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Infusion shown effective for acquired von Willebrand disease
Acquired von Willebrand disease (aVWD) is a rare and serious condition associated with lymphoproliferative disorders, malignancy, autoimmune disorders, and cardiovascular disease. It is most commonly caused by monoclonal gammopathy of undetermined significance (MGUS), which acts to clear von Willebrand factor from the patient’s bloodstream. However, a continuous-infusion of plasma-derived von Willebrand factor (VWF) concentrate provided adequate hemostasis in aVWD resulting from MGUS, according to Kathryn E. Dane, PharmD, of Johns Hopkins University, Baltimore, and colleagues.
The infusion rapidly achieved target ristocetin cofactor activity with or without intravenous immunoglobulin in three patients, as detailed in the report published online in Blood Advances.
The three consecutive patients with aVWD were treated with plasma-derived VWF concentrate administered for periprocedural optimization (patient 1, an 85-year old woman) or to treat bleeding episodes (patient 2, an 88-year-old man; and patient 3, a 53-year-old woman). Factor VIII activity was measured via a 1-stage clotting test and von Willebrand factor activity was measured with a ristocetin cofactor assay.
Promising results
All three patients demonstrated increased VWF ristocetin cofactor and factor VIII activities within hours of initiation of the continuous infusion concentrate, according to the report.
“We hypothesize that the efficacy of CI VWF concentrate in aVWD may be related to continuous provision of VWF, allowing binding and neutralization of anti-VWF IgG antibodies, and providing adequate circulating unbound VWF for appropriate hemostatic efficacy,” the researchers concluded.
The authors reported that they had no competing financial interests.
Acquired von Willebrand disease (aVWD) is a rare and serious condition associated with lymphoproliferative disorders, malignancy, autoimmune disorders, and cardiovascular disease. It is most commonly caused by monoclonal gammopathy of undetermined significance (MGUS), which acts to clear von Willebrand factor from the patient’s bloodstream. However, a continuous-infusion of plasma-derived von Willebrand factor (VWF) concentrate provided adequate hemostasis in aVWD resulting from MGUS, according to Kathryn E. Dane, PharmD, of Johns Hopkins University, Baltimore, and colleagues.
The infusion rapidly achieved target ristocetin cofactor activity with or without intravenous immunoglobulin in three patients, as detailed in the report published online in Blood Advances.
The three consecutive patients with aVWD were treated with plasma-derived VWF concentrate administered for periprocedural optimization (patient 1, an 85-year old woman) or to treat bleeding episodes (patient 2, an 88-year-old man; and patient 3, a 53-year-old woman). Factor VIII activity was measured via a 1-stage clotting test and von Willebrand factor activity was measured with a ristocetin cofactor assay.
Promising results
All three patients demonstrated increased VWF ristocetin cofactor and factor VIII activities within hours of initiation of the continuous infusion concentrate, according to the report.
“We hypothesize that the efficacy of CI VWF concentrate in aVWD may be related to continuous provision of VWF, allowing binding and neutralization of anti-VWF IgG antibodies, and providing adequate circulating unbound VWF for appropriate hemostatic efficacy,” the researchers concluded.
The authors reported that they had no competing financial interests.
Acquired von Willebrand disease (aVWD) is a rare and serious condition associated with lymphoproliferative disorders, malignancy, autoimmune disorders, and cardiovascular disease. It is most commonly caused by monoclonal gammopathy of undetermined significance (MGUS), which acts to clear von Willebrand factor from the patient’s bloodstream. However, a continuous-infusion of plasma-derived von Willebrand factor (VWF) concentrate provided adequate hemostasis in aVWD resulting from MGUS, according to Kathryn E. Dane, PharmD, of Johns Hopkins University, Baltimore, and colleagues.
The infusion rapidly achieved target ristocetin cofactor activity with or without intravenous immunoglobulin in three patients, as detailed in the report published online in Blood Advances.
The three consecutive patients with aVWD were treated with plasma-derived VWF concentrate administered for periprocedural optimization (patient 1, an 85-year old woman) or to treat bleeding episodes (patient 2, an 88-year-old man; and patient 3, a 53-year-old woman). Factor VIII activity was measured via a 1-stage clotting test and von Willebrand factor activity was measured with a ristocetin cofactor assay.
Promising results
All three patients demonstrated increased VWF ristocetin cofactor and factor VIII activities within hours of initiation of the continuous infusion concentrate, according to the report.
“We hypothesize that the efficacy of CI VWF concentrate in aVWD may be related to continuous provision of VWF, allowing binding and neutralization of anti-VWF IgG antibodies, and providing adequate circulating unbound VWF for appropriate hemostatic efficacy,” the researchers concluded.
The authors reported that they had no competing financial interests.
FROM BLOOD ADVANCES
Shorter HCC screening intervals benefit high-risk patients
Ultrasonography screening intervals of less than 6-12 months were associated with early detection of hepatocellular carcinoma, as well as increased life expectancy and quality of life, according to data from a nationwide comparative effectiveness study of nearly 60,000 patients in Taiwan.
Many international societies, including the American Association for the Study of Liver Diseases, the Asian Pacific Association for the Study of the Liver, and the European Association for the Study of the Liver, recommend abdominal ultrasonography screening for hepatocellular carcinoma (HCC) with or without alpha-fetoprotein every 6 months for patients at increased risk for HCC, wrote Shih-Chiang Kuo, MD, of National Cheng Kung University, Tainan, Taiwan, and colleagues.
However, some studies do not support this recommendation, and data suggest that “adherence to regular screenings by high-risk patients has been inadequate, leading to reduced overall benefits of ultrasonography screening in real-world practice,” and the impact of screening schedules on quality of life has not been assessed, they said.
In a study published in JAMA Network Open, the researchers identified adults with newly diagnosed HCC from 2002 through 2015 using data from the Taiwan National Cancer Registry. Barcelona Clinic Liver Cancer (BCLC) staging information was available for 42,081 men and 17,113 women; the average age was 62 years for men and 69 years for women. The patients were divided into five cohorts based on the time between their last ultrasonography screening and an index date of 90 days before their HCC diagnosis. These groups were 6 months (0-6 months), 12 months (7-12 months), 24 months (13-24 months), 36 months (25-36 months), and longer than 36 months.
“For both sexes, the proportions of patients with HCC classified as being in earlier stages (stage 0 and A) were higher in subcohorts with shorter screening intervals since the most recent ultrasonography,” the researchers wrote.
The researchers also assessed quality of life measures using the European Quality of Life Five-Dimensions in 807 men (3,370 repeated assessments) and 252 women (1,044 repeated assessments). Among men, the loss of quality of life expectancy in terms of quality of life years (QALYs) was 10.0, 11.1, 12.1, 13.1, and 14.6 for screening intervals of 6 months, 12 months, 24 months, 36 months, and beyond 36 months, respectively. The corresponding QALYs for women at the same screening intervals were 9.0, 9.7, 10.3, 10.7, and 11.4, respectively.
In a subgroup analysis according to underlying liver disease, patients with underlying hepatitis B virus infection or cirrhosis showed the greatest benefits from shorter screening intervals. For those with hepatitis B virus infection, abdominal ultrasonography screening 6 months or less prior to diagnosis of HCC was associated with an additional 4.8 QALYs for men and 2.8 QALYs for women, compared with screening longer than 36 months prior to diagnosis. The corresponding savings in QALY for men and women with underlying cirrhosis was 4.8 QALYs and 2.4 QALYs. Patients with no underlying liver disease also benefited from shorter intervals, with potential savings of 3.2 QALYs for men and 1.6 QALYs for women in the 6-month screening groups, compared with the longer than 36 months groups.
However, less than half of the men overall underwent screening withing 6 months or 12 months before diagnosis (31.4% and 39.3%, respectively); for women, 42.2% received screening within 6 months of diagnosis and 51.9% received screening within 12 months.
The study findings were limited by several factors including the use of only the last screening before diagnosis, which allows the possibility that patients in the 6- or 12-month groups did not have regular screening, the researchers noted. In addition, the lack of data on quality of life for women with BCLC stage D might have caused an underestimation of quality of life loss, they said. However, the results were strengthened by the use of a national database and long follow-up period, they said.
The results support intervals of 6-12 months or less for regular ultrasonography screening as a way to improve early detection of HCC, “and may save lives and improve utility for patients with HCC from a lifetime perspective,” the researchers emphasized. “Because people with underlying risk factors (including hepatitis B virus or hepatitis C virus infection, cirrhosis, and alcoholic liver disease) showed only slightly more frequent ultrasonography screening than those without underlying risk factors, we recommend improving this clinical practice,” they concluded.
Impact of identifying risk
“This study is important because HCC remains the third leading cause of cancer deaths, and the 5-year survival rate is low,” said Atsushi Sakuraba, MD, of the University of Chicago, in an interview.
Dr. Sakuraba said that he was not surprised by any of the study findings. “Earlier diagnosis of cancer is often associated with improved outcome in many cancers,” he noted.
However, “Overutilization of resources may lead to increased health care costs, so correct identification of high-risk populations is needed,” Dr. Sakuraba said.
Additional research is warranted in several areas in order to make an impact on clinical practice, Dr. Sakuraba said, notably, “confirmation in other countries and ethnicities where the incidence of viral hepatitis varies.” Comparison to other tests, such as tumor markers, CT, and MRI, is needed as well, he concluded.
The study was supported by the Taiwan Ministry of Science and Technology. The researchers had no financial conflicts to disclose. Dr. Sakuraba had no financial conflicts to disclose.
Ultrasonography screening intervals of less than 6-12 months were associated with early detection of hepatocellular carcinoma, as well as increased life expectancy and quality of life, according to data from a nationwide comparative effectiveness study of nearly 60,000 patients in Taiwan.
Many international societies, including the American Association for the Study of Liver Diseases, the Asian Pacific Association for the Study of the Liver, and the European Association for the Study of the Liver, recommend abdominal ultrasonography screening for hepatocellular carcinoma (HCC) with or without alpha-fetoprotein every 6 months for patients at increased risk for HCC, wrote Shih-Chiang Kuo, MD, of National Cheng Kung University, Tainan, Taiwan, and colleagues.
However, some studies do not support this recommendation, and data suggest that “adherence to regular screenings by high-risk patients has been inadequate, leading to reduced overall benefits of ultrasonography screening in real-world practice,” and the impact of screening schedules on quality of life has not been assessed, they said.
In a study published in JAMA Network Open, the researchers identified adults with newly diagnosed HCC from 2002 through 2015 using data from the Taiwan National Cancer Registry. Barcelona Clinic Liver Cancer (BCLC) staging information was available for 42,081 men and 17,113 women; the average age was 62 years for men and 69 years for women. The patients were divided into five cohorts based on the time between their last ultrasonography screening and an index date of 90 days before their HCC diagnosis. These groups were 6 months (0-6 months), 12 months (7-12 months), 24 months (13-24 months), 36 months (25-36 months), and longer than 36 months.
“For both sexes, the proportions of patients with HCC classified as being in earlier stages (stage 0 and A) were higher in subcohorts with shorter screening intervals since the most recent ultrasonography,” the researchers wrote.
The researchers also assessed quality of life measures using the European Quality of Life Five-Dimensions in 807 men (3,370 repeated assessments) and 252 women (1,044 repeated assessments). Among men, the loss of quality of life expectancy in terms of quality of life years (QALYs) was 10.0, 11.1, 12.1, 13.1, and 14.6 for screening intervals of 6 months, 12 months, 24 months, 36 months, and beyond 36 months, respectively. The corresponding QALYs for women at the same screening intervals were 9.0, 9.7, 10.3, 10.7, and 11.4, respectively.
In a subgroup analysis according to underlying liver disease, patients with underlying hepatitis B virus infection or cirrhosis showed the greatest benefits from shorter screening intervals. For those with hepatitis B virus infection, abdominal ultrasonography screening 6 months or less prior to diagnosis of HCC was associated with an additional 4.8 QALYs for men and 2.8 QALYs for women, compared with screening longer than 36 months prior to diagnosis. The corresponding savings in QALY for men and women with underlying cirrhosis was 4.8 QALYs and 2.4 QALYs. Patients with no underlying liver disease also benefited from shorter intervals, with potential savings of 3.2 QALYs for men and 1.6 QALYs for women in the 6-month screening groups, compared with the longer than 36 months groups.
However, less than half of the men overall underwent screening withing 6 months or 12 months before diagnosis (31.4% and 39.3%, respectively); for women, 42.2% received screening within 6 months of diagnosis and 51.9% received screening within 12 months.
The study findings were limited by several factors including the use of only the last screening before diagnosis, which allows the possibility that patients in the 6- or 12-month groups did not have regular screening, the researchers noted. In addition, the lack of data on quality of life for women with BCLC stage D might have caused an underestimation of quality of life loss, they said. However, the results were strengthened by the use of a national database and long follow-up period, they said.
The results support intervals of 6-12 months or less for regular ultrasonography screening as a way to improve early detection of HCC, “and may save lives and improve utility for patients with HCC from a lifetime perspective,” the researchers emphasized. “Because people with underlying risk factors (including hepatitis B virus or hepatitis C virus infection, cirrhosis, and alcoholic liver disease) showed only slightly more frequent ultrasonography screening than those without underlying risk factors, we recommend improving this clinical practice,” they concluded.
Impact of identifying risk
“This study is important because HCC remains the third leading cause of cancer deaths, and the 5-year survival rate is low,” said Atsushi Sakuraba, MD, of the University of Chicago, in an interview.
Dr. Sakuraba said that he was not surprised by any of the study findings. “Earlier diagnosis of cancer is often associated with improved outcome in many cancers,” he noted.
However, “Overutilization of resources may lead to increased health care costs, so correct identification of high-risk populations is needed,” Dr. Sakuraba said.
Additional research is warranted in several areas in order to make an impact on clinical practice, Dr. Sakuraba said, notably, “confirmation in other countries and ethnicities where the incidence of viral hepatitis varies.” Comparison to other tests, such as tumor markers, CT, and MRI, is needed as well, he concluded.
The study was supported by the Taiwan Ministry of Science and Technology. The researchers had no financial conflicts to disclose. Dr. Sakuraba had no financial conflicts to disclose.
Ultrasonography screening intervals of less than 6-12 months were associated with early detection of hepatocellular carcinoma, as well as increased life expectancy and quality of life, according to data from a nationwide comparative effectiveness study of nearly 60,000 patients in Taiwan.
Many international societies, including the American Association for the Study of Liver Diseases, the Asian Pacific Association for the Study of the Liver, and the European Association for the Study of the Liver, recommend abdominal ultrasonography screening for hepatocellular carcinoma (HCC) with or without alpha-fetoprotein every 6 months for patients at increased risk for HCC, wrote Shih-Chiang Kuo, MD, of National Cheng Kung University, Tainan, Taiwan, and colleagues.
However, some studies do not support this recommendation, and data suggest that “adherence to regular screenings by high-risk patients has been inadequate, leading to reduced overall benefits of ultrasonography screening in real-world practice,” and the impact of screening schedules on quality of life has not been assessed, they said.
In a study published in JAMA Network Open, the researchers identified adults with newly diagnosed HCC from 2002 through 2015 using data from the Taiwan National Cancer Registry. Barcelona Clinic Liver Cancer (BCLC) staging information was available for 42,081 men and 17,113 women; the average age was 62 years for men and 69 years for women. The patients were divided into five cohorts based on the time between their last ultrasonography screening and an index date of 90 days before their HCC diagnosis. These groups were 6 months (0-6 months), 12 months (7-12 months), 24 months (13-24 months), 36 months (25-36 months), and longer than 36 months.
“For both sexes, the proportions of patients with HCC classified as being in earlier stages (stage 0 and A) were higher in subcohorts with shorter screening intervals since the most recent ultrasonography,” the researchers wrote.
The researchers also assessed quality of life measures using the European Quality of Life Five-Dimensions in 807 men (3,370 repeated assessments) and 252 women (1,044 repeated assessments). Among men, the loss of quality of life expectancy in terms of quality of life years (QALYs) was 10.0, 11.1, 12.1, 13.1, and 14.6 for screening intervals of 6 months, 12 months, 24 months, 36 months, and beyond 36 months, respectively. The corresponding QALYs for women at the same screening intervals were 9.0, 9.7, 10.3, 10.7, and 11.4, respectively.
In a subgroup analysis according to underlying liver disease, patients with underlying hepatitis B virus infection or cirrhosis showed the greatest benefits from shorter screening intervals. For those with hepatitis B virus infection, abdominal ultrasonography screening 6 months or less prior to diagnosis of HCC was associated with an additional 4.8 QALYs for men and 2.8 QALYs for women, compared with screening longer than 36 months prior to diagnosis. The corresponding savings in QALY for men and women with underlying cirrhosis was 4.8 QALYs and 2.4 QALYs. Patients with no underlying liver disease also benefited from shorter intervals, with potential savings of 3.2 QALYs for men and 1.6 QALYs for women in the 6-month screening groups, compared with the longer than 36 months groups.
However, less than half of the men overall underwent screening withing 6 months or 12 months before diagnosis (31.4% and 39.3%, respectively); for women, 42.2% received screening within 6 months of diagnosis and 51.9% received screening within 12 months.
The study findings were limited by several factors including the use of only the last screening before diagnosis, which allows the possibility that patients in the 6- or 12-month groups did not have regular screening, the researchers noted. In addition, the lack of data on quality of life for women with BCLC stage D might have caused an underestimation of quality of life loss, they said. However, the results were strengthened by the use of a national database and long follow-up period, they said.
The results support intervals of 6-12 months or less for regular ultrasonography screening as a way to improve early detection of HCC, “and may save lives and improve utility for patients with HCC from a lifetime perspective,” the researchers emphasized. “Because people with underlying risk factors (including hepatitis B virus or hepatitis C virus infection, cirrhosis, and alcoholic liver disease) showed only slightly more frequent ultrasonography screening than those without underlying risk factors, we recommend improving this clinical practice,” they concluded.
Impact of identifying risk
“This study is important because HCC remains the third leading cause of cancer deaths, and the 5-year survival rate is low,” said Atsushi Sakuraba, MD, of the University of Chicago, in an interview.
Dr. Sakuraba said that he was not surprised by any of the study findings. “Earlier diagnosis of cancer is often associated with improved outcome in many cancers,” he noted.
However, “Overutilization of resources may lead to increased health care costs, so correct identification of high-risk populations is needed,” Dr. Sakuraba said.
Additional research is warranted in several areas in order to make an impact on clinical practice, Dr. Sakuraba said, notably, “confirmation in other countries and ethnicities where the incidence of viral hepatitis varies.” Comparison to other tests, such as tumor markers, CT, and MRI, is needed as well, he concluded.
The study was supported by the Taiwan Ministry of Science and Technology. The researchers had no financial conflicts to disclose. Dr. Sakuraba had no financial conflicts to disclose.
FROM JAMA NETWORK OPEN
One in three cancer articles on social media has wrong info
Of the 200 most popular articles (50 each for prostate, lung, breast, and colorectal cancer), about a third (32.5%, n = 65) contained misinformation.
Among these articles containing misinformation, 76.9% (50/65) contained harmful information.
“The Internet is a leading source of health misinformation,” the study authors wrote. This is “particularly true for social media, where false information spreads faster and more broadly than fact-checked information,” they said, citing other research.
“We need to address these issues head on,” said lead author Skyler Johnson, MD, of the University of Utah’s Huntsman Cancer Institute in Salt Lake City.
“As a medical community, we can’t ignore the problem of cancer misinformation on social media or ask our patients to ignore it. We must empathize with our patients and help them when they encounter this type of information,” he said in a statement. “My goal is to help answer their questions, and provide cancer patients with accurate information that will give them the best chance for the best outcome.”
The study was published online July 22 in the Journal of the National Cancer Institute.
The study period ran from 2018 to 2019, and looked at articles posted on social media platforms Facebook, Reddit, Twitter, or Pinterest. Popularity was measured by engagement with readers, such as upvotes, comments, reactions, and shares.
Some of the articles came from long-established news entities such as CBS News, The New York Times, and medical journals, while others came from fleeting crowdfunding web pages and fledging nontraditional news sites.
One example of popular and harmful misinformation highlighted by Dr. Johnson in an interview was titled, “44-Year-Old Mother Claims CBD Oil Cured Her of Breast Cancer within 5 Months.” Posted on truththeory.com in February 2018, the article is tagged as “opinion” by the publisher and in turn links to another news story about the same woman in the UK’s Daily Mail newspaper.
The ideas and claims in such articles can be very influential, Jennifer L. Lycette, MD, suggested in a recent blog post.
“After 18 years as a cancer doctor, it sadly doesn’t come as a surprise anymore when a patient declines treatment recommendations and instead opts for ‘alternative’ treatment,” she wrote.
Sometimes, misinformation is not sensational but is still effective via clever wording and presentation, observed Brian G. Southwell, PhD, of Duke University, Durham, N.C., who has studied patients and misinformation.
“It isn’t the falsehood that is somehow magically attractive, per se, but the way that misinformation is often framed that can make it attractive,” he said in an interview.
Dr. Southwell recommends that clinicians be proactive about medical misinformation.
“Rather than expect patients to raise concerns without prompting, health care providers should invite conversations about potential misinformation with their patients,” he wrote in a recent essay in the American Journal of Public Health.
In short, ask patients what they know about the treatment of their cancer, he suggests.
“Patients don’t typically know that the misinformation they are encountering is misinformation,” said Dr. Southwell. “Approaching patients with compassion and empathy is a good first step.”
Study details
For the study, reported by Johnson et al., two National Comprehensive Cancer Network panel members were selected as content experts for each of the four cancers and were tasked with reviewing the primary medical claims in each article. The experts then completed a set of ratings to arrive at the proportion of misinformation and potential for harm in each article.
Of the 200 articles, 41.5% were from nontraditional news (digital only), 37.5% were from traditional news sources (online versions of print and/or broadcast media), 17% were from medical journals, 3% were from a crowdfunding site, and 1% were from personal blogs.
This expert review concluded that nearly one-third of the articles contained misinformation, as noted above. The misinformation was described as misleading (title not supported by text or statistics/data do not support conclusion, 28.8%), strength of the evidence mischaracterized (weak evidence portrayed as strong or vice versa, 27.7%) and unproven therapies (not studied or insufficient evidence, 26.7%).
Notably, the median number of engagements, such as likes on Twitter, for articles with misinformation was greater than that of factual articles (median, 2,300 vs. 1,600; P = .05).
In total, 30.5% of all 200 articles contained harmful information. This was described as harmful inaction (could lead to delay or not seeking medical attention for treatable/curable condition, 31.0%), economic harm (out-of-pocket financial costs associated with treatment/travel, 27.7%), harmful action (potentially toxic effects of the suggested test/treatment, 17.0%), and harmful interactions (known/unknown medical interactions with curative therapies, 16.2%).
The median number of engagements for articles with harmful information was statistically significantly greater than that of articles with correct information (median, 2,300 vs. 1,500; P = .007).
A limitation of the study is that it included only the most popular English language cancer articles.
This study was funded in part by the Huntsman Cancer Institute. Dr. Johnson, Dr. Lycette, and Dr. Southwell have disclosed no relevant financial relationships. Some study authors have ties to the pharmaceutical industry.
A version of this article first appeared on Medscape.com.
Of the 200 most popular articles (50 each for prostate, lung, breast, and colorectal cancer), about a third (32.5%, n = 65) contained misinformation.
Among these articles containing misinformation, 76.9% (50/65) contained harmful information.
“The Internet is a leading source of health misinformation,” the study authors wrote. This is “particularly true for social media, where false information spreads faster and more broadly than fact-checked information,” they said, citing other research.
“We need to address these issues head on,” said lead author Skyler Johnson, MD, of the University of Utah’s Huntsman Cancer Institute in Salt Lake City.
“As a medical community, we can’t ignore the problem of cancer misinformation on social media or ask our patients to ignore it. We must empathize with our patients and help them when they encounter this type of information,” he said in a statement. “My goal is to help answer their questions, and provide cancer patients with accurate information that will give them the best chance for the best outcome.”
The study was published online July 22 in the Journal of the National Cancer Institute.
The study period ran from 2018 to 2019, and looked at articles posted on social media platforms Facebook, Reddit, Twitter, or Pinterest. Popularity was measured by engagement with readers, such as upvotes, comments, reactions, and shares.
Some of the articles came from long-established news entities such as CBS News, The New York Times, and medical journals, while others came from fleeting crowdfunding web pages and fledging nontraditional news sites.
One example of popular and harmful misinformation highlighted by Dr. Johnson in an interview was titled, “44-Year-Old Mother Claims CBD Oil Cured Her of Breast Cancer within 5 Months.” Posted on truththeory.com in February 2018, the article is tagged as “opinion” by the publisher and in turn links to another news story about the same woman in the UK’s Daily Mail newspaper.
The ideas and claims in such articles can be very influential, Jennifer L. Lycette, MD, suggested in a recent blog post.
“After 18 years as a cancer doctor, it sadly doesn’t come as a surprise anymore when a patient declines treatment recommendations and instead opts for ‘alternative’ treatment,” she wrote.
Sometimes, misinformation is not sensational but is still effective via clever wording and presentation, observed Brian G. Southwell, PhD, of Duke University, Durham, N.C., who has studied patients and misinformation.
“It isn’t the falsehood that is somehow magically attractive, per se, but the way that misinformation is often framed that can make it attractive,” he said in an interview.
Dr. Southwell recommends that clinicians be proactive about medical misinformation.
“Rather than expect patients to raise concerns without prompting, health care providers should invite conversations about potential misinformation with their patients,” he wrote in a recent essay in the American Journal of Public Health.
In short, ask patients what they know about the treatment of their cancer, he suggests.
“Patients don’t typically know that the misinformation they are encountering is misinformation,” said Dr. Southwell. “Approaching patients with compassion and empathy is a good first step.”
Study details
For the study, reported by Johnson et al., two National Comprehensive Cancer Network panel members were selected as content experts for each of the four cancers and were tasked with reviewing the primary medical claims in each article. The experts then completed a set of ratings to arrive at the proportion of misinformation and potential for harm in each article.
Of the 200 articles, 41.5% were from nontraditional news (digital only), 37.5% were from traditional news sources (online versions of print and/or broadcast media), 17% were from medical journals, 3% were from a crowdfunding site, and 1% were from personal blogs.
This expert review concluded that nearly one-third of the articles contained misinformation, as noted above. The misinformation was described as misleading (title not supported by text or statistics/data do not support conclusion, 28.8%), strength of the evidence mischaracterized (weak evidence portrayed as strong or vice versa, 27.7%) and unproven therapies (not studied or insufficient evidence, 26.7%).
Notably, the median number of engagements, such as likes on Twitter, for articles with misinformation was greater than that of factual articles (median, 2,300 vs. 1,600; P = .05).
In total, 30.5% of all 200 articles contained harmful information. This was described as harmful inaction (could lead to delay or not seeking medical attention for treatable/curable condition, 31.0%), economic harm (out-of-pocket financial costs associated with treatment/travel, 27.7%), harmful action (potentially toxic effects of the suggested test/treatment, 17.0%), and harmful interactions (known/unknown medical interactions with curative therapies, 16.2%).
The median number of engagements for articles with harmful information was statistically significantly greater than that of articles with correct information (median, 2,300 vs. 1,500; P = .007).
A limitation of the study is that it included only the most popular English language cancer articles.
This study was funded in part by the Huntsman Cancer Institute. Dr. Johnson, Dr. Lycette, and Dr. Southwell have disclosed no relevant financial relationships. Some study authors have ties to the pharmaceutical industry.
A version of this article first appeared on Medscape.com.
Of the 200 most popular articles (50 each for prostate, lung, breast, and colorectal cancer), about a third (32.5%, n = 65) contained misinformation.
Among these articles containing misinformation, 76.9% (50/65) contained harmful information.
“The Internet is a leading source of health misinformation,” the study authors wrote. This is “particularly true for social media, where false information spreads faster and more broadly than fact-checked information,” they said, citing other research.
“We need to address these issues head on,” said lead author Skyler Johnson, MD, of the University of Utah’s Huntsman Cancer Institute in Salt Lake City.
“As a medical community, we can’t ignore the problem of cancer misinformation on social media or ask our patients to ignore it. We must empathize with our patients and help them when they encounter this type of information,” he said in a statement. “My goal is to help answer their questions, and provide cancer patients with accurate information that will give them the best chance for the best outcome.”
The study was published online July 22 in the Journal of the National Cancer Institute.
The study period ran from 2018 to 2019, and looked at articles posted on social media platforms Facebook, Reddit, Twitter, or Pinterest. Popularity was measured by engagement with readers, such as upvotes, comments, reactions, and shares.
Some of the articles came from long-established news entities such as CBS News, The New York Times, and medical journals, while others came from fleeting crowdfunding web pages and fledging nontraditional news sites.
One example of popular and harmful misinformation highlighted by Dr. Johnson in an interview was titled, “44-Year-Old Mother Claims CBD Oil Cured Her of Breast Cancer within 5 Months.” Posted on truththeory.com in February 2018, the article is tagged as “opinion” by the publisher and in turn links to another news story about the same woman in the UK’s Daily Mail newspaper.
The ideas and claims in such articles can be very influential, Jennifer L. Lycette, MD, suggested in a recent blog post.
“After 18 years as a cancer doctor, it sadly doesn’t come as a surprise anymore when a patient declines treatment recommendations and instead opts for ‘alternative’ treatment,” she wrote.
Sometimes, misinformation is not sensational but is still effective via clever wording and presentation, observed Brian G. Southwell, PhD, of Duke University, Durham, N.C., who has studied patients and misinformation.
“It isn’t the falsehood that is somehow magically attractive, per se, but the way that misinformation is often framed that can make it attractive,” he said in an interview.
Dr. Southwell recommends that clinicians be proactive about medical misinformation.
“Rather than expect patients to raise concerns without prompting, health care providers should invite conversations about potential misinformation with their patients,” he wrote in a recent essay in the American Journal of Public Health.
In short, ask patients what they know about the treatment of their cancer, he suggests.
“Patients don’t typically know that the misinformation they are encountering is misinformation,” said Dr. Southwell. “Approaching patients with compassion and empathy is a good first step.”
Study details
For the study, reported by Johnson et al., two National Comprehensive Cancer Network panel members were selected as content experts for each of the four cancers and were tasked with reviewing the primary medical claims in each article. The experts then completed a set of ratings to arrive at the proportion of misinformation and potential for harm in each article.
Of the 200 articles, 41.5% were from nontraditional news (digital only), 37.5% were from traditional news sources (online versions of print and/or broadcast media), 17% were from medical journals, 3% were from a crowdfunding site, and 1% were from personal blogs.
This expert review concluded that nearly one-third of the articles contained misinformation, as noted above. The misinformation was described as misleading (title not supported by text or statistics/data do not support conclusion, 28.8%), strength of the evidence mischaracterized (weak evidence portrayed as strong or vice versa, 27.7%) and unproven therapies (not studied or insufficient evidence, 26.7%).
Notably, the median number of engagements, such as likes on Twitter, for articles with misinformation was greater than that of factual articles (median, 2,300 vs. 1,600; P = .05).
In total, 30.5% of all 200 articles contained harmful information. This was described as harmful inaction (could lead to delay or not seeking medical attention for treatable/curable condition, 31.0%), economic harm (out-of-pocket financial costs associated with treatment/travel, 27.7%), harmful action (potentially toxic effects of the suggested test/treatment, 17.0%), and harmful interactions (known/unknown medical interactions with curative therapies, 16.2%).
The median number of engagements for articles with harmful information was statistically significantly greater than that of articles with correct information (median, 2,300 vs. 1,500; P = .007).
A limitation of the study is that it included only the most popular English language cancer articles.
This study was funded in part by the Huntsman Cancer Institute. Dr. Johnson, Dr. Lycette, and Dr. Southwell have disclosed no relevant financial relationships. Some study authors have ties to the pharmaceutical industry.
A version of this article first appeared on Medscape.com.
Bone drugs for prostate cancer may result in survival benefit
Results from a retrospective study show that the addition of bone resorption inhibitors (BRIs), including zoledronic acid and denosumab (Xgeva), to abiraterone plus prednisolone was associated with significantly longer overall survival (OS). The median OS was increased by nearly 9 months among recipients, compared with men who didn’t receive these drugs in this setting.
The findings were published online July 22, 2021, in JAMA Network Open.
All men with prostate cancer should receive BRIs “as the disease reaches the castration resistance with bone metastases stage, as recommended by the international guidelines,” lead author Edoardo Francini, MD, PhD, of the University of Florence (Italy) said in a comment.
While there is no evidence that BRIs – when used alone – may improve survival in metastatic castration-resistant prostate cancer (mCRPC) with bone involvement, there has been a “suggestion” of a survival benefit with BRIs when combined with other anticancer therapies in this setting, say the authors.
So Dr. Francini and a team of international coinvestigators looked at the medical records of men with mCRPC and bone metastases treated at eight institutions in Canada, Europe, and the United States and focused on patients who received abiraterone acetate (with prednisone) because it is the most common first-line therapy in this setting.
Patients were classified by receipt versus nonreceipt of concomitant BRIs and subclassified by volume of disease (high or low volume).
There were two cohorts in the study population: 529 men (71.0%) who received abiraterone alone and 216 men (29.0%) who received abiraterone plus BRIs. The median follow-up was 23.5 months.
Patients in the BRI cohort experienced significantly longer OS compared with those in the abiraterone alone cohort (31.8 vs. 23.0 months; hazard ratio, 0.65; P < .001).
Notably, the OS benefit in the BRI cohort was greater for patients with high-volume versus low-volume disease (33.6 vs. 19.7 months; HR, 0.51; P < .001).
Dr. Francini hopes the new study results can effect change. “Hopefully, clinicians will be more inclined to use bone resorption inhibitors in combination with abiraterone acetate plus prednisone as soon as the disease reaches the castration-resistance with bone metastases stage, as recommended by the international guidelines.”
Importance of bone-targeted drugs
“This study highlights the importance of bone-targeted therapy in current practice for men with mCRPC and bone metastases,” Samuel Takvorian, MD, and Naomi Haas, MD, of the University of Pennsylvania, Philadelphia, wrote in an accompanying editorial.
But the study also reveals that work needs to be done to get clinicians to prescribe BRIs, they said, and that clinical pathways and behavioral “nudges” could help promote adoption.
Most (71%) of the men in this study did not get bone protective drug therapy, they pointed out, even though they were being treated at major hospital systems.
So, why aren’t more men receiving BRIs?
“I think this is less likely due to poor communication from professional societies (the guidelines are clear) and more likely due to bone health being low on the list of priorities for these patients and clinician uncertainty and/or lack of appreciation of the clinical benefit of these agents,” Dr. Takvorian said in an interview.
“When prostate cancer progresses to the castration-resistant phase, clinicians (and patients) rightfully are focused on the next cancer-directed therapy. However, this may be at the expense of supportive care, like bone agents, which often gets short shrift,” he added.
As would be expected, the men who were taking BRIs had a significantly shorter time to first skeletal-related events (SREs), compared with those who were not (32.4 vs. 42.7 months; HR, 1.27; P = .04), and the risk of a first SRE was more than double in the subgroup with low-volume disease (HR, 2.29; P < .001).
“These SREs collectively represent a clinically meaningful outcome that is often measured in clinical trials,” the editorialists observed. In the current study, SREs were comprised of pathological fractures, spinal cord compression, or the need for surgery or radiotherapy to bone.
“Up to one-half of men with mCRPC, the advanced and often fatal stage of disease, experience SREs, which are associated with considerable morbidity, decreased survival, and increased health care utilization and costs,” they wrote.
Costly vs. inexpensive BRI
The study found no difference in the OS benefit between the different BRIs used, that is, between that seen with zoledronic acid versus denosumab.
The editorialists suggested that this finding is important, even though it “must be considered preliminary given the limitations of a retrospective study.” These results add “to data suggesting that these agents are comparably beneficial; thus, decisions between them should focus on clinical factors, such as kidney function, patient preference, and cost.”
The two agents differ mechanistically, they added, with zoledronic acid preferentially inhibiting osteoclast proliferation and denosumab inhibiting an important factor in osteoclast maturation.
In terms of having differentiating characteristics, the editorialists say that zoledronic acid is “more often associated with acute phase reactions and required monitoring of kidney function” while “denosumab conferred a higher risk of hypocalcemia.” Rates of osteonecrosis of the jaw are comparable.
International guidelines endorse the use of either agent for the treatment of men with mCRPC. But “some argue that the marginal benefit of denosumab must be weighed against its dramatically higher cost (the annual cost of zoledronic acid is approximately $140 vs. $29,000 for denosumab),” the editorialists said.
The dramatically higher cost of denosumab versus zoledronic acid has also been noted by other oncologists treating patients with other cancers, including multiple myeloma.
In addition to drug costs, there is another issue at stake: the prescribing oncologist is reimbursed by Medicare Part D at 6% for whichever drug is chosen, which represents a “financial conflict” for oncologists, said Vincent Rajkumar, MD, professor of medicine and a hematologist/oncologist at the Mayo Clinic, Rochester, Minn.
There is also a difference in how the drugs are administered, which may influence patient preference, the myeloma experts noted. Zoledronic acid is given intravenously every 3 months and requires a 15-minute infusion at a center, while denosumab needs to be given more frequently (every month) but is administered by subcutaneous injection.
Dr. Francini reported receiving grants from Roche Italia and personal fees for research travel from Janssen-Cilag outside the submitted work. A number of other authors disclosed financial ties to Janssen or Amgen, makers of abiraterone and denosumab, respectively. The editorialists reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Results from a retrospective study show that the addition of bone resorption inhibitors (BRIs), including zoledronic acid and denosumab (Xgeva), to abiraterone plus prednisolone was associated with significantly longer overall survival (OS). The median OS was increased by nearly 9 months among recipients, compared with men who didn’t receive these drugs in this setting.
The findings were published online July 22, 2021, in JAMA Network Open.
All men with prostate cancer should receive BRIs “as the disease reaches the castration resistance with bone metastases stage, as recommended by the international guidelines,” lead author Edoardo Francini, MD, PhD, of the University of Florence (Italy) said in a comment.
While there is no evidence that BRIs – when used alone – may improve survival in metastatic castration-resistant prostate cancer (mCRPC) with bone involvement, there has been a “suggestion” of a survival benefit with BRIs when combined with other anticancer therapies in this setting, say the authors.
So Dr. Francini and a team of international coinvestigators looked at the medical records of men with mCRPC and bone metastases treated at eight institutions in Canada, Europe, and the United States and focused on patients who received abiraterone acetate (with prednisone) because it is the most common first-line therapy in this setting.
Patients were classified by receipt versus nonreceipt of concomitant BRIs and subclassified by volume of disease (high or low volume).
There were two cohorts in the study population: 529 men (71.0%) who received abiraterone alone and 216 men (29.0%) who received abiraterone plus BRIs. The median follow-up was 23.5 months.
Patients in the BRI cohort experienced significantly longer OS compared with those in the abiraterone alone cohort (31.8 vs. 23.0 months; hazard ratio, 0.65; P < .001).
Notably, the OS benefit in the BRI cohort was greater for patients with high-volume versus low-volume disease (33.6 vs. 19.7 months; HR, 0.51; P < .001).
Dr. Francini hopes the new study results can effect change. “Hopefully, clinicians will be more inclined to use bone resorption inhibitors in combination with abiraterone acetate plus prednisone as soon as the disease reaches the castration-resistance with bone metastases stage, as recommended by the international guidelines.”
Importance of bone-targeted drugs
“This study highlights the importance of bone-targeted therapy in current practice for men with mCRPC and bone metastases,” Samuel Takvorian, MD, and Naomi Haas, MD, of the University of Pennsylvania, Philadelphia, wrote in an accompanying editorial.
But the study also reveals that work needs to be done to get clinicians to prescribe BRIs, they said, and that clinical pathways and behavioral “nudges” could help promote adoption.
Most (71%) of the men in this study did not get bone protective drug therapy, they pointed out, even though they were being treated at major hospital systems.
So, why aren’t more men receiving BRIs?
“I think this is less likely due to poor communication from professional societies (the guidelines are clear) and more likely due to bone health being low on the list of priorities for these patients and clinician uncertainty and/or lack of appreciation of the clinical benefit of these agents,” Dr. Takvorian said in an interview.
“When prostate cancer progresses to the castration-resistant phase, clinicians (and patients) rightfully are focused on the next cancer-directed therapy. However, this may be at the expense of supportive care, like bone agents, which often gets short shrift,” he added.
As would be expected, the men who were taking BRIs had a significantly shorter time to first skeletal-related events (SREs), compared with those who were not (32.4 vs. 42.7 months; HR, 1.27; P = .04), and the risk of a first SRE was more than double in the subgroup with low-volume disease (HR, 2.29; P < .001).
“These SREs collectively represent a clinically meaningful outcome that is often measured in clinical trials,” the editorialists observed. In the current study, SREs were comprised of pathological fractures, spinal cord compression, or the need for surgery or radiotherapy to bone.
“Up to one-half of men with mCRPC, the advanced and often fatal stage of disease, experience SREs, which are associated with considerable morbidity, decreased survival, and increased health care utilization and costs,” they wrote.
Costly vs. inexpensive BRI
The study found no difference in the OS benefit between the different BRIs used, that is, between that seen with zoledronic acid versus denosumab.
The editorialists suggested that this finding is important, even though it “must be considered preliminary given the limitations of a retrospective study.” These results add “to data suggesting that these agents are comparably beneficial; thus, decisions between them should focus on clinical factors, such as kidney function, patient preference, and cost.”
The two agents differ mechanistically, they added, with zoledronic acid preferentially inhibiting osteoclast proliferation and denosumab inhibiting an important factor in osteoclast maturation.
In terms of having differentiating characteristics, the editorialists say that zoledronic acid is “more often associated with acute phase reactions and required monitoring of kidney function” while “denosumab conferred a higher risk of hypocalcemia.” Rates of osteonecrosis of the jaw are comparable.
International guidelines endorse the use of either agent for the treatment of men with mCRPC. But “some argue that the marginal benefit of denosumab must be weighed against its dramatically higher cost (the annual cost of zoledronic acid is approximately $140 vs. $29,000 for denosumab),” the editorialists said.
The dramatically higher cost of denosumab versus zoledronic acid has also been noted by other oncologists treating patients with other cancers, including multiple myeloma.
In addition to drug costs, there is another issue at stake: the prescribing oncologist is reimbursed by Medicare Part D at 6% for whichever drug is chosen, which represents a “financial conflict” for oncologists, said Vincent Rajkumar, MD, professor of medicine and a hematologist/oncologist at the Mayo Clinic, Rochester, Minn.
There is also a difference in how the drugs are administered, which may influence patient preference, the myeloma experts noted. Zoledronic acid is given intravenously every 3 months and requires a 15-minute infusion at a center, while denosumab needs to be given more frequently (every month) but is administered by subcutaneous injection.
Dr. Francini reported receiving grants from Roche Italia and personal fees for research travel from Janssen-Cilag outside the submitted work. A number of other authors disclosed financial ties to Janssen or Amgen, makers of abiraterone and denosumab, respectively. The editorialists reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Results from a retrospective study show that the addition of bone resorption inhibitors (BRIs), including zoledronic acid and denosumab (Xgeva), to abiraterone plus prednisolone was associated with significantly longer overall survival (OS). The median OS was increased by nearly 9 months among recipients, compared with men who didn’t receive these drugs in this setting.
The findings were published online July 22, 2021, in JAMA Network Open.
All men with prostate cancer should receive BRIs “as the disease reaches the castration resistance with bone metastases stage, as recommended by the international guidelines,” lead author Edoardo Francini, MD, PhD, of the University of Florence (Italy) said in a comment.
While there is no evidence that BRIs – when used alone – may improve survival in metastatic castration-resistant prostate cancer (mCRPC) with bone involvement, there has been a “suggestion” of a survival benefit with BRIs when combined with other anticancer therapies in this setting, say the authors.
So Dr. Francini and a team of international coinvestigators looked at the medical records of men with mCRPC and bone metastases treated at eight institutions in Canada, Europe, and the United States and focused on patients who received abiraterone acetate (with prednisone) because it is the most common first-line therapy in this setting.
Patients were classified by receipt versus nonreceipt of concomitant BRIs and subclassified by volume of disease (high or low volume).
There were two cohorts in the study population: 529 men (71.0%) who received abiraterone alone and 216 men (29.0%) who received abiraterone plus BRIs. The median follow-up was 23.5 months.
Patients in the BRI cohort experienced significantly longer OS compared with those in the abiraterone alone cohort (31.8 vs. 23.0 months; hazard ratio, 0.65; P < .001).
Notably, the OS benefit in the BRI cohort was greater for patients with high-volume versus low-volume disease (33.6 vs. 19.7 months; HR, 0.51; P < .001).
Dr. Francini hopes the new study results can effect change. “Hopefully, clinicians will be more inclined to use bone resorption inhibitors in combination with abiraterone acetate plus prednisone as soon as the disease reaches the castration-resistance with bone metastases stage, as recommended by the international guidelines.”
Importance of bone-targeted drugs
“This study highlights the importance of bone-targeted therapy in current practice for men with mCRPC and bone metastases,” Samuel Takvorian, MD, and Naomi Haas, MD, of the University of Pennsylvania, Philadelphia, wrote in an accompanying editorial.
But the study also reveals that work needs to be done to get clinicians to prescribe BRIs, they said, and that clinical pathways and behavioral “nudges” could help promote adoption.
Most (71%) of the men in this study did not get bone protective drug therapy, they pointed out, even though they were being treated at major hospital systems.
So, why aren’t more men receiving BRIs?
“I think this is less likely due to poor communication from professional societies (the guidelines are clear) and more likely due to bone health being low on the list of priorities for these patients and clinician uncertainty and/or lack of appreciation of the clinical benefit of these agents,” Dr. Takvorian said in an interview.
“When prostate cancer progresses to the castration-resistant phase, clinicians (and patients) rightfully are focused on the next cancer-directed therapy. However, this may be at the expense of supportive care, like bone agents, which often gets short shrift,” he added.
As would be expected, the men who were taking BRIs had a significantly shorter time to first skeletal-related events (SREs), compared with those who were not (32.4 vs. 42.7 months; HR, 1.27; P = .04), and the risk of a first SRE was more than double in the subgroup with low-volume disease (HR, 2.29; P < .001).
“These SREs collectively represent a clinically meaningful outcome that is often measured in clinical trials,” the editorialists observed. In the current study, SREs were comprised of pathological fractures, spinal cord compression, or the need for surgery or radiotherapy to bone.
“Up to one-half of men with mCRPC, the advanced and often fatal stage of disease, experience SREs, which are associated with considerable morbidity, decreased survival, and increased health care utilization and costs,” they wrote.
Costly vs. inexpensive BRI
The study found no difference in the OS benefit between the different BRIs used, that is, between that seen with zoledronic acid versus denosumab.
The editorialists suggested that this finding is important, even though it “must be considered preliminary given the limitations of a retrospective study.” These results add “to data suggesting that these agents are comparably beneficial; thus, decisions between them should focus on clinical factors, such as kidney function, patient preference, and cost.”
The two agents differ mechanistically, they added, with zoledronic acid preferentially inhibiting osteoclast proliferation and denosumab inhibiting an important factor in osteoclast maturation.
In terms of having differentiating characteristics, the editorialists say that zoledronic acid is “more often associated with acute phase reactions and required monitoring of kidney function” while “denosumab conferred a higher risk of hypocalcemia.” Rates of osteonecrosis of the jaw are comparable.
International guidelines endorse the use of either agent for the treatment of men with mCRPC. But “some argue that the marginal benefit of denosumab must be weighed against its dramatically higher cost (the annual cost of zoledronic acid is approximately $140 vs. $29,000 for denosumab),” the editorialists said.
The dramatically higher cost of denosumab versus zoledronic acid has also been noted by other oncologists treating patients with other cancers, including multiple myeloma.
In addition to drug costs, there is another issue at stake: the prescribing oncologist is reimbursed by Medicare Part D at 6% for whichever drug is chosen, which represents a “financial conflict” for oncologists, said Vincent Rajkumar, MD, professor of medicine and a hematologist/oncologist at the Mayo Clinic, Rochester, Minn.
There is also a difference in how the drugs are administered, which may influence patient preference, the myeloma experts noted. Zoledronic acid is given intravenously every 3 months and requires a 15-minute infusion at a center, while denosumab needs to be given more frequently (every month) but is administered by subcutaneous injection.
Dr. Francini reported receiving grants from Roche Italia and personal fees for research travel from Janssen-Cilag outside the submitted work. A number of other authors disclosed financial ties to Janssen or Amgen, makers of abiraterone and denosumab, respectively. The editorialists reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
CDC to show vaccinated people infected with Delta remain contagious
and infect others, the New York Times reported on July 29.
The revelation is one reason the agency reversed course this week and said fully vaccinated people should go back to wearing masks in many cases.
The new findings also are a reversal from what scientists had believed to be true about other variants of the virus, the New York Times said. The bottom line is that the CDC data shows people with so-called breakthrough cases of the Delta variant may be just as contagious as unvaccinated people, even if they do not show symptoms.
ABC News reported earlier on Jul 29 that the CDC’s updated mask guidance followed an outbreak on Cape Cod, where crowds gathered for the Fourth of July.
As of July 29, 882 people were tied to the outbreak centered in Provincetown, Mass. Of those who live in Massachusetts, 74% were unvaccinated. ABC said the majority were showing symptoms of COVID-19.
A version of this article first appeared on Medscape.com.
and infect others, the New York Times reported on July 29.
The revelation is one reason the agency reversed course this week and said fully vaccinated people should go back to wearing masks in many cases.
The new findings also are a reversal from what scientists had believed to be true about other variants of the virus, the New York Times said. The bottom line is that the CDC data shows people with so-called breakthrough cases of the Delta variant may be just as contagious as unvaccinated people, even if they do not show symptoms.
ABC News reported earlier on Jul 29 that the CDC’s updated mask guidance followed an outbreak on Cape Cod, where crowds gathered for the Fourth of July.
As of July 29, 882 people were tied to the outbreak centered in Provincetown, Mass. Of those who live in Massachusetts, 74% were unvaccinated. ABC said the majority were showing symptoms of COVID-19.
A version of this article first appeared on Medscape.com.
and infect others, the New York Times reported on July 29.
The revelation is one reason the agency reversed course this week and said fully vaccinated people should go back to wearing masks in many cases.
The new findings also are a reversal from what scientists had believed to be true about other variants of the virus, the New York Times said. The bottom line is that the CDC data shows people with so-called breakthrough cases of the Delta variant may be just as contagious as unvaccinated people, even if they do not show symptoms.
ABC News reported earlier on Jul 29 that the CDC’s updated mask guidance followed an outbreak on Cape Cod, where crowds gathered for the Fourth of July.
As of July 29, 882 people were tied to the outbreak centered in Provincetown, Mass. Of those who live in Massachusetts, 74% were unvaccinated. ABC said the majority were showing symptoms of COVID-19.
A version of this article first appeared on Medscape.com.
Short sleep is linked to future dementia
, according to a new analysis of data from the Whitehall II cohort study.
Previous work had identified links between short sleep duration and dementia risk, but few studies examined sleep habits long before onset of dementia. Those that did produced inconsistent results, according to Séverine Sabia, PhD, who is a research associate at Inserm (France) and the University College London.
“One potential reason for these inconstancies is the large range of ages of the study populations, and the small number of participants within each sleep duration group. The novelty of our study is to examine this association among almost 8,000 participants with a follow-up of 30 years, using repeated measures of sleep duration starting in midlife to consider sleep duration at specific ages,” Dr. Sabia said in an interview. She presented the research at the 2021 Alzheimer’s Association International Conference.
Those previous studies found a U-shaped association between sleep duration and dementia risk, with lowest risk associated with 7-8 hours of sleep, but greater risk for shorter and longer durations. However, because the studies had follow-up periods shorter than 10 years, they are at greater risk of reverse causation bias. Longer follow-up studies tended to have small sample sizes or to focus on older adults.
The longer follow-up in the current study makes for a more compelling case, said Claire Sexton, DPhil, director of Scientific Programs & Outreach for the Alzheimer’s Association. Observations of short or long sleep closer to the onset of symptoms could just be a warning sign of dementia. “But looking at age 50, age 60 ... if you’re seeing those relationships, then it’s less likely that it is just purely prodromal,” said Dr. Sexton. But it still doesn’t necessarily confirm causation. “It could also be a risk factor,” Dr. Sexton added.
Multifactorial risk
Dr. Sabia also noted that the magnitude of risk was similar to that seen with smoking or obesity, and many factors play a role in dementia risk. “Even if the risk of dementia was 30% higher in those with persistent short sleep duration, in absolute terms, the percentage of those with persistent short duration who developed dementia was 8%, and 6% in those with persistent sleep duration of 7 hours. Dementia is a multifactorial disease, which means that several factors are likely to influence its onset. Sleep duration is one of them, but if a person has poor sleep and does not manage to increase it, there are other important prevention measures. It is important to keep a healthy lifestyle and cardiometabolic measures in the normal range. All together it is likely to be beneficial for brain health in later life,” she said.
Dr. Sexton agreed. “With sleep we’re still trying to tease apart what aspect of sleep is important. Is it the sleep duration? Is it the quality of sleep? Is it certain sleep stages?” she said.
Regardless of sleep’s potential influence on dementia risk, both Dr. Sexton and Dr. Sabia noted the importance of sleep for general health. “These types of problems are very prevalent, so it’s good for people to be aware of them. And then if they notice any problems with their sleep, or any changes, to go and see their health care provider, and to be discussing them, and then to be investigating the cause, and to see whether changes in sleep hygiene and treatments for insomnia could address these sleep problems,” said Dr. Sexton.
Decades of data
During the Whitehall II study, researchers assessed average sleep duration (“How many hours of sleep do you have on an average weeknight?”) six times over 30 years of follow-up. Dr. Sabia’s group extracted self-reported sleep duration data at ages 50, 60, and 70. Short sleep duration was defined as fewer than 5 hours, or 6 hours. Normal sleep duration was defined as 7 hours. Long duration was defined as 8 hours or more.
A questioner during the Q&A period noted that this grouping is a little unusual. Many studies define 7-8 hours as normal. Dr. Sabia answered that they were unable to examine periods of 9 hours or more due to the nature of the data, and the lowest associated risk was found at 7 hours.
The researchers analyzed data from 7,959 participants (33.0% women). At age 50, compared with 7 hours of sleep, 6 or few hours of sleep was associated with a higher risk of dementia over the ensuing 25 years of follow-up (hazard ratio [HR], 1.22; 95% confidence interval [CI], 1.01-1.48). The same was true at age 60 (15 years of follow-up HR, 1.37; 95% CI, 1.10-1.72). There was a trend at age 70 (8 years follow-up; HR, 1.24; 95% CI, 0.98-1.57). For 8 or more hours of sleep, there were trends toward increased risk at age 50 (HR, 1.25; 95% CI, 0.98-1.60). Long sleep at age 60 and 70 was associated with heightened risk, but the confidence intervals were well outside statistical significance.
Twenty percent of participants had persistent short sleep over the course of follow-up, 37% had persistent normal sleep, and 7% had persistent long sleep. Seven percent of participants experienced a change from normal sleep to short sleep, 16% had a change from short sleep to normal sleep, and 13% had a change from normal sleep to long sleep.
Persistent short sleep between age 50 and 70 was associated with a 30% increased risk of dementia (HR, 1.30; 95% CI, 1.00-1.69). There were no statistically significant associations between dementia risk and any of the changing sleep pattern groups.
Dr. Sabia and Dr. Sexton have no relevant financial disclosures.
, according to a new analysis of data from the Whitehall II cohort study.
Previous work had identified links between short sleep duration and dementia risk, but few studies examined sleep habits long before onset of dementia. Those that did produced inconsistent results, according to Séverine Sabia, PhD, who is a research associate at Inserm (France) and the University College London.
“One potential reason for these inconstancies is the large range of ages of the study populations, and the small number of participants within each sleep duration group. The novelty of our study is to examine this association among almost 8,000 participants with a follow-up of 30 years, using repeated measures of sleep duration starting in midlife to consider sleep duration at specific ages,” Dr. Sabia said in an interview. She presented the research at the 2021 Alzheimer’s Association International Conference.
Those previous studies found a U-shaped association between sleep duration and dementia risk, with lowest risk associated with 7-8 hours of sleep, but greater risk for shorter and longer durations. However, because the studies had follow-up periods shorter than 10 years, they are at greater risk of reverse causation bias. Longer follow-up studies tended to have small sample sizes or to focus on older adults.
The longer follow-up in the current study makes for a more compelling case, said Claire Sexton, DPhil, director of Scientific Programs & Outreach for the Alzheimer’s Association. Observations of short or long sleep closer to the onset of symptoms could just be a warning sign of dementia. “But looking at age 50, age 60 ... if you’re seeing those relationships, then it’s less likely that it is just purely prodromal,” said Dr. Sexton. But it still doesn’t necessarily confirm causation. “It could also be a risk factor,” Dr. Sexton added.
Multifactorial risk
Dr. Sabia also noted that the magnitude of risk was similar to that seen with smoking or obesity, and many factors play a role in dementia risk. “Even if the risk of dementia was 30% higher in those with persistent short sleep duration, in absolute terms, the percentage of those with persistent short duration who developed dementia was 8%, and 6% in those with persistent sleep duration of 7 hours. Dementia is a multifactorial disease, which means that several factors are likely to influence its onset. Sleep duration is one of them, but if a person has poor sleep and does not manage to increase it, there are other important prevention measures. It is important to keep a healthy lifestyle and cardiometabolic measures in the normal range. All together it is likely to be beneficial for brain health in later life,” she said.
Dr. Sexton agreed. “With sleep we’re still trying to tease apart what aspect of sleep is important. Is it the sleep duration? Is it the quality of sleep? Is it certain sleep stages?” she said.
Regardless of sleep’s potential influence on dementia risk, both Dr. Sexton and Dr. Sabia noted the importance of sleep for general health. “These types of problems are very prevalent, so it’s good for people to be aware of them. And then if they notice any problems with their sleep, or any changes, to go and see their health care provider, and to be discussing them, and then to be investigating the cause, and to see whether changes in sleep hygiene and treatments for insomnia could address these sleep problems,” said Dr. Sexton.
Decades of data
During the Whitehall II study, researchers assessed average sleep duration (“How many hours of sleep do you have on an average weeknight?”) six times over 30 years of follow-up. Dr. Sabia’s group extracted self-reported sleep duration data at ages 50, 60, and 70. Short sleep duration was defined as fewer than 5 hours, or 6 hours. Normal sleep duration was defined as 7 hours. Long duration was defined as 8 hours or more.
A questioner during the Q&A period noted that this grouping is a little unusual. Many studies define 7-8 hours as normal. Dr. Sabia answered that they were unable to examine periods of 9 hours or more due to the nature of the data, and the lowest associated risk was found at 7 hours.
The researchers analyzed data from 7,959 participants (33.0% women). At age 50, compared with 7 hours of sleep, 6 or few hours of sleep was associated with a higher risk of dementia over the ensuing 25 years of follow-up (hazard ratio [HR], 1.22; 95% confidence interval [CI], 1.01-1.48). The same was true at age 60 (15 years of follow-up HR, 1.37; 95% CI, 1.10-1.72). There was a trend at age 70 (8 years follow-up; HR, 1.24; 95% CI, 0.98-1.57). For 8 or more hours of sleep, there were trends toward increased risk at age 50 (HR, 1.25; 95% CI, 0.98-1.60). Long sleep at age 60 and 70 was associated with heightened risk, but the confidence intervals were well outside statistical significance.
Twenty percent of participants had persistent short sleep over the course of follow-up, 37% had persistent normal sleep, and 7% had persistent long sleep. Seven percent of participants experienced a change from normal sleep to short sleep, 16% had a change from short sleep to normal sleep, and 13% had a change from normal sleep to long sleep.
Persistent short sleep between age 50 and 70 was associated with a 30% increased risk of dementia (HR, 1.30; 95% CI, 1.00-1.69). There were no statistically significant associations between dementia risk and any of the changing sleep pattern groups.
Dr. Sabia and Dr. Sexton have no relevant financial disclosures.
, according to a new analysis of data from the Whitehall II cohort study.
Previous work had identified links between short sleep duration and dementia risk, but few studies examined sleep habits long before onset of dementia. Those that did produced inconsistent results, according to Séverine Sabia, PhD, who is a research associate at Inserm (France) and the University College London.
“One potential reason for these inconstancies is the large range of ages of the study populations, and the small number of participants within each sleep duration group. The novelty of our study is to examine this association among almost 8,000 participants with a follow-up of 30 years, using repeated measures of sleep duration starting in midlife to consider sleep duration at specific ages,” Dr. Sabia said in an interview. She presented the research at the 2021 Alzheimer’s Association International Conference.
Those previous studies found a U-shaped association between sleep duration and dementia risk, with lowest risk associated with 7-8 hours of sleep, but greater risk for shorter and longer durations. However, because the studies had follow-up periods shorter than 10 years, they are at greater risk of reverse causation bias. Longer follow-up studies tended to have small sample sizes or to focus on older adults.
The longer follow-up in the current study makes for a more compelling case, said Claire Sexton, DPhil, director of Scientific Programs & Outreach for the Alzheimer’s Association. Observations of short or long sleep closer to the onset of symptoms could just be a warning sign of dementia. “But looking at age 50, age 60 ... if you’re seeing those relationships, then it’s less likely that it is just purely prodromal,” said Dr. Sexton. But it still doesn’t necessarily confirm causation. “It could also be a risk factor,” Dr. Sexton added.
Multifactorial risk
Dr. Sabia also noted that the magnitude of risk was similar to that seen with smoking or obesity, and many factors play a role in dementia risk. “Even if the risk of dementia was 30% higher in those with persistent short sleep duration, in absolute terms, the percentage of those with persistent short duration who developed dementia was 8%, and 6% in those with persistent sleep duration of 7 hours. Dementia is a multifactorial disease, which means that several factors are likely to influence its onset. Sleep duration is one of them, but if a person has poor sleep and does not manage to increase it, there are other important prevention measures. It is important to keep a healthy lifestyle and cardiometabolic measures in the normal range. All together it is likely to be beneficial for brain health in later life,” she said.
Dr. Sexton agreed. “With sleep we’re still trying to tease apart what aspect of sleep is important. Is it the sleep duration? Is it the quality of sleep? Is it certain sleep stages?” she said.
Regardless of sleep’s potential influence on dementia risk, both Dr. Sexton and Dr. Sabia noted the importance of sleep for general health. “These types of problems are very prevalent, so it’s good for people to be aware of them. And then if they notice any problems with their sleep, or any changes, to go and see their health care provider, and to be discussing them, and then to be investigating the cause, and to see whether changes in sleep hygiene and treatments for insomnia could address these sleep problems,” said Dr. Sexton.
Decades of data
During the Whitehall II study, researchers assessed average sleep duration (“How many hours of sleep do you have on an average weeknight?”) six times over 30 years of follow-up. Dr. Sabia’s group extracted self-reported sleep duration data at ages 50, 60, and 70. Short sleep duration was defined as fewer than 5 hours, or 6 hours. Normal sleep duration was defined as 7 hours. Long duration was defined as 8 hours or more.
A questioner during the Q&A period noted that this grouping is a little unusual. Many studies define 7-8 hours as normal. Dr. Sabia answered that they were unable to examine periods of 9 hours or more due to the nature of the data, and the lowest associated risk was found at 7 hours.
The researchers analyzed data from 7,959 participants (33.0% women). At age 50, compared with 7 hours of sleep, 6 or few hours of sleep was associated with a higher risk of dementia over the ensuing 25 years of follow-up (hazard ratio [HR], 1.22; 95% confidence interval [CI], 1.01-1.48). The same was true at age 60 (15 years of follow-up HR, 1.37; 95% CI, 1.10-1.72). There was a trend at age 70 (8 years follow-up; HR, 1.24; 95% CI, 0.98-1.57). For 8 or more hours of sleep, there were trends toward increased risk at age 50 (HR, 1.25; 95% CI, 0.98-1.60). Long sleep at age 60 and 70 was associated with heightened risk, but the confidence intervals were well outside statistical significance.
Twenty percent of participants had persistent short sleep over the course of follow-up, 37% had persistent normal sleep, and 7% had persistent long sleep. Seven percent of participants experienced a change from normal sleep to short sleep, 16% had a change from short sleep to normal sleep, and 13% had a change from normal sleep to long sleep.
Persistent short sleep between age 50 and 70 was associated with a 30% increased risk of dementia (HR, 1.30; 95% CI, 1.00-1.69). There were no statistically significant associations between dementia risk and any of the changing sleep pattern groups.
Dr. Sabia and Dr. Sexton have no relevant financial disclosures.
FROM AAIC 2021
The Precision Oncology Program for Cancer of the Prostate (POPCaP) Network: A Veterans Affairs/Prostate Cancer Foundation Collaboration(FULL)
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.
1. Montgomery B, Williams C. Prostate cancer federal health care data trends. https://www.mdedge.com/fedprac/article/208077/oncology/prostate-cancer-federal-health-care-data-trends. Published September 1, 2019. Accessed July 16, 2020.
2. Robinson D, Van Allen EM, Wu YM, et al. Integrative clinical genomics of advanced prostate cancer [published correction appears in Cell. 2015 Jul 16;162(2):454]. Cell. 2015;161(5):1215-1228. doi:10.1016/j.cell.2015.05.001
3. Quigley DA, Dang HX, Zhao SG, et al. Genomic hallmarks and structural variation in metastatic prostate cancer [published correction appears in Cell. 2018 Oct 18;175(3):889]. Cell. 2018;174(3):758-769.e9. doi:10.1016/j.cell.2018.06.039
4. Pritchard CC, Offit K, Nelson PS. DNA-repair gene mutations in metastatic prostate cancer. N Engl J Med. 2016;375(18):1804-1805. doi:10.1056/NEJMc1611137
5. Guillem JG. Molecular diagnosis of hereditary nonpolyposis colon cancer. N Engl J Med. 1998;339(13):924-925. doi:10.1056/nejm199809243391316
6. Ryan S, Jenkins MA, Win AK. Risk of prostate cancer in Lynch syndrome: a systematic review and meta-analysis. Cancer Epidemiol Biomarkers Prev. 2014;23(3):437-449. doi:10.1158/1055-9965.EPI-13-1165
7. Abida W, Cheng ML, Armenia J, et al. Analysis of the prevalence of microsatellite instability in prostate cancer and response to immune checkpoint blockade. JAMA Oncol. 2019;5(4):471-478. doi:10.1001/jamaoncol.2018.5801
8. Graham LS, Montgomery B, Cheng HH, et al. Mismatch repair deficiency in metastatic prostate cancer: Response to PD-1 blockade and standard therapies. PLoS One. 2020;15(5):e0233260. Published 2020 May 26. doi:10.1371/journal.pone.0233260
9. Yu HA, Planchard D, Lovly CM. Sequencing therapy for genetically defined subgroups of non-small cell lung cancer. Am Soc Clin Oncol Educ Book. 2018;38:726-739. doi:10.1200/EDBK_201331
10. Pritchard CC, Mateo J, Walsh MF, et al. Inherited DNA-repair gene mutations in men with metastatic prostate cancer. N Engl J Med. 2016;375(5):443-453. doi:10.1056/NEJMoa1603144
11. Farmer H, McCabe N, Lord CJ, et al. Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature. 2005;434(7035):917-921. doi:10.1038/nature03445
12. Abida W, Campbell D, Patnaik A, et al. Preliminary results from the TRITON2 study of rucaparib in patients with DNA damage repair deficiency metastatic, castration resistant prostate cancer: updated analyses. Ann Oncol. 2019;30(suppl 5): v325-v355. doi:10.1093/annonc/mdz248
13. de Bono J, Mateo J, Fizazi K, et al. Olaparib for metastatic castration-resistant prostate cancer. N Engl J Med. 2020;382(22):2091-2102. doi:10.1056/NEJMoa1911440
14. Graff JN, Huang GD. Leveraging Veterans Health Administration clinical and research resources to accelerate discovery and testing in precision oncology. Fed Pract. 2020;37(suppl 4):S62-S67. doi: 10.12788/fp.0028
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.
1. Montgomery B, Williams C. Prostate cancer federal health care data trends. https://www.mdedge.com/fedprac/article/208077/oncology/prostate-cancer-federal-health-care-data-trends. Published September 1, 2019. Accessed July 16, 2020.
2. Robinson D, Van Allen EM, Wu YM, et al. Integrative clinical genomics of advanced prostate cancer [published correction appears in Cell. 2015 Jul 16;162(2):454]. Cell. 2015;161(5):1215-1228. doi:10.1016/j.cell.2015.05.001
3. Quigley DA, Dang HX, Zhao SG, et al. Genomic hallmarks and structural variation in metastatic prostate cancer [published correction appears in Cell. 2018 Oct 18;175(3):889]. Cell. 2018;174(3):758-769.e9. doi:10.1016/j.cell.2018.06.039
4. Pritchard CC, Offit K, Nelson PS. DNA-repair gene mutations in metastatic prostate cancer. N Engl J Med. 2016;375(18):1804-1805. doi:10.1056/NEJMc1611137
5. Guillem JG. Molecular diagnosis of hereditary nonpolyposis colon cancer. N Engl J Med. 1998;339(13):924-925. doi:10.1056/nejm199809243391316
6. Ryan S, Jenkins MA, Win AK. Risk of prostate cancer in Lynch syndrome: a systematic review and meta-analysis. Cancer Epidemiol Biomarkers Prev. 2014;23(3):437-449. doi:10.1158/1055-9965.EPI-13-1165
7. Abida W, Cheng ML, Armenia J, et al. Analysis of the prevalence of microsatellite instability in prostate cancer and response to immune checkpoint blockade. JAMA Oncol. 2019;5(4):471-478. doi:10.1001/jamaoncol.2018.5801
8. Graham LS, Montgomery B, Cheng HH, et al. Mismatch repair deficiency in metastatic prostate cancer: Response to PD-1 blockade and standard therapies. PLoS One. 2020;15(5):e0233260. Published 2020 May 26. doi:10.1371/journal.pone.0233260
9. Yu HA, Planchard D, Lovly CM. Sequencing therapy for genetically defined subgroups of non-small cell lung cancer. Am Soc Clin Oncol Educ Book. 2018;38:726-739. doi:10.1200/EDBK_201331
10. Pritchard CC, Mateo J, Walsh MF, et al. Inherited DNA-repair gene mutations in men with metastatic prostate cancer. N Engl J Med. 2016;375(5):443-453. doi:10.1056/NEJMoa1603144
11. Farmer H, McCabe N, Lord CJ, et al. Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature. 2005;434(7035):917-921. doi:10.1038/nature03445
12. Abida W, Campbell D, Patnaik A, et al. Preliminary results from the TRITON2 study of rucaparib in patients with DNA damage repair deficiency metastatic, castration resistant prostate cancer: updated analyses. Ann Oncol. 2019;30(suppl 5): v325-v355. doi:10.1093/annonc/mdz248
13. de Bono J, Mateo J, Fizazi K, et al. Olaparib for metastatic castration-resistant prostate cancer. N Engl J Med. 2020;382(22):2091-2102. doi:10.1056/NEJMoa1911440
14. Graff JN, Huang GD. Leveraging Veterans Health Administration clinical and research resources to accelerate discovery and testing in precision oncology. Fed Pract. 2020;37(suppl 4):S62-S67. doi: 10.12788/fp.0028
1. Montgomery B, Williams C. Prostate cancer federal health care data trends. https://www.mdedge.com/fedprac/article/208077/oncology/prostate-cancer-federal-health-care-data-trends. Published September 1, 2019. Accessed July 16, 2020.
2. Robinson D, Van Allen EM, Wu YM, et al. Integrative clinical genomics of advanced prostate cancer [published correction appears in Cell. 2015 Jul 16;162(2):454]. Cell. 2015;161(5):1215-1228. doi:10.1016/j.cell.2015.05.001
3. Quigley DA, Dang HX, Zhao SG, et al. Genomic hallmarks and structural variation in metastatic prostate cancer [published correction appears in Cell. 2018 Oct 18;175(3):889]. Cell. 2018;174(3):758-769.e9. doi:10.1016/j.cell.2018.06.039
4. Pritchard CC, Offit K, Nelson PS. DNA-repair gene mutations in metastatic prostate cancer. N Engl J Med. 2016;375(18):1804-1805. doi:10.1056/NEJMc1611137
5. Guillem JG. Molecular diagnosis of hereditary nonpolyposis colon cancer. N Engl J Med. 1998;339(13):924-925. doi:10.1056/nejm199809243391316
6. Ryan S, Jenkins MA, Win AK. Risk of prostate cancer in Lynch syndrome: a systematic review and meta-analysis. Cancer Epidemiol Biomarkers Prev. 2014;23(3):437-449. doi:10.1158/1055-9965.EPI-13-1165
7. Abida W, Cheng ML, Armenia J, et al. Analysis of the prevalence of microsatellite instability in prostate cancer and response to immune checkpoint blockade. JAMA Oncol. 2019;5(4):471-478. doi:10.1001/jamaoncol.2018.5801
8. Graham LS, Montgomery B, Cheng HH, et al. Mismatch repair deficiency in metastatic prostate cancer: Response to PD-1 blockade and standard therapies. PLoS One. 2020;15(5):e0233260. Published 2020 May 26. doi:10.1371/journal.pone.0233260
9. Yu HA, Planchard D, Lovly CM. Sequencing therapy for genetically defined subgroups of non-small cell lung cancer. Am Soc Clin Oncol Educ Book. 2018;38:726-739. doi:10.1200/EDBK_201331
10. Pritchard CC, Mateo J, Walsh MF, et al. Inherited DNA-repair gene mutations in men with metastatic prostate cancer. N Engl J Med. 2016;375(5):443-453. doi:10.1056/NEJMoa1603144
11. Farmer H, McCabe N, Lord CJ, et al. Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature. 2005;434(7035):917-921. doi:10.1038/nature03445
12. Abida W, Campbell D, Patnaik A, et al. Preliminary results from the TRITON2 study of rucaparib in patients with DNA damage repair deficiency metastatic, castration resistant prostate cancer: updated analyses. Ann Oncol. 2019;30(suppl 5): v325-v355. doi:10.1093/annonc/mdz248
13. de Bono J, Mateo J, Fizazi K, et al. Olaparib for metastatic castration-resistant prostate cancer. N Engl J Med. 2020;382(22):2091-2102. doi:10.1056/NEJMoa1911440
14. Graff JN, Huang GD. Leveraging Veterans Health Administration clinical and research resources to accelerate discovery and testing in precision oncology. Fed Pract. 2020;37(suppl 4):S62-S67. doi: 10.12788/fp.0028
Integrating Germline Genetics Into Precision Oncology Practice in the Veterans Health Administration: Challenges and Opportunities (FULL)
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 information, independent of somatic variation, can influence the choice of targeted cancer therapies. For example, Mandelker and colleagues identified germline variants that would impact the treatment of 38 (3.7%) of 1,040 patients with cancer.4 Individuals with a germline pathogenic variant in a DNA repair gene (eg, BRCA1, BRCA2, ATM, CHEK2) are candidates for platinum chemotherapy and poly-(adenosine diphosphate-ribose) polymerase (PARP) inhibitors that target the inability of a tumor to repair double-stranded DNA breaks.5,6 Individuals with a germline pathogenic variant in the MSH2, MLH1, MSH6, PMS2 or EPCAM genes (ie, Lynch syndrome) have tumors that are deficient in mismatch repair, and these tumors are responsive to inhibitors of the programmed death 1 (PD1) pathway.7,8
In addition to changing treatment decisions, identifying pathogenic germline variants can have health, reproductive, and psychosocial implications for the patient and the patient’s family members.9,10 A pathogenic germline variant can imply disease risk for both the patient and his or her relatives. In these cases, it is important to ascertain family history, understand the mode of inheritance, identify at-risk relatives, review the associated phenotype, and discuss management and prevention options for the patient and for family members. For example, a germline pathogenic variant in the BRCA2 gene is associated with increased risk for breast, ovarian, pancreatic, gastric, bile duct, and laryngeal cancer, and melanoma.11 Knowledge of these increased cancer risks could inform cancer prevention and early detection options, such as more frequent and intensive surveillance starting at younger ages compared with that of average-risk individuals, use of chemoprevention treatments, and for those at highest risk, risk-reducing surgical procedures. Therefore, reporting germline test results requires the clinician to take on additional responsibilities beyond those required when reporting only somatic variants.
Because of the complexities inherent in germline genetic testing, it traditionally is offered in the context of a genetic consultation, comprised of genetic evaluation and genetic counseling (Figure). Clinical geneticists are physicians certified by the American Board of Medical Genetics and Genomics (a member board of the American Board of Medical Specialties) who received special training in the diagnosis and management of medical genetic conditions; they are trained to perform all aspects of a genetic consultation across the clinical spectrum and lifespan of a patient.12 In contrast, genetic counselors have a master’s degree in genetic counseling, a communication process that facilitates patient decision making surrounding the genetic evaluation.13 Most work as members of a team to ensure provision of comprehensive clinical genetic services. Genetic counselors are licensed in most states, and licensure in some states sanctions the ordering of genetic tests by genetic counselors. Genetics nurses are licensed professional nurses with special education and training in genetics who function in diverse roles in industry, education, research, and clinical care.14 Genetics nurses in clinical care perform risk assessment based on personal and family history, recognize and identify genetic conditions and predispositions, and discuss the implications of this with patients and their families. Advanced practice nurses (APRNs) have additional training that allows for diagnosis, interpretation of results, and surveillance and management recommendations.15
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.
In 2010, in response to increased demand for clinical genetics services, the VA launched the Genomic Medicine Service (GMS), a national program with a centralized team of 9 genetic counselors based in Salt Lake City. GMS provides telehealth genetic counseling services exclusively to veterans onsite and at about 90 VA facilities across the country. More recently, the addition of a clinical geneticist and APRN with genetics expertise has allowed GMS to provide more comprehensive genetic consultative services.
All VA genetics programs are currently at full capacity with long waits for an appointment. To expand clinical genetic services, the VA genetics professionals responding to our survey reported a need for additional support (eg, administrative, care coordination, clinical), resources (eg, clinical space, salary support), and organizational change (eg, division of Medical Genetics at facility level, services provided at the level of the Veterans Integrated Service Network). Given the dearth of genetic care providers in the community, referral to non-VA care is not a viable option in many markets. In addition, avoiding referral outside of the VA could help to ensure continuity of care, more efficient care, and reduce the risk of duplication of testing, and polypharmacy.34-37
As part of its precision oncology initiative, VA is focusing on building clinical genetics services capacity. To increase access to clinical genetic services and appropriate genetic testing, the VA needs more genetics professionals, including clinical geneticists, genetic counselors, and genetic nurses–ideally a workforce study could be performed to inform the right staffing mix needed. To grow the genetics workforce in the long term, the VA could leverage its academic affiliations to train the next generation of genetics professionals. The VA has an important role in training medical professionals. By forming affiliations with medical schools and universities, the VA has become the largest provider of health care training in the US.38
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.
1. Zullig LL, Sims KJ, McNeil R, et al. Cancer incidence among patients of the U.S. Veterans Affairs Health Care System: 2010 update. Mil Med. 2017;182(7):e1883-e1891. doi:10.7205/MILMED-D-16-00371
2. Li MM, Chao E, Esplin ED, et al. Points to consider for reporting of germline variation in patients undergoing tumor testing: a statement of the American College of Medical Genetics and Genomics (ACMG). Genet Med. 2020;22(7):1142-1148. doi:10.1038/s41436-020-0783-8
3. Malone ER, Oliva M, Sabatini PJB, Stockley TL, Siu LL. Molecular profiling for precision cancer therapies. Genome Med. 2020;12(1):8. Published 2020 Jan 14. doi:10.1186/s13073-019-0703-1
4. Mandelker D, Zhang L, Kemel Y, et al. Mutation detection in patients with advanced cancer by universal sequencing of cancer-related genes in tumor and normal DNA vs guideline-based germline testing [published correction appears in JAMA. 2018 Dec 11;320(22):2381]. JAMA. 2017;318(9):825-835. doi:10.1001/jama.2017.11137
5. Mateo J, Carreira S, Sandhu S, et al. DNA-repair defects and olaparib in metastatic prostate cancer. N Engl J Med. 2015;373(18):1697-1708. doi:10.1056/NEJMoa1506859
6. Ratta R, Guida A, Scotté F, et al. PARP inhibitors as a new therapeutic option in metastatic prostate cancer: a systematic review [published online ahead of print, 2020 May 4]. Prostate Cancer Prostatic Dis. 2020;10.1038/s41391-020-0233-3. doi:10.1038/s41391-020-0233-3
7. Le DT, Uram JN, Wang H, et al. PD-1 Blockade in tumors with mismatch-repair deficiency. N Engl J Med. 2015;372(26):2509-2520. doi:10.1056/NEJMoa1500596
8. Graham LS, Montgomery B, Cheng HH, et al. Mismatch repair deficiency in metastatic prostate cancer: Response to PD-1 blockade and standard therapies. PLoS One. 2020;15(5):e0233260. doi:10.1371/journal.pone.0233260
9. Robson ME, Storm CD, Weitzel J, Wollins DS, Offit K; American Society of Clinical Oncology. American Society of Clinical Oncology policy statement update: genetic and genomic testing for cancer susceptibility. J Clin Oncol. 2010;28(5):893-901. doi:10.1200/JCO.2009.27.0660
10. Riley BD, Culver JO, Skrzynia C, et al. Essential elements of genetic cancer risk assessment, counseling, and testing: updated recommendations of the National Society of Genetic Counselors. J Genet Couns. 2012;21(2):151-161. doi:10.1007/s10897-011-9462-x
11. Petrucelli N, Daly MB, Pal T. BRCA1- and BRCA2-associated hereditary breast and ovarian cancer. In: Adam MP, Ardinger HH, Pagon RA, et al, eds. GeneReviews. Seattle, WA: University of Washington, Seattle; 1993.
12. ACMG Board of Directors. Scope of practice: a statement of the American College of Medical Genetics and Genomics (ACMG). Genet Med. 2015;17(9):e3. doi:10.1038/gim.2015.94
13. National Society of Genetic Counselors’ Definition Task Force, Resta R, Biesecker BB, et al. A new definition of Genetic Counseling: National Society of Genetic Counselors’ Task Force report. J Genet Couns. 2006;15(2):77-83. doi:10.1007/s10897-005-9014-3
14. Calzone KA, Cashion A, Feetham S, et al. Nurses transforming health care using genetics and genomics [published correction appears in Nurs Outlook. 2010;58(3):163]. Nurs Outlook. 2010;58(1):26-35. doi:10.1016/j.outlook.2009.05.001
15. US Department of Veterans Affairs, Veterans Health Administration, Office of Nursing Services. 2018 Office of Nursing Services (ONS) Annual Brief. https://www.va.gov/nursing/docs/about/2018_ONS_Annual_Report_Brief.pdf. Accessed July 21, 2020.
16. Lerman C, Croyle RT. Emotional and behavioral responses to genetic testing for susceptibility to cancer. Oncology (Williston Park). 1996;10(2):191-202.
17. Bonadona V, Saltel P, Desseigne F, et al. Cancer patients who experienced diagnostic genetic testing for cancer susceptibility: reactions and behavior after the disclosure of a positive test result. Cancer Epidemiol Biomarkers Prev. 2002;11(1):97-104.
18. Murakami Y, Okamura H, Sugano K, et al. Psychologic distress after disclosure of genetic test results regarding hereditary nonpolyposis colorectal carcinoma. Cancer. 2004;101(2):395-403. doi:10.1002/cncr.20363
19. Brierley KL, Campfield D, Ducaine W, et al. Errors in delivery of cancer genetics services: implications for practice. Conn Med. 2010;74(7):413-423.
20. Dhar SU, Cooper HP, Wang T, et al. Significant differences among physician specialties in management recommendations of BRCA1 mutation carriers. Breast Cancer Res Treat. 2011;129(1):221-227. doi:10.1007/s10549-011-1449-7
21. Plon SE, Cooper HP, Parks B, et al. Genetic testing and cancer risk management recommendations by physicians for at-risk relatives. Genet Med. 2011;13(2):148-154. doi:10.1097/GIM.0b013e318207f564
22. Bellcross CA, Kolor K, Goddard KA, Coates RJ, Reyes M, Khoury MJ. Awareness and utilization of BRCA1/2 testing among U.S. primary care physicians. Am J Prev Med. 2011;40(1):61-66. doi:10.1016/j.amepre.2010.09.027
23. Pal T, Cragun D, Lewis C, et al. A statewide survey of practitioners to assess knowledge and clinical practices regarding hereditary breast and ovarian cancer. Genet Test Mol Biomarkers. 2013;17(5):367-375. doi:10.1089/gtmb.2012.0381
24. Bensend TA, Veach PM, Niendorf KB. What’s the harm? Genetic counselor perceptions of adverse effects of genetics service provision by non-genetics professionals. J Genet Couns. 2014;23(1):48-63. doi:10.1007/s10897-013-9605-3
25. Teng I, Spigelman A. Attitudes and knowledge of medical practitioners to hereditary cancer clinics and cancer genetic testing. Fam Cancer. 2014;13(2):311-324. doi:10.1007/s10689-013-9695-y
26. Mikat-Stevens NA, Larson IA, Tarini BA. Primary-care providers’ perceived barriers to integration of genetics services: a systematic review of the literature. Genet Med. 2015;17(3):169-176. doi:10.1038/gim.2014.101
27. Scheuner MT, Hilborne L, Brown J, Lubin IM; members of the RAND Molecular Genetic Test Report Advisory Board. A report template for molecular genetic tests designed to improve communication between the clinician and laboratory. Genet Test Mol Biomarkers. 2012;16(7):761-769. doi:10.1089/gtmb.2011.0328
28. Scheuner MT, Peredo J, Tangney K, et al. Electronic health record interventions at the point of care improve documentation of care processes and decrease orders for genetic tests commonly ordered by nongeneticists. Genet Med. 2017;19(1):112-120. doi:10.1038/gim.2016.73
29. Cooksey JA, Forte G, Benkendorf J, Blitzer MG. The state of the medical geneticist workforce: findings of the 2003 survey of American Board of Medical Genetics certified geneticists. Genet Med. 2005;7(6):439-443. doi:10.1097/01.gim.0000172416.35285.9f
30. Institute of Medicine. Roundtable on Translating Genomic-Based Research for Health. Washington, DC: National Academies Press; 2009. https://www.ncbi.nlm.nih.gov/books/NBK26394. Accessed July 22, 2020.
31. Hoskovec JM, Bennett RL, Carey ME, et al. Projecting the supply and demand for certified genetic counselors: a workforce study. J Genet Couns. 2018;27(1):16-20. doi:10.1007/s10897-017-0158-8
32. Penon-Portmann M, Chang J, Cheng M, Shieh JT. Genetics workforce: distribution of genetics services and challenges to health care in California. Genet Med. 2020;22(1):227-231. doi:10.1038/s41436-019-0628-5
33. Spoont M, Greer N, Su J, Fitzgerald P, Rutks I, Wilt TJ. Rural vs. Urban Ambulatory Health Care: A Systematic Review. Washington, DC: US Department of Veterans Affairs; 2011. https://www.hsrd.research.va.gov/publications/esp/ambulatory.cfm. Accessed July 21, 2020.
34. Mehrotra A, Forrest CB, Lin CY. Dropping the baton: specialty referrals in the United States. Milbank Q. 2011;89(1):39-68. doi:10.1111/j.1468-0009.2011.00619.x
35. Walsh J, Harrison JD, Young JM, Butow PN, Solomon MJ, Masya L. What are the current barriers to effective cancer care coordination? A qualitative study. BMC Health Serv Res. 2010;10:132. Published 2010 May 20. doi:10.1186/1472-6963-10-132
36. McDonald KM, Schultz E, Albin L, et al. Care Coordination Measures Atlas. Version 4. Agency for Healthcare Research and Quality Publication No. 14-0037. https://www.ahrq.gov/sites/default/files/publications/files/ccm_atlas.pdf. Updated June 2014. Accessed July 22, 2020.
37. Greenwood-Lee J, Jewett L, Woodhouse L, Marshall DA. A categorisation of problems and solutions to improve patient referrals from primary to specialty care. BMC Health Serv Res. 2018;18(1):986. Published 2018 Dec 20. doi:10.1186/s12913-018-3745-y
38. US Department of Veterans Affairs, Office of Academic Affiliations. Our medical and dental training program. https://www.va.gov/oaa/gme_default.asp. Updated January 7, 2020. Accessed July 21, 2020.
39. Scheuner MT, Marshall N, Lanto A, et al. Delivery of clinical genetic consultative services in the Veterans Health Administration. Genet Med. 2014;16(8):609-619. doi:10.1038/gim.2013.202.
40. Battista RN, Blancquaert I, Laberge AM, van Schendel N, Leduc N. Genetics in health care: an overview of current and emerging models. Public Health Genomics. 2012;15(1):34-45. doi:10.1159/000328846
41. Emery J. The GRAIDS Trial: the development and evaluation of computer decision support for cancer genetic risk assessment in primary care. Ann Hum Biol. 2005;32(2):218-227. doi:10.1080/03014460500074921
42. Scheuner MT, Hamilton AB, Peredo J, et al. A cancer genetics toolkit improves access to genetic services through documentation and use of the family history by primary-care clinicians. Genet Med. 2014;16(1):60-69. doi:10.1038/gim.2013.75
43. Scheuner MT, Peredo J, Tangney K, et al. Electronic health record interventions at the point of care improve documentation of care processes and decrease orders for genetic tests commonly ordered by nongeneticists. Genet Med. 2017;19(1):112-120. doi:10.1038/gim.2016.73
44. Hamilton AB, Oishi S, Yano EM, Gammage CE, Marshall NJ, Scheuner MT. Factors influencing organizational adoption and implementation of clinical genetic services. Genet Med. 2014;16(3):238-245. doi:10.1038/gim.2013.101
45. Sperber NR, Andrews SM, Voils CI, Green GL, Provenzale D, Knight S. Barriers and facilitators to adoption of genomic services for colorectal care within the Veterans Health Administration. J Pers Med. 2016;6(2):16. Published 2016 Apr 28. doi:10.3390/jpm6020016
46. US Department of Veterans Affairs, Health Services Research and Development. Genomics. https://www.hsrd.research.va.gov/research/portfolio_description.cfm?Sulu=17. Updated July 21, 2020. Accessed June 22, 2020.
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 information, independent of somatic variation, can influence the choice of targeted cancer therapies. For example, Mandelker and colleagues identified germline variants that would impact the treatment of 38 (3.7%) of 1,040 patients with cancer.4 Individuals with a germline pathogenic variant in a DNA repair gene (eg, BRCA1, BRCA2, ATM, CHEK2) are candidates for platinum chemotherapy and poly-(adenosine diphosphate-ribose) polymerase (PARP) inhibitors that target the inability of a tumor to repair double-stranded DNA breaks.5,6 Individuals with a germline pathogenic variant in the MSH2, MLH1, MSH6, PMS2 or EPCAM genes (ie, Lynch syndrome) have tumors that are deficient in mismatch repair, and these tumors are responsive to inhibitors of the programmed death 1 (PD1) pathway.7,8
In addition to changing treatment decisions, identifying pathogenic germline variants can have health, reproductive, and psychosocial implications for the patient and the patient’s family members.9,10 A pathogenic germline variant can imply disease risk for both the patient and his or her relatives. In these cases, it is important to ascertain family history, understand the mode of inheritance, identify at-risk relatives, review the associated phenotype, and discuss management and prevention options for the patient and for family members. For example, a germline pathogenic variant in the BRCA2 gene is associated with increased risk for breast, ovarian, pancreatic, gastric, bile duct, and laryngeal cancer, and melanoma.11 Knowledge of these increased cancer risks could inform cancer prevention and early detection options, such as more frequent and intensive surveillance starting at younger ages compared with that of average-risk individuals, use of chemoprevention treatments, and for those at highest risk, risk-reducing surgical procedures. Therefore, reporting germline test results requires the clinician to take on additional responsibilities beyond those required when reporting only somatic variants.
Because of the complexities inherent in germline genetic testing, it traditionally is offered in the context of a genetic consultation, comprised of genetic evaluation and genetic counseling (Figure). Clinical geneticists are physicians certified by the American Board of Medical Genetics and Genomics (a member board of the American Board of Medical Specialties) who received special training in the diagnosis and management of medical genetic conditions; they are trained to perform all aspects of a genetic consultation across the clinical spectrum and lifespan of a patient.12 In contrast, genetic counselors have a master’s degree in genetic counseling, a communication process that facilitates patient decision making surrounding the genetic evaluation.13 Most work as members of a team to ensure provision of comprehensive clinical genetic services. Genetic counselors are licensed in most states, and licensure in some states sanctions the ordering of genetic tests by genetic counselors. Genetics nurses are licensed professional nurses with special education and training in genetics who function in diverse roles in industry, education, research, and clinical care.14 Genetics nurses in clinical care perform risk assessment based on personal and family history, recognize and identify genetic conditions and predispositions, and discuss the implications of this with patients and their families. Advanced practice nurses (APRNs) have additional training that allows for diagnosis, interpretation of results, and surveillance and management recommendations.15
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.
In 2010, in response to increased demand for clinical genetics services, the VA launched the Genomic Medicine Service (GMS), a national program with a centralized team of 9 genetic counselors based in Salt Lake City. GMS provides telehealth genetic counseling services exclusively to veterans onsite and at about 90 VA facilities across the country. More recently, the addition of a clinical geneticist and APRN with genetics expertise has allowed GMS to provide more comprehensive genetic consultative services.
All VA genetics programs are currently at full capacity with long waits for an appointment. To expand clinical genetic services, the VA genetics professionals responding to our survey reported a need for additional support (eg, administrative, care coordination, clinical), resources (eg, clinical space, salary support), and organizational change (eg, division of Medical Genetics at facility level, services provided at the level of the Veterans Integrated Service Network). Given the dearth of genetic care providers in the community, referral to non-VA care is not a viable option in many markets. In addition, avoiding referral outside of the VA could help to ensure continuity of care, more efficient care, and reduce the risk of duplication of testing, and polypharmacy.34-37
As part of its precision oncology initiative, VA is focusing on building clinical genetics services capacity. To increase access to clinical genetic services and appropriate genetic testing, the VA needs more genetics professionals, including clinical geneticists, genetic counselors, and genetic nurses–ideally a workforce study could be performed to inform the right staffing mix needed. To grow the genetics workforce in the long term, the VA could leverage its academic affiliations to train the next generation of genetics professionals. The VA has an important role in training medical professionals. By forming affiliations with medical schools and universities, the VA has become the largest provider of health care training in the US.38
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 information, independent of somatic variation, can influence the choice of targeted cancer therapies. For example, Mandelker and colleagues identified germline variants that would impact the treatment of 38 (3.7%) of 1,040 patients with cancer.4 Individuals with a germline pathogenic variant in a DNA repair gene (eg, BRCA1, BRCA2, ATM, CHEK2) are candidates for platinum chemotherapy and poly-(adenosine diphosphate-ribose) polymerase (PARP) inhibitors that target the inability of a tumor to repair double-stranded DNA breaks.5,6 Individuals with a germline pathogenic variant in the MSH2, MLH1, MSH6, PMS2 or EPCAM genes (ie, Lynch syndrome) have tumors that are deficient in mismatch repair, and these tumors are responsive to inhibitors of the programmed death 1 (PD1) pathway.7,8
In addition to changing treatment decisions, identifying pathogenic germline variants can have health, reproductive, and psychosocial implications for the patient and the patient’s family members.9,10 A pathogenic germline variant can imply disease risk for both the patient and his or her relatives. In these cases, it is important to ascertain family history, understand the mode of inheritance, identify at-risk relatives, review the associated phenotype, and discuss management and prevention options for the patient and for family members. For example, a germline pathogenic variant in the BRCA2 gene is associated with increased risk for breast, ovarian, pancreatic, gastric, bile duct, and laryngeal cancer, and melanoma.11 Knowledge of these increased cancer risks could inform cancer prevention and early detection options, such as more frequent and intensive surveillance starting at younger ages compared with that of average-risk individuals, use of chemoprevention treatments, and for those at highest risk, risk-reducing surgical procedures. Therefore, reporting germline test results requires the clinician to take on additional responsibilities beyond those required when reporting only somatic variants.
Because of the complexities inherent in germline genetic testing, it traditionally is offered in the context of a genetic consultation, comprised of genetic evaluation and genetic counseling (Figure). Clinical geneticists are physicians certified by the American Board of Medical Genetics and Genomics (a member board of the American Board of Medical Specialties) who received special training in the diagnosis and management of medical genetic conditions; they are trained to perform all aspects of a genetic consultation across the clinical spectrum and lifespan of a patient.12 In contrast, genetic counselors have a master’s degree in genetic counseling, a communication process that facilitates patient decision making surrounding the genetic evaluation.13 Most work as members of a team to ensure provision of comprehensive clinical genetic services. Genetic counselors are licensed in most states, and licensure in some states sanctions the ordering of genetic tests by genetic counselors. Genetics nurses are licensed professional nurses with special education and training in genetics who function in diverse roles in industry, education, research, and clinical care.14 Genetics nurses in clinical care perform risk assessment based on personal and family history, recognize and identify genetic conditions and predispositions, and discuss the implications of this with patients and their families. Advanced practice nurses (APRNs) have additional training that allows for diagnosis, interpretation of results, and surveillance and management recommendations.15
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.
In 2010, in response to increased demand for clinical genetics services, the VA launched the Genomic Medicine Service (GMS), a national program with a centralized team of 9 genetic counselors based in Salt Lake City. GMS provides telehealth genetic counseling services exclusively to veterans onsite and at about 90 VA facilities across the country. More recently, the addition of a clinical geneticist and APRN with genetics expertise has allowed GMS to provide more comprehensive genetic consultative services.
All VA genetics programs are currently at full capacity with long waits for an appointment. To expand clinical genetic services, the VA genetics professionals responding to our survey reported a need for additional support (eg, administrative, care coordination, clinical), resources (eg, clinical space, salary support), and organizational change (eg, division of Medical Genetics at facility level, services provided at the level of the Veterans Integrated Service Network). Given the dearth of genetic care providers in the community, referral to non-VA care is not a viable option in many markets. In addition, avoiding referral outside of the VA could help to ensure continuity of care, more efficient care, and reduce the risk of duplication of testing, and polypharmacy.34-37
As part of its precision oncology initiative, VA is focusing on building clinical genetics services capacity. To increase access to clinical genetic services and appropriate genetic testing, the VA needs more genetics professionals, including clinical geneticists, genetic counselors, and genetic nurses–ideally a workforce study could be performed to inform the right staffing mix needed. To grow the genetics workforce in the long term, the VA could leverage its academic affiliations to train the next generation of genetics professionals. The VA has an important role in training medical professionals. By forming affiliations with medical schools and universities, the VA has become the largest provider of health care training in the US.38
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.
1. Zullig LL, Sims KJ, McNeil R, et al. Cancer incidence among patients of the U.S. Veterans Affairs Health Care System: 2010 update. Mil Med. 2017;182(7):e1883-e1891. doi:10.7205/MILMED-D-16-00371
2. Li MM, Chao E, Esplin ED, et al. Points to consider for reporting of germline variation in patients undergoing tumor testing: a statement of the American College of Medical Genetics and Genomics (ACMG). Genet Med. 2020;22(7):1142-1148. doi:10.1038/s41436-020-0783-8
3. Malone ER, Oliva M, Sabatini PJB, Stockley TL, Siu LL. Molecular profiling for precision cancer therapies. Genome Med. 2020;12(1):8. Published 2020 Jan 14. doi:10.1186/s13073-019-0703-1
4. Mandelker D, Zhang L, Kemel Y, et al. Mutation detection in patients with advanced cancer by universal sequencing of cancer-related genes in tumor and normal DNA vs guideline-based germline testing [published correction appears in JAMA. 2018 Dec 11;320(22):2381]. JAMA. 2017;318(9):825-835. doi:10.1001/jama.2017.11137
5. Mateo J, Carreira S, Sandhu S, et al. DNA-repair defects and olaparib in metastatic prostate cancer. N Engl J Med. 2015;373(18):1697-1708. doi:10.1056/NEJMoa1506859
6. Ratta R, Guida A, Scotté F, et al. PARP inhibitors as a new therapeutic option in metastatic prostate cancer: a systematic review [published online ahead of print, 2020 May 4]. Prostate Cancer Prostatic Dis. 2020;10.1038/s41391-020-0233-3. doi:10.1038/s41391-020-0233-3
7. Le DT, Uram JN, Wang H, et al. PD-1 Blockade in tumors with mismatch-repair deficiency. N Engl J Med. 2015;372(26):2509-2520. doi:10.1056/NEJMoa1500596
8. Graham LS, Montgomery B, Cheng HH, et al. Mismatch repair deficiency in metastatic prostate cancer: Response to PD-1 blockade and standard therapies. PLoS One. 2020;15(5):e0233260. doi:10.1371/journal.pone.0233260
9. Robson ME, Storm CD, Weitzel J, Wollins DS, Offit K; American Society of Clinical Oncology. American Society of Clinical Oncology policy statement update: genetic and genomic testing for cancer susceptibility. J Clin Oncol. 2010;28(5):893-901. doi:10.1200/JCO.2009.27.0660
10. Riley BD, Culver JO, Skrzynia C, et al. Essential elements of genetic cancer risk assessment, counseling, and testing: updated recommendations of the National Society of Genetic Counselors. J Genet Couns. 2012;21(2):151-161. doi:10.1007/s10897-011-9462-x
11. Petrucelli N, Daly MB, Pal T. BRCA1- and BRCA2-associated hereditary breast and ovarian cancer. In: Adam MP, Ardinger HH, Pagon RA, et al, eds. GeneReviews. Seattle, WA: University of Washington, Seattle; 1993.
12. ACMG Board of Directors. Scope of practice: a statement of the American College of Medical Genetics and Genomics (ACMG). Genet Med. 2015;17(9):e3. doi:10.1038/gim.2015.94
13. National Society of Genetic Counselors’ Definition Task Force, Resta R, Biesecker BB, et al. A new definition of Genetic Counseling: National Society of Genetic Counselors’ Task Force report. J Genet Couns. 2006;15(2):77-83. doi:10.1007/s10897-005-9014-3
14. Calzone KA, Cashion A, Feetham S, et al. Nurses transforming health care using genetics and genomics [published correction appears in Nurs Outlook. 2010;58(3):163]. Nurs Outlook. 2010;58(1):26-35. doi:10.1016/j.outlook.2009.05.001
15. US Department of Veterans Affairs, Veterans Health Administration, Office of Nursing Services. 2018 Office of Nursing Services (ONS) Annual Brief. https://www.va.gov/nursing/docs/about/2018_ONS_Annual_Report_Brief.pdf. Accessed July 21, 2020.
16. Lerman C, Croyle RT. Emotional and behavioral responses to genetic testing for susceptibility to cancer. Oncology (Williston Park). 1996;10(2):191-202.
17. Bonadona V, Saltel P, Desseigne F, et al. Cancer patients who experienced diagnostic genetic testing for cancer susceptibility: reactions and behavior after the disclosure of a positive test result. Cancer Epidemiol Biomarkers Prev. 2002;11(1):97-104.
18. Murakami Y, Okamura H, Sugano K, et al. Psychologic distress after disclosure of genetic test results regarding hereditary nonpolyposis colorectal carcinoma. Cancer. 2004;101(2):395-403. doi:10.1002/cncr.20363
19. Brierley KL, Campfield D, Ducaine W, et al. Errors in delivery of cancer genetics services: implications for practice. Conn Med. 2010;74(7):413-423.
20. Dhar SU, Cooper HP, Wang T, et al. Significant differences among physician specialties in management recommendations of BRCA1 mutation carriers. Breast Cancer Res Treat. 2011;129(1):221-227. doi:10.1007/s10549-011-1449-7
21. Plon SE, Cooper HP, Parks B, et al. Genetic testing and cancer risk management recommendations by physicians for at-risk relatives. Genet Med. 2011;13(2):148-154. doi:10.1097/GIM.0b013e318207f564
22. Bellcross CA, Kolor K, Goddard KA, Coates RJ, Reyes M, Khoury MJ. Awareness and utilization of BRCA1/2 testing among U.S. primary care physicians. Am J Prev Med. 2011;40(1):61-66. doi:10.1016/j.amepre.2010.09.027
23. Pal T, Cragun D, Lewis C, et al. A statewide survey of practitioners to assess knowledge and clinical practices regarding hereditary breast and ovarian cancer. Genet Test Mol Biomarkers. 2013;17(5):367-375. doi:10.1089/gtmb.2012.0381
24. Bensend TA, Veach PM, Niendorf KB. What’s the harm? Genetic counselor perceptions of adverse effects of genetics service provision by non-genetics professionals. J Genet Couns. 2014;23(1):48-63. doi:10.1007/s10897-013-9605-3
25. Teng I, Spigelman A. Attitudes and knowledge of medical practitioners to hereditary cancer clinics and cancer genetic testing. Fam Cancer. 2014;13(2):311-324. doi:10.1007/s10689-013-9695-y
26. Mikat-Stevens NA, Larson IA, Tarini BA. Primary-care providers’ perceived barriers to integration of genetics services: a systematic review of the literature. Genet Med. 2015;17(3):169-176. doi:10.1038/gim.2014.101
27. Scheuner MT, Hilborne L, Brown J, Lubin IM; members of the RAND Molecular Genetic Test Report Advisory Board. A report template for molecular genetic tests designed to improve communication between the clinician and laboratory. Genet Test Mol Biomarkers. 2012;16(7):761-769. doi:10.1089/gtmb.2011.0328
28. Scheuner MT, Peredo J, Tangney K, et al. Electronic health record interventions at the point of care improve documentation of care processes and decrease orders for genetic tests commonly ordered by nongeneticists. Genet Med. 2017;19(1):112-120. doi:10.1038/gim.2016.73
29. Cooksey JA, Forte G, Benkendorf J, Blitzer MG. The state of the medical geneticist workforce: findings of the 2003 survey of American Board of Medical Genetics certified geneticists. Genet Med. 2005;7(6):439-443. doi:10.1097/01.gim.0000172416.35285.9f
30. Institute of Medicine. Roundtable on Translating Genomic-Based Research for Health. Washington, DC: National Academies Press; 2009. https://www.ncbi.nlm.nih.gov/books/NBK26394. Accessed July 22, 2020.
31. Hoskovec JM, Bennett RL, Carey ME, et al. Projecting the supply and demand for certified genetic counselors: a workforce study. J Genet Couns. 2018;27(1):16-20. doi:10.1007/s10897-017-0158-8
32. Penon-Portmann M, Chang J, Cheng M, Shieh JT. Genetics workforce: distribution of genetics services and challenges to health care in California. Genet Med. 2020;22(1):227-231. doi:10.1038/s41436-019-0628-5
33. Spoont M, Greer N, Su J, Fitzgerald P, Rutks I, Wilt TJ. Rural vs. Urban Ambulatory Health Care: A Systematic Review. Washington, DC: US Department of Veterans Affairs; 2011. https://www.hsrd.research.va.gov/publications/esp/ambulatory.cfm. Accessed July 21, 2020.
34. Mehrotra A, Forrest CB, Lin CY. Dropping the baton: specialty referrals in the United States. Milbank Q. 2011;89(1):39-68. doi:10.1111/j.1468-0009.2011.00619.x
35. Walsh J, Harrison JD, Young JM, Butow PN, Solomon MJ, Masya L. What are the current barriers to effective cancer care coordination? A qualitative study. BMC Health Serv Res. 2010;10:132. Published 2010 May 20. doi:10.1186/1472-6963-10-132
36. McDonald KM, Schultz E, Albin L, et al. Care Coordination Measures Atlas. Version 4. Agency for Healthcare Research and Quality Publication No. 14-0037. https://www.ahrq.gov/sites/default/files/publications/files/ccm_atlas.pdf. Updated June 2014. Accessed July 22, 2020.
37. Greenwood-Lee J, Jewett L, Woodhouse L, Marshall DA. A categorisation of problems and solutions to improve patient referrals from primary to specialty care. BMC Health Serv Res. 2018;18(1):986. Published 2018 Dec 20. doi:10.1186/s12913-018-3745-y
38. US Department of Veterans Affairs, Office of Academic Affiliations. Our medical and dental training program. https://www.va.gov/oaa/gme_default.asp. Updated January 7, 2020. Accessed July 21, 2020.
39. Scheuner MT, Marshall N, Lanto A, et al. Delivery of clinical genetic consultative services in the Veterans Health Administration. Genet Med. 2014;16(8):609-619. doi:10.1038/gim.2013.202.
40. Battista RN, Blancquaert I, Laberge AM, van Schendel N, Leduc N. Genetics in health care: an overview of current and emerging models. Public Health Genomics. 2012;15(1):34-45. doi:10.1159/000328846
41. Emery J. The GRAIDS Trial: the development and evaluation of computer decision support for cancer genetic risk assessment in primary care. Ann Hum Biol. 2005;32(2):218-227. doi:10.1080/03014460500074921
42. Scheuner MT, Hamilton AB, Peredo J, et al. A cancer genetics toolkit improves access to genetic services through documentation and use of the family history by primary-care clinicians. Genet Med. 2014;16(1):60-69. doi:10.1038/gim.2013.75
43. Scheuner MT, Peredo J, Tangney K, et al. Electronic health record interventions at the point of care improve documentation of care processes and decrease orders for genetic tests commonly ordered by nongeneticists. Genet Med. 2017;19(1):112-120. doi:10.1038/gim.2016.73
44. Hamilton AB, Oishi S, Yano EM, Gammage CE, Marshall NJ, Scheuner MT. Factors influencing organizational adoption and implementation of clinical genetic services. Genet Med. 2014;16(3):238-245. doi:10.1038/gim.2013.101
45. Sperber NR, Andrews SM, Voils CI, Green GL, Provenzale D, Knight S. Barriers and facilitators to adoption of genomic services for colorectal care within the Veterans Health Administration. J Pers Med. 2016;6(2):16. Published 2016 Apr 28. doi:10.3390/jpm6020016
46. US Department of Veterans Affairs, Health Services Research and Development. Genomics. https://www.hsrd.research.va.gov/research/portfolio_description.cfm?Sulu=17. Updated July 21, 2020. Accessed June 22, 2020.
1. Zullig LL, Sims KJ, McNeil R, et al. Cancer incidence among patients of the U.S. Veterans Affairs Health Care System: 2010 update. Mil Med. 2017;182(7):e1883-e1891. doi:10.7205/MILMED-D-16-00371
2. Li MM, Chao E, Esplin ED, et al. Points to consider for reporting of germline variation in patients undergoing tumor testing: a statement of the American College of Medical Genetics and Genomics (ACMG). Genet Med. 2020;22(7):1142-1148. doi:10.1038/s41436-020-0783-8
3. Malone ER, Oliva M, Sabatini PJB, Stockley TL, Siu LL. Molecular profiling for precision cancer therapies. Genome Med. 2020;12(1):8. Published 2020 Jan 14. doi:10.1186/s13073-019-0703-1
4. Mandelker D, Zhang L, Kemel Y, et al. Mutation detection in patients with advanced cancer by universal sequencing of cancer-related genes in tumor and normal DNA vs guideline-based germline testing [published correction appears in JAMA. 2018 Dec 11;320(22):2381]. JAMA. 2017;318(9):825-835. doi:10.1001/jama.2017.11137
5. Mateo J, Carreira S, Sandhu S, et al. DNA-repair defects and olaparib in metastatic prostate cancer. N Engl J Med. 2015;373(18):1697-1708. doi:10.1056/NEJMoa1506859
6. Ratta R, Guida A, Scotté F, et al. PARP inhibitors as a new therapeutic option in metastatic prostate cancer: a systematic review [published online ahead of print, 2020 May 4]. Prostate Cancer Prostatic Dis. 2020;10.1038/s41391-020-0233-3. doi:10.1038/s41391-020-0233-3
7. Le DT, Uram JN, Wang H, et al. PD-1 Blockade in tumors with mismatch-repair deficiency. N Engl J Med. 2015;372(26):2509-2520. doi:10.1056/NEJMoa1500596
8. Graham LS, Montgomery B, Cheng HH, et al. Mismatch repair deficiency in metastatic prostate cancer: Response to PD-1 blockade and standard therapies. PLoS One. 2020;15(5):e0233260. doi:10.1371/journal.pone.0233260
9. Robson ME, Storm CD, Weitzel J, Wollins DS, Offit K; American Society of Clinical Oncology. American Society of Clinical Oncology policy statement update: genetic and genomic testing for cancer susceptibility. J Clin Oncol. 2010;28(5):893-901. doi:10.1200/JCO.2009.27.0660
10. Riley BD, Culver JO, Skrzynia C, et al. Essential elements of genetic cancer risk assessment, counseling, and testing: updated recommendations of the National Society of Genetic Counselors. J Genet Couns. 2012;21(2):151-161. doi:10.1007/s10897-011-9462-x
11. Petrucelli N, Daly MB, Pal T. BRCA1- and BRCA2-associated hereditary breast and ovarian cancer. In: Adam MP, Ardinger HH, Pagon RA, et al, eds. GeneReviews. Seattle, WA: University of Washington, Seattle; 1993.
12. ACMG Board of Directors. Scope of practice: a statement of the American College of Medical Genetics and Genomics (ACMG). Genet Med. 2015;17(9):e3. doi:10.1038/gim.2015.94
13. National Society of Genetic Counselors’ Definition Task Force, Resta R, Biesecker BB, et al. A new definition of Genetic Counseling: National Society of Genetic Counselors’ Task Force report. J Genet Couns. 2006;15(2):77-83. doi:10.1007/s10897-005-9014-3
14. Calzone KA, Cashion A, Feetham S, et al. Nurses transforming health care using genetics and genomics [published correction appears in Nurs Outlook. 2010;58(3):163]. Nurs Outlook. 2010;58(1):26-35. doi:10.1016/j.outlook.2009.05.001
15. US Department of Veterans Affairs, Veterans Health Administration, Office of Nursing Services. 2018 Office of Nursing Services (ONS) Annual Brief. https://www.va.gov/nursing/docs/about/2018_ONS_Annual_Report_Brief.pdf. Accessed July 21, 2020.
16. Lerman C, Croyle RT. Emotional and behavioral responses to genetic testing for susceptibility to cancer. Oncology (Williston Park). 1996;10(2):191-202.
17. Bonadona V, Saltel P, Desseigne F, et al. Cancer patients who experienced diagnostic genetic testing for cancer susceptibility: reactions and behavior after the disclosure of a positive test result. Cancer Epidemiol Biomarkers Prev. 2002;11(1):97-104.
18. Murakami Y, Okamura H, Sugano K, et al. Psychologic distress after disclosure of genetic test results regarding hereditary nonpolyposis colorectal carcinoma. Cancer. 2004;101(2):395-403. doi:10.1002/cncr.20363
19. Brierley KL, Campfield D, Ducaine W, et al. Errors in delivery of cancer genetics services: implications for practice. Conn Med. 2010;74(7):413-423.
20. Dhar SU, Cooper HP, Wang T, et al. Significant differences among physician specialties in management recommendations of BRCA1 mutation carriers. Breast Cancer Res Treat. 2011;129(1):221-227. doi:10.1007/s10549-011-1449-7
21. Plon SE, Cooper HP, Parks B, et al. Genetic testing and cancer risk management recommendations by physicians for at-risk relatives. Genet Med. 2011;13(2):148-154. doi:10.1097/GIM.0b013e318207f564
22. Bellcross CA, Kolor K, Goddard KA, Coates RJ, Reyes M, Khoury MJ. Awareness and utilization of BRCA1/2 testing among U.S. primary care physicians. Am J Prev Med. 2011;40(1):61-66. doi:10.1016/j.amepre.2010.09.027
23. Pal T, Cragun D, Lewis C, et al. A statewide survey of practitioners to assess knowledge and clinical practices regarding hereditary breast and ovarian cancer. Genet Test Mol Biomarkers. 2013;17(5):367-375. doi:10.1089/gtmb.2012.0381
24. Bensend TA, Veach PM, Niendorf KB. What’s the harm? Genetic counselor perceptions of adverse effects of genetics service provision by non-genetics professionals. J Genet Couns. 2014;23(1):48-63. doi:10.1007/s10897-013-9605-3
25. Teng I, Spigelman A. Attitudes and knowledge of medical practitioners to hereditary cancer clinics and cancer genetic testing. Fam Cancer. 2014;13(2):311-324. doi:10.1007/s10689-013-9695-y
26. Mikat-Stevens NA, Larson IA, Tarini BA. Primary-care providers’ perceived barriers to integration of genetics services: a systematic review of the literature. Genet Med. 2015;17(3):169-176. doi:10.1038/gim.2014.101
27. Scheuner MT, Hilborne L, Brown J, Lubin IM; members of the RAND Molecular Genetic Test Report Advisory Board. A report template for molecular genetic tests designed to improve communication between the clinician and laboratory. Genet Test Mol Biomarkers. 2012;16(7):761-769. doi:10.1089/gtmb.2011.0328
28. Scheuner MT, Peredo J, Tangney K, et al. Electronic health record interventions at the point of care improve documentation of care processes and decrease orders for genetic tests commonly ordered by nongeneticists. Genet Med. 2017;19(1):112-120. doi:10.1038/gim.2016.73
29. Cooksey JA, Forte G, Benkendorf J, Blitzer MG. The state of the medical geneticist workforce: findings of the 2003 survey of American Board of Medical Genetics certified geneticists. Genet Med. 2005;7(6):439-443. doi:10.1097/01.gim.0000172416.35285.9f
30. Institute of Medicine. Roundtable on Translating Genomic-Based Research for Health. Washington, DC: National Academies Press; 2009. https://www.ncbi.nlm.nih.gov/books/NBK26394. Accessed July 22, 2020.
31. Hoskovec JM, Bennett RL, Carey ME, et al. Projecting the supply and demand for certified genetic counselors: a workforce study. J Genet Couns. 2018;27(1):16-20. doi:10.1007/s10897-017-0158-8
32. Penon-Portmann M, Chang J, Cheng M, Shieh JT. Genetics workforce: distribution of genetics services and challenges to health care in California. Genet Med. 2020;22(1):227-231. doi:10.1038/s41436-019-0628-5
33. Spoont M, Greer N, Su J, Fitzgerald P, Rutks I, Wilt TJ. Rural vs. Urban Ambulatory Health Care: A Systematic Review. Washington, DC: US Department of Veterans Affairs; 2011. https://www.hsrd.research.va.gov/publications/esp/ambulatory.cfm. Accessed July 21, 2020.
34. Mehrotra A, Forrest CB, Lin CY. Dropping the baton: specialty referrals in the United States. Milbank Q. 2011;89(1):39-68. doi:10.1111/j.1468-0009.2011.00619.x
35. Walsh J, Harrison JD, Young JM, Butow PN, Solomon MJ, Masya L. What are the current barriers to effective cancer care coordination? A qualitative study. BMC Health Serv Res. 2010;10:132. Published 2010 May 20. doi:10.1186/1472-6963-10-132
36. McDonald KM, Schultz E, Albin L, et al. Care Coordination Measures Atlas. Version 4. Agency for Healthcare Research and Quality Publication No. 14-0037. https://www.ahrq.gov/sites/default/files/publications/files/ccm_atlas.pdf. Updated June 2014. Accessed July 22, 2020.
37. Greenwood-Lee J, Jewett L, Woodhouse L, Marshall DA. A categorisation of problems and solutions to improve patient referrals from primary to specialty care. BMC Health Serv Res. 2018;18(1):986. Published 2018 Dec 20. doi:10.1186/s12913-018-3745-y
38. US Department of Veterans Affairs, Office of Academic Affiliations. Our medical and dental training program. https://www.va.gov/oaa/gme_default.asp. Updated January 7, 2020. Accessed July 21, 2020.
39. Scheuner MT, Marshall N, Lanto A, et al. Delivery of clinical genetic consultative services in the Veterans Health Administration. Genet Med. 2014;16(8):609-619. doi:10.1038/gim.2013.202.
40. Battista RN, Blancquaert I, Laberge AM, van Schendel N, Leduc N. Genetics in health care: an overview of current and emerging models. Public Health Genomics. 2012;15(1):34-45. doi:10.1159/000328846
41. Emery J. The GRAIDS Trial: the development and evaluation of computer decision support for cancer genetic risk assessment in primary care. Ann Hum Biol. 2005;32(2):218-227. doi:10.1080/03014460500074921
42. Scheuner MT, Hamilton AB, Peredo J, et al. A cancer genetics toolkit improves access to genetic services through documentation and use of the family history by primary-care clinicians. Genet Med. 2014;16(1):60-69. doi:10.1038/gim.2013.75
43. Scheuner MT, Peredo J, Tangney K, et al. Electronic health record interventions at the point of care improve documentation of care processes and decrease orders for genetic tests commonly ordered by nongeneticists. Genet Med. 2017;19(1):112-120. doi:10.1038/gim.2016.73
44. Hamilton AB, Oishi S, Yano EM, Gammage CE, Marshall NJ, Scheuner MT. Factors influencing organizational adoption and implementation of clinical genetic services. Genet Med. 2014;16(3):238-245. doi:10.1038/gim.2013.101
45. Sperber NR, Andrews SM, Voils CI, Green GL, Provenzale D, Knight S. Barriers and facilitators to adoption of genomic services for colorectal care within the Veterans Health Administration. J Pers Med. 2016;6(2):16. Published 2016 Apr 28. doi:10.3390/jpm6020016
46. US Department of Veterans Affairs, Health Services Research and Development. Genomics. https://www.hsrd.research.va.gov/research/portfolio_description.cfm?Sulu=17. Updated July 21, 2020. Accessed June 22, 2020.
Introduction: Precision Oncology Changes the Game for VA Health Care (FULL)
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.
1. How the VA is using AI to target cancer, https://www.theatlantic.com/sponsored/ibm-2018/watson-va-cancer/1925. Accessed August 6, 2020.
2. Kelley MJ. VA National Precision Oncology Program. Fed Pract. 2020;37 (suppl 4):S22-S27. doi:10.12788/fp.0037
3. Levine RD, Ekanayake RN, Martin AC, et al. Prostate Cancer Foundation-Department of Veterans Affairs partnership: a model of public-private collaboration to advance treatment and care of invasive cancers. Fed Pract. 2020;37(suppl 4):S32-S37. doi: 10.12788/fp.0035
4. Montgomery B, Rettig M, Kasten J, Muralidhar S, Myrie K, Ramoni R. The Precision Oncology Program for Cancer of the Prostate (POPCaP) network: a Veterans Affairs/Prostate Cancer Foundation collaboration. Fed Pract. 2020;37(suppl 4):S48-S53. doi:10.12788/fp.0021
5. Graff JN, Huang GD. Leveraging Veterans Health Administration clinical and research resources to accelerate discovery and testing in precision oncology. Fed Pract. 2020;37(suppl 4):S62-S67. doi:10.12788/fp.0028
6. Moghanaki D, Hagan M. Strategic initiatives for veterans with lung cancer. Fed Pract. 2020;37(suppl 4):S76-S80. doi:10.12788/fp.0019
7. Scheuner MT, Myrie K, Peredo J, et al. Integrating germline genetics into precision oncology practice in the Veterans Health Administration: challenges and opportunities. Fed Pract. 2020;37(suppl 4):S82-S88. doi:10.12788/fp.0033
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.
1. How the VA is using AI to target cancer, https://www.theatlantic.com/sponsored/ibm-2018/watson-va-cancer/1925. Accessed August 6, 2020.
2. Kelley MJ. VA National Precision Oncology Program. Fed Pract. 2020;37 (suppl 4):S22-S27. doi:10.12788/fp.0037
3. Levine RD, Ekanayake RN, Martin AC, et al. Prostate Cancer Foundation-Department of Veterans Affairs partnership: a model of public-private collaboration to advance treatment and care of invasive cancers. Fed Pract. 2020;37(suppl 4):S32-S37. doi: 10.12788/fp.0035
4. Montgomery B, Rettig M, Kasten J, Muralidhar S, Myrie K, Ramoni R. The Precision Oncology Program for Cancer of the Prostate (POPCaP) network: a Veterans Affairs/Prostate Cancer Foundation collaboration. Fed Pract. 2020;37(suppl 4):S48-S53. doi:10.12788/fp.0021
5. Graff JN, Huang GD. Leveraging Veterans Health Administration clinical and research resources to accelerate discovery and testing in precision oncology. Fed Pract. 2020;37(suppl 4):S62-S67. doi:10.12788/fp.0028
6. Moghanaki D, Hagan M. Strategic initiatives for veterans with lung cancer. Fed Pract. 2020;37(suppl 4):S76-S80. doi:10.12788/fp.0019
7. Scheuner MT, Myrie K, Peredo J, et al. Integrating germline genetics into precision oncology practice in the Veterans Health Administration: challenges and opportunities. Fed Pract. 2020;37(suppl 4):S82-S88. doi:10.12788/fp.0033
1. How the VA is using AI to target cancer, https://www.theatlantic.com/sponsored/ibm-2018/watson-va-cancer/1925. Accessed August 6, 2020.
2. Kelley MJ. VA National Precision Oncology Program. Fed Pract. 2020;37 (suppl 4):S22-S27. doi:10.12788/fp.0037
3. Levine RD, Ekanayake RN, Martin AC, et al. Prostate Cancer Foundation-Department of Veterans Affairs partnership: a model of public-private collaboration to advance treatment and care of invasive cancers. Fed Pract. 2020;37(suppl 4):S32-S37. doi: 10.12788/fp.0035
4. Montgomery B, Rettig M, Kasten J, Muralidhar S, Myrie K, Ramoni R. The Precision Oncology Program for Cancer of the Prostate (POPCaP) network: a Veterans Affairs/Prostate Cancer Foundation collaboration. Fed Pract. 2020;37(suppl 4):S48-S53. doi:10.12788/fp.0021
5. Graff JN, Huang GD. Leveraging Veterans Health Administration clinical and research resources to accelerate discovery and testing in precision oncology. Fed Pract. 2020;37(suppl 4):S62-S67. doi:10.12788/fp.0028
6. Moghanaki D, Hagan M. Strategic initiatives for veterans with lung cancer. Fed Pract. 2020;37(suppl 4):S76-S80. doi:10.12788/fp.0019
7. Scheuner MT, Myrie K, Peredo J, et al. Integrating germline genetics into precision oncology practice in the Veterans Health Administration: challenges and opportunities. Fed Pract. 2020;37(suppl 4):S82-S88. doi:10.12788/fp.0033
VA National Precision Oncology Program (FULL)
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.
The paradigm of precision oncology, in contrast, utilizes unique, patient-specific molecular characteristics to guide prescribing of antineoplastic agents (Figure 2). These molecular characteristics are frequently tumoral but also may be nontumoral, such as germline genetic variants and even nonhuman, such as the gut microbiome as has been proposed as predictive of response to immune checkpoint inhibitors.1,2
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.
The second step of annotation is assignment of the actionability of the variant, using a level of evidence (LoE) scale from 1 (on-label indication) to 4 (absence of clinical evidence; ie, only preclinical or theoretical evidence). Initially, NPOP used an adaptation of the LoE scales from WfG and OncoKB but now mostly uses the recently revised OncoKB LoE. Actionability also includes prediction of resistance to a treatment (LoE level R1 and R2). An example of a resistance gene variant is a KRAS mutation in colorectal cancer, which predicts lack of clinical benefit from anti- EGFR antibodies. It is important to note that a determination of actionability requires 3 inputs: gene, variant, and tumor type. A BRAF V600E mutation in melanoma has different medications with level 1 LoE than does the same mutation in colorectal cancer, for example.
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.
1. Lima ZS, Ghadamzadeh M, Arashloo FT, Amjad G, Ebadi MR, Younesi L. Recent advances of therapeutic targets based on the molecular signature in breast cancer: genetic mutations and implications for current treatment paradigms. J Hematol Oncol. 2019;12(1):38. Published 2019 Apr 11. doi:10.1186/s13045-019-0725-6
2. Fessler J, Matson V, Gajewski TF. Exploring the emerging role of the microbiome in cancer immunotherapy. J Immunother Cancer. 2019;7(1):108. Published 2019 Apr 17. doi:10.1186/s40425-019-0574-4
3. Kiang DT, Kennedy BJ. Tamoxifen (antiestrogen) therapy in advanced breast cancer. Ann Intern Med. 1977;87(6):687- 690. doi:10.7326/0003-4819-87-6-687.
4. Paez JG, Jänne PA, Lee JC, et al. EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science. 2004;304(5676):1497-1500. doi:10.1126/science.1099314
5. Poonnen P, Duffy J, Hintze BJ, et al. Genomic analysis of metastatic solid tumors in veterans: findings from the VHA National Precision Oncology Program. J Clin Oncol. 2019;37(suppl 15):3074. doi:10.1200/JCO.2019.37.15_suppl.3074
6. Katsoulakis E, Duffy JE, Hintze B, Spector NL, Kelley MJ. Comparison of annotation services for nextgeneration sequencing in a large-scale precision oncology program. JCO Precis Oncol. 2020(4):212-221. doi:10.1200/PO.19.00118
7. Drilon A, Laetsch TW, Kummar S, et al. Efficacy of larotrectinib in TRK fusion-positive cancers in adults and children. N Engl J Med. 2018;378(8):731-739. doi:10.1056/NEJMoa1714448
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.
The paradigm of precision oncology, in contrast, utilizes unique, patient-specific molecular characteristics to guide prescribing of antineoplastic agents (Figure 2). These molecular characteristics are frequently tumoral but also may be nontumoral, such as germline genetic variants and even nonhuman, such as the gut microbiome as has been proposed as predictive of response to immune checkpoint inhibitors.1,2
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.
The second step of annotation is assignment of the actionability of the variant, using a level of evidence (LoE) scale from 1 (on-label indication) to 4 (absence of clinical evidence; ie, only preclinical or theoretical evidence). Initially, NPOP used an adaptation of the LoE scales from WfG and OncoKB but now mostly uses the recently revised OncoKB LoE. Actionability also includes prediction of resistance to a treatment (LoE level R1 and R2). An example of a resistance gene variant is a KRAS mutation in colorectal cancer, which predicts lack of clinical benefit from anti- EGFR antibodies. It is important to note that a determination of actionability requires 3 inputs: gene, variant, and tumor type. A BRAF V600E mutation in melanoma has different medications with level 1 LoE than does the same mutation in colorectal cancer, for example.
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.
The paradigm of precision oncology, in contrast, utilizes unique, patient-specific molecular characteristics to guide prescribing of antineoplastic agents (Figure 2). These molecular characteristics are frequently tumoral but also may be nontumoral, such as germline genetic variants and even nonhuman, such as the gut microbiome as has been proposed as predictive of response to immune checkpoint inhibitors.1,2
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.
The second step of annotation is assignment of the actionability of the variant, using a level of evidence (LoE) scale from 1 (on-label indication) to 4 (absence of clinical evidence; ie, only preclinical or theoretical evidence). Initially, NPOP used an adaptation of the LoE scales from WfG and OncoKB but now mostly uses the recently revised OncoKB LoE. Actionability also includes prediction of resistance to a treatment (LoE level R1 and R2). An example of a resistance gene variant is a KRAS mutation in colorectal cancer, which predicts lack of clinical benefit from anti- EGFR antibodies. It is important to note that a determination of actionability requires 3 inputs: gene, variant, and tumor type. A BRAF V600E mutation in melanoma has different medications with level 1 LoE than does the same mutation in colorectal cancer, for example.
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.
1. Lima ZS, Ghadamzadeh M, Arashloo FT, Amjad G, Ebadi MR, Younesi L. Recent advances of therapeutic targets based on the molecular signature in breast cancer: genetic mutations and implications for current treatment paradigms. J Hematol Oncol. 2019;12(1):38. Published 2019 Apr 11. doi:10.1186/s13045-019-0725-6
2. Fessler J, Matson V, Gajewski TF. Exploring the emerging role of the microbiome in cancer immunotherapy. J Immunother Cancer. 2019;7(1):108. Published 2019 Apr 17. doi:10.1186/s40425-019-0574-4
3. Kiang DT, Kennedy BJ. Tamoxifen (antiestrogen) therapy in advanced breast cancer. Ann Intern Med. 1977;87(6):687- 690. doi:10.7326/0003-4819-87-6-687.
4. Paez JG, Jänne PA, Lee JC, et al. EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science. 2004;304(5676):1497-1500. doi:10.1126/science.1099314
5. Poonnen P, Duffy J, Hintze BJ, et al. Genomic analysis of metastatic solid tumors in veterans: findings from the VHA National Precision Oncology Program. J Clin Oncol. 2019;37(suppl 15):3074. doi:10.1200/JCO.2019.37.15_suppl.3074
6. Katsoulakis E, Duffy JE, Hintze B, Spector NL, Kelley MJ. Comparison of annotation services for nextgeneration sequencing in a large-scale precision oncology program. JCO Precis Oncol. 2020(4):212-221. doi:10.1200/PO.19.00118
7. Drilon A, Laetsch TW, Kummar S, et al. Efficacy of larotrectinib in TRK fusion-positive cancers in adults and children. N Engl J Med. 2018;378(8):731-739. doi:10.1056/NEJMoa1714448
1. Lima ZS, Ghadamzadeh M, Arashloo FT, Amjad G, Ebadi MR, Younesi L. Recent advances of therapeutic targets based on the molecular signature in breast cancer: genetic mutations and implications for current treatment paradigms. J Hematol Oncol. 2019;12(1):38. Published 2019 Apr 11. doi:10.1186/s13045-019-0725-6
2. Fessler J, Matson V, Gajewski TF. Exploring the emerging role of the microbiome in cancer immunotherapy. J Immunother Cancer. 2019;7(1):108. Published 2019 Apr 17. doi:10.1186/s40425-019-0574-4
3. Kiang DT, Kennedy BJ. Tamoxifen (antiestrogen) therapy in advanced breast cancer. Ann Intern Med. 1977;87(6):687- 690. doi:10.7326/0003-4819-87-6-687.
4. Paez JG, Jänne PA, Lee JC, et al. EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science. 2004;304(5676):1497-1500. doi:10.1126/science.1099314
5. Poonnen P, Duffy J, Hintze BJ, et al. Genomic analysis of metastatic solid tumors in veterans: findings from the VHA National Precision Oncology Program. J Clin Oncol. 2019;37(suppl 15):3074. doi:10.1200/JCO.2019.37.15_suppl.3074
6. Katsoulakis E, Duffy JE, Hintze B, Spector NL, Kelley MJ. Comparison of annotation services for nextgeneration sequencing in a large-scale precision oncology program. JCO Precis Oncol. 2020(4):212-221. doi:10.1200/PO.19.00118
7. Drilon A, Laetsch TW, Kummar S, et al. Efficacy of larotrectinib in TRK fusion-positive cancers in adults and children. N Engl J Med. 2018;378(8):731-739. doi:10.1056/NEJMoa1714448