly, including blood, hair, and gastrointestinal tract cells, which often leads to adverse effects. Sometimes complications from chemotherapy may shorten a person’s life, and certainly the quality of life during and after these treatments could be diminished. The improvements in cancer care occurred more rapidly once scientists had the tools to learn about individual tumors.

In the summer of 2000, researchers announced that the human genome had been sequenced.⁶ The genome (ie, DNA) consists of introns and exons that form a map for human development. Exons can be converted to proteins that carry out specific actions, such as helping in cell growth, cell death, or DNA repair. Solving the human genome itself did not lead directly to cures, but it did represent a huge advance in medical research. As time passed, sequencing genomes became more affordable, and sequencing just the exome alone was even cheaper.⁷ Treatments for cancer began to expand with the help of these tools, but questions as to the true benefit of targeted therapy also grew.⁸

Physicians and scientists have amassed more information about cancer cells and have applied this knowledge to active drug development. In 2001, the FDA approved the first targeted therapy, imatinib, for the treatment of chronic myelogenous leukemia (CML). This rapidly improved patient survival through targeting the mutated protein that leads to CML, rather than just aiming for rapidly dividing cells.⁹ Those mutations for which there is a drug to target, such as the BCR-ABL translocation in CML, are called actionable mutations.

Precision Oncology Program for Prostate Cancer

In 2016, the VA and the Prostate Cancer Foundation (PCF) established the Precision Oncology Program for Prostate Cancer (POPCaP) Centers of Excellence (COE). This partnership was formed to accelerate treatment and cure for veterans with prostate cancer. The VA Greater Los Angeles Healthcare System in California and VA Puget Sound Health Care System in Washington led this effort, and their principal investigators continue to co-lead POPCaP. Since its inception, 9 additional funded POPCaP COEs have joined, each with a mandate to sequence the tumors of men with metastatic prostate cancer.

The more that is learned about a tumor, the more likely it is that researchers can find mutations that are that tumor’s Achilles heel and defeat it. In fact, many drugs that can target mutations are already available. For example, BRCA2 is an actionable mutation that can be exploited by knocking out another key DNA repair mechanism in the cell, PARP. Today, the effort of sequencing has led to a rich database of mutations present in men with metastatic prostate cancer.

Although there are many targeted therapies, most have not been studied formally in prostate cancer. Occasionally, clinicians treating patients will use these drugs in an unapproved way, hoping that there will be anticancer activity. It is difficult to estimate the likelihood of success with a drug in this situation, and the safety profile may not be well described in that setting. Treatment decisions for incurable cancers must be made knowing the risks and benefits. This helps in shared decision making between the clinician and patient and informs choices concerning which laboratory tests to order and how often to see the patient. However, treatment decisions are sometimes made with the hope of activity when a cancer is known to be incurable. Very little data, which are critical to determine whether this helps or hurts patients, support this approach.

Some data suggest that sequencing and giving a drug for an actionable mutation may lead to better outcomes for patients. Sequencing of pancreatic tumors by Pishvaian and colleagues revealed that 282 of 1,082 (26%) samples harbored actionable mutations.¹⁰ Those patients who received a drug that targeted their actionable mutation (n = 46; 24%) lived longer when compared with those who had an actionable mutation but did not receive a drug that targeted it (hazard ratio [HR] 0.42 [95% CI, 0.26-0.68; P = .0004]). Additionally, those who received therapy for an actionable mutation lived longer when compared with those who did not have an actionable mutation (HR 0.34 [95% CI, 0.22-0.53; P < .001]). While this finding is intriguing, it does not mean that treating actionable mutations outside of a clinical trial should be done. To this end, VA established Prostate cancer Analysis for Therapy CHoice (PATCH) as a clinical trials network within POPCaP.

Prostate Cancer Analysis

The overall PATCH vision is designed for clinical care and research work to together toward improved care for those with prostate cancer (Figure 1). The resources necessary for successful translational research are substantial, and PATCH aims to streamline those resources. PATCH will support innovative, precision-based clinical research at the POPCaP COEs through its 5 arms.

Arm 1. Dedicated personnel ensure veteran access to trials in PATCH by giving patients and providers accurate information about available trial options; aiding veterans in traveling from home VA to a POPCaP COE for participation on a study; and maintaining the Committee for Veteran Participation in PATCH, where veterans will be represented and asked to provide input into the PATCH process.

Arm 2. Coordinators at the coordinating COE in Portland, Orgeon, train investigators and study staff at the local POPCaP COEs to ensure research can be performed in a safe and responsible way.

Arm 3. Personnel experienced in conducting clinical trials liaise with investigators at VA Central Institutional Review Board, monitor trials, build databases for appropriate and efficient data collection, and manage high-risk studies conducted under an Investigational New Drug application. This group works closely with biostatisticians to choose appropriate trial designs, estimate numbers of patients needed, and interpret data once they are collected.

Arm 4. Protocol development and data dissemination is coordinated by a group to assist investigators in drafting protocols and reviewing abstracts and manuscripts.

Arm 5. A core group manages contracts and budgets, as well as relationships between VA and industry, where funding and drugs may be obtained.

Clinical Trials

There are currently 2 clinical trials in PATCH; 4 additional trials await funding decisions, and more trials are in the concept stage. BRACeD (NCT04038502) is a phase 2 trial examining platinum and taxane chemotherapy in tumors with HRD (specifically, BRCA1, BRCA2, and PALB2). About 15% to 20% of men with advanced prostate cancer will have a DNA repair defect in the tumor that could make them eligible for this study. The primary endpoint is progression-free survival.

A second study, CHOMP (NCT04104893), is a phase 2 trial examining the efficacy of immunotherapy (PD-1 inhibition) in tumors having mismatch repair deficiency or CDK12-/-. Each of those is found in about 7% of men with metastatic prostate cancer, and full accrual of a trial with rare mutations could take 5 to 10 years without a systematic approach of sequencing and identifying potential participants. The primary endpoint is a composite of radiographic response by iRECIST (immune response evaluation criteria in solid tumors), progression-free survival at 6 months and prostate specific antigen reduction by ≥ 50% in ≤ 12 weeks. With 11 POPCaP COEs sequencing the tumors of every man with metastatic prostate cancer, identifying men with the appropriate mutation is possible. PATCH will aid the sites in recruitment through outreach and coordination of travel.

Industry Partnerships

PATCH depends upon pharmaceutical industry partners, as clinical trials of even 40 patients can require significant funding and trial resources to operate. Furthermore, many drugs of interest are not available outside of a clinical trial, and partnerships enable VA researchers to access these medications. PATCH also benefits greatly from foundation partners, such as the PCF, which has made POPCaP possible and will continue to connect talented researchers with VA resources. Finally, access to other publicly available research funds, such as those from VA Office of Research and Development, National Institutes of Health, and US Department of Defense (DoD) Congressionally Directed Research Program are needed for trials.

Funding for these trials remains limited despite public health and broader interests in addressing important questions. Accelerated accrual through PATCH may be an attractive partnership opportunity for companies, foundations and government funding agencies to support the PATCH efforts.

Both POPCaP and PATCH highlight the potential promise of precision oncology within the nation’s largest integrated health care system. The VHA patient population enables prostate cancer researchers to serve an important early target. It also provides a foundational platform for a broader set of activities. These include a tailored approach to identifying tumor profiles and other patient characteristics that may help to elevate standard of care for other common cancers including ones affecting the lungs and/or head and neck.

To this end, VA has been working with the National Cancer Institute (NCI) and DoD to establish a national infrastructure for precision oncology across multiple cancer types.¹² In addition to clinical capabilities and the ability to run clinical trials that can accrue sufficient patients to answer key questions, we have developed capabilities for data collection and sharing, and analytical tools to support a learning health care system approach as a core element to precision oncology.

Besides having a research-specific context, such informatics and information technology systems enable clinicians to obtain and apply decision-making data rapidly for a specific patient and cancer type. These systems take particular advantage of the extensive electronic health record that underlies the VHA system, integrating real-world evidence into rigorous trials for precision oncology and other diseases. This is important for facilitating prerequisite activities for quality assessments for incorporation into databases (with appropriate permissions) to enhance treatment options. These activities are a key focus of the APOLLO initiative.¹³ While a more in-depth discussion of the importance of informatics is beyond the scope of this article, the field represents an important investment that is needed to achieve the goals of precision oncology.

In addition to informatics and data handling capabilities, VA has a longstanding tradition of designing and coordinating multisite clinical trials. This dates to the time of World War II when returning veterans had a high prevalence of tuberculosis. Since then, VA has contributed extensively to landmark findings in cardiovascular disease and surgery, mental health, infectious disease, and cancer. It was a VA study that helped establish colonoscopy as a standard for colorectal cancer screening by detecting colonic neoplasms in asymptomatic patients.¹⁴

From such investigations, the VA Cooperative Studies Program (CSP) has developed many strategies to conduct multisite clinical trials. But, CSP also has organized its sites methodically for operational efficiency and the ability to maintain institutional knowledge that crosses different types of studies and diseases. Using its Network of Dedicated Enrollment Sites (NODES) model, VA partnered with NCI to more effectively address administrative and regulatory requirements for initiating trials and recruiting veterans into cancer clinical trials.¹⁵ This partnership—the NCI And VA Interagency Group to Accelerate Trials Enrollment (NAVIGATE)—supports 12 sites with a central CSP Coordinating Center (CSPCC).

CSPCC provides support, shares best practices and provides organizational commitment at the senior levels of both agencies to overcome potential barriers. The goals and strategies are described by Schiller and colleagues.¹⁶ While still in its early stage as a cancer research network, NAVIGATE may be integrated with POPCaP and other parts of VA clinical research enterprise. This would allow us to specialize in advancing oncology care and to leverage capabilities more specifically to precision oncology. With an emphasis on recruitment, NAVIGATE has established capabilities with VA Informatics and Computing Infrastructure to quickly identify patients who may be eligible for particular clinical trials. We envision further refining these capabilities for precision oncology trials that incorporate genetic and other information for individual patients. VA also hopes to inform trial sponsors about design considerations. This is important since networked investigators will have direct insights into patient-level factors, which may help with more effectively identifying and enrolling them into trials for their particular cancers.

Conclusions

VA may have an opportunity to reach out to veterans who may not have immediate access to facilities running clinical trials. As it develops capabilities to bring the trial to the veteran, VA could have more virtual and/or centralized recruitment strategies. This would broaden opportunities for considering novel approaches that may not rely on a more traditional facility-based recruitment approach.

Ultimately, VA can be a critical part of a national effort to fight and, perhaps even, defeat cancers. With its extensive resources and capabilities, VA has the ability to advance a precision oncology agenda that provides veterans with the highest standard of care. It has built upon many key elements in clinical, technological and scientific fields of study that would challenge most health care systems given the extensive costs involved. In addition, creating strong partnerships with organizations such as PCF, NCI, and DoD that are complementary in resources and expertise will help VA to build a national network for cancer care. Putting this all together will support and facilitate a vision for more precise care for any veteran with cancer by more rapidly enabling the testing and approval of medications developed for this purpose.

Acknowledgments

The authors would like to thank Daphne Swancutt for comments and edits on drafts of this article.

In May 2020, the US Food and Drug Administration (FDA) approved the first 2 targeted treatments for prostate cancer, specifically, the poly-(adenosine diphosphate-ribose) polymerase (PARP) inhibitors rucaparib and olaparib.^1,2 For these medications to work, the tumor must have a homologous recombination deficiency (HRD), which is a form of DNA repair deficiency. The PARP pathway is important for DNA repair, and PARP inhibition leads to “synthetic lethality” in cancer cells that already are deficient in DNA repair mechanisms.³ Now, there is evidence that patients with prostate cancer who have HRD tumors and receive PARP inhibitors live longer when compared with those who receive standard of care options.⁴ These findings offer hope for patients with prostate cancer. They also demonstrate the process and potential benefits of precision oncology efforts; namely, targeted treatments for specific tumor types in cancer patients.

This article discusses the challenges and opportunities of precision oncology for US Department of Veterans Affairs (VA) Veterans Health Administration (VHA). First, the article will discuss working with relatively rare mutations. Second, the article will examine how the trials of olaparib and rucaparib illuminate the VHA contribution to research on new therapies for patients with cancer. Finally, the article will explore the ways in which VHA is becoming a major national contributor in drug discovery and approval of precision medications.

Precision Oncology

Despite advances in screening and treatment, an estimated 600,000 people in the US will die of cancer in 2020.⁵ Meaningful advances in cancer care depend on both laboratory and clinical research. This combination, known as translational research, takes discoveries in the laboratory and applies them to patients and vice versa. Successful translational research requires many components. These include talented scientists to form hypotheses and perform the work; money for supplies and equipment; platforms for timely dissemination of knowledge; well-trained clinicians to treat patients and lead research teams; and patients to participate in clinical trials. In precision oncology, the ability to find patients for the trials can be daunting, particularly in cases where the frequency of the mutation of interest is low.

During the 20th century, with few exceptions, physicians caring for patients with cancer had blunt instruments at their disposal. Surgery and radiation could lead to survival if the cancer was caught early enough. Systemic therapies, such as chemotherapy, rarely cured but could prolong life in some patients. However, chemotherapy is imprecise and targets any cell growing rapidly, including blood, hair, and gastrointestinal tract cells, which often leads to adverse effects. Sometimes complications from chemotherapy may shorten a person’s life, and certainly the quality of life during and after these treatments could be diminished. The improvements in cancer care occurred more rapidly once scientists had the tools to learn about individual tumors.

In the summer of 2000, researchers announced that the human genome had been sequenced.⁶ The genome (ie, DNA) consists of introns and exons that form a map for human development. Exons can be converted to proteins that carry out specific actions, such as helping in cell growth, cell death, or DNA repair. Solving the human genome itself did not lead directly to cures, but it did represent a huge advance in medical research. As time passed, sequencing genomes became more affordable, and sequencing just the exome alone was even cheaper.⁷ Treatments for cancer began to expand with the help of these tools, but questions as to the true benefit of targeted therapy also grew.⁸

Physicians and scientists have amassed more information about cancer cells and have applied this knowledge to active drug development. In 2001, the FDA approved the first targeted therapy, imatinib, for the treatment of chronic myelogenous leukemia (CML). This rapidly improved patient survival through targeting the mutated protein that leads to CML, rather than just aiming for rapidly dividing cells.⁹ Those mutations for which there is a drug to target, such as the BCR-ABL translocation in CML, are called actionable mutations.

Precision Oncology Program for Prostate Cancer

In 2016, the VA and the Prostate Cancer Foundation (PCF) established the Precision Oncology Program for Prostate Cancer (POPCaP) Centers of Excellence (COE). This partnership was formed to accelerate treatment and cure for veterans with prostate cancer. The VA Greater Los Angeles Healthcare System in California and VA Puget Sound Health Care System in Washington led this effort, and their principal investigators continue to co-lead POPCaP. Since its inception, 9 additional funded POPCaP COEs have joined, each with a mandate to sequence the tumors of men with metastatic prostate cancer.

The more that is learned about a tumor, the more likely it is that researchers can find mutations that are that tumor’s Achilles heel and defeat it. In fact, many drugs that can target mutations are already available. For example, BRCA2 is an actionable mutation that can be exploited by knocking out another key DNA repair mechanism in the cell, PARP. Today, the effort of sequencing has led to a rich database of mutations present in men with metastatic prostate cancer.

Although there are many targeted therapies, most have not been studied formally in prostate cancer. Occasionally, clinicians treating patients will use these drugs in an unapproved way, hoping that there will be anticancer activity. It is difficult to estimate the likelihood of success with a drug in this situation, and the safety profile may not be well described in that setting. Treatment decisions for incurable cancers must be made knowing the risks and benefits. This helps in shared decision making between the clinician and patient and informs choices concerning which laboratory tests to order and how often to see the patient. However, treatment decisions are sometimes made with the hope of activity when a cancer is known to be incurable. Very little data, which are critical to determine whether this helps or hurts patients, support this approach.

Some data suggest that sequencing and giving a drug for an actionable mutation may lead to better outcomes for patients. Sequencing of pancreatic tumors by Pishvaian and colleagues revealed that 282 of 1,082 (26%) samples harbored actionable mutations.¹⁰ Those patients who received a drug that targeted their actionable mutation (n = 46; 24%) lived longer when compared with those who had an actionable mutation but did not receive a drug that targeted it (hazard ratio [HR] 0.42 [95% CI, 0.26-0.68; P = .0004]). Additionally, those who received therapy for an actionable mutation lived longer when compared with those who did not have an actionable mutation (HR 0.34 [95% CI, 0.22-0.53; P < .001]). While this finding is intriguing, it does not mean that treating actionable mutations outside of a clinical trial should be done. To this end, VA established Prostate cancer Analysis for Therapy CHoice (PATCH) as a clinical trials network within POPCaP.

Prostate Cancer Analysis

The overall PATCH vision is designed for clinical care and research work to together toward improved care for those with prostate cancer (Figure 1). The resources necessary for successful translational research are substantial, and PATCH aims to streamline those resources. PATCH will support innovative, precision-based clinical research at the POPCaP COEs through its 5 arms.

Arm 1. Dedicated personnel ensure veteran access to trials in PATCH by giving patients and providers accurate information about available trial options; aiding veterans in traveling from home VA to a POPCaP COE for participation on a study; and maintaining the Committee for Veteran Participation in PATCH, where veterans will be represented and asked to provide input into the PATCH process.

Arm 2. Coordinators at the coordinating COE in Portland, Orgeon, train investigators and study staff at the local POPCaP COEs to ensure research can be performed in a safe and responsible way.

Arm 3. Personnel experienced in conducting clinical trials liaise with investigators at VA Central Institutional Review Board, monitor trials, build databases for appropriate and efficient data collection, and manage high-risk studies conducted under an Investigational New Drug application. This group works closely with biostatisticians to choose appropriate trial designs, estimate numbers of patients needed, and interpret data once they are collected.

Arm 4. Protocol development and data dissemination is coordinated by a group to assist investigators in drafting protocols and reviewing abstracts and manuscripts.

Arm 5. A core group manages contracts and budgets, as well as relationships between VA and industry, where funding and drugs may be obtained.

Clinical Trials

There are currently 2 clinical trials in PATCH; 4 additional trials await funding decisions, and more trials are in the concept stage. BRACeD (NCT04038502) is a phase 2 trial examining platinum and taxane chemotherapy in tumors with HRD (specifically, BRCA1, BRCA2, and PALB2). About 15% to 20% of men with advanced prostate cancer will have a DNA repair defect in the tumor that could make them eligible for this study. The primary endpoint is progression-free survival.

A second study, CHOMP (NCT04104893), is a phase 2 trial examining the efficacy of immunotherapy (PD-1 inhibition) in tumors having mismatch repair deficiency or CDK12-/-. Each of those is found in about 7% of men with metastatic prostate cancer, and full accrual of a trial with rare mutations could take 5 to 10 years without a systematic approach of sequencing and identifying potential participants. The primary endpoint is a composite of radiographic response by iRECIST (immune response evaluation criteria in solid tumors), progression-free survival at 6 months and prostate specific antigen reduction by ≥ 50% in ≤ 12 weeks. With 11 POPCaP COEs sequencing the tumors of every man with metastatic prostate cancer, identifying men with the appropriate mutation is possible. PATCH will aid the sites in recruitment through outreach and coordination of travel.

Industry Partnerships

PATCH depends upon pharmaceutical industry partners, as clinical trials of even 40 patients can require significant funding and trial resources to operate. Furthermore, many drugs of interest are not available outside of a clinical trial, and partnerships enable VA researchers to access these medications. PATCH also benefits greatly from foundation partners, such as the PCF, which has made POPCaP possible and will continue to connect talented researchers with VA resources. Finally, access to other publicly available research funds, such as those from VA Office of Research and Development, National Institutes of Health, and US Department of Defense (DoD) Congressionally Directed Research Program are needed for trials.

Funding for these trials remains limited despite public health and broader interests in addressing important questions. Accelerated accrual through PATCH may be an attractive partnership opportunity for companies, foundations and government funding agencies to support the PATCH efforts.

Both POPCaP and PATCH highlight the potential promise of precision oncology within the nation’s largest integrated health care system. The VHA patient population enables prostate cancer researchers to serve an important early target. It also provides a foundational platform for a broader set of activities. These include a tailored approach to identifying tumor profiles and other patient characteristics that may help to elevate standard of care for other common cancers including ones affecting the lungs and/or head and neck.

To this end, VA has been working with the National Cancer Institute (NCI) and DoD to establish a national infrastructure for precision oncology across multiple cancer types.¹² In addition to clinical capabilities and the ability to run clinical trials that can accrue sufficient patients to answer key questions, we have developed capabilities for data collection and sharing, and analytical tools to support a learning health care system approach as a core element to precision oncology.

Besides having a research-specific context, such informatics and information technology systems enable clinicians to obtain and apply decision-making data rapidly for a specific patient and cancer type. These systems take particular advantage of the extensive electronic health record that underlies the VHA system, integrating real-world evidence into rigorous trials for precision oncology and other diseases. This is important for facilitating prerequisite activities for quality assessments for incorporation into databases (with appropriate permissions) to enhance treatment options. These activities are a key focus of the APOLLO initiative.¹³ While a more in-depth discussion of the importance of informatics is beyond the scope of this article, the field represents an important investment that is needed to achieve the goals of precision oncology.

In addition to informatics and data handling capabilities, VA has a longstanding tradition of designing and coordinating multisite clinical trials. This dates to the time of World War II when returning veterans had a high prevalence of tuberculosis. Since then, VA has contributed extensively to landmark findings in cardiovascular disease and surgery, mental health, infectious disease, and cancer. It was a VA study that helped establish colonoscopy as a standard for colorectal cancer screening by detecting colonic neoplasms in asymptomatic patients.¹⁴

From such investigations, the VA Cooperative Studies Program (CSP) has developed many strategies to conduct multisite clinical trials. But, CSP also has organized its sites methodically for operational efficiency and the ability to maintain institutional knowledge that crosses different types of studies and diseases. Using its Network of Dedicated Enrollment Sites (NODES) model, VA partnered with NCI to more effectively address administrative and regulatory requirements for initiating trials and recruiting veterans into cancer clinical trials.¹⁵ This partnership—the NCI And VA Interagency Group to Accelerate Trials Enrollment (NAVIGATE)—supports 12 sites with a central CSP Coordinating Center (CSPCC).

CSPCC provides support, shares best practices and provides organizational commitment at the senior levels of both agencies to overcome potential barriers. The goals and strategies are described by Schiller and colleagues.¹⁶ While still in its early stage as a cancer research network, NAVIGATE may be integrated with POPCaP and other parts of VA clinical research enterprise. This would allow us to specialize in advancing oncology care and to leverage capabilities more specifically to precision oncology. With an emphasis on recruitment, NAVIGATE has established capabilities with VA Informatics and Computing Infrastructure to quickly identify patients who may be eligible for particular clinical trials. We envision further refining these capabilities for precision oncology trials that incorporate genetic and other information for individual patients. VA also hopes to inform trial sponsors about design considerations. This is important since networked investigators will have direct insights into patient-level factors, which may help with more effectively identifying and enrolling them into trials for their particular cancers.

Conclusions

VA may have an opportunity to reach out to veterans who may not have immediate access to facilities running clinical trials. As it develops capabilities to bring the trial to the veteran, VA could have more virtual and/or centralized recruitment strategies. This would broaden opportunities for considering novel approaches that may not rely on a more traditional facility-based recruitment approach.

Ultimately, VA can be a critical part of a national effort to fight and, perhaps even, defeat cancers. With its extensive resources and capabilities, VA has the ability to advance a precision oncology agenda that provides veterans with the highest standard of care. It has built upon many key elements in clinical, technological and scientific fields of study that would challenge most health care systems given the extensive costs involved. In addition, creating strong partnerships with organizations such as PCF, NCI, and DoD that are complementary in resources and expertise will help VA to build a national network for cancer care. Putting this all together will support and facilitate a vision for more precise care for any veteran with cancer by more rapidly enabling the testing and approval of medications developed for this purpose.

Acknowledgments

The authors would like to thank Daphne Swancutt for comments and edits on drafts of this article.

For > 90 years, the US Department of Veterans Affairs (VA) has been in the vanguard of cancer research and treatment—improving the lives of veterans and all Americans. In 1932, recognizing the intrinsic link between research and clinical care, the Edward Hines, Jr. VA Hospital in Chicago, Illinois, established a tumor research laboratory to complement the work of its cancer treatment center. As the first VA laboratory to receive funding specifically for research, the new facility symbolized a paradigm shift in thinking about cancer treatment.

Today, through its National Precision Oncology Program (NPOP), the Veterans Health Administration (VHA) has embarked upon another paradigm shift—one that also puts research front and center by leveraging VHA’s unique assets as a learning health care system. As noted by Montgomery and colleagues, “given its size, integration and capabilities, the VA is an ideal setting for rapid learning cycles of testing and implementing best practices at scale.”¹ The articles in this special issue, which focus on the 2 cancers that affects the most veterans—prostate and lung—show the transformative work underway to develop a new model of collaboration in cancer care.

At VHA, research and practice are not just proximal; they are truly integrated in the service of enhancing veterans’ outcomes. For example, > 60% of VA researchers are clinicians who also provide direct patient care. As observed by Levine and colleagues, “meaningful advances in cancer care depend on both laboratory and clinical research. This combination, known as translational research, takes discoveries in the laboratory and applies them to patients and vice versa.”²

For example, it was physician-scientist Donald Gleason, MD, PhD, who in the 1960s pioneered the standardized system that helps doctors better assess and treat prostate cancer (the Gleason score). More recently, physician-scientists Matthew Rettig, MD, and Bruce Montgomery, MD, both leading experts in prostate cancer research, were instrumental to VA’s partnership with the Prostate Cancer Foundation (PCF) to establish a national network for oncology trials serving veterans.

Having an embedded research program within the nation’s largest integrated health care system also provides the VA with the ability to conduct large-scale, multisite clinical trials. Since the 1940s, the VA Cooperative Studies Program (CSP) has generated key research findings across a range of diseases, including cancer, and provided definitive evidence and learning. In 1994, CSP launched its Prostate Cancer Intervention vs Observation Trial (PIVOT) study to determine whether observation is as effective as surgery for early-stage prostate cancer. Today, through the CSP, VA researchers are conducting a randomized, phase 3 clinical trial called VA Lung cancer surgery Or stereotactic Radiotherapy trial (VALOR) that will assess which of the 2 modalities is better when treating veterans with operable early-stage non-small cell lung cancer.

Additionally, VA is privileged to serve a patient population so dedicated to their country that many volunteer to serve again as participants in VA research clinical trials. In fact, Levine and colleagues credit the patients willing to enter clinical trials for the collective call to action and “critical philanthropic investment” that led to the Precision Oncology Program for Cancer of the Prostate (POPCaP).²

As a learning health care system, we also have been mindful of lessons drawn from the ongoing COVID-19 public health crisis. Almost overnight, VHA shifted from in-person to virtual visits to minimize the risk for veterans and their families. At the same time, we limited in-person clinical research visits to those that were required for the Veterans’ health or well-being and conducted large numbers of virtual research visits. (Notably, the current crisis motivated accelerated study regarding virtual research trials, clarifying which touchpoints must be face-to-face and which have been face-to-face due mainly to convention.) In parallel, we also launched numerous clinical studies focused on the fight against COVID-19. Our capacity to transition both clinical care and research is due in no small part to our preexisting and strong foundation in telehealth.

With one-third of our patient population living in rural areas, these achievements are vital to our commitment of “no veteran left behind.” These efforts were recently boosted by VHA’s newest partnership with the Bristol Myers Squibb Foundation to establish a national teleoncology center that will enable all veterans to benefit from new research advances no matter where they live.

Precision oncology represents a new model of collaboration in cancer care among clinicians, operations leaders, researchers and veterans. By leveraging the many assets that have contributed to VA’s success as a learning health care system, we can fulfill the promise of providing leading edge cancer care to all veterans.

For > 90 years, the US Department of Veterans Affairs (VA) has been in the vanguard of cancer research and treatment—improving the lives of veterans and all Americans. In 1932, recognizing the intrinsic link between research and clinical care, the Edward Hines, Jr. VA Hospital in Chicago, Illinois, established a tumor research laboratory to complement the work of its cancer treatment center. As the first VA laboratory to receive funding specifically for research, the new facility symbolized a paradigm shift in thinking about cancer treatment.

Today, through its National Precision Oncology Program (NPOP), the Veterans Health Administration (VHA) has embarked upon another paradigm shift—one that also puts research front and center by leveraging VHA’s unique assets as a learning health care system. As noted by Montgomery and colleagues, “given its size, integration and capabilities, the VA is an ideal setting for rapid learning cycles of testing and implementing best practices at scale.”¹ The articles in this special issue, which focus on the 2 cancers that affects the most veterans—prostate and lung—show the transformative work underway to develop a new model of collaboration in cancer care.

At VHA, research and practice are not just proximal; they are truly integrated in the service of enhancing veterans’ outcomes. For example, > 60% of VA researchers are clinicians who also provide direct patient care. As observed by Levine and colleagues, “meaningful advances in cancer care depend on both laboratory and clinical research. This combination, known as translational research, takes discoveries in the laboratory and applies them to patients and vice versa.”²

For example, it was physician-scientist Donald Gleason, MD, PhD, who in the 1960s pioneered the standardized system that helps doctors better assess and treat prostate cancer (the Gleason score). More recently, physician-scientists Matthew Rettig, MD, and Bruce Montgomery, MD, both leading experts in prostate cancer research, were instrumental to VA’s partnership with the Prostate Cancer Foundation (PCF) to establish a national network for oncology trials serving veterans.

Having an embedded research program within the nation’s largest integrated health care system also provides the VA with the ability to conduct large-scale, multisite clinical trials. Since the 1940s, the VA Cooperative Studies Program (CSP) has generated key research findings across a range of diseases, including cancer, and provided definitive evidence and learning. In 1994, CSP launched its Prostate Cancer Intervention vs Observation Trial (PIVOT) study to determine whether observation is as effective as surgery for early-stage prostate cancer. Today, through the CSP, VA researchers are conducting a randomized, phase 3 clinical trial called VA Lung cancer surgery Or stereotactic Radiotherapy trial (VALOR) that will assess which of the 2 modalities is better when treating veterans with operable early-stage non-small cell lung cancer.

Additionally, VA is privileged to serve a patient population so dedicated to their country that many volunteer to serve again as participants in VA research clinical trials. In fact, Levine and colleagues credit the patients willing to enter clinical trials for the collective call to action and “critical philanthropic investment” that led to the Precision Oncology Program for Cancer of the Prostate (POPCaP).²

As a learning health care system, we also have been mindful of lessons drawn from the ongoing COVID-19 public health crisis. Almost overnight, VHA shifted from in-person to virtual visits to minimize the risk for veterans and their families. At the same time, we limited in-person clinical research visits to those that were required for the Veterans’ health or well-being and conducted large numbers of virtual research visits. (Notably, the current crisis motivated accelerated study regarding virtual research trials, clarifying which touchpoints must be face-to-face and which have been face-to-face due mainly to convention.) In parallel, we also launched numerous clinical studies focused on the fight against COVID-19. Our capacity to transition both clinical care and research is due in no small part to our preexisting and strong foundation in telehealth.

With one-third of our patient population living in rural areas, these achievements are vital to our commitment of “no veteran left behind.” These efforts were recently boosted by VHA’s newest partnership with the Bristol Myers Squibb Foundation to establish a national teleoncology center that will enable all veterans to benefit from new research advances no matter where they live.

Precision oncology represents a new model of collaboration in cancer care among clinicians, operations leaders, researchers and veterans. By leveraging the many assets that have contributed to VA’s success as a learning health care system, we can fulfill the promise of providing leading edge cancer care to all veterans.

For > 90 years, the US Department of Veterans Affairs (VA) has been in the vanguard of cancer research and treatment—improving the lives of veterans and all Americans. In 1932, recognizing the intrinsic link between research and clinical care, the Edward Hines, Jr. VA Hospital in Chicago, Illinois, established a tumor research laboratory to complement the work of its cancer treatment center. As the first VA laboratory to receive funding specifically for research, the new facility symbolized a paradigm shift in thinking about cancer treatment.

Today, through its National Precision Oncology Program (NPOP), the Veterans Health Administration (VHA) has embarked upon another paradigm shift—one that also puts research front and center by leveraging VHA’s unique assets as a learning health care system. As noted by Montgomery and colleagues, “given its size, integration and capabilities, the VA is an ideal setting for rapid learning cycles of testing and implementing best practices at scale.”¹ The articles in this special issue, which focus on the 2 cancers that affects the most veterans—prostate and lung—show the transformative work underway to develop a new model of collaboration in cancer care.

At VHA, research and practice are not just proximal; they are truly integrated in the service of enhancing veterans’ outcomes. For example, > 60% of VA researchers are clinicians who also provide direct patient care. As observed by Levine and colleagues, “meaningful advances in cancer care depend on both laboratory and clinical research. This combination, known as translational research, takes discoveries in the laboratory and applies them to patients and vice versa.”²

For example, it was physician-scientist Donald Gleason, MD, PhD, who in the 1960s pioneered the standardized system that helps doctors better assess and treat prostate cancer (the Gleason score). More recently, physician-scientists Matthew Rettig, MD, and Bruce Montgomery, MD, both leading experts in prostate cancer research, were instrumental to VA’s partnership with the Prostate Cancer Foundation (PCF) to establish a national network for oncology trials serving veterans.

Having an embedded research program within the nation’s largest integrated health care system also provides the VA with the ability to conduct large-scale, multisite clinical trials. Since the 1940s, the VA Cooperative Studies Program (CSP) has generated key research findings across a range of diseases, including cancer, and provided definitive evidence and learning. In 1994, CSP launched its Prostate Cancer Intervention vs Observation Trial (PIVOT) study to determine whether observation is as effective as surgery for early-stage prostate cancer. Today, through the CSP, VA researchers are conducting a randomized, phase 3 clinical trial called VA Lung cancer surgery Or stereotactic Radiotherapy trial (VALOR) that will assess which of the 2 modalities is better when treating veterans with operable early-stage non-small cell lung cancer.

Additionally, VA is privileged to serve a patient population so dedicated to their country that many volunteer to serve again as participants in VA research clinical trials. In fact, Levine and colleagues credit the patients willing to enter clinical trials for the collective call to action and “critical philanthropic investment” that led to the Precision Oncology Program for Cancer of the Prostate (POPCaP).²

As a learning health care system, we also have been mindful of lessons drawn from the ongoing COVID-19 public health crisis. Almost overnight, VHA shifted from in-person to virtual visits to minimize the risk for veterans and their families. At the same time, we limited in-person clinical research visits to those that were required for the Veterans’ health or well-being and conducted large numbers of virtual research visits. (Notably, the current crisis motivated accelerated study regarding virtual research trials, clarifying which touchpoints must be face-to-face and which have been face-to-face due mainly to convention.) In parallel, we also launched numerous clinical studies focused on the fight against COVID-19. Our capacity to transition both clinical care and research is due in no small part to our preexisting and strong foundation in telehealth.

With one-third of our patient population living in rural areas, these achievements are vital to our commitment of “no veteran left behind.” These efforts were recently boosted by VHA’s newest partnership with the Bristol Myers Squibb Foundation to establish a national teleoncology center that will enable all veterans to benefit from new research advances no matter where they live.

Precision oncology represents a new model of collaboration in cancer care among clinicians, operations leaders, researchers and veterans. By leveraging the many assets that have contributed to VA’s success as a learning health care system, we can fulfill the promise of providing leading edge cancer care to all veterans.

In late 2016, the US Department of Veterans Affairs (VA) and the Prostate Cancer Foundation (PCF) announced a multiyear public-private partnership to deliver precision oncology and best-in-class care to all veterans battling prostate cancer.¹ The creation of this partnership was due to several favorable factors. At that time, VA Secretary Robert A. McDonald had created the Secretary’s Center for Strategic Partnerships. This Center provided a mechanism for nonprofit and industry partners to collaborate with the VA, thereby advancing partnerships that served the VA mission of “serving and honoring…America’s veterans.”^1,2 Concurrently, Vice President Joseph Biden’s Cancer Moonshot (later renamed the Beau Biden Cancer Moonshot) charged PCF and other cancer-focused organizations with the ambitious goal of making a decade’s worth of advancements in cancer prevention, diagnosis, and treatment in 5 years.³ As such, both organizations were positioned to recognize and address the unique prostate cancer challenges faced by male veterans, which ultimately led to the PCF-VA partnership.

A number of factors have allowed the PCF-VA partnership to scale the Centers of Excellence (COE) program. This article seeks to highlight the strategic organizing and mobilization techniques employed by the PCF-VA partnership, which can inform future public-private hybrid initiatives focused on precision medicine.

Executive Leadership as Patient Advocates

From its creation, the PCF-VA partnership placed as much importance on veteran patient care as it has on making oncologic advances. The fact that this focus came primarily from executive leadership was critical to the partnership’s success. PCF board members emphasized the significance of prioritizing veterans and military families in cancer research efforts.

A notable example is S. Ward “Trip” Casscells, MD, a veteran who was deployed to Iraq in 2006 and subsequently served as US Department of Defense Assistant Secretary of Defense for Health Affairs. He focused much of his leadership on ensuring that veterans and military families, having performed a critical service for the country, were served with this same degree of excellence when it came to health.⁴ Fellow PCF Board member Lawrence Stupski, spoke publicly about his drug-resistant form of prostate cancer, bringing awareness to the complexity of ending death and suffering from the disease.⁵ Like Casscells, Stupski has a military service background, and served in Vietnam in 1968 as an officer in the US Navy. Both participated in multiple prostate cancer clinical trials themselves, serving as models of veteran trial participants. This visibility and leadership created a culture where veterans were not just instrumental in advancing cancer research, but also representative of a responsibility to ensure high-quality care for an underserved and at-risk community (Figure 1).

VHA Economy of Scale

Utilizing the vast capacity of the Veterans Health Administration (VHA) for care was integral to the success of the partnership. The VHA serves 9 million veterans each year in 1,255 health care facilities, which include 170 medical centers and 1,075 outpatient clinics.⁶ As the nation’s largest integrated health care system, the VHA approaches cancer care with a single electronic health record system across all of its facilities, featuring comprehensive clinical outcome documentation.⁷ The VHA’s systemwide DNA sequence platform, through the National Precision Oncology Program (NPOP), also provided an optimal area for research and standardization of precision oncology practices on a national scale.⁸

Centers of Excellence: An Adaptable Model

The primary thrust of the partnership centers on the PCF-VA COEs, which form the Precision Oncology Program for Cancer of the Prostate (POPCaP) network. Over the last 4 years, PCF-deployed philanthropy has established 12 PCF-VA COEs, located in the Bronx and Manhattan, New York; Tampa Bay, Florida; Los Angeles, California; Seattle, Washington; Chicago, Illinois; Philadelphia, Pennsylvania; Ann Arbor, Michigan; Durham, North Carolina; Washington, DC; Boston, Massachusetts; and Portland, Oregon. Sites were initially chosen based on strong connections to academic medical centers, National Cancer Institute-designated comprehensive care centers, and physician-scientists who were professionally invested in precision prostate cancer oncology. Drawing on PCF’s existing networks helped to identify these areas, which were already rich in human and technological capital, before expanding to areas that were less resource rich. Future health partnerships may therefore consider capitalizing on existing relationships to spark initial growth, which can provide pathways for scaling.

In collaboration with NPOP, COEs work to sequence genomic and somatic tissue from veterans with metastatic prostate cancer, connect patients to appropriate clinical trials and treatment pathways, and advance guidelines for precision cancer care. Certain aspects of COE operations remain constant across all facilities. Annual progress reports, comprising of a written report, slide deck of accomplishments, and bulleted delineation of challenges and future plans are required of all COE-funded investigators. All COEs also are tasked with hiring a center coordinator, instituting a standardized sequencing and mutation reporting protocol, participating in consortium-wide phase 3 studies, and engaging in monthly conference calls to assess progress. A complete list of requirements is found in the Table.

However, the methods through which these goals must be completed is at the discretion of the COE investigators. Each COE, due to institutional and patient variance, experiences distinctive challenges and must mold its practice to fit existing capacities. For example, certain sites optimized workflow by training coordinators to analyze specimens, thereby improving care speed for veteran patients. Other COEs maximized nearby resources by hiring offsite specialists such as genetic counselors and interventional radiologists. By providing the freedom to design site-specific methodology, the PCF-VA partnership allows each COE to meet the award goals through any appropriate path using the funds provided, increasing efficiency and optimizing progress. This diversity of protocol also helped to expand the capabilities of the POPCaP Network, allowing sites to specialize in areas of interest in precision oncology. This eventually helped to inform future initiatives.

Accelerating Clinical Trials

A critical feature of the POPCaP network is the Prostate Cancer Analysis for Therapy Choice (PATCH) plexus.⁹ Through this investigative umbrella, veterans who are sequenced at any COE are given access to clinical trials at sites across POPCaP. Funding is available to support veteran travel to these sites, decreasing the chance that a veteran’s location is a barrier to treatment. In this way, the PCF-VA partnership continues to broaden treatment scopes for tens of thousands of veterans while simultaneously advancing clinical knowledge of precision oncology.

Fostering a Scientific Community

The PCF-VA partnership’s COE initiative capitalizes on resources from both nonprofit and public sectors to cultivate dynamic scientific discourse and investigative support. Through monthly meetings of the NPOP Molecular Oncology Tumor Board, COE investigators receive guidance and education to better assist veterans sequenced through their programs. Another example of enriched scientific collaboration are the Dream Team investigators, who were collaboratively funded by PCF, Stand Up 2 Cancer, and the American Association for Cancer Research.¹⁰ These teams made significant strides in genomic profiling of advanced prostate cancer and outpatient computed tomography-guided metastatic bone biopsy techniques. Through the PCF-VA partnership, COE researchers benefited from these investigators’ insight and expertise during regular check-in calls with investigators. PCF’s Prescription Pad, also connects all investigators to current therapies and trials, better informing them of future directions for their own work (Figure 3).^11,12

The PCF-VA partnership also facilitates peer-to-peer communication through regular inperson and virtual meetings of investigators, coordinators, and other stakeholders. These meetings allow the creation of focused working groups composed of COE leaders across the nation. The working groups seek to improve all aspects of functionality, including operational roadblocks, sequencing and phenotyping protocols, and addressing health service disparities. The VA Puget Sound Health Care System in Seattle, Washington, and the West Los Angeles VA Medical Center in California both are mentorship sites that play instrumental roles in guiding newer sites through challenges, such as obtaining rapid pathology results and navigating the VA system. This interinvestigator communication also helps to recruit new junior and senior investigators to POPCaP, thereby broadening the network’s reach.

Future Pathways

In line with the mission outlined in the MOU of developing treatments for veteran populations, the PCF-VA partnership has actively pursued addressing veteran health inequities. In 2018, a $2.5 million gift from Robert F. Smith, Founder, Chairman, and Chief Executive Officer of Vista Equity Partners, set up the Chicago COE with the express purpose of serving African American veterans, who represent men at highest risk of prostate cancer incidence and mortality.¹³ A regularly convened health disparities working group explores future efforts. This group, composed of VA investigators, epidemiologists, geneticists, and other field leaders, seeks to advance the most compelling approaches to eliminate inequities in prostate cancer care.

A novel nursing initiative that focuses on the role of nurses in providing genetic services for prostate cancer is being developed. The need for new genetic care models and significant barriers to genetic service delivery have been well-documented for prostate cancer.¹⁴ The initiative provides nurses with opportunities to train with POPCaP and VA geneticists, enroll in a City of Hope genetics course, and to join a collaborative of geneticists, medical oncologists, and nurse practitioners.¹⁵ By furthering nursing education and leadership, the initiative empowers nurses to fill the gaps in veteran health care, particularly in genomics-based precision oncology.

The COE platform also has provided the foundation for the building of COEs for other cancers relevant to veterans, such as lung cancer. This expansion of COE function helps to further the VA goal of not only creating COEs, but a system of excellence. More recently, COE infrastructure has been leveraged in the fight against COVID-19 through HITCH, a clinical trial investigating the use of temporary androgen suppression in improving clinical outcomes of veterans with COVID-19.¹⁶ This expansion of function also provides a mechanism for COEs to continue to be funded in the future: attracting federal capital, private philanthropy, and industrial support is dependent on realized and expanded goals, as well as demonstrable progress in veteran care.

Conclusions

The PCF-VA partnership serves as an example of a public-private health partnership pursuing strategic pathways and bold goals to ensure that every eligible veteran has access to precision oncology. These pathways include advocacy on the part of executive leadership, recognizing existing economies of scale, building compelling narratives to maximize funding, creating flexible requirements, and facilitating a robust, resource-rich scientific network. This partnership already has opened doors to future initiatives and continues to adapt to a rapidly changing health landscape. The discussed strategies have the potential to inform future health initiatives and showcase how a systemic approach to eradicating health inequities can greatly benefit underserved communities.

The success of the PCF-VA partnership represents more than just an efficient partnership model. The partnership’s emphasis on veterans, who exemplify service, highlights the extent to which cancer patients sacrifice to contribute to medical research. This service necessitates a service in kind: all health stakeholders share the responsibility to rapidly advance therapies and care, both to honor the patients who have come before, and to meet the needs of patients with treatment resistant forms of the disease urgently awaiting precision breakthroughs and cures.

In late 2016, the US Department of Veterans Affairs (VA) and the Prostate Cancer Foundation (PCF) announced a multiyear public-private partnership to deliver precision oncology and best-in-class care to all veterans battling prostate cancer.¹ The creation of this partnership was due to several favorable factors. At that time, VA Secretary Robert A. McDonald had created the Secretary’s Center for Strategic Partnerships. This Center provided a mechanism for nonprofit and industry partners to collaborate with the VA, thereby advancing partnerships that served the VA mission of “serving and honoring…America’s veterans.”^1,2 Concurrently, Vice President Joseph Biden’s Cancer Moonshot (later renamed the Beau Biden Cancer Moonshot) charged PCF and other cancer-focused organizations with the ambitious goal of making a decade’s worth of advancements in cancer prevention, diagnosis, and treatment in 5 years.³ As such, both organizations were positioned to recognize and address the unique prostate cancer challenges faced by male veterans, which ultimately led to the PCF-VA partnership.

A number of factors have allowed the PCF-VA partnership to scale the Centers of Excellence (COE) program. This article seeks to highlight the strategic organizing and mobilization techniques employed by the PCF-VA partnership, which can inform future public-private hybrid initiatives focused on precision medicine.

Executive Leadership as Patient Advocates

From its creation, the PCF-VA partnership placed as much importance on veteran patient care as it has on making oncologic advances. The fact that this focus came primarily from executive leadership was critical to the partnership’s success. PCF board members emphasized the significance of prioritizing veterans and military families in cancer research efforts.

A notable example is S. Ward “Trip” Casscells, MD, a veteran who was deployed to Iraq in 2006 and subsequently served as US Department of Defense Assistant Secretary of Defense for Health Affairs. He focused much of his leadership on ensuring that veterans and military families, having performed a critical service for the country, were served with this same degree of excellence when it came to health.⁴ Fellow PCF Board member Lawrence Stupski, spoke publicly about his drug-resistant form of prostate cancer, bringing awareness to the complexity of ending death and suffering from the disease.⁵ Like Casscells, Stupski has a military service background, and served in Vietnam in 1968 as an officer in the US Navy. Both participated in multiple prostate cancer clinical trials themselves, serving as models of veteran trial participants. This visibility and leadership created a culture where veterans were not just instrumental in advancing cancer research, but also representative of a responsibility to ensure high-quality care for an underserved and at-risk community (Figure 1).

VHA Economy of Scale

Utilizing the vast capacity of the Veterans Health Administration (VHA) for care was integral to the success of the partnership. The VHA serves 9 million veterans each year in 1,255 health care facilities, which include 170 medical centers and 1,075 outpatient clinics.⁶ As the nation’s largest integrated health care system, the VHA approaches cancer care with a single electronic health record system across all of its facilities, featuring comprehensive clinical outcome documentation.⁷ The VHA’s systemwide DNA sequence platform, through the National Precision Oncology Program (NPOP), also provided an optimal area for research and standardization of precision oncology practices on a national scale.⁸

Centers of Excellence: An Adaptable Model

The primary thrust of the partnership centers on the PCF-VA COEs, which form the Precision Oncology Program for Cancer of the Prostate (POPCaP) network. Over the last 4 years, PCF-deployed philanthropy has established 12 PCF-VA COEs, located in the Bronx and Manhattan, New York; Tampa Bay, Florida; Los Angeles, California; Seattle, Washington; Chicago, Illinois; Philadelphia, Pennsylvania; Ann Arbor, Michigan; Durham, North Carolina; Washington, DC; Boston, Massachusetts; and Portland, Oregon. Sites were initially chosen based on strong connections to academic medical centers, National Cancer Institute-designated comprehensive care centers, and physician-scientists who were professionally invested in precision prostate cancer oncology. Drawing on PCF’s existing networks helped to identify these areas, which were already rich in human and technological capital, before expanding to areas that were less resource rich. Future health partnerships may therefore consider capitalizing on existing relationships to spark initial growth, which can provide pathways for scaling.

In collaboration with NPOP, COEs work to sequence genomic and somatic tissue from veterans with metastatic prostate cancer, connect patients to appropriate clinical trials and treatment pathways, and advance guidelines for precision cancer care. Certain aspects of COE operations remain constant across all facilities. Annual progress reports, comprising of a written report, slide deck of accomplishments, and bulleted delineation of challenges and future plans are required of all COE-funded investigators. All COEs also are tasked with hiring a center coordinator, instituting a standardized sequencing and mutation reporting protocol, participating in consortium-wide phase 3 studies, and engaging in monthly conference calls to assess progress. A complete list of requirements is found in the Table.

However, the methods through which these goals must be completed is at the discretion of the COE investigators. Each COE, due to institutional and patient variance, experiences distinctive challenges and must mold its practice to fit existing capacities. For example, certain sites optimized workflow by training coordinators to analyze specimens, thereby improving care speed for veteran patients. Other COEs maximized nearby resources by hiring offsite specialists such as genetic counselors and interventional radiologists. By providing the freedom to design site-specific methodology, the PCF-VA partnership allows each COE to meet the award goals through any appropriate path using the funds provided, increasing efficiency and optimizing progress. This diversity of protocol also helped to expand the capabilities of the POPCaP Network, allowing sites to specialize in areas of interest in precision oncology. This eventually helped to inform future initiatives.

Accelerating Clinical Trials

A critical feature of the POPCaP network is the Prostate Cancer Analysis for Therapy Choice (PATCH) plexus.⁹ Through this investigative umbrella, veterans who are sequenced at any COE are given access to clinical trials at sites across POPCaP. Funding is available to support veteran travel to these sites, decreasing the chance that a veteran’s location is a barrier to treatment. In this way, the PCF-VA partnership continues to broaden treatment scopes for tens of thousands of veterans while simultaneously advancing clinical knowledge of precision oncology.

Fostering a Scientific Community

The PCF-VA partnership’s COE initiative capitalizes on resources from both nonprofit and public sectors to cultivate dynamic scientific discourse and investigative support. Through monthly meetings of the NPOP Molecular Oncology Tumor Board, COE investigators receive guidance and education to better assist veterans sequenced through their programs. Another example of enriched scientific collaboration are the Dream Team investigators, who were collaboratively funded by PCF, Stand Up 2 Cancer, and the American Association for Cancer Research.¹⁰ These teams made significant strides in genomic profiling of advanced prostate cancer and outpatient computed tomography-guided metastatic bone biopsy techniques. Through the PCF-VA partnership, COE researchers benefited from these investigators’ insight and expertise during regular check-in calls with investigators. PCF’s Prescription Pad, also connects all investigators to current therapies and trials, better informing them of future directions for their own work (Figure 3).^11,12

The PCF-VA partnership also facilitates peer-to-peer communication through regular inperson and virtual meetings of investigators, coordinators, and other stakeholders. These meetings allow the creation of focused working groups composed of COE leaders across the nation. The working groups seek to improve all aspects of functionality, including operational roadblocks, sequencing and phenotyping protocols, and addressing health service disparities. The VA Puget Sound Health Care System in Seattle, Washington, and the West Los Angeles VA Medical Center in California both are mentorship sites that play instrumental roles in guiding newer sites through challenges, such as obtaining rapid pathology results and navigating the VA system. This interinvestigator communication also helps to recruit new junior and senior investigators to POPCaP, thereby broadening the network’s reach.

Future Pathways

In line with the mission outlined in the MOU of developing treatments for veteran populations, the PCF-VA partnership has actively pursued addressing veteran health inequities. In 2018, a $2.5 million gift from Robert F. Smith, Founder, Chairman, and Chief Executive Officer of Vista Equity Partners, set up the Chicago COE with the express purpose of serving African American veterans, who represent men at highest risk of prostate cancer incidence and mortality.¹³ A regularly convened health disparities working group explores future efforts. This group, composed of VA investigators, epidemiologists, geneticists, and other field leaders, seeks to advance the most compelling approaches to eliminate inequities in prostate cancer care.

A novel nursing initiative that focuses on the role of nurses in providing genetic services for prostate cancer is being developed. The need for new genetic care models and significant barriers to genetic service delivery have been well-documented for prostate cancer.¹⁴ The initiative provides nurses with opportunities to train with POPCaP and VA geneticists, enroll in a City of Hope genetics course, and to join a collaborative of geneticists, medical oncologists, and nurse practitioners.¹⁵ By furthering nursing education and leadership, the initiative empowers nurses to fill the gaps in veteran health care, particularly in genomics-based precision oncology.

The COE platform also has provided the foundation for the building of COEs for other cancers relevant to veterans, such as lung cancer. This expansion of COE function helps to further the VA goal of not only creating COEs, but a system of excellence. More recently, COE infrastructure has been leveraged in the fight against COVID-19 through HITCH, a clinical trial investigating the use of temporary androgen suppression in improving clinical outcomes of veterans with COVID-19.¹⁶ This expansion of function also provides a mechanism for COEs to continue to be funded in the future: attracting federal capital, private philanthropy, and industrial support is dependent on realized and expanded goals, as well as demonstrable progress in veteran care.

Conclusions

The PCF-VA partnership serves as an example of a public-private health partnership pursuing strategic pathways and bold goals to ensure that every eligible veteran has access to precision oncology. These pathways include advocacy on the part of executive leadership, recognizing existing economies of scale, building compelling narratives to maximize funding, creating flexible requirements, and facilitating a robust, resource-rich scientific network. This partnership already has opened doors to future initiatives and continues to adapt to a rapidly changing health landscape. The discussed strategies have the potential to inform future health initiatives and showcase how a systemic approach to eradicating health inequities can greatly benefit underserved communities.

The success of the PCF-VA partnership represents more than just an efficient partnership model. The partnership’s emphasis on veterans, who exemplify service, highlights the extent to which cancer patients sacrifice to contribute to medical research. This service necessitates a service in kind: all health stakeholders share the responsibility to rapidly advance therapies and care, both to honor the patients who have come before, and to meet the needs of patients with treatment resistant forms of the disease urgently awaiting precision breakthroughs and cures.

In late 2016, the US Department of Veterans Affairs (VA) and the Prostate Cancer Foundation (PCF) announced a multiyear public-private partnership to deliver precision oncology and best-in-class care to all veterans battling prostate cancer.¹ The creation of this partnership was due to several favorable factors. At that time, VA Secretary Robert A. McDonald had created the Secretary’s Center for Strategic Partnerships. This Center provided a mechanism for nonprofit and industry partners to collaborate with the VA, thereby advancing partnerships that served the VA mission of “serving and honoring…America’s veterans.”^1,2 Concurrently, Vice President Joseph Biden’s Cancer Moonshot (later renamed the Beau Biden Cancer Moonshot) charged PCF and other cancer-focused organizations with the ambitious goal of making a decade’s worth of advancements in cancer prevention, diagnosis, and treatment in 5 years.³ As such, both organizations were positioned to recognize and address the unique prostate cancer challenges faced by male veterans, which ultimately led to the PCF-VA partnership.

A number of factors have allowed the PCF-VA partnership to scale the Centers of Excellence (COE) program. This article seeks to highlight the strategic organizing and mobilization techniques employed by the PCF-VA partnership, which can inform future public-private hybrid initiatives focused on precision medicine.

Executive Leadership as Patient Advocates

From its creation, the PCF-VA partnership placed as much importance on veteran patient care as it has on making oncologic advances. The fact that this focus came primarily from executive leadership was critical to the partnership’s success. PCF board members emphasized the significance of prioritizing veterans and military families in cancer research efforts.

A notable example is S. Ward “Trip” Casscells, MD, a veteran who was deployed to Iraq in 2006 and subsequently served as US Department of Defense Assistant Secretary of Defense for Health Affairs. He focused much of his leadership on ensuring that veterans and military families, having performed a critical service for the country, were served with this same degree of excellence when it came to health.⁴ Fellow PCF Board member Lawrence Stupski, spoke publicly about his drug-resistant form of prostate cancer, bringing awareness to the complexity of ending death and suffering from the disease.⁵ Like Casscells, Stupski has a military service background, and served in Vietnam in 1968 as an officer in the US Navy. Both participated in multiple prostate cancer clinical trials themselves, serving as models of veteran trial participants. This visibility and leadership created a culture where veterans were not just instrumental in advancing cancer research, but also representative of a responsibility to ensure high-quality care for an underserved and at-risk community (Figure 1).

VHA Economy of Scale

Utilizing the vast capacity of the Veterans Health Administration (VHA) for care was integral to the success of the partnership. The VHA serves 9 million veterans each year in 1,255 health care facilities, which include 170 medical centers and 1,075 outpatient clinics.⁶ As the nation’s largest integrated health care system, the VHA approaches cancer care with a single electronic health record system across all of its facilities, featuring comprehensive clinical outcome documentation.⁷ The VHA’s systemwide DNA sequence platform, through the National Precision Oncology Program (NPOP), also provided an optimal area for research and standardization of precision oncology practices on a national scale.⁸

Centers of Excellence: An Adaptable Model

The primary thrust of the partnership centers on the PCF-VA COEs, which form the Precision Oncology Program for Cancer of the Prostate (POPCaP) network. Over the last 4 years, PCF-deployed philanthropy has established 12 PCF-VA COEs, located in the Bronx and Manhattan, New York; Tampa Bay, Florida; Los Angeles, California; Seattle, Washington; Chicago, Illinois; Philadelphia, Pennsylvania; Ann Arbor, Michigan; Durham, North Carolina; Washington, DC; Boston, Massachusetts; and Portland, Oregon. Sites were initially chosen based on strong connections to academic medical centers, National Cancer Institute-designated comprehensive care centers, and physician-scientists who were professionally invested in precision prostate cancer oncology. Drawing on PCF’s existing networks helped to identify these areas, which were already rich in human and technological capital, before expanding to areas that were less resource rich. Future health partnerships may therefore consider capitalizing on existing relationships to spark initial growth, which can provide pathways for scaling.

In collaboration with NPOP, COEs work to sequence genomic and somatic tissue from veterans with metastatic prostate cancer, connect patients to appropriate clinical trials and treatment pathways, and advance guidelines for precision cancer care. Certain aspects of COE operations remain constant across all facilities. Annual progress reports, comprising of a written report, slide deck of accomplishments, and bulleted delineation of challenges and future plans are required of all COE-funded investigators. All COEs also are tasked with hiring a center coordinator, instituting a standardized sequencing and mutation reporting protocol, participating in consortium-wide phase 3 studies, and engaging in monthly conference calls to assess progress. A complete list of requirements is found in the Table.

However, the methods through which these goals must be completed is at the discretion of the COE investigators. Each COE, due to institutional and patient variance, experiences distinctive challenges and must mold its practice to fit existing capacities. For example, certain sites optimized workflow by training coordinators to analyze specimens, thereby improving care speed for veteran patients. Other COEs maximized nearby resources by hiring offsite specialists such as genetic counselors and interventional radiologists. By providing the freedom to design site-specific methodology, the PCF-VA partnership allows each COE to meet the award goals through any appropriate path using the funds provided, increasing efficiency and optimizing progress. This diversity of protocol also helped to expand the capabilities of the POPCaP Network, allowing sites to specialize in areas of interest in precision oncology. This eventually helped to inform future initiatives.

Accelerating Clinical Trials

A critical feature of the POPCaP network is the Prostate Cancer Analysis for Therapy Choice (PATCH) plexus.⁹ Through this investigative umbrella, veterans who are sequenced at any COE are given access to clinical trials at sites across POPCaP. Funding is available to support veteran travel to these sites, decreasing the chance that a veteran’s location is a barrier to treatment. In this way, the PCF-VA partnership continues to broaden treatment scopes for tens of thousands of veterans while simultaneously advancing clinical knowledge of precision oncology.

Fostering a Scientific Community

The PCF-VA partnership’s COE initiative capitalizes on resources from both nonprofit and public sectors to cultivate dynamic scientific discourse and investigative support. Through monthly meetings of the NPOP Molecular Oncology Tumor Board, COE investigators receive guidance and education to better assist veterans sequenced through their programs. Another example of enriched scientific collaboration are the Dream Team investigators, who were collaboratively funded by PCF, Stand Up 2 Cancer, and the American Association for Cancer Research.¹⁰ These teams made significant strides in genomic profiling of advanced prostate cancer and outpatient computed tomography-guided metastatic bone biopsy techniques. Through the PCF-VA partnership, COE researchers benefited from these investigators’ insight and expertise during regular check-in calls with investigators. PCF’s Prescription Pad, also connects all investigators to current therapies and trials, better informing them of future directions for their own work (Figure 3).^11,12

The PCF-VA partnership also facilitates peer-to-peer communication through regular inperson and virtual meetings of investigators, coordinators, and other stakeholders. These meetings allow the creation of focused working groups composed of COE leaders across the nation. The working groups seek to improve all aspects of functionality, including operational roadblocks, sequencing and phenotyping protocols, and addressing health service disparities. The VA Puget Sound Health Care System in Seattle, Washington, and the West Los Angeles VA Medical Center in California both are mentorship sites that play instrumental roles in guiding newer sites through challenges, such as obtaining rapid pathology results and navigating the VA system. This interinvestigator communication also helps to recruit new junior and senior investigators to POPCaP, thereby broadening the network’s reach.

Future Pathways

In line with the mission outlined in the MOU of developing treatments for veteran populations, the PCF-VA partnership has actively pursued addressing veteran health inequities. In 2018, a $2.5 million gift from Robert F. Smith, Founder, Chairman, and Chief Executive Officer of Vista Equity Partners, set up the Chicago COE with the express purpose of serving African American veterans, who represent men at highest risk of prostate cancer incidence and mortality.¹³ A regularly convened health disparities working group explores future efforts. This group, composed of VA investigators, epidemiologists, geneticists, and other field leaders, seeks to advance the most compelling approaches to eliminate inequities in prostate cancer care.

A novel nursing initiative that focuses on the role of nurses in providing genetic services for prostate cancer is being developed. The need for new genetic care models and significant barriers to genetic service delivery have been well-documented for prostate cancer.¹⁴ The initiative provides nurses with opportunities to train with POPCaP and VA geneticists, enroll in a City of Hope genetics course, and to join a collaborative of geneticists, medical oncologists, and nurse practitioners.¹⁵ By furthering nursing education and leadership, the initiative empowers nurses to fill the gaps in veteran health care, particularly in genomics-based precision oncology.

The COE platform also has provided the foundation for the building of COEs for other cancers relevant to veterans, such as lung cancer. This expansion of COE function helps to further the VA goal of not only creating COEs, but a system of excellence. More recently, COE infrastructure has been leveraged in the fight against COVID-19 through HITCH, a clinical trial investigating the use of temporary androgen suppression in improving clinical outcomes of veterans with COVID-19.¹⁶ This expansion of function also provides a mechanism for COEs to continue to be funded in the future: attracting federal capital, private philanthropy, and industrial support is dependent on realized and expanded goals, as well as demonstrable progress in veteran care.

Conclusions

The PCF-VA partnership serves as an example of a public-private health partnership pursuing strategic pathways and bold goals to ensure that every eligible veteran has access to precision oncology. These pathways include advocacy on the part of executive leadership, recognizing existing economies of scale, building compelling narratives to maximize funding, creating flexible requirements, and facilitating a robust, resource-rich scientific network. This partnership already has opened doors to future initiatives and continues to adapt to a rapidly changing health landscape. The discussed strategies have the potential to inform future health initiatives and showcase how a systemic approach to eradicating health inequities can greatly benefit underserved communities.

The success of the PCF-VA partnership represents more than just an efficient partnership model. The partnership’s emphasis on veterans, who exemplify service, highlights the extent to which cancer patients sacrifice to contribute to medical research. This service necessitates a service in kind: all health stakeholders share the responsibility to rapidly advance therapies and care, both to honor the patients who have come before, and to meet the needs of patients with treatment resistant forms of the disease urgently awaiting precision breakthroughs and cures.

A remote monitoring system was highly effective in managing symptoms and improving quality of life among patients with cancer who were receiving chemotherapy, say researchers reporting the first clinical trial of the new approach.

The study tested the Advanced Symptom Management System (ASyMS) for patients with various cancer types who were undergoing treatment at cancer centers in several European countries. The study primarily focused on patients who were being treated with curative intent.

The 24-hour monitoring system optimized symptom management in a manner safe, secure, and in “real time,” the team reports. This is particularly relevant during the COVID-19 pandemic, they note.

“Our findings suggest that an evidence based remote monitoring intervention, such as ASyMS, has potential for implementation into routine care to make a meaningful difference to people with cancer,” the authors conclude.

The findings were published online in BMJ.

The results show that “ASyMS can be implemented across multiple countries within diverse health care systems,” commented lead author Roma Maguire, PhD, a professor of digital health and care at the University of Strathclyde, in Glasgow, and director of the Health and Care Futures initiative.

So far, the system has only been used in clinical research studies, but “our findings do suggest that it is feasible to implement our system on a wider scale,” she added.

The study cohort included 829 patients with various cancers, including nonmetastatic breast cancer, colorectal cancer, Hodgkin disease, and non-Hodgkin lymphoma. The patients were receiving first-line adjuvant chemotherapy or chemotherapy for the first time in 5 years. They were recruited from 12 cancer centers in Austria, Greece, Norway, the Republic of Ireland, and the United Kingdom.

Patients were randomly assigned to receive ASyMS (n = 415) or standard care (n = 414) during six cycles of chemotherapy.

The primary outcome was symptom burden, as determined using the Memorial Symptom Assessment Scale. Secondary outcomes included health-related quality of life, as determined by results on the Functional Assessment of Cancer Therapy–General, the Supportive Care Needs Survey–Short Form, the State-Trait Anxiety Inventory–Revised, the Communication and Attitudinal Self-Efficacy scale for cancer, and the Work Limitations Questionnaire.

Patients in the intervention group completed a daily symptom questionnaire on a handheld ASyMS device, which generated alerts to health care professionals if any intervention was needed. The patients were also provided with advice and information on how to manage their symptoms themselves.

Among patients using ASyMS, symptom burden remained at prechemotherapy levels over all six chemotherapy cycles. Conversely, the control group reported an increase in symptom burden from cycle 1; symptom burden slowly decreased during the remaining chemotherapy cycles.

Overall, the investigators found that, among the patients who used ASyMS, psychological and physical symptoms were significantly reduced, along with the level of distress associated with each symptom.

In addition, for the patients who used ASyMS, health-related quality-of-life scores were higher across all cycles. The authors note that the improvements in health-related quality of life are consistent with findings from recent trials of the use of remote monitoring systems in chemotherapy care. The intervention group also experienced significant improvements regarding the need for supportive care.

Improvements in symptom burden differed among countries. The greatest improvements were seen among patients with breast cancer, Hodgkin disease, or non-Hodgkin lymphoma in Austria, Ireland, and the United Kingdom. The reasons for these differences are unclear, the authors note. ASyMS was developed in the United Kingdom, and it’s possible that ASyMS is more effective in countries that have health care systems similar to the system in the United Kingdom, they suggest.

The incidence of adverse events was similar for the two groups, although the rate of neutropenia was higher among patients using ASyMS (n = 125; 64%) in comparison with the standard-care group ( n = 71; 36%). Three deaths occurred in each study arm. The number of planned hospital admissions was similar between the two groups (34 vs. 38), as was the number of unplanned hospital admissions (120 vs. 109). No ASyMS device-related incidents were reported.

The trial was funded by the European Commission and was sponsored by the University of Strathclyde. Dr. Maguire has disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

A remote monitoring system was highly effective in managing symptoms and improving quality of life among patients with cancer who were receiving chemotherapy, say researchers reporting the first clinical trial of the new approach.

The study tested the Advanced Symptom Management System (ASyMS) for patients with various cancer types who were undergoing treatment at cancer centers in several European countries. The study primarily focused on patients who were being treated with curative intent.

The 24-hour monitoring system optimized symptom management in a manner safe, secure, and in “real time,” the team reports. This is particularly relevant during the COVID-19 pandemic, they note.

“Our findings suggest that an evidence based remote monitoring intervention, such as ASyMS, has potential for implementation into routine care to make a meaningful difference to people with cancer,” the authors conclude.

The findings were published online in BMJ.

The results show that “ASyMS can be implemented across multiple countries within diverse health care systems,” commented lead author Roma Maguire, PhD, a professor of digital health and care at the University of Strathclyde, in Glasgow, and director of the Health and Care Futures initiative.

So far, the system has only been used in clinical research studies, but “our findings do suggest that it is feasible to implement our system on a wider scale,” she added.

The study cohort included 829 patients with various cancers, including nonmetastatic breast cancer, colorectal cancer, Hodgkin disease, and non-Hodgkin lymphoma. The patients were receiving first-line adjuvant chemotherapy or chemotherapy for the first time in 5 years. They were recruited from 12 cancer centers in Austria, Greece, Norway, the Republic of Ireland, and the United Kingdom.

Patients were randomly assigned to receive ASyMS (n = 415) or standard care (n = 414) during six cycles of chemotherapy.

The primary outcome was symptom burden, as determined using the Memorial Symptom Assessment Scale. Secondary outcomes included health-related quality of life, as determined by results on the Functional Assessment of Cancer Therapy–General, the Supportive Care Needs Survey–Short Form, the State-Trait Anxiety Inventory–Revised, the Communication and Attitudinal Self-Efficacy scale for cancer, and the Work Limitations Questionnaire.

Patients in the intervention group completed a daily symptom questionnaire on a handheld ASyMS device, which generated alerts to health care professionals if any intervention was needed. The patients were also provided with advice and information on how to manage their symptoms themselves.

Among patients using ASyMS, symptom burden remained at prechemotherapy levels over all six chemotherapy cycles. Conversely, the control group reported an increase in symptom burden from cycle 1; symptom burden slowly decreased during the remaining chemotherapy cycles.

Overall, the investigators found that, among the patients who used ASyMS, psychological and physical symptoms were significantly reduced, along with the level of distress associated with each symptom.

In addition, for the patients who used ASyMS, health-related quality-of-life scores were higher across all cycles. The authors note that the improvements in health-related quality of life are consistent with findings from recent trials of the use of remote monitoring systems in chemotherapy care. The intervention group also experienced significant improvements regarding the need for supportive care.

Improvements in symptom burden differed among countries. The greatest improvements were seen among patients with breast cancer, Hodgkin disease, or non-Hodgkin lymphoma in Austria, Ireland, and the United Kingdom. The reasons for these differences are unclear, the authors note. ASyMS was developed in the United Kingdom, and it’s possible that ASyMS is more effective in countries that have health care systems similar to the system in the United Kingdom, they suggest.

The incidence of adverse events was similar for the two groups, although the rate of neutropenia was higher among patients using ASyMS (n = 125; 64%) in comparison with the standard-care group ( n = 71; 36%). Three deaths occurred in each study arm. The number of planned hospital admissions was similar between the two groups (34 vs. 38), as was the number of unplanned hospital admissions (120 vs. 109). No ASyMS device-related incidents were reported.

The trial was funded by the European Commission and was sponsored by the University of Strathclyde. Dr. Maguire has disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

A remote monitoring system was highly effective in managing symptoms and improving quality of life among patients with cancer who were receiving chemotherapy, say researchers reporting the first clinical trial of the new approach.

The study tested the Advanced Symptom Management System (ASyMS) for patients with various cancer types who were undergoing treatment at cancer centers in several European countries. The study primarily focused on patients who were being treated with curative intent.

The 24-hour monitoring system optimized symptom management in a manner safe, secure, and in “real time,” the team reports. This is particularly relevant during the COVID-19 pandemic, they note.

“Our findings suggest that an evidence based remote monitoring intervention, such as ASyMS, has potential for implementation into routine care to make a meaningful difference to people with cancer,” the authors conclude.

The findings were published online in BMJ.

The results show that “ASyMS can be implemented across multiple countries within diverse health care systems,” commented lead author Roma Maguire, PhD, a professor of digital health and care at the University of Strathclyde, in Glasgow, and director of the Health and Care Futures initiative.

So far, the system has only been used in clinical research studies, but “our findings do suggest that it is feasible to implement our system on a wider scale,” she added.

The study cohort included 829 patients with various cancers, including nonmetastatic breast cancer, colorectal cancer, Hodgkin disease, and non-Hodgkin lymphoma. The patients were receiving first-line adjuvant chemotherapy or chemotherapy for the first time in 5 years. They were recruited from 12 cancer centers in Austria, Greece, Norway, the Republic of Ireland, and the United Kingdom.

Patients were randomly assigned to receive ASyMS (n = 415) or standard care (n = 414) during six cycles of chemotherapy.

The primary outcome was symptom burden, as determined using the Memorial Symptom Assessment Scale. Secondary outcomes included health-related quality of life, as determined by results on the Functional Assessment of Cancer Therapy–General, the Supportive Care Needs Survey–Short Form, the State-Trait Anxiety Inventory–Revised, the Communication and Attitudinal Self-Efficacy scale for cancer, and the Work Limitations Questionnaire.

Patients in the intervention group completed a daily symptom questionnaire on a handheld ASyMS device, which generated alerts to health care professionals if any intervention was needed. The patients were also provided with advice and information on how to manage their symptoms themselves.

Among patients using ASyMS, symptom burden remained at prechemotherapy levels over all six chemotherapy cycles. Conversely, the control group reported an increase in symptom burden from cycle 1; symptom burden slowly decreased during the remaining chemotherapy cycles.

Overall, the investigators found that, among the patients who used ASyMS, psychological and physical symptoms were significantly reduced, along with the level of distress associated with each symptom.

In addition, for the patients who used ASyMS, health-related quality-of-life scores were higher across all cycles. The authors note that the improvements in health-related quality of life are consistent with findings from recent trials of the use of remote monitoring systems in chemotherapy care. The intervention group also experienced significant improvements regarding the need for supportive care.

Improvements in symptom burden differed among countries. The greatest improvements were seen among patients with breast cancer, Hodgkin disease, or non-Hodgkin lymphoma in Austria, Ireland, and the United Kingdom. The reasons for these differences are unclear, the authors note. ASyMS was developed in the United Kingdom, and it’s possible that ASyMS is more effective in countries that have health care systems similar to the system in the United Kingdom, they suggest.

The incidence of adverse events was similar for the two groups, although the rate of neutropenia was higher among patients using ASyMS (n = 125; 64%) in comparison with the standard-care group ( n = 71; 36%). Three deaths occurred in each study arm. The number of planned hospital admissions was similar between the two groups (34 vs. 38), as was the number of unplanned hospital admissions (120 vs. 109). No ASyMS device-related incidents were reported.

The trial was funded by the European Commission and was sponsored by the University of Strathclyde. Dr. Maguire has disclosed no relevant financial relationships.

A version of this article first appeared on Medscape.com.

Wrong-site surgery

Florida regulators have imposed a fine and other measures on a Tampa doctor who made a crucial error prior to his patient’s testicular surgery, as a story in the Miami Herald, among other news sites, reports.

On Sept. 10, 2019, a patient referred to in state documents as “C.F.” showed up for a procedure – a varicocelectomy – that would remove the enlarged veins in his left testicle. His doctor that day was Raul Fernandez-Crespo, MD, a urologist who had been licensed to practice in Florida since April of the same year. Dr. Fernandez-Crespo completed his urology residency at the University of Puerto Rico in 2019.

Following a conversation with C.F., Dr. Fernandez-Crespo designated what he believed was the proper surgical site – his patient’s right testicle.

He then proceeded to operate, but at some point during the procedure – news accounts don’t make clear when or how he became aware of his error – he realized C.F. had actually consented to a left-testicle varicocelectomy. With his patient still sedated, Dr. Fernandez-Crespo also completed the second procedure.

His mistake came to the attention of the Department of Health, which filed an administrative complaint against the surgeon. On June 17, 2021, the department’s medical licensing body, the Florida Board of Medicine, handed down its final order about the case.

In addition to imposing a $2,500 fine on Dr. Fernandez-Crespo and issuing “a letter of concern” – a public document that can be used as evidence in any relevant future disciplinary action against him – regulators said the surgeon must reimburse $2,045.56 to the department for its case-related administrative costs; take a 5-hour CME course in risk management or attend 8 hours of board disciplinary hearings; and, finally, give a 1-hour lecture on wrong-site surgeries at a board-approved medical facility.

Before this, Dr. Fernandez-Crespo had no previous disciplinary history with the Florida Board of Medicine.
 

Huge judgment after fertility procedure goes wrong

A Connecticut couple whose fertility and prenatal care at a state university health center proved disastrous will receive millions of dollars in damages, according to a report in the Hartford Courant.

In 2014, Jean-Marie Monroe-Lynch and her husband, Aaron Lynch, went to UConn Health, in Farmington, for treatment of Jean-Marie’s infertility. Her care was overseen by the Center for Advanced Reproductive Services (CARS), a private company then under contract with UConn Health. (The contract, which ended in 2014, obligated UConn to provide CARS providers with medical malpractice coverage.)

There, Jean-Marie was inseminated with sperm from a donor who turned out to be a carrier for cytomegalovirus (CMV), the herpes virus that can cause severe birth defects, or fetal death, when contracted by a pregnant woman. The insemination resulted in a twin pregnancy, a boy and a girl. The girl, Shay, died in utero after several of her organs became infected with CMV; the boy, Joshua, was born with severe mental and physical disabilities.

In their suit, Ms. Monroe-Lynch and her husband alleged that they were never cautioned about the risks associated with using a sperm donor whose blood had tested positive for CMV antibodies. Their suit further alleged that, at the 20-week ultrasound, UConn’s prenatal team failed to detect evidence of congenital CMV infection and again failed, at the 22-week ultrasound, to properly recognize and respond to abnormal findings.

“They totally dropped the ball,” said the couple’s attorney. “If you’re a pregnant woman and contract the virus for the first time, the results can be devastating.” 

CARS disputes this conclusion, arguing that the plaintiffs failed to prove as a “matter of scientific fact” that Ms. Monroe-Lynch was infected with CMV as the result of her intrauterine insemination.

But Superior Court Judge Mark H. Taylor disagreed. In his 107-page ruling, he said that the court “agrees with the vast majority of superior courts, concluding that a physician providing obstetric care owes a direct duty to a mother to prevent harm to her child during gestation and delivery.”

Jean-Marie Monroe-Lynch and Aaron Lynch received a $37.6 million award, consisting of $24.1 million in economic damages and $13.5 million in noneconomic damages.

Their surviving child, Joshua, will reportedly require a lifetime of medical and other care. In the meantime, UConn Health vows to appeal the Superior Court’s decision.
 

COVID patient’s relative demands justice for fatal outcome

An Indiana man whose grandfather recently died after suffering a stroke is calling on state lawmakers to rethink legislation passed earlier this year to protect health care providers during the COVID-19 pandemic, according to a story reported by CBS4Indy.

Late last year, Daniel Enlow’s 83-year-old grandfather, Edward Rigney, was checked into Eskenazi Hospital, in Indianapolis. Mr. Rigney suffered from COPD and had also been diagnosed with COVID-19.

At some point during his hospitalization, medical staff attempted to place what seems to have been an arterial line in order to monitor his condition. During the procedure, or at some point shortly thereafter, an “iatrogenic air embolus” was released into his veins and caused a stroke, according to medical records and Mr. Rigney’s death certificate.

“I started asking for medical records because I wanted to know what was happening leading up to it in black and white in front of me,” said Mr. Enlow, who wished to present his evidence to a medical review panel, as required by Indiana law. The first step in this process would have been to consult with a medical malpractice attorney, but several declined to take his case.

Why? Because a pair of bills passed by Indiana legislators in early 2021 make COVID-19–related suits – even tangentially related ones – potentially difficult to take to court.

The bills raised the bar to file a medical malpractice claim in COVID-19 cases and to allow only those that involve “gross negligence or willful or wanton misconduct.”

“In the vast majority of cases, it’s impossible to prove that,” said Fred Schultz, immediate past president of the Indiana Trial Lawyers Association, who lobbied against the legislation.

The bills were never designed to offer “blanket freedom,” said GOP State Senator Aaron Freeman, sponsor of one of the bills. “If something is being used in a way that it is a complete bar to certain claims, then maybe we need to go back and look at it and open that up a little bit and make it less restrictive. I’m certainly open to having those conversations.”

Meanwhile, Mr. Enlow has vowed to keep pushing in the name of his late grandfather. The hospital’s parent company, Eskenazi Health, has declined to comment.

A version of this article first appeared on Medscape.com.

Wrong-site surgery

Florida regulators have imposed a fine and other measures on a Tampa doctor who made a crucial error prior to his patient’s testicular surgery, as a story in the Miami Herald, among other news sites, reports.

On Sept. 10, 2019, a patient referred to in state documents as “C.F.” showed up for a procedure – a varicocelectomy – that would remove the enlarged veins in his left testicle. His doctor that day was Raul Fernandez-Crespo, MD, a urologist who had been licensed to practice in Florida since April of the same year. Dr. Fernandez-Crespo completed his urology residency at the University of Puerto Rico in 2019.

Following a conversation with C.F., Dr. Fernandez-Crespo designated what he believed was the proper surgical site – his patient’s right testicle.

He then proceeded to operate, but at some point during the procedure – news accounts don’t make clear when or how he became aware of his error – he realized C.F. had actually consented to a left-testicle varicocelectomy. With his patient still sedated, Dr. Fernandez-Crespo also completed the second procedure.

His mistake came to the attention of the Department of Health, which filed an administrative complaint against the surgeon. On June 17, 2021, the department’s medical licensing body, the Florida Board of Medicine, handed down its final order about the case.

In addition to imposing a $2,500 fine on Dr. Fernandez-Crespo and issuing “a letter of concern” – a public document that can be used as evidence in any relevant future disciplinary action against him – regulators said the surgeon must reimburse $2,045.56 to the department for its case-related administrative costs; take a 5-hour CME course in risk management or attend 8 hours of board disciplinary hearings; and, finally, give a 1-hour lecture on wrong-site surgeries at a board-approved medical facility.

Before this, Dr. Fernandez-Crespo had no previous disciplinary history with the Florida Board of Medicine.
 

Huge judgment after fertility procedure goes wrong

A Connecticut couple whose fertility and prenatal care at a state university health center proved disastrous will receive millions of dollars in damages, according to a report in the Hartford Courant.

In 2014, Jean-Marie Monroe-Lynch and her husband, Aaron Lynch, went to UConn Health, in Farmington, for treatment of Jean-Marie’s infertility. Her care was overseen by the Center for Advanced Reproductive Services (CARS), a private company then under contract with UConn Health. (The contract, which ended in 2014, obligated UConn to provide CARS providers with medical malpractice coverage.)

There, Jean-Marie was inseminated with sperm from a donor who turned out to be a carrier for cytomegalovirus (CMV), the herpes virus that can cause severe birth defects, or fetal death, when contracted by a pregnant woman. The insemination resulted in a twin pregnancy, a boy and a girl. The girl, Shay, died in utero after several of her organs became infected with CMV; the boy, Joshua, was born with severe mental and physical disabilities.

In their suit, Ms. Monroe-Lynch and her husband alleged that they were never cautioned about the risks associated with using a sperm donor whose blood had tested positive for CMV antibodies. Their suit further alleged that, at the 20-week ultrasound, UConn’s prenatal team failed to detect evidence of congenital CMV infection and again failed, at the 22-week ultrasound, to properly recognize and respond to abnormal findings.

“They totally dropped the ball,” said the couple’s attorney. “If you’re a pregnant woman and contract the virus for the first time, the results can be devastating.” 

CARS disputes this conclusion, arguing that the plaintiffs failed to prove as a “matter of scientific fact” that Ms. Monroe-Lynch was infected with CMV as the result of her intrauterine insemination.

But Superior Court Judge Mark H. Taylor disagreed. In his 107-page ruling, he said that the court “agrees with the vast majority of superior courts, concluding that a physician providing obstetric care owes a direct duty to a mother to prevent harm to her child during gestation and delivery.”

Jean-Marie Monroe-Lynch and Aaron Lynch received a $37.6 million award, consisting of $24.1 million in economic damages and $13.5 million in noneconomic damages.

Their surviving child, Joshua, will reportedly require a lifetime of medical and other care. In the meantime, UConn Health vows to appeal the Superior Court’s decision.
 

COVID patient’s relative demands justice for fatal outcome

An Indiana man whose grandfather recently died after suffering a stroke is calling on state lawmakers to rethink legislation passed earlier this year to protect health care providers during the COVID-19 pandemic, according to a story reported by CBS4Indy.

Late last year, Daniel Enlow’s 83-year-old grandfather, Edward Rigney, was checked into Eskenazi Hospital, in Indianapolis. Mr. Rigney suffered from COPD and had also been diagnosed with COVID-19.

At some point during his hospitalization, medical staff attempted to place what seems to have been an arterial line in order to monitor his condition. During the procedure, or at some point shortly thereafter, an “iatrogenic air embolus” was released into his veins and caused a stroke, according to medical records and Mr. Rigney’s death certificate.

“I started asking for medical records because I wanted to know what was happening leading up to it in black and white in front of me,” said Mr. Enlow, who wished to present his evidence to a medical review panel, as required by Indiana law. The first step in this process would have been to consult with a medical malpractice attorney, but several declined to take his case.

Why? Because a pair of bills passed by Indiana legislators in early 2021 make COVID-19–related suits – even tangentially related ones – potentially difficult to take to court.

The bills raised the bar to file a medical malpractice claim in COVID-19 cases and to allow only those that involve “gross negligence or willful or wanton misconduct.”

“In the vast majority of cases, it’s impossible to prove that,” said Fred Schultz, immediate past president of the Indiana Trial Lawyers Association, who lobbied against the legislation.

The bills were never designed to offer “blanket freedom,” said GOP State Senator Aaron Freeman, sponsor of one of the bills. “If something is being used in a way that it is a complete bar to certain claims, then maybe we need to go back and look at it and open that up a little bit and make it less restrictive. I’m certainly open to having those conversations.”

Meanwhile, Mr. Enlow has vowed to keep pushing in the name of his late grandfather. The hospital’s parent company, Eskenazi Health, has declined to comment.

A version of this article first appeared on Medscape.com.

Wrong-site surgery

Florida regulators have imposed a fine and other measures on a Tampa doctor who made a crucial error prior to his patient’s testicular surgery, as a story in the Miami Herald, among other news sites, reports.

On Sept. 10, 2019, a patient referred to in state documents as “C.F.” showed up for a procedure – a varicocelectomy – that would remove the enlarged veins in his left testicle. His doctor that day was Raul Fernandez-Crespo, MD, a urologist who had been licensed to practice in Florida since April of the same year. Dr. Fernandez-Crespo completed his urology residency at the University of Puerto Rico in 2019.

Following a conversation with C.F., Dr. Fernandez-Crespo designated what he believed was the proper surgical site – his patient’s right testicle.

He then proceeded to operate, but at some point during the procedure – news accounts don’t make clear when or how he became aware of his error – he realized C.F. had actually consented to a left-testicle varicocelectomy. With his patient still sedated, Dr. Fernandez-Crespo also completed the second procedure.

His mistake came to the attention of the Department of Health, which filed an administrative complaint against the surgeon. On June 17, 2021, the department’s medical licensing body, the Florida Board of Medicine, handed down its final order about the case.

In addition to imposing a $2,500 fine on Dr. Fernandez-Crespo and issuing “a letter of concern” – a public document that can be used as evidence in any relevant future disciplinary action against him – regulators said the surgeon must reimburse $2,045.56 to the department for its case-related administrative costs; take a 5-hour CME course in risk management or attend 8 hours of board disciplinary hearings; and, finally, give a 1-hour lecture on wrong-site surgeries at a board-approved medical facility.

Before this, Dr. Fernandez-Crespo had no previous disciplinary history with the Florida Board of Medicine.
 

Huge judgment after fertility procedure goes wrong

A Connecticut couple whose fertility and prenatal care at a state university health center proved disastrous will receive millions of dollars in damages, according to a report in the Hartford Courant.

In 2014, Jean-Marie Monroe-Lynch and her husband, Aaron Lynch, went to UConn Health, in Farmington, for treatment of Jean-Marie’s infertility. Her care was overseen by the Center for Advanced Reproductive Services (CARS), a private company then under contract with UConn Health. (The contract, which ended in 2014, obligated UConn to provide CARS providers with medical malpractice coverage.)

There, Jean-Marie was inseminated with sperm from a donor who turned out to be a carrier for cytomegalovirus (CMV), the herpes virus that can cause severe birth defects, or fetal death, when contracted by a pregnant woman. The insemination resulted in a twin pregnancy, a boy and a girl. The girl, Shay, died in utero after several of her organs became infected with CMV; the boy, Joshua, was born with severe mental and physical disabilities.

In their suit, Ms. Monroe-Lynch and her husband alleged that they were never cautioned about the risks associated with using a sperm donor whose blood had tested positive for CMV antibodies. Their suit further alleged that, at the 20-week ultrasound, UConn’s prenatal team failed to detect evidence of congenital CMV infection and again failed, at the 22-week ultrasound, to properly recognize and respond to abnormal findings.

“They totally dropped the ball,” said the couple’s attorney. “If you’re a pregnant woman and contract the virus for the first time, the results can be devastating.” 

CARS disputes this conclusion, arguing that the plaintiffs failed to prove as a “matter of scientific fact” that Ms. Monroe-Lynch was infected with CMV as the result of her intrauterine insemination.

But Superior Court Judge Mark H. Taylor disagreed. In his 107-page ruling, he said that the court “agrees with the vast majority of superior courts, concluding that a physician providing obstetric care owes a direct duty to a mother to prevent harm to her child during gestation and delivery.”

Jean-Marie Monroe-Lynch and Aaron Lynch received a $37.6 million award, consisting of $24.1 million in economic damages and $13.5 million in noneconomic damages.

Their surviving child, Joshua, will reportedly require a lifetime of medical and other care. In the meantime, UConn Health vows to appeal the Superior Court’s decision.
 

COVID patient’s relative demands justice for fatal outcome

An Indiana man whose grandfather recently died after suffering a stroke is calling on state lawmakers to rethink legislation passed earlier this year to protect health care providers during the COVID-19 pandemic, according to a story reported by CBS4Indy.

Late last year, Daniel Enlow’s 83-year-old grandfather, Edward Rigney, was checked into Eskenazi Hospital, in Indianapolis. Mr. Rigney suffered from COPD and had also been diagnosed with COVID-19.

At some point during his hospitalization, medical staff attempted to place what seems to have been an arterial line in order to monitor his condition. During the procedure, or at some point shortly thereafter, an “iatrogenic air embolus” was released into his veins and caused a stroke, according to medical records and Mr. Rigney’s death certificate.

“I started asking for medical records because I wanted to know what was happening leading up to it in black and white in front of me,” said Mr. Enlow, who wished to present his evidence to a medical review panel, as required by Indiana law. The first step in this process would have been to consult with a medical malpractice attorney, but several declined to take his case.

Why? Because a pair of bills passed by Indiana legislators in early 2021 make COVID-19–related suits – even tangentially related ones – potentially difficult to take to court.

The bills raised the bar to file a medical malpractice claim in COVID-19 cases and to allow only those that involve “gross negligence or willful or wanton misconduct.”

“In the vast majority of cases, it’s impossible to prove that,” said Fred Schultz, immediate past president of the Indiana Trial Lawyers Association, who lobbied against the legislation.

The bills were never designed to offer “blanket freedom,” said GOP State Senator Aaron Freeman, sponsor of one of the bills. “If something is being used in a way that it is a complete bar to certain claims, then maybe we need to go back and look at it and open that up a little bit and make it less restrictive. I’m certainly open to having those conversations.”

Meanwhile, Mr. Enlow has vowed to keep pushing in the name of his late grandfather. The hospital’s parent company, Eskenazi Health, has declined to comment.

A version of this article first appeared on Medscape.com.