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Circulating Tumor DNA Predicts Early Treatment Response in Patients With HER2-Positive Cancers
This was the main finding of new data presented by study author Razelle Kurzrock, MD, at the American Association for Cancer Research annual meeting.
“We found that on-treatment ctDNA can detect progression before standard-of-care response assessments. These data suggest that monitoring ctDNA can provide clinicians with important prognostic information that may guide treatment decisions,” Dr. Kurzrock, professor at the Medical College of Wisconsin, Milwaukee, said during her presentation.
Commenting on the clinical implications of these findings during an interview, she said the results suggest that ctDNA dynamics provide an early window into predicting response to targeted therapies in patients with HER2-altered cancers, confirming previous findings of the predictive value of ctDNA in other cancer types.
“Such monitoring may be useful in clinical trials and eventually in practice,” she added.
Need for new methods to predict early tumor response
Limitations of standard radiographic tumor assessments present challenges in determining clinical response, particularly for patients receiving targeted therapies.
During her talk, Dr. Kurzrock explained that although targeted therapies are effective for patients with specific molecular alterations, standard imaging assessments fail to uncover molecular-level changes within tumors, limiting the ability of clinicians to accurately assess a patient’s response to targeted therapies.
“In addition to limitations with imaging, patients and physicians want to know as soon as possible whether or not the agents are effective, especially if there are side effects,” Dr. Kurzrock during an interview. She added that monitoring early response may be especially important across tumor types, as HER2 therapies are increasingly being considered in the pan-cancer setting.
Commenting on the potential use of this method in other cancer types with HER2 alterations, Pashtoon Murtaza Kasi, MD, MS, noted that since the study relied on a tumor-informed assay, it would be applicable across diverse tumor types.
“It is less about tissue type but more about that particular patient’s tumor at that instant in time for which a unique barcode is created,” said Dr. Kasi, a medical oncologist at Weill Cornell Medicine, New York, who was not involved in the study.
In an interview, he added that the shedding and biology would affect the assay’s performance for some tissue types.
Design of patient-specific ctDNA assays
In this retrospective study, the researchers examined ctDNA dynamics in 58 patients with various HER2-positive tumor types, including breast, colorectal, and other solid malignancies harboring HER2 alterations. All the patients received combination HER2-targeted therapy with trastuzumab and pertuzumab in the phase 2 basket trial My Pathway (NCT02091141).
By leveraging comprehensive genomic profiling of each patient’s tumor, the researchers designed personalized ctDNA assays, tracking 2-16 tumor-specific genetic variants in the patients’ blood samples. FoundationOne Tracker was used to detect and quantify ctDNA at baseline and the third cycle of therapy (cycle 3 day 1, or C3D1).
During an interview, Dr. Kurzrock explained that FoundationOne Tracker is a personalized ctDNA monitoring assay that allows for the detection of ctDNA in plasma, enabling ongoing liquid-based monitoring and highly sensitive quantification of ctDNA levels as mean tumor molecules per milliliter of plasma.
Among the 52 patients for whom personalized ctDNA assays were successfully designed, 48 (92.3%) had ctDNA data available at baseline, with a median of 100.7 tumor molecules per milliliter of plasma. Most patients (89.6%) were deemed ctDNA-positive, with a median of 119.5 tumor molecules per milliliter of plasma.
Changes in ctDNA levels predict patient survival
The researchers found that patients who experienced a greater than 90% decline in ctDNA levels by the third treatment cycle had significantly longer overall survival (OS) than those with less than 90% ctDNA decline or any increase. According to data presented by Dr. Kurzrock, the median OS was not reached in the group with greater than 90% decline in on-treatment ctDNA levels, versus 9.4 months in the group with less than 90% decline or ctDNA increase (P = .007). These findings held true when the analysis was limited to the 14 patients with colorectal cancer, in which median OS was not reached in the group with greater than 90% decline in on-treatment ctDNA levels, versus 10.2 months in the group with less than 90% decline or ctDNA increase (P = 0.04).
Notably, the prognostic significance of ctDNA changes remained even among patients exhibiting radiographic stable disease, underscoring the limitations of relying solely on anatomic tumor measurements and highlighting the potential for ctDNA monitoring to complement standard clinical assessments. In the subset of patients with radiographic stable disease, those with a greater than 90% ctDNA decline had significantly longer OS than those with less ctDNA reduction (not reached versus 9.4 months; P = .01).
“When used as a complement to imaging, tissue-informed ctDNA monitoring with FoundationOne Tracker can provide more accuracy than imaging alone,” Dr. Kurzrock noted in an interview.
Dr. Kasi echoed Dr. Kurzrock’s enthusiasm regarding the clinical usefulness of these findings, saying, “Not only can you see very early on in whom the ctDNA is going down and clearing, but you can also tell apart within the group who has ‘stable disease’ as to who is deriving more benefit.”
The researchers also observed that increases in on-treatment ctDNA levels often preceded radiographic evidence of disease progression by a median of 1.3 months. These findings highlight the potential for ctDNA monitoring to complement standard clinical assessments, allowing us to detect treatment response and disease progression earlier than what is possible with imaging alone, Dr. Kurzrock explained during her talk. “This early warning signal could allow clinicians to intervene and modify treatment strategies before overt clinical deterioration,” she said.
In an interview, Dr. Kasi highlighted that this high sensitivity and specificity and the short half-life of the tumor-informed ctDNA assay make this liquid biopsy of great clinical value. “The short half-life of a few hours means that if you do an intervention to treat cancer with HER2-directed therapy, you can very quickly assess response to therapy way earlier than traditional radiographic methods.”
Dr. Kasi cautioned, however, that this assay would not capture whether new mutations or HER2 loss occurred at the time of resistance. “A repeat tissue biopsy or a next-generation sequencing-based plasma-only assay would be required for that,” he said.
Implementation of ctDNA monitoring in clinical trials
Dr. Kurzrock acknowledged that further research is needed to validate these results in larger, prospective cohorts before FoundationOne Tracker is adopted in the clinic. She noted, however, that this retrospective analysis, along with results from previous studies, provides a rationale for the use of ctDNA monitoring in clinical trials.
“In some centers like ours, ctDNA monitoring is already part of our standard of care since not only does it help from a physician standpoint to have a more accurate and early assessment of response, but patients also appreciate the information gained from ctDNA dynamics,” Dr. Kasi said in an interview. He explained that when radiographic findings are equivocal, ctDNA monitoring is an additional tool in their toolbox to help guide care.
He noted, however, that the cost is a challenge for implementing ctDNA monitoring as a complementary tool for real-time treatment response monitoring. “For serial monitoring, helping to reduce costs would be important in the long run,” he said in an interview. He added that obtaining sufficient tissue for testing using a tumor-informed assay can present a logistical challenge, at least for the first test. “You need sufficient tissue to make the barcode that you then follow along,” he explained.
“Developing guidelines through systematic studies about testing cadence would also be important. This would help establish whether ctDNA monitoring is helpful,” Dr. Kasi said in an interview. He explained that in some situations, biological variables affect the shedding and detection of ctDNA beyond the assay — in those cases, ctDNA monitoring may not be helpful. “Like any test, it is not meant for every patient or clinical question,” Dr. Kasi concluded.
Dr. Kurzrock and Dr. Kasi reported no relationships with entities whose primary business is producing, marketing, selling, reselling, or distributing healthcare products used by or on patients.
This was the main finding of new data presented by study author Razelle Kurzrock, MD, at the American Association for Cancer Research annual meeting.
“We found that on-treatment ctDNA can detect progression before standard-of-care response assessments. These data suggest that monitoring ctDNA can provide clinicians with important prognostic information that may guide treatment decisions,” Dr. Kurzrock, professor at the Medical College of Wisconsin, Milwaukee, said during her presentation.
Commenting on the clinical implications of these findings during an interview, she said the results suggest that ctDNA dynamics provide an early window into predicting response to targeted therapies in patients with HER2-altered cancers, confirming previous findings of the predictive value of ctDNA in other cancer types.
“Such monitoring may be useful in clinical trials and eventually in practice,” she added.
Need for new methods to predict early tumor response
Limitations of standard radiographic tumor assessments present challenges in determining clinical response, particularly for patients receiving targeted therapies.
During her talk, Dr. Kurzrock explained that although targeted therapies are effective for patients with specific molecular alterations, standard imaging assessments fail to uncover molecular-level changes within tumors, limiting the ability of clinicians to accurately assess a patient’s response to targeted therapies.
“In addition to limitations with imaging, patients and physicians want to know as soon as possible whether or not the agents are effective, especially if there are side effects,” Dr. Kurzrock during an interview. She added that monitoring early response may be especially important across tumor types, as HER2 therapies are increasingly being considered in the pan-cancer setting.
Commenting on the potential use of this method in other cancer types with HER2 alterations, Pashtoon Murtaza Kasi, MD, MS, noted that since the study relied on a tumor-informed assay, it would be applicable across diverse tumor types.
“It is less about tissue type but more about that particular patient’s tumor at that instant in time for which a unique barcode is created,” said Dr. Kasi, a medical oncologist at Weill Cornell Medicine, New York, who was not involved in the study.
In an interview, he added that the shedding and biology would affect the assay’s performance for some tissue types.
Design of patient-specific ctDNA assays
In this retrospective study, the researchers examined ctDNA dynamics in 58 patients with various HER2-positive tumor types, including breast, colorectal, and other solid malignancies harboring HER2 alterations. All the patients received combination HER2-targeted therapy with trastuzumab and pertuzumab in the phase 2 basket trial My Pathway (NCT02091141).
By leveraging comprehensive genomic profiling of each patient’s tumor, the researchers designed personalized ctDNA assays, tracking 2-16 tumor-specific genetic variants in the patients’ blood samples. FoundationOne Tracker was used to detect and quantify ctDNA at baseline and the third cycle of therapy (cycle 3 day 1, or C3D1).
During an interview, Dr. Kurzrock explained that FoundationOne Tracker is a personalized ctDNA monitoring assay that allows for the detection of ctDNA in plasma, enabling ongoing liquid-based monitoring and highly sensitive quantification of ctDNA levels as mean tumor molecules per milliliter of plasma.
Among the 52 patients for whom personalized ctDNA assays were successfully designed, 48 (92.3%) had ctDNA data available at baseline, with a median of 100.7 tumor molecules per milliliter of plasma. Most patients (89.6%) were deemed ctDNA-positive, with a median of 119.5 tumor molecules per milliliter of plasma.
Changes in ctDNA levels predict patient survival
The researchers found that patients who experienced a greater than 90% decline in ctDNA levels by the third treatment cycle had significantly longer overall survival (OS) than those with less than 90% ctDNA decline or any increase. According to data presented by Dr. Kurzrock, the median OS was not reached in the group with greater than 90% decline in on-treatment ctDNA levels, versus 9.4 months in the group with less than 90% decline or ctDNA increase (P = .007). These findings held true when the analysis was limited to the 14 patients with colorectal cancer, in which median OS was not reached in the group with greater than 90% decline in on-treatment ctDNA levels, versus 10.2 months in the group with less than 90% decline or ctDNA increase (P = 0.04).
Notably, the prognostic significance of ctDNA changes remained even among patients exhibiting radiographic stable disease, underscoring the limitations of relying solely on anatomic tumor measurements and highlighting the potential for ctDNA monitoring to complement standard clinical assessments. In the subset of patients with radiographic stable disease, those with a greater than 90% ctDNA decline had significantly longer OS than those with less ctDNA reduction (not reached versus 9.4 months; P = .01).
“When used as a complement to imaging, tissue-informed ctDNA monitoring with FoundationOne Tracker can provide more accuracy than imaging alone,” Dr. Kurzrock noted in an interview.
Dr. Kasi echoed Dr. Kurzrock’s enthusiasm regarding the clinical usefulness of these findings, saying, “Not only can you see very early on in whom the ctDNA is going down and clearing, but you can also tell apart within the group who has ‘stable disease’ as to who is deriving more benefit.”
The researchers also observed that increases in on-treatment ctDNA levels often preceded radiographic evidence of disease progression by a median of 1.3 months. These findings highlight the potential for ctDNA monitoring to complement standard clinical assessments, allowing us to detect treatment response and disease progression earlier than what is possible with imaging alone, Dr. Kurzrock explained during her talk. “This early warning signal could allow clinicians to intervene and modify treatment strategies before overt clinical deterioration,” she said.
In an interview, Dr. Kasi highlighted that this high sensitivity and specificity and the short half-life of the tumor-informed ctDNA assay make this liquid biopsy of great clinical value. “The short half-life of a few hours means that if you do an intervention to treat cancer with HER2-directed therapy, you can very quickly assess response to therapy way earlier than traditional radiographic methods.”
Dr. Kasi cautioned, however, that this assay would not capture whether new mutations or HER2 loss occurred at the time of resistance. “A repeat tissue biopsy or a next-generation sequencing-based plasma-only assay would be required for that,” he said.
Implementation of ctDNA monitoring in clinical trials
Dr. Kurzrock acknowledged that further research is needed to validate these results in larger, prospective cohorts before FoundationOne Tracker is adopted in the clinic. She noted, however, that this retrospective analysis, along with results from previous studies, provides a rationale for the use of ctDNA monitoring in clinical trials.
“In some centers like ours, ctDNA monitoring is already part of our standard of care since not only does it help from a physician standpoint to have a more accurate and early assessment of response, but patients also appreciate the information gained from ctDNA dynamics,” Dr. Kasi said in an interview. He explained that when radiographic findings are equivocal, ctDNA monitoring is an additional tool in their toolbox to help guide care.
He noted, however, that the cost is a challenge for implementing ctDNA monitoring as a complementary tool for real-time treatment response monitoring. “For serial monitoring, helping to reduce costs would be important in the long run,” he said in an interview. He added that obtaining sufficient tissue for testing using a tumor-informed assay can present a logistical challenge, at least for the first test. “You need sufficient tissue to make the barcode that you then follow along,” he explained.
“Developing guidelines through systematic studies about testing cadence would also be important. This would help establish whether ctDNA monitoring is helpful,” Dr. Kasi said in an interview. He explained that in some situations, biological variables affect the shedding and detection of ctDNA beyond the assay — in those cases, ctDNA monitoring may not be helpful. “Like any test, it is not meant for every patient or clinical question,” Dr. Kasi concluded.
Dr. Kurzrock and Dr. Kasi reported no relationships with entities whose primary business is producing, marketing, selling, reselling, or distributing healthcare products used by or on patients.
This was the main finding of new data presented by study author Razelle Kurzrock, MD, at the American Association for Cancer Research annual meeting.
“We found that on-treatment ctDNA can detect progression before standard-of-care response assessments. These data suggest that monitoring ctDNA can provide clinicians with important prognostic information that may guide treatment decisions,” Dr. Kurzrock, professor at the Medical College of Wisconsin, Milwaukee, said during her presentation.
Commenting on the clinical implications of these findings during an interview, she said the results suggest that ctDNA dynamics provide an early window into predicting response to targeted therapies in patients with HER2-altered cancers, confirming previous findings of the predictive value of ctDNA in other cancer types.
“Such monitoring may be useful in clinical trials and eventually in practice,” she added.
Need for new methods to predict early tumor response
Limitations of standard radiographic tumor assessments present challenges in determining clinical response, particularly for patients receiving targeted therapies.
During her talk, Dr. Kurzrock explained that although targeted therapies are effective for patients with specific molecular alterations, standard imaging assessments fail to uncover molecular-level changes within tumors, limiting the ability of clinicians to accurately assess a patient’s response to targeted therapies.
“In addition to limitations with imaging, patients and physicians want to know as soon as possible whether or not the agents are effective, especially if there are side effects,” Dr. Kurzrock during an interview. She added that monitoring early response may be especially important across tumor types, as HER2 therapies are increasingly being considered in the pan-cancer setting.
Commenting on the potential use of this method in other cancer types with HER2 alterations, Pashtoon Murtaza Kasi, MD, MS, noted that since the study relied on a tumor-informed assay, it would be applicable across diverse tumor types.
“It is less about tissue type but more about that particular patient’s tumor at that instant in time for which a unique barcode is created,” said Dr. Kasi, a medical oncologist at Weill Cornell Medicine, New York, who was not involved in the study.
In an interview, he added that the shedding and biology would affect the assay’s performance for some tissue types.
Design of patient-specific ctDNA assays
In this retrospective study, the researchers examined ctDNA dynamics in 58 patients with various HER2-positive tumor types, including breast, colorectal, and other solid malignancies harboring HER2 alterations. All the patients received combination HER2-targeted therapy with trastuzumab and pertuzumab in the phase 2 basket trial My Pathway (NCT02091141).
By leveraging comprehensive genomic profiling of each patient’s tumor, the researchers designed personalized ctDNA assays, tracking 2-16 tumor-specific genetic variants in the patients’ blood samples. FoundationOne Tracker was used to detect and quantify ctDNA at baseline and the third cycle of therapy (cycle 3 day 1, or C3D1).
During an interview, Dr. Kurzrock explained that FoundationOne Tracker is a personalized ctDNA monitoring assay that allows for the detection of ctDNA in plasma, enabling ongoing liquid-based monitoring and highly sensitive quantification of ctDNA levels as mean tumor molecules per milliliter of plasma.
Among the 52 patients for whom personalized ctDNA assays were successfully designed, 48 (92.3%) had ctDNA data available at baseline, with a median of 100.7 tumor molecules per milliliter of plasma. Most patients (89.6%) were deemed ctDNA-positive, with a median of 119.5 tumor molecules per milliliter of plasma.
Changes in ctDNA levels predict patient survival
The researchers found that patients who experienced a greater than 90% decline in ctDNA levels by the third treatment cycle had significantly longer overall survival (OS) than those with less than 90% ctDNA decline or any increase. According to data presented by Dr. Kurzrock, the median OS was not reached in the group with greater than 90% decline in on-treatment ctDNA levels, versus 9.4 months in the group with less than 90% decline or ctDNA increase (P = .007). These findings held true when the analysis was limited to the 14 patients with colorectal cancer, in which median OS was not reached in the group with greater than 90% decline in on-treatment ctDNA levels, versus 10.2 months in the group with less than 90% decline or ctDNA increase (P = 0.04).
Notably, the prognostic significance of ctDNA changes remained even among patients exhibiting radiographic stable disease, underscoring the limitations of relying solely on anatomic tumor measurements and highlighting the potential for ctDNA monitoring to complement standard clinical assessments. In the subset of patients with radiographic stable disease, those with a greater than 90% ctDNA decline had significantly longer OS than those with less ctDNA reduction (not reached versus 9.4 months; P = .01).
“When used as a complement to imaging, tissue-informed ctDNA monitoring with FoundationOne Tracker can provide more accuracy than imaging alone,” Dr. Kurzrock noted in an interview.
Dr. Kasi echoed Dr. Kurzrock’s enthusiasm regarding the clinical usefulness of these findings, saying, “Not only can you see very early on in whom the ctDNA is going down and clearing, but you can also tell apart within the group who has ‘stable disease’ as to who is deriving more benefit.”
The researchers also observed that increases in on-treatment ctDNA levels often preceded radiographic evidence of disease progression by a median of 1.3 months. These findings highlight the potential for ctDNA monitoring to complement standard clinical assessments, allowing us to detect treatment response and disease progression earlier than what is possible with imaging alone, Dr. Kurzrock explained during her talk. “This early warning signal could allow clinicians to intervene and modify treatment strategies before overt clinical deterioration,” she said.
In an interview, Dr. Kasi highlighted that this high sensitivity and specificity and the short half-life of the tumor-informed ctDNA assay make this liquid biopsy of great clinical value. “The short half-life of a few hours means that if you do an intervention to treat cancer with HER2-directed therapy, you can very quickly assess response to therapy way earlier than traditional radiographic methods.”
Dr. Kasi cautioned, however, that this assay would not capture whether new mutations or HER2 loss occurred at the time of resistance. “A repeat tissue biopsy or a next-generation sequencing-based plasma-only assay would be required for that,” he said.
Implementation of ctDNA monitoring in clinical trials
Dr. Kurzrock acknowledged that further research is needed to validate these results in larger, prospective cohorts before FoundationOne Tracker is adopted in the clinic. She noted, however, that this retrospective analysis, along with results from previous studies, provides a rationale for the use of ctDNA monitoring in clinical trials.
“In some centers like ours, ctDNA monitoring is already part of our standard of care since not only does it help from a physician standpoint to have a more accurate and early assessment of response, but patients also appreciate the information gained from ctDNA dynamics,” Dr. Kasi said in an interview. He explained that when radiographic findings are equivocal, ctDNA monitoring is an additional tool in their toolbox to help guide care.
He noted, however, that the cost is a challenge for implementing ctDNA monitoring as a complementary tool for real-time treatment response monitoring. “For serial monitoring, helping to reduce costs would be important in the long run,” he said in an interview. He added that obtaining sufficient tissue for testing using a tumor-informed assay can present a logistical challenge, at least for the first test. “You need sufficient tissue to make the barcode that you then follow along,” he explained.
“Developing guidelines through systematic studies about testing cadence would also be important. This would help establish whether ctDNA monitoring is helpful,” Dr. Kasi said in an interview. He explained that in some situations, biological variables affect the shedding and detection of ctDNA beyond the assay — in those cases, ctDNA monitoring may not be helpful. “Like any test, it is not meant for every patient or clinical question,” Dr. Kasi concluded.
Dr. Kurzrock and Dr. Kasi reported no relationships with entities whose primary business is producing, marketing, selling, reselling, or distributing healthcare products used by or on patients.
FROM AACR 2024
Repeat MCED Testing May ID Early-Stage and Unscreened Cancers
This was the conclusion of recent data presented by Ora Karp Gordon, MD, MS, during a session at the American Association for Cancer Research annual meeting.
The MCED test, known as Galleri, was made clinically available in the United States in April 2021. Developed by GRAIL LLC, the test analyzes cell-free DNA in the blood using targeted methylation analysis and machine learning to detect the presence of a cancer signal and determine its organ of origin or cancer signal origin. The initial screening of over 53,000 individuals with the Galleri test detected a cancer signal in 1.1% of participants.
The new real-world analysis examines the outcomes of repeat MCED testing in 5,794 individuals.
The study looked at individuals who initially received a ‘no cancer signal detected’ result and then underwent a second Galleri test. Over 80% of participants received their follow-up test 10-18 months after the first, with a median interval between blood draws of 12.9 months.
“The repeat tests detect those cancer cases that have reached the detection threshold since their last MCED test, which should be less than one year of incidence,” Dr. Gordon, professor at Saint John’s Cancer Institute, Santa Monica, California, said in an interview. “We are just now starting to see results from patients who get their second and even third round of screening.”
“Galleri is recommended to be used annually in addition to USPSTF [US Preventive Services Task Force]–recommended cancer screening tests, like mammography and colonoscopy,” she said.
This recommendation is based on a modeling study suggesting that annual screening would improve stage shift, diagnostic yield, and potentially mortality when compared to biennial screening, although biennial screening was still favorable compared with no screening, she explained.
Early Real-World Evidence of Repeat Testing
Among the cohort of 5,794 individuals who received repeat testing, 26 received a positive cancer signal on their second test, yielding a cancer signal detection rate of 0.45% (95% CI: 0.31%-0.66%). The cancer signal detection rate was slightly higher in men. The rate was 0.50% (95% CI: 0.32%-0.81%; 17 of 3367) in men versus 0.37% (95% CI: 0.2%-0.7%; 9 of 2427) in women.
During her presentation, Dr. Gordon highlighted that the repeat testing signal detection rate was lower than the initial 0.95% rate (95% CI: 0.87-1.0; 510 of 53,744) seen in the previous larger cohort of patients who were retested at 1 year.
She acknowledged that the lower cancer signal detection rate of repeat testing may indicate some degree of ‘early adopter’ bias, where those who return for a second test are systematically different from the general screening population. This could suggest that broader population-level screening may yield different results, she continued.
Shift Toward Unscreened Cancers
The top cancer types identified in the second round of testing were lymphoid, head and neck, bladder/urothelial, colorectal, and anal cancers. Clinicians were able to confirm clinical outcomes in 12 of 26 cases, in which cancer signals were detected. Of those 12 cases, 8 individuals received a cancer diagnosis and 4 did not have cancer. The remaining 14 of 26 cases in which cancer signals were detected are still under investigation.
“We found a shift away from USPSTF screen-detected cancers, like breast, lung, and prostate, and relative increase in unscreened urinary, head and neck, and lymphoid cancers, with 75% of cancers being those without any screening guidelines,” Dr. Gordon said in an interview.
She added that patients who choose to retest may have different cancer rates for several reasons, including bias toward a population that is health conscious and adhered to all recommended cancer screening.
“So the shift toward unscreened cancers is not unexpected and highlights the value of Galleri,” she said, but also acknowledged that “continued monitoring is needed to see if this translates in a persistent finding over time and tests.”
Shift Toward Early-Stage Cancers
Staging information was available for five cases, and Dr. Gordon highlighted in her talk that four of these confirmed cancers were stage I, including cancers of the anus, head and neck, bladder, and lymphoma. The fifth confirmed cancer with staging information was stage IV ovarian cancer.
“It is still early, and the numbers are very small, but the detection of early-stage cancers with second annual testing is very encouraging as these are the cases where MCED testing could have the greatest impact in improving outcomes through earlier treatment,” Dr. Gordon told this publication.
During an interview after the talk, Kenneth L. Kehl, MD, MPH, echoed that data must be confirmed in larger cohorts.
“The shift toward earlier stage cancers that are less detectable by standard screening methods is an interesting result, but we need to be cautious since the numbers were relatively small, and we do not have data on cancers that were diagnosed among patients whose second MCED test was also negative,” said Dr. Kehl, a medical oncologist at Dana-Farber Cancer Institute, Boston.
MCED Results Could Help Direct Diagnostic Workup
The test’s ability to predict the organ of origin was highly accurate, correctly identifying the cancer type in all eight confirmed cases. Among the eight cases with a confirmed cancer diagnosis, the accuracy of the first prediction was 100%, and diagnoses included invasive cancers across multiple tissues and organs, including anus, colon, head and neck, urothelial tract, ovary, and the lymphatic system.
“The fact that the site of origin for 100% of confirmed cancers was accurately predicted with GRAIL’s CSO by Galleri test confirms the promise that this can guide workup when a cancer signal is detected,” Dr. Gordon noted in the interview.
Looking Ahead
Dr. Kehl, who was not involved in the MCED study, noted in an interview that “further data on test characteristics beyond positive predictive value, including the sensitivity, specificity, and negative predictive value, as well as demonstration of clinical benefit — ideally in a randomized trial — will likely be required for MCED testing to become a standard public health recommendation.”
He added that challenges associated with implementing annual screening with MCED tests include the risks of both false positives and false negatives as testing becomes more widely available.
“False positives cause anxiety and lead to additional testing that may carry its own risks, and we need to understand if potentially false negative tests will be associated with less uptake of established screening strategies,” Dr. Kehl said in an interview. However, he noted that serial testing could lead to more frequent diagnoses of early-stage cancers that may be less detectable by standard methods.
Dr. Gordon reported financial relationships with GRAIL LLC and Genetic Technologies Corporation. Dr. Kehl reported no relationships with entities whose primary business is producing, marketing, selling, reselling, or distributing healthcare products used by or on patients.
This was the conclusion of recent data presented by Ora Karp Gordon, MD, MS, during a session at the American Association for Cancer Research annual meeting.
The MCED test, known as Galleri, was made clinically available in the United States in April 2021. Developed by GRAIL LLC, the test analyzes cell-free DNA in the blood using targeted methylation analysis and machine learning to detect the presence of a cancer signal and determine its organ of origin or cancer signal origin. The initial screening of over 53,000 individuals with the Galleri test detected a cancer signal in 1.1% of participants.
The new real-world analysis examines the outcomes of repeat MCED testing in 5,794 individuals.
The study looked at individuals who initially received a ‘no cancer signal detected’ result and then underwent a second Galleri test. Over 80% of participants received their follow-up test 10-18 months after the first, with a median interval between blood draws of 12.9 months.
“The repeat tests detect those cancer cases that have reached the detection threshold since their last MCED test, which should be less than one year of incidence,” Dr. Gordon, professor at Saint John’s Cancer Institute, Santa Monica, California, said in an interview. “We are just now starting to see results from patients who get their second and even third round of screening.”
“Galleri is recommended to be used annually in addition to USPSTF [US Preventive Services Task Force]–recommended cancer screening tests, like mammography and colonoscopy,” she said.
This recommendation is based on a modeling study suggesting that annual screening would improve stage shift, diagnostic yield, and potentially mortality when compared to biennial screening, although biennial screening was still favorable compared with no screening, she explained.
Early Real-World Evidence of Repeat Testing
Among the cohort of 5,794 individuals who received repeat testing, 26 received a positive cancer signal on their second test, yielding a cancer signal detection rate of 0.45% (95% CI: 0.31%-0.66%). The cancer signal detection rate was slightly higher in men. The rate was 0.50% (95% CI: 0.32%-0.81%; 17 of 3367) in men versus 0.37% (95% CI: 0.2%-0.7%; 9 of 2427) in women.
During her presentation, Dr. Gordon highlighted that the repeat testing signal detection rate was lower than the initial 0.95% rate (95% CI: 0.87-1.0; 510 of 53,744) seen in the previous larger cohort of patients who were retested at 1 year.
She acknowledged that the lower cancer signal detection rate of repeat testing may indicate some degree of ‘early adopter’ bias, where those who return for a second test are systematically different from the general screening population. This could suggest that broader population-level screening may yield different results, she continued.
Shift Toward Unscreened Cancers
The top cancer types identified in the second round of testing were lymphoid, head and neck, bladder/urothelial, colorectal, and anal cancers. Clinicians were able to confirm clinical outcomes in 12 of 26 cases, in which cancer signals were detected. Of those 12 cases, 8 individuals received a cancer diagnosis and 4 did not have cancer. The remaining 14 of 26 cases in which cancer signals were detected are still under investigation.
“We found a shift away from USPSTF screen-detected cancers, like breast, lung, and prostate, and relative increase in unscreened urinary, head and neck, and lymphoid cancers, with 75% of cancers being those without any screening guidelines,” Dr. Gordon said in an interview.
She added that patients who choose to retest may have different cancer rates for several reasons, including bias toward a population that is health conscious and adhered to all recommended cancer screening.
“So the shift toward unscreened cancers is not unexpected and highlights the value of Galleri,” she said, but also acknowledged that “continued monitoring is needed to see if this translates in a persistent finding over time and tests.”
Shift Toward Early-Stage Cancers
Staging information was available for five cases, and Dr. Gordon highlighted in her talk that four of these confirmed cancers were stage I, including cancers of the anus, head and neck, bladder, and lymphoma. The fifth confirmed cancer with staging information was stage IV ovarian cancer.
“It is still early, and the numbers are very small, but the detection of early-stage cancers with second annual testing is very encouraging as these are the cases where MCED testing could have the greatest impact in improving outcomes through earlier treatment,” Dr. Gordon told this publication.
During an interview after the talk, Kenneth L. Kehl, MD, MPH, echoed that data must be confirmed in larger cohorts.
“The shift toward earlier stage cancers that are less detectable by standard screening methods is an interesting result, but we need to be cautious since the numbers were relatively small, and we do not have data on cancers that were diagnosed among patients whose second MCED test was also negative,” said Dr. Kehl, a medical oncologist at Dana-Farber Cancer Institute, Boston.
MCED Results Could Help Direct Diagnostic Workup
The test’s ability to predict the organ of origin was highly accurate, correctly identifying the cancer type in all eight confirmed cases. Among the eight cases with a confirmed cancer diagnosis, the accuracy of the first prediction was 100%, and diagnoses included invasive cancers across multiple tissues and organs, including anus, colon, head and neck, urothelial tract, ovary, and the lymphatic system.
“The fact that the site of origin for 100% of confirmed cancers was accurately predicted with GRAIL’s CSO by Galleri test confirms the promise that this can guide workup when a cancer signal is detected,” Dr. Gordon noted in the interview.
Looking Ahead
Dr. Kehl, who was not involved in the MCED study, noted in an interview that “further data on test characteristics beyond positive predictive value, including the sensitivity, specificity, and negative predictive value, as well as demonstration of clinical benefit — ideally in a randomized trial — will likely be required for MCED testing to become a standard public health recommendation.”
He added that challenges associated with implementing annual screening with MCED tests include the risks of both false positives and false negatives as testing becomes more widely available.
“False positives cause anxiety and lead to additional testing that may carry its own risks, and we need to understand if potentially false negative tests will be associated with less uptake of established screening strategies,” Dr. Kehl said in an interview. However, he noted that serial testing could lead to more frequent diagnoses of early-stage cancers that may be less detectable by standard methods.
Dr. Gordon reported financial relationships with GRAIL LLC and Genetic Technologies Corporation. Dr. Kehl reported no relationships with entities whose primary business is producing, marketing, selling, reselling, or distributing healthcare products used by or on patients.
This was the conclusion of recent data presented by Ora Karp Gordon, MD, MS, during a session at the American Association for Cancer Research annual meeting.
The MCED test, known as Galleri, was made clinically available in the United States in April 2021. Developed by GRAIL LLC, the test analyzes cell-free DNA in the blood using targeted methylation analysis and machine learning to detect the presence of a cancer signal and determine its organ of origin or cancer signal origin. The initial screening of over 53,000 individuals with the Galleri test detected a cancer signal in 1.1% of participants.
The new real-world analysis examines the outcomes of repeat MCED testing in 5,794 individuals.
The study looked at individuals who initially received a ‘no cancer signal detected’ result and then underwent a second Galleri test. Over 80% of participants received their follow-up test 10-18 months after the first, with a median interval between blood draws of 12.9 months.
“The repeat tests detect those cancer cases that have reached the detection threshold since their last MCED test, which should be less than one year of incidence,” Dr. Gordon, professor at Saint John’s Cancer Institute, Santa Monica, California, said in an interview. “We are just now starting to see results from patients who get their second and even third round of screening.”
“Galleri is recommended to be used annually in addition to USPSTF [US Preventive Services Task Force]–recommended cancer screening tests, like mammography and colonoscopy,” she said.
This recommendation is based on a modeling study suggesting that annual screening would improve stage shift, diagnostic yield, and potentially mortality when compared to biennial screening, although biennial screening was still favorable compared with no screening, she explained.
Early Real-World Evidence of Repeat Testing
Among the cohort of 5,794 individuals who received repeat testing, 26 received a positive cancer signal on their second test, yielding a cancer signal detection rate of 0.45% (95% CI: 0.31%-0.66%). The cancer signal detection rate was slightly higher in men. The rate was 0.50% (95% CI: 0.32%-0.81%; 17 of 3367) in men versus 0.37% (95% CI: 0.2%-0.7%; 9 of 2427) in women.
During her presentation, Dr. Gordon highlighted that the repeat testing signal detection rate was lower than the initial 0.95% rate (95% CI: 0.87-1.0; 510 of 53,744) seen in the previous larger cohort of patients who were retested at 1 year.
She acknowledged that the lower cancer signal detection rate of repeat testing may indicate some degree of ‘early adopter’ bias, where those who return for a second test are systematically different from the general screening population. This could suggest that broader population-level screening may yield different results, she continued.
Shift Toward Unscreened Cancers
The top cancer types identified in the second round of testing were lymphoid, head and neck, bladder/urothelial, colorectal, and anal cancers. Clinicians were able to confirm clinical outcomes in 12 of 26 cases, in which cancer signals were detected. Of those 12 cases, 8 individuals received a cancer diagnosis and 4 did not have cancer. The remaining 14 of 26 cases in which cancer signals were detected are still under investigation.
“We found a shift away from USPSTF screen-detected cancers, like breast, lung, and prostate, and relative increase in unscreened urinary, head and neck, and lymphoid cancers, with 75% of cancers being those without any screening guidelines,” Dr. Gordon said in an interview.
She added that patients who choose to retest may have different cancer rates for several reasons, including bias toward a population that is health conscious and adhered to all recommended cancer screening.
“So the shift toward unscreened cancers is not unexpected and highlights the value of Galleri,” she said, but also acknowledged that “continued monitoring is needed to see if this translates in a persistent finding over time and tests.”
Shift Toward Early-Stage Cancers
Staging information was available for five cases, and Dr. Gordon highlighted in her talk that four of these confirmed cancers were stage I, including cancers of the anus, head and neck, bladder, and lymphoma. The fifth confirmed cancer with staging information was stage IV ovarian cancer.
“It is still early, and the numbers are very small, but the detection of early-stage cancers with second annual testing is very encouraging as these are the cases where MCED testing could have the greatest impact in improving outcomes through earlier treatment,” Dr. Gordon told this publication.
During an interview after the talk, Kenneth L. Kehl, MD, MPH, echoed that data must be confirmed in larger cohorts.
“The shift toward earlier stage cancers that are less detectable by standard screening methods is an interesting result, but we need to be cautious since the numbers were relatively small, and we do not have data on cancers that were diagnosed among patients whose second MCED test was also negative,” said Dr. Kehl, a medical oncologist at Dana-Farber Cancer Institute, Boston.
MCED Results Could Help Direct Diagnostic Workup
The test’s ability to predict the organ of origin was highly accurate, correctly identifying the cancer type in all eight confirmed cases. Among the eight cases with a confirmed cancer diagnosis, the accuracy of the first prediction was 100%, and diagnoses included invasive cancers across multiple tissues and organs, including anus, colon, head and neck, urothelial tract, ovary, and the lymphatic system.
“The fact that the site of origin for 100% of confirmed cancers was accurately predicted with GRAIL’s CSO by Galleri test confirms the promise that this can guide workup when a cancer signal is detected,” Dr. Gordon noted in the interview.
Looking Ahead
Dr. Kehl, who was not involved in the MCED study, noted in an interview that “further data on test characteristics beyond positive predictive value, including the sensitivity, specificity, and negative predictive value, as well as demonstration of clinical benefit — ideally in a randomized trial — will likely be required for MCED testing to become a standard public health recommendation.”
He added that challenges associated with implementing annual screening with MCED tests include the risks of both false positives and false negatives as testing becomes more widely available.
“False positives cause anxiety and lead to additional testing that may carry its own risks, and we need to understand if potentially false negative tests will be associated with less uptake of established screening strategies,” Dr. Kehl said in an interview. However, he noted that serial testing could lead to more frequent diagnoses of early-stage cancers that may be less detectable by standard methods.
Dr. Gordon reported financial relationships with GRAIL LLC and Genetic Technologies Corporation. Dr. Kehl reported no relationships with entities whose primary business is producing, marketing, selling, reselling, or distributing healthcare products used by or on patients.
FROM AACR 2024
ImPrint Identifies Patients With Breast Cancer Likely to Respond to Neoadjuvant Immunotherapy
SAN DIEGO — Using ImPrint, an immune-related biomarker, clinicians can identify patients with breast cancer who are likely to respond to neoadjuvant immunotherapy, according to data from the ongoing phase 2 I-SPY2 trial.
Patient selection based on ImPrint class can result in high response rates and spare nonresponders the toxicities of immunotherapy, said Denise M. Wolf, PhD, during her presentation of the study results at the annual meeting of the American Association for Cancer Research (AACR).
“Our results show that patients with ER+/HER2-/ImPrint+ breast cancer have a very high probability of achieving complete response to immunotherapy, whereas those who are ER+/HER2-/ImPrint- have a low probability of responding,” noted Dr. Wolf, PhD, MSc of the University of California, San Francisco (UCSF), in an interview.
She added that, although effective, immunotherapy also carries the risk of serious immune-related toxicities, and knowledge of ImPrint class can help patients and physicians determine whether immunotherapy is a good treatment option. “Many patients will be willing to take the risk of immunotherapy toxicities if their odds of responding are very high, as is the case for ImPrint+ patients, but [are] likely less enthused with a low likelihood of response,” Dr. Wolf said during the interview.
Need for Predictive Biomarkers for Neoadjuvant Immunotherapy
Although neoadjuvant immunotherapy has become the standard treatment for patients with early-stage triple-negative breast cancer (TNBC), chemotherapy remains the mainstay of treatment for patients with hormone receptor–positive (HR+), human epidermal growth factor receptor 2–negative (HER2-) breast cancer. The I-SPY2 clinical trial is the first randomized clinical study to assess the efficacy of immunotherapy in the high-risk population of patients with HR+/HER2-, Dr. Wolf said. Data from this study suggest that a subset of HR+/HER2- patients may also derive substantial benefit from this approach compared with standard chemotherapy.
“We and others have previously observed that a minority of ER+/HER2- breast cancers are enriched for tumor-infiltrating lymphocytes and that high levels of immune-related gene signatures associate with improved survival in this subtype, as well as in TNBC,” noted Dr. Wolf during an interview.
She explained that patients with high-risk ER+/HER2- breast cancer were not responding to any of the experimental agent classes tested in the trial and showed particularly poor outcomes, and that she and her colleagues “wanted to see if immune-oncology agents would impact response in these patients.”
ImPrint, an Immune Expression Signature
Preliminary data from the I-SPY2 trial showed that immune-related gene signatures were associated with pathologic complete response (pCR) in patients with HR+/HER2- breast cancer treated with immunotherapy. This observation allowed investigators to develop a clinically applicable immune classifier, termed ImPrint, to predict response to immunotherapy in this population.
This immune classifier is a 53-gene signature developed using data from the first anti–programmed death-1 (PD-1) arm that included patients treated with pembrolizumab, explained Dr. Wolf.
Performance of ImPrint in Patients With HR+/HER2- Breast Cancer
Dr. Wolf presented new data on the performance of ImPrint in 204 patients with high-risk HR+/HER2- breast cancer from the following five immunotherapy arms of the I-SPY2 trial, at the meeting. These arms included: anti–PD-1, anti–PDL-1 plus PARP inhibitor, anti–PD-1/TLR9 dual immunotherapy, and anti–PD-1 with or without LAG3 inhibitor. Data from 191 patients treated with the current standard of care (paclitaxel followed by adriamycin and cyclophosphamide cytoxan) were included in the analysis as a control.
The pCR in the entire population across these five immunotherapy arms was 33%. The response rate in the control arm was 13.5%.
“The high pCR in the immunotherapy groups is remarkable given the traditionally poor response of HR+/HER2- tumors to standard neoadjuvant chemotherapy,” said Ritu Aneja, PhD, the associate dean for research and innovation at the University of Alabama at Birmingham and a breast cancer expert, who was not involved in the I-SPY2 trial.
When patients were stratified according to ImPrint status, significant differences were observed among the groups. In this analysis, 28% of HR+/HER2- patients were classified as ImPrint positive (likely sensitive) based on ImPrint expression levels in pretreatment mRNA samples, and these individuals achieved pCR rates as high as 76% with immunotherapy.
In comparison, pCR rates were only 16% in ImPrint-negative (likely resistant) patients. The highest response rate was observed in the anti–PD-1/TLR9 dual immunotherapy arm, with a pCR rate of greater than 90% in ImPrint-positive patients. In the control arm, pCR rates were 33% in ImPrint-positive and 8% in ImPrint-negative patients.
“These results suggest that a subset of [patients with] high-risk HR+/HER2- breast cancers is highly sensitive to immunotherapy,” said Dr. Aneja in an interview. “By using a specific and sensitive selection strategy like ImPrint, we may be able to identify patients who can achieve pCR rates similar to what we see with the best neoadjuvant therapies in triple-negative and HER2-positive disease.”
Ability of ImPrint to Predict Long-Term Outcomes
During her talk, Dr. Wolf explained that she and her research team currently do not have sufficient follow-up data to assess the ability of ImPrint to predict long-term outcomes. Therefore, they used the pCR data to predict long-term disease-free survival (DRFS) outcomes. Based on their model, HR+/HER2-/ImPrint+ patients treated with immunotherapy were estimated to have a 91% 5-year DRFS rate, compared with 80% for those receiving standard chemotherapy alone. This represents a 52% reduction in the risk of disease recurrence.
“This suggests not only a higher immediate response rate to therapy but also potential long-term benefits for patients identified as ImPrint+,” Dr. Aneja said, commenting on the significance of the DRFS data, during the interview, She added that the ability to predict longer-term outcomes is a critical advantage in selecting the most effective treatment strategies for patients.
Comparison of ImPrint With Other Biomarkers
The investigators compared ImPrint to other potential biomarkers for immunotherapy response, including MammaPrint (ultra) High2 risk (MP2) and tumor grade. During her talk, Dr. Wolf showed data demonstrating that ImPrint is a more precise predictor of pCR, with higher response rates than either of those other markers.
The pCR rates for MP2 and grade III were 56% and 45%, respectively, which are much smaller than the pCR rates observed for ImPrint+ patients (75%).
“This difference underscores ImPrint’s effectiveness in distinguishing patients who could benefit from immunotherapy, offering a pCR prediction accuracy that is significantly higher than seen with other biomarkers that have been proposed as selection markers for neoadjuvant immunotherapy trials in HR+/HER2- breast cancers, such as MP2 and tumor grade,” said Dr. Aneja, during the interview.
Looking Ahead — Implementation of Imprint for Patient Selection
Dr. Aneja echoed that the findings from the I-SPY2 trial advocate for the integration of biomarker-driven approaches, particularly the use of the ImPrint classifier, into the treatment planning process for high-risk HR+/HER2- breast cancer.
“This approach can enable clinicians to identify patients who are more likely to benefit from immunotherapy, thus personalizing treatment strategies and potentially enhancing treatment efficacy while minimizing exposure to unnecessary toxicity for those unlikely to respond,” she said.
Dr. Aneja added that while the I-SPY2 trial offers promising data on ImPrint’s efficacy, additional prospective studies are needed to validate these findings across diverse patient populations and settings, as well as the correlation between biomarker positivity and long-term clinical outcomes, including DRFS and overall survival. “This will help to better understand the full spectrum of benefits provided by immunotherapies in biomarker-selected patient groups,” she said.
Dr. Wolf and Dr. Aneja reported no relationships with entities whose primary business is producing, marketing, selling, reselling, or distributing healthcare products used by or on patients.
SAN DIEGO — Using ImPrint, an immune-related biomarker, clinicians can identify patients with breast cancer who are likely to respond to neoadjuvant immunotherapy, according to data from the ongoing phase 2 I-SPY2 trial.
Patient selection based on ImPrint class can result in high response rates and spare nonresponders the toxicities of immunotherapy, said Denise M. Wolf, PhD, during her presentation of the study results at the annual meeting of the American Association for Cancer Research (AACR).
“Our results show that patients with ER+/HER2-/ImPrint+ breast cancer have a very high probability of achieving complete response to immunotherapy, whereas those who are ER+/HER2-/ImPrint- have a low probability of responding,” noted Dr. Wolf, PhD, MSc of the University of California, San Francisco (UCSF), in an interview.
She added that, although effective, immunotherapy also carries the risk of serious immune-related toxicities, and knowledge of ImPrint class can help patients and physicians determine whether immunotherapy is a good treatment option. “Many patients will be willing to take the risk of immunotherapy toxicities if their odds of responding are very high, as is the case for ImPrint+ patients, but [are] likely less enthused with a low likelihood of response,” Dr. Wolf said during the interview.
Need for Predictive Biomarkers for Neoadjuvant Immunotherapy
Although neoadjuvant immunotherapy has become the standard treatment for patients with early-stage triple-negative breast cancer (TNBC), chemotherapy remains the mainstay of treatment for patients with hormone receptor–positive (HR+), human epidermal growth factor receptor 2–negative (HER2-) breast cancer. The I-SPY2 clinical trial is the first randomized clinical study to assess the efficacy of immunotherapy in the high-risk population of patients with HR+/HER2-, Dr. Wolf said. Data from this study suggest that a subset of HR+/HER2- patients may also derive substantial benefit from this approach compared with standard chemotherapy.
“We and others have previously observed that a minority of ER+/HER2- breast cancers are enriched for tumor-infiltrating lymphocytes and that high levels of immune-related gene signatures associate with improved survival in this subtype, as well as in TNBC,” noted Dr. Wolf during an interview.
She explained that patients with high-risk ER+/HER2- breast cancer were not responding to any of the experimental agent classes tested in the trial and showed particularly poor outcomes, and that she and her colleagues “wanted to see if immune-oncology agents would impact response in these patients.”
ImPrint, an Immune Expression Signature
Preliminary data from the I-SPY2 trial showed that immune-related gene signatures were associated with pathologic complete response (pCR) in patients with HR+/HER2- breast cancer treated with immunotherapy. This observation allowed investigators to develop a clinically applicable immune classifier, termed ImPrint, to predict response to immunotherapy in this population.
This immune classifier is a 53-gene signature developed using data from the first anti–programmed death-1 (PD-1) arm that included patients treated with pembrolizumab, explained Dr. Wolf.
Performance of ImPrint in Patients With HR+/HER2- Breast Cancer
Dr. Wolf presented new data on the performance of ImPrint in 204 patients with high-risk HR+/HER2- breast cancer from the following five immunotherapy arms of the I-SPY2 trial, at the meeting. These arms included: anti–PD-1, anti–PDL-1 plus PARP inhibitor, anti–PD-1/TLR9 dual immunotherapy, and anti–PD-1 with or without LAG3 inhibitor. Data from 191 patients treated with the current standard of care (paclitaxel followed by adriamycin and cyclophosphamide cytoxan) were included in the analysis as a control.
The pCR in the entire population across these five immunotherapy arms was 33%. The response rate in the control arm was 13.5%.
“The high pCR in the immunotherapy groups is remarkable given the traditionally poor response of HR+/HER2- tumors to standard neoadjuvant chemotherapy,” said Ritu Aneja, PhD, the associate dean for research and innovation at the University of Alabama at Birmingham and a breast cancer expert, who was not involved in the I-SPY2 trial.
When patients were stratified according to ImPrint status, significant differences were observed among the groups. In this analysis, 28% of HR+/HER2- patients were classified as ImPrint positive (likely sensitive) based on ImPrint expression levels in pretreatment mRNA samples, and these individuals achieved pCR rates as high as 76% with immunotherapy.
In comparison, pCR rates were only 16% in ImPrint-negative (likely resistant) patients. The highest response rate was observed in the anti–PD-1/TLR9 dual immunotherapy arm, with a pCR rate of greater than 90% in ImPrint-positive patients. In the control arm, pCR rates were 33% in ImPrint-positive and 8% in ImPrint-negative patients.
“These results suggest that a subset of [patients with] high-risk HR+/HER2- breast cancers is highly sensitive to immunotherapy,” said Dr. Aneja in an interview. “By using a specific and sensitive selection strategy like ImPrint, we may be able to identify patients who can achieve pCR rates similar to what we see with the best neoadjuvant therapies in triple-negative and HER2-positive disease.”
Ability of ImPrint to Predict Long-Term Outcomes
During her talk, Dr. Wolf explained that she and her research team currently do not have sufficient follow-up data to assess the ability of ImPrint to predict long-term outcomes. Therefore, they used the pCR data to predict long-term disease-free survival (DRFS) outcomes. Based on their model, HR+/HER2-/ImPrint+ patients treated with immunotherapy were estimated to have a 91% 5-year DRFS rate, compared with 80% for those receiving standard chemotherapy alone. This represents a 52% reduction in the risk of disease recurrence.
“This suggests not only a higher immediate response rate to therapy but also potential long-term benefits for patients identified as ImPrint+,” Dr. Aneja said, commenting on the significance of the DRFS data, during the interview, She added that the ability to predict longer-term outcomes is a critical advantage in selecting the most effective treatment strategies for patients.
Comparison of ImPrint With Other Biomarkers
The investigators compared ImPrint to other potential biomarkers for immunotherapy response, including MammaPrint (ultra) High2 risk (MP2) and tumor grade. During her talk, Dr. Wolf showed data demonstrating that ImPrint is a more precise predictor of pCR, with higher response rates than either of those other markers.
The pCR rates for MP2 and grade III were 56% and 45%, respectively, which are much smaller than the pCR rates observed for ImPrint+ patients (75%).
“This difference underscores ImPrint’s effectiveness in distinguishing patients who could benefit from immunotherapy, offering a pCR prediction accuracy that is significantly higher than seen with other biomarkers that have been proposed as selection markers for neoadjuvant immunotherapy trials in HR+/HER2- breast cancers, such as MP2 and tumor grade,” said Dr. Aneja, during the interview.
Looking Ahead — Implementation of Imprint for Patient Selection
Dr. Aneja echoed that the findings from the I-SPY2 trial advocate for the integration of biomarker-driven approaches, particularly the use of the ImPrint classifier, into the treatment planning process for high-risk HR+/HER2- breast cancer.
“This approach can enable clinicians to identify patients who are more likely to benefit from immunotherapy, thus personalizing treatment strategies and potentially enhancing treatment efficacy while minimizing exposure to unnecessary toxicity for those unlikely to respond,” she said.
Dr. Aneja added that while the I-SPY2 trial offers promising data on ImPrint’s efficacy, additional prospective studies are needed to validate these findings across diverse patient populations and settings, as well as the correlation between biomarker positivity and long-term clinical outcomes, including DRFS and overall survival. “This will help to better understand the full spectrum of benefits provided by immunotherapies in biomarker-selected patient groups,” she said.
Dr. Wolf and Dr. Aneja reported no relationships with entities whose primary business is producing, marketing, selling, reselling, or distributing healthcare products used by or on patients.
SAN DIEGO — Using ImPrint, an immune-related biomarker, clinicians can identify patients with breast cancer who are likely to respond to neoadjuvant immunotherapy, according to data from the ongoing phase 2 I-SPY2 trial.
Patient selection based on ImPrint class can result in high response rates and spare nonresponders the toxicities of immunotherapy, said Denise M. Wolf, PhD, during her presentation of the study results at the annual meeting of the American Association for Cancer Research (AACR).
“Our results show that patients with ER+/HER2-/ImPrint+ breast cancer have a very high probability of achieving complete response to immunotherapy, whereas those who are ER+/HER2-/ImPrint- have a low probability of responding,” noted Dr. Wolf, PhD, MSc of the University of California, San Francisco (UCSF), in an interview.
She added that, although effective, immunotherapy also carries the risk of serious immune-related toxicities, and knowledge of ImPrint class can help patients and physicians determine whether immunotherapy is a good treatment option. “Many patients will be willing to take the risk of immunotherapy toxicities if their odds of responding are very high, as is the case for ImPrint+ patients, but [are] likely less enthused with a low likelihood of response,” Dr. Wolf said during the interview.
Need for Predictive Biomarkers for Neoadjuvant Immunotherapy
Although neoadjuvant immunotherapy has become the standard treatment for patients with early-stage triple-negative breast cancer (TNBC), chemotherapy remains the mainstay of treatment for patients with hormone receptor–positive (HR+), human epidermal growth factor receptor 2–negative (HER2-) breast cancer. The I-SPY2 clinical trial is the first randomized clinical study to assess the efficacy of immunotherapy in the high-risk population of patients with HR+/HER2-, Dr. Wolf said. Data from this study suggest that a subset of HR+/HER2- patients may also derive substantial benefit from this approach compared with standard chemotherapy.
“We and others have previously observed that a minority of ER+/HER2- breast cancers are enriched for tumor-infiltrating lymphocytes and that high levels of immune-related gene signatures associate with improved survival in this subtype, as well as in TNBC,” noted Dr. Wolf during an interview.
She explained that patients with high-risk ER+/HER2- breast cancer were not responding to any of the experimental agent classes tested in the trial and showed particularly poor outcomes, and that she and her colleagues “wanted to see if immune-oncology agents would impact response in these patients.”
ImPrint, an Immune Expression Signature
Preliminary data from the I-SPY2 trial showed that immune-related gene signatures were associated with pathologic complete response (pCR) in patients with HR+/HER2- breast cancer treated with immunotherapy. This observation allowed investigators to develop a clinically applicable immune classifier, termed ImPrint, to predict response to immunotherapy in this population.
This immune classifier is a 53-gene signature developed using data from the first anti–programmed death-1 (PD-1) arm that included patients treated with pembrolizumab, explained Dr. Wolf.
Performance of ImPrint in Patients With HR+/HER2- Breast Cancer
Dr. Wolf presented new data on the performance of ImPrint in 204 patients with high-risk HR+/HER2- breast cancer from the following five immunotherapy arms of the I-SPY2 trial, at the meeting. These arms included: anti–PD-1, anti–PDL-1 plus PARP inhibitor, anti–PD-1/TLR9 dual immunotherapy, and anti–PD-1 with or without LAG3 inhibitor. Data from 191 patients treated with the current standard of care (paclitaxel followed by adriamycin and cyclophosphamide cytoxan) were included in the analysis as a control.
The pCR in the entire population across these five immunotherapy arms was 33%. The response rate in the control arm was 13.5%.
“The high pCR in the immunotherapy groups is remarkable given the traditionally poor response of HR+/HER2- tumors to standard neoadjuvant chemotherapy,” said Ritu Aneja, PhD, the associate dean for research and innovation at the University of Alabama at Birmingham and a breast cancer expert, who was not involved in the I-SPY2 trial.
When patients were stratified according to ImPrint status, significant differences were observed among the groups. In this analysis, 28% of HR+/HER2- patients were classified as ImPrint positive (likely sensitive) based on ImPrint expression levels in pretreatment mRNA samples, and these individuals achieved pCR rates as high as 76% with immunotherapy.
In comparison, pCR rates were only 16% in ImPrint-negative (likely resistant) patients. The highest response rate was observed in the anti–PD-1/TLR9 dual immunotherapy arm, with a pCR rate of greater than 90% in ImPrint-positive patients. In the control arm, pCR rates were 33% in ImPrint-positive and 8% in ImPrint-negative patients.
“These results suggest that a subset of [patients with] high-risk HR+/HER2- breast cancers is highly sensitive to immunotherapy,” said Dr. Aneja in an interview. “By using a specific and sensitive selection strategy like ImPrint, we may be able to identify patients who can achieve pCR rates similar to what we see with the best neoadjuvant therapies in triple-negative and HER2-positive disease.”
Ability of ImPrint to Predict Long-Term Outcomes
During her talk, Dr. Wolf explained that she and her research team currently do not have sufficient follow-up data to assess the ability of ImPrint to predict long-term outcomes. Therefore, they used the pCR data to predict long-term disease-free survival (DRFS) outcomes. Based on their model, HR+/HER2-/ImPrint+ patients treated with immunotherapy were estimated to have a 91% 5-year DRFS rate, compared with 80% for those receiving standard chemotherapy alone. This represents a 52% reduction in the risk of disease recurrence.
“This suggests not only a higher immediate response rate to therapy but also potential long-term benefits for patients identified as ImPrint+,” Dr. Aneja said, commenting on the significance of the DRFS data, during the interview, She added that the ability to predict longer-term outcomes is a critical advantage in selecting the most effective treatment strategies for patients.
Comparison of ImPrint With Other Biomarkers
The investigators compared ImPrint to other potential biomarkers for immunotherapy response, including MammaPrint (ultra) High2 risk (MP2) and tumor grade. During her talk, Dr. Wolf showed data demonstrating that ImPrint is a more precise predictor of pCR, with higher response rates than either of those other markers.
The pCR rates for MP2 and grade III were 56% and 45%, respectively, which are much smaller than the pCR rates observed for ImPrint+ patients (75%).
“This difference underscores ImPrint’s effectiveness in distinguishing patients who could benefit from immunotherapy, offering a pCR prediction accuracy that is significantly higher than seen with other biomarkers that have been proposed as selection markers for neoadjuvant immunotherapy trials in HR+/HER2- breast cancers, such as MP2 and tumor grade,” said Dr. Aneja, during the interview.
Looking Ahead — Implementation of Imprint for Patient Selection
Dr. Aneja echoed that the findings from the I-SPY2 trial advocate for the integration of biomarker-driven approaches, particularly the use of the ImPrint classifier, into the treatment planning process for high-risk HR+/HER2- breast cancer.
“This approach can enable clinicians to identify patients who are more likely to benefit from immunotherapy, thus personalizing treatment strategies and potentially enhancing treatment efficacy while minimizing exposure to unnecessary toxicity for those unlikely to respond,” she said.
Dr. Aneja added that while the I-SPY2 trial offers promising data on ImPrint’s efficacy, additional prospective studies are needed to validate these findings across diverse patient populations and settings, as well as the correlation between biomarker positivity and long-term clinical outcomes, including DRFS and overall survival. “This will help to better understand the full spectrum of benefits provided by immunotherapies in biomarker-selected patient groups,” she said.
Dr. Wolf and Dr. Aneja reported no relationships with entities whose primary business is producing, marketing, selling, reselling, or distributing healthcare products used by or on patients.
Less Than 50% of Accelerated Approvals Show Clinical Benefit
despite being on the US market for more than 5 years, according to a new study.
Under the program, drugs are approved for marketing if they show benefit in surrogate markers thought to indicate efficacy. Progression-free survival, tumor response, and duration of response are the most used surrogate markers for accelerated approvals of cancer drugs. These are based largely on imaging studies that show either a stop in growth in the case of progression-free survival or tumor shrinkage in the case of tumor response.
Following accelerated approvals, companies are then supposed to show actual clinical benefit in confirmatory trials.
The problem with relying on surrogate markers for drug approvals is that they don’t always correlate with longer survival or improved quality of life, said Edward Cliff, MBBS, who presented the findings at the American Association for Cancer Research 2024 annual meeting (abstract 918). The study was also published in JAMA to coincide with the meeting presentation.
In some cancers, these markers work well, but in others they don’t, said Dr. Cliff, a hematology trainee at Brigham and Women’s Hospital, Boston, when the work was conducted, and now a hematology fellow at the Peter MacCallum Cancer Centre in Melbourne, Australia.
To determine whether cancer drugs granted accelerated approval ultimately show an overall survival or quality of life benefit, researchers reviewed 46 cancer drugs granted accelerated approvals between 2013 and 2017. Twenty (43%) were granted full approval after demonstrating survival or quality-of-life benefits.
Nine, however, were converted to full approvals on the basis of surrogate markers. These include a full approval for pembrolizumab in previously treated recurrent or refractory head and neck squamous cell carcinoma and a full approval for nivolumab for refractory locally advanced or metastatic urothelial carcinoma, both based on tumor response rate and duration of response.
Of the remaining 17 drugs evaluated in the trial, 10 have been withdrawn and seven do not yet have confirmatory trial results.
The reliance on surrogate markers means that these drugs are used for treatment, covered by insurance, and added to guidelines — all without solid evidence of real-world clinical benefit, said Dr. Cliff.
However, the goal should not be to do away with the accelerated approval process, because it sometimes does deliver powerful agents to patients quickly. Instead, Dr. Cliff told this news organization, the system needs to be improved so that “we keep the speed while getting certainty around clinical benefits” with robust and timely confirmatory trials.
In the meantime, “clinicians should communicate with patients about any residual uncertainty of clinical benefit when they offer novel therapies,” Dr. Cliff explained. “It’s important for them to have the information.”
There has been some progress on the issue. In December 2022, the US Congress passed the Food and Drug Administration Omnibus Reform Act. Among other things, the Act requires companies to have confirmation trials underway as a condition for accelerated approval, and to provide regular reports on their progress. The Act also expedites the withdrawal process for drugs that don’t show a benefit.
The Act has been put to the test twice recently. In February, FDA used the expedited process to remove the multiple myeloma drug melphalan flufenamide from the market. Melphalan flufenamide hadn’t been sold in the US for quite some time, so the process wasn’t contentious.
In March, Regeneron announced that accelerated approval for the follicular and diffuse B cell lymphoma drug odronextamab has been delayed pending enrollment in a confirmatory trial.
“There have been some promising steps,” Dr. Cliff said, but much work needs to be done.
Study moderator Shivaani Kummar, MD, agreed, noting that “the data is showing that the confirmatory trials aren’t happening at the pace which they should.”
But the solution is not to curtail approvals; it’s to make sure that accelerated approval commitments are met, said Dr. Kummar.
Still, “as a practicing oncologist, I welcome the accelerated pathway,” Dr. Kummar, a medical oncologist/hematologist at Oregon Health & Science University, Portland, told this news organization. “I want the availability to my patients.”
Having drugs approved on the basis of surrogate markers doesn’t necessarily mean patients are getting ineffective therapies, Dr. Kummar noted. For instance, if an agent just shrinks the tumor, it can sometimes still be “a huge clinical benefit because it can take the symptoms away.”
As for prescribing drugs based on accelerated approvals, she said she tells her patients that trials have been promising, but we don’t know what the long-term effects are. She and her patient then make a decision together.
The study was funded by Arnold Ventures. Dr. Kummar reported support from several companies, including Bayer, Gilead, and others. Dr. Cliff had no disclosures.
A version of this article appeared on Medscape.com.
despite being on the US market for more than 5 years, according to a new study.
Under the program, drugs are approved for marketing if they show benefit in surrogate markers thought to indicate efficacy. Progression-free survival, tumor response, and duration of response are the most used surrogate markers for accelerated approvals of cancer drugs. These are based largely on imaging studies that show either a stop in growth in the case of progression-free survival or tumor shrinkage in the case of tumor response.
Following accelerated approvals, companies are then supposed to show actual clinical benefit in confirmatory trials.
The problem with relying on surrogate markers for drug approvals is that they don’t always correlate with longer survival or improved quality of life, said Edward Cliff, MBBS, who presented the findings at the American Association for Cancer Research 2024 annual meeting (abstract 918). The study was also published in JAMA to coincide with the meeting presentation.
In some cancers, these markers work well, but in others they don’t, said Dr. Cliff, a hematology trainee at Brigham and Women’s Hospital, Boston, when the work was conducted, and now a hematology fellow at the Peter MacCallum Cancer Centre in Melbourne, Australia.
To determine whether cancer drugs granted accelerated approval ultimately show an overall survival or quality of life benefit, researchers reviewed 46 cancer drugs granted accelerated approvals between 2013 and 2017. Twenty (43%) were granted full approval after demonstrating survival or quality-of-life benefits.
Nine, however, were converted to full approvals on the basis of surrogate markers. These include a full approval for pembrolizumab in previously treated recurrent or refractory head and neck squamous cell carcinoma and a full approval for nivolumab for refractory locally advanced or metastatic urothelial carcinoma, both based on tumor response rate and duration of response.
Of the remaining 17 drugs evaluated in the trial, 10 have been withdrawn and seven do not yet have confirmatory trial results.
The reliance on surrogate markers means that these drugs are used for treatment, covered by insurance, and added to guidelines — all without solid evidence of real-world clinical benefit, said Dr. Cliff.
However, the goal should not be to do away with the accelerated approval process, because it sometimes does deliver powerful agents to patients quickly. Instead, Dr. Cliff told this news organization, the system needs to be improved so that “we keep the speed while getting certainty around clinical benefits” with robust and timely confirmatory trials.
In the meantime, “clinicians should communicate with patients about any residual uncertainty of clinical benefit when they offer novel therapies,” Dr. Cliff explained. “It’s important for them to have the information.”
There has been some progress on the issue. In December 2022, the US Congress passed the Food and Drug Administration Omnibus Reform Act. Among other things, the Act requires companies to have confirmation trials underway as a condition for accelerated approval, and to provide regular reports on their progress. The Act also expedites the withdrawal process for drugs that don’t show a benefit.
The Act has been put to the test twice recently. In February, FDA used the expedited process to remove the multiple myeloma drug melphalan flufenamide from the market. Melphalan flufenamide hadn’t been sold in the US for quite some time, so the process wasn’t contentious.
In March, Regeneron announced that accelerated approval for the follicular and diffuse B cell lymphoma drug odronextamab has been delayed pending enrollment in a confirmatory trial.
“There have been some promising steps,” Dr. Cliff said, but much work needs to be done.
Study moderator Shivaani Kummar, MD, agreed, noting that “the data is showing that the confirmatory trials aren’t happening at the pace which they should.”
But the solution is not to curtail approvals; it’s to make sure that accelerated approval commitments are met, said Dr. Kummar.
Still, “as a practicing oncologist, I welcome the accelerated pathway,” Dr. Kummar, a medical oncologist/hematologist at Oregon Health & Science University, Portland, told this news organization. “I want the availability to my patients.”
Having drugs approved on the basis of surrogate markers doesn’t necessarily mean patients are getting ineffective therapies, Dr. Kummar noted. For instance, if an agent just shrinks the tumor, it can sometimes still be “a huge clinical benefit because it can take the symptoms away.”
As for prescribing drugs based on accelerated approvals, she said she tells her patients that trials have been promising, but we don’t know what the long-term effects are. She and her patient then make a decision together.
The study was funded by Arnold Ventures. Dr. Kummar reported support from several companies, including Bayer, Gilead, and others. Dr. Cliff had no disclosures.
A version of this article appeared on Medscape.com.
despite being on the US market for more than 5 years, according to a new study.
Under the program, drugs are approved for marketing if they show benefit in surrogate markers thought to indicate efficacy. Progression-free survival, tumor response, and duration of response are the most used surrogate markers for accelerated approvals of cancer drugs. These are based largely on imaging studies that show either a stop in growth in the case of progression-free survival or tumor shrinkage in the case of tumor response.
Following accelerated approvals, companies are then supposed to show actual clinical benefit in confirmatory trials.
The problem with relying on surrogate markers for drug approvals is that they don’t always correlate with longer survival or improved quality of life, said Edward Cliff, MBBS, who presented the findings at the American Association for Cancer Research 2024 annual meeting (abstract 918). The study was also published in JAMA to coincide with the meeting presentation.
In some cancers, these markers work well, but in others they don’t, said Dr. Cliff, a hematology trainee at Brigham and Women’s Hospital, Boston, when the work was conducted, and now a hematology fellow at the Peter MacCallum Cancer Centre in Melbourne, Australia.
To determine whether cancer drugs granted accelerated approval ultimately show an overall survival or quality of life benefit, researchers reviewed 46 cancer drugs granted accelerated approvals between 2013 and 2017. Twenty (43%) were granted full approval after demonstrating survival or quality-of-life benefits.
Nine, however, were converted to full approvals on the basis of surrogate markers. These include a full approval for pembrolizumab in previously treated recurrent or refractory head and neck squamous cell carcinoma and a full approval for nivolumab for refractory locally advanced or metastatic urothelial carcinoma, both based on tumor response rate and duration of response.
Of the remaining 17 drugs evaluated in the trial, 10 have been withdrawn and seven do not yet have confirmatory trial results.
The reliance on surrogate markers means that these drugs are used for treatment, covered by insurance, and added to guidelines — all without solid evidence of real-world clinical benefit, said Dr. Cliff.
However, the goal should not be to do away with the accelerated approval process, because it sometimes does deliver powerful agents to patients quickly. Instead, Dr. Cliff told this news organization, the system needs to be improved so that “we keep the speed while getting certainty around clinical benefits” with robust and timely confirmatory trials.
In the meantime, “clinicians should communicate with patients about any residual uncertainty of clinical benefit when they offer novel therapies,” Dr. Cliff explained. “It’s important for them to have the information.”
There has been some progress on the issue. In December 2022, the US Congress passed the Food and Drug Administration Omnibus Reform Act. Among other things, the Act requires companies to have confirmation trials underway as a condition for accelerated approval, and to provide regular reports on their progress. The Act also expedites the withdrawal process for drugs that don’t show a benefit.
The Act has been put to the test twice recently. In February, FDA used the expedited process to remove the multiple myeloma drug melphalan flufenamide from the market. Melphalan flufenamide hadn’t been sold in the US for quite some time, so the process wasn’t contentious.
In March, Regeneron announced that accelerated approval for the follicular and diffuse B cell lymphoma drug odronextamab has been delayed pending enrollment in a confirmatory trial.
“There have been some promising steps,” Dr. Cliff said, but much work needs to be done.
Study moderator Shivaani Kummar, MD, agreed, noting that “the data is showing that the confirmatory trials aren’t happening at the pace which they should.”
But the solution is not to curtail approvals; it’s to make sure that accelerated approval commitments are met, said Dr. Kummar.
Still, “as a practicing oncologist, I welcome the accelerated pathway,” Dr. Kummar, a medical oncologist/hematologist at Oregon Health & Science University, Portland, told this news organization. “I want the availability to my patients.”
Having drugs approved on the basis of surrogate markers doesn’t necessarily mean patients are getting ineffective therapies, Dr. Kummar noted. For instance, if an agent just shrinks the tumor, it can sometimes still be “a huge clinical benefit because it can take the symptoms away.”
As for prescribing drugs based on accelerated approvals, she said she tells her patients that trials have been promising, but we don’t know what the long-term effects are. She and her patient then make a decision together.
The study was funded by Arnold Ventures. Dr. Kummar reported support from several companies, including Bayer, Gilead, and others. Dr. Cliff had no disclosures.
A version of this article appeared on Medscape.com.
FDA Expands Enhertu Indication to HER2-Positive Solid Tumors
The agent had already been approved for several cancer types, including certain patients with unresectable or metastatic HER2-positive breast cancer as well as adults with locally advanced or metastatic HER2-positive gastric or gastroesophageal junction adenocarcinoma who had received a prior trastuzumab-based regimen.
The current accelerated approval is the first tumor-agnostic approval of a HER2-directed therapy and antibody drug conjugate.
“Until approval of trastuzumab deruxtecan, patients with metastatic HER2-positive tumors have had limited treatment options,” Funda Meric-Bernstam, MD, chair of investigational cancer therapeutics at the University of Texas MD Anderson Cancer Center, Houston, said in an AstraZeneca press statement. “Based on the clinically meaningful response rates across clinical trials, this tumor-agnostic approval means that patients may now be treated with a HER2-directed medicine.”
Approval was based on findings in 192 patients enrolled in either the DESTINY-PanTumor02 trial, the DESTINY-Lung01 trial, or the DESTINY-CRC02 trial. Patients in the multicenter trials underwent treatment until disease progression, death, withdrawal of consent or unacceptable toxicity.
Confirmed objective response rates were 51.4%, 52.9%, and 46.9% in the three studies, respectively. Median duration of response was 19.4, 6.9, and 5.5 months, respectively.
The most common adverse reactions occurring in at least 20% of patients included decreased white blood cell count, hemoglobin, lymphocyte count, and neutrophil count, as well as nausea, fatigue, platelet count, vomiting, alopecia, diarrhea, stomatitis, and upper respiratory tract infection.
Full prescribing information includes a boxed warning about the risk for interstitial lung disease and embryo-fetal toxicity.
The recommended dosage is 5.4 mg/kg given as an intravenous infusion one every 3 weeks until disease progression or unacceptable toxicity.
A version of this article appeared on Medscape.com.
The agent had already been approved for several cancer types, including certain patients with unresectable or metastatic HER2-positive breast cancer as well as adults with locally advanced or metastatic HER2-positive gastric or gastroesophageal junction adenocarcinoma who had received a prior trastuzumab-based regimen.
The current accelerated approval is the first tumor-agnostic approval of a HER2-directed therapy and antibody drug conjugate.
“Until approval of trastuzumab deruxtecan, patients with metastatic HER2-positive tumors have had limited treatment options,” Funda Meric-Bernstam, MD, chair of investigational cancer therapeutics at the University of Texas MD Anderson Cancer Center, Houston, said in an AstraZeneca press statement. “Based on the clinically meaningful response rates across clinical trials, this tumor-agnostic approval means that patients may now be treated with a HER2-directed medicine.”
Approval was based on findings in 192 patients enrolled in either the DESTINY-PanTumor02 trial, the DESTINY-Lung01 trial, or the DESTINY-CRC02 trial. Patients in the multicenter trials underwent treatment until disease progression, death, withdrawal of consent or unacceptable toxicity.
Confirmed objective response rates were 51.4%, 52.9%, and 46.9% in the three studies, respectively. Median duration of response was 19.4, 6.9, and 5.5 months, respectively.
The most common adverse reactions occurring in at least 20% of patients included decreased white blood cell count, hemoglobin, lymphocyte count, and neutrophil count, as well as nausea, fatigue, platelet count, vomiting, alopecia, diarrhea, stomatitis, and upper respiratory tract infection.
Full prescribing information includes a boxed warning about the risk for interstitial lung disease and embryo-fetal toxicity.
The recommended dosage is 5.4 mg/kg given as an intravenous infusion one every 3 weeks until disease progression or unacceptable toxicity.
A version of this article appeared on Medscape.com.
The agent had already been approved for several cancer types, including certain patients with unresectable or metastatic HER2-positive breast cancer as well as adults with locally advanced or metastatic HER2-positive gastric or gastroesophageal junction adenocarcinoma who had received a prior trastuzumab-based regimen.
The current accelerated approval is the first tumor-agnostic approval of a HER2-directed therapy and antibody drug conjugate.
“Until approval of trastuzumab deruxtecan, patients with metastatic HER2-positive tumors have had limited treatment options,” Funda Meric-Bernstam, MD, chair of investigational cancer therapeutics at the University of Texas MD Anderson Cancer Center, Houston, said in an AstraZeneca press statement. “Based on the clinically meaningful response rates across clinical trials, this tumor-agnostic approval means that patients may now be treated with a HER2-directed medicine.”
Approval was based on findings in 192 patients enrolled in either the DESTINY-PanTumor02 trial, the DESTINY-Lung01 trial, or the DESTINY-CRC02 trial. Patients in the multicenter trials underwent treatment until disease progression, death, withdrawal of consent or unacceptable toxicity.
Confirmed objective response rates were 51.4%, 52.9%, and 46.9% in the three studies, respectively. Median duration of response was 19.4, 6.9, and 5.5 months, respectively.
The most common adverse reactions occurring in at least 20% of patients included decreased white blood cell count, hemoglobin, lymphocyte count, and neutrophil count, as well as nausea, fatigue, platelet count, vomiting, alopecia, diarrhea, stomatitis, and upper respiratory tract infection.
Full prescribing information includes a boxed warning about the risk for interstitial lung disease and embryo-fetal toxicity.
The recommended dosage is 5.4 mg/kg given as an intravenous infusion one every 3 weeks until disease progression or unacceptable toxicity.
A version of this article appeared on Medscape.com.
Virtual Reality Brings Relief to Hospitalized Patients With Cancer
suggests a new randomized controlled trial.
While both interventions brought some pain relief, VR therapy yielded greater, longer-lasting comfort, reported lead author Hunter Groninger, MD, of MedStar Health Research Institute, Hyattsville, Maryland, and colleagues.
“Investigators have explored immersive VR interventions in cancer populations for a variety of indications including anxiety, depression, fatigue, and procedure‐associated pain, particularly among patients with pediatric cancer and adult breast cancer,” the investigators wrote in Cancer. “Nevertheless, despite growing evidence supporting the efficacy of VR‐delivered interventions for analgesia, few data address its role to mitigate cancer‐related pain specifically.”
To address this knowledge gap, Dr. Groninger and colleagues enrolled 128 adult hospitalized patients with cancer of any kind, all of whom had moderate to severe pain (self-reported score at least 4 out of 10) within the past 24 hours.
Study Methods and Results
Patients were randomized to receive either 10 minutes of immersive VR distraction therapy or 10 minutes of two-dimensional guided imagery distraction therapy.
“[The VR therapy] provides noncompetitive experiences in which the user can move around and explore natural environments (e.g., beachscape, forest) from standing, seated, or fixed positions, including within a hospital bed or chair,” the investigators wrote. “We provided over‐the‐ear headphones to assure high sound quality for the experience in the virtual natural environment.”
The two-dimensional intervention, delivered via electronic tablet, featured a meditation with images of natural landscapes and instrumental background music.
“We chose this active control because it is readily available and reflects content similar to relaxation‐focused television channels that are increasingly common in hospital settings,” the investigators noted.
Compared with this more common approach, patients who received VR therapy had significantly greater immediate reduction in pain (mean change in pain score, –1.4 vs –0.7; P = .03). Twenty-four hours later, improvements in the VR group generally persisted, while pain level in the two-dimensional group returned almost to baseline (P = .004). In addition, patients in the VR group reported significantly greater improvements in general distress and pain bothersomeness.
“VR therapies may modulate the pain experience by reducing the level of attention paid to noxious stimuli, thereby suppressing transmission of painful sensations via pain processing pathways to the cerebral cortex, particularly with more active VR experiences compared to passive experiences,” the investigators wrote.
Downsides to Using VR
Although VR brought more benefit, participants in the VR group more often reported difficulty using the intervention compared with those who interacted with an electronic tablet.
Plus, one VR user described mild dizziness that resolved with pharmacologic intervention. Still, approximately 9 out of 10 participants in each group reported willingness to try the intervention again.
Future VR Research
“Virtual reality is a rapidly evolving technology with a wealth of potential patient‐facing applications,” the investigators wrote. “Future studies should explore repeated use, optimal dosing, and impact on VR therapy on opioid analgesic requirements as well as usability testing, VR content preferences and facilitators of analgesia, and barriers and facilitators to use in acute care settings.”
This study was supported by the American Cancer Society. The investigators disclosed no conflicts of interest.
suggests a new randomized controlled trial.
While both interventions brought some pain relief, VR therapy yielded greater, longer-lasting comfort, reported lead author Hunter Groninger, MD, of MedStar Health Research Institute, Hyattsville, Maryland, and colleagues.
“Investigators have explored immersive VR interventions in cancer populations for a variety of indications including anxiety, depression, fatigue, and procedure‐associated pain, particularly among patients with pediatric cancer and adult breast cancer,” the investigators wrote in Cancer. “Nevertheless, despite growing evidence supporting the efficacy of VR‐delivered interventions for analgesia, few data address its role to mitigate cancer‐related pain specifically.”
To address this knowledge gap, Dr. Groninger and colleagues enrolled 128 adult hospitalized patients with cancer of any kind, all of whom had moderate to severe pain (self-reported score at least 4 out of 10) within the past 24 hours.
Study Methods and Results
Patients were randomized to receive either 10 minutes of immersive VR distraction therapy or 10 minutes of two-dimensional guided imagery distraction therapy.
“[The VR therapy] provides noncompetitive experiences in which the user can move around and explore natural environments (e.g., beachscape, forest) from standing, seated, or fixed positions, including within a hospital bed or chair,” the investigators wrote. “We provided over‐the‐ear headphones to assure high sound quality for the experience in the virtual natural environment.”
The two-dimensional intervention, delivered via electronic tablet, featured a meditation with images of natural landscapes and instrumental background music.
“We chose this active control because it is readily available and reflects content similar to relaxation‐focused television channels that are increasingly common in hospital settings,” the investigators noted.
Compared with this more common approach, patients who received VR therapy had significantly greater immediate reduction in pain (mean change in pain score, –1.4 vs –0.7; P = .03). Twenty-four hours later, improvements in the VR group generally persisted, while pain level in the two-dimensional group returned almost to baseline (P = .004). In addition, patients in the VR group reported significantly greater improvements in general distress and pain bothersomeness.
“VR therapies may modulate the pain experience by reducing the level of attention paid to noxious stimuli, thereby suppressing transmission of painful sensations via pain processing pathways to the cerebral cortex, particularly with more active VR experiences compared to passive experiences,” the investigators wrote.
Downsides to Using VR
Although VR brought more benefit, participants in the VR group more often reported difficulty using the intervention compared with those who interacted with an electronic tablet.
Plus, one VR user described mild dizziness that resolved with pharmacologic intervention. Still, approximately 9 out of 10 participants in each group reported willingness to try the intervention again.
Future VR Research
“Virtual reality is a rapidly evolving technology with a wealth of potential patient‐facing applications,” the investigators wrote. “Future studies should explore repeated use, optimal dosing, and impact on VR therapy on opioid analgesic requirements as well as usability testing, VR content preferences and facilitators of analgesia, and barriers and facilitators to use in acute care settings.”
This study was supported by the American Cancer Society. The investigators disclosed no conflicts of interest.
suggests a new randomized controlled trial.
While both interventions brought some pain relief, VR therapy yielded greater, longer-lasting comfort, reported lead author Hunter Groninger, MD, of MedStar Health Research Institute, Hyattsville, Maryland, and colleagues.
“Investigators have explored immersive VR interventions in cancer populations for a variety of indications including anxiety, depression, fatigue, and procedure‐associated pain, particularly among patients with pediatric cancer and adult breast cancer,” the investigators wrote in Cancer. “Nevertheless, despite growing evidence supporting the efficacy of VR‐delivered interventions for analgesia, few data address its role to mitigate cancer‐related pain specifically.”
To address this knowledge gap, Dr. Groninger and colleagues enrolled 128 adult hospitalized patients with cancer of any kind, all of whom had moderate to severe pain (self-reported score at least 4 out of 10) within the past 24 hours.
Study Methods and Results
Patients were randomized to receive either 10 minutes of immersive VR distraction therapy or 10 minutes of two-dimensional guided imagery distraction therapy.
“[The VR therapy] provides noncompetitive experiences in which the user can move around and explore natural environments (e.g., beachscape, forest) from standing, seated, or fixed positions, including within a hospital bed or chair,” the investigators wrote. “We provided over‐the‐ear headphones to assure high sound quality for the experience in the virtual natural environment.”
The two-dimensional intervention, delivered via electronic tablet, featured a meditation with images of natural landscapes and instrumental background music.
“We chose this active control because it is readily available and reflects content similar to relaxation‐focused television channels that are increasingly common in hospital settings,” the investigators noted.
Compared with this more common approach, patients who received VR therapy had significantly greater immediate reduction in pain (mean change in pain score, –1.4 vs –0.7; P = .03). Twenty-four hours later, improvements in the VR group generally persisted, while pain level in the two-dimensional group returned almost to baseline (P = .004). In addition, patients in the VR group reported significantly greater improvements in general distress and pain bothersomeness.
“VR therapies may modulate the pain experience by reducing the level of attention paid to noxious stimuli, thereby suppressing transmission of painful sensations via pain processing pathways to the cerebral cortex, particularly with more active VR experiences compared to passive experiences,” the investigators wrote.
Downsides to Using VR
Although VR brought more benefit, participants in the VR group more often reported difficulty using the intervention compared with those who interacted with an electronic tablet.
Plus, one VR user described mild dizziness that resolved with pharmacologic intervention. Still, approximately 9 out of 10 participants in each group reported willingness to try the intervention again.
Future VR Research
“Virtual reality is a rapidly evolving technology with a wealth of potential patient‐facing applications,” the investigators wrote. “Future studies should explore repeated use, optimal dosing, and impact on VR therapy on opioid analgesic requirements as well as usability testing, VR content preferences and facilitators of analgesia, and barriers and facilitators to use in acute care settings.”
This study was supported by the American Cancer Society. The investigators disclosed no conflicts of interest.
FROM CANCER
Should Opioids Be Used for Chronic Cancer Pain?
from legal concerns to threats of violence, say the authors of new research.
These findings suggest that evidence-based, systematic guidance is needed to steer opioid usage in cancer survivorship, wrote lead author Hailey W. Bulls, PhD, of the University of Pittsburgh, and colleagues.
“Prescription opioids are considered the standard of care to treat moderate to severe cancer pain during active treatment, yet guidance in the posttreatment survivorship phase is much less clear,” the investigators wrote. “Existing clinical resources recognize that opioid prescribing in survivorship is complex and nuanced and that the relative benefits and risks in this population are not fully understood.”
Who Should Manage Chronic Cancer Pain?
Despite the knowledge gap, survivors are typically excluded from long-term opioid use studies, leaving providers in a largely data-free zone. Simultaneously, patients who had been receiving focused care during their cancer treatment find themselves with an ill-defined health care team.
“Without a clear transition of care, survivors may seek pain management services from a variety of specialties, including oncologists, palliative care clinicians, primary care clinicians, and pain management specialists,” the investigators wrote. “However, many clinicians may view pain management to be outside of their skill set and may not be well equipped to handle opioid continuation or deprescribing [or] to manage the potential consequences of long‐term opioid use like side effects, misuse, and/or opioid use disorder.”
What Factors Guide Opioid Prescribing Practices for Chronic Cancer Pain?
To learn more about prescribing practices in this setting, Dr. Bulls and colleagues conducted qualitative interviews with 20 providers representing four specialties: oncology (n = 5), palliative care (n = 8), primary care (n = 5), and pain management (n = 2). Eighteen of these participants were physicians and two were advanced practice providers. Average time in clinical practice was about 16 years.
These interviews yielded three themes.
First, no “medical home” exists for chronic pain management in cancer survivors.
“Although clinicians generally agreed that minimizing the role of opioids in chronic pain management in cancer survivors was desirable, they described a lack of common treatment protocols to guide pain management in survivorship,” the investigators wrote.
Second, the interviews revealed that prescribing strategies are partly driven by peer pressure, sometimes leading to tension between providers and feelings of self-doubt.
“I feel like there’s been this weird judgment thing that’s happened [to] the prescribers,” one primary care provider said during the interview. “Because, when I trained … pain was a vital sign, and we were supposed to treat pain, and now I feel like we’re all being judged for that.”
The third theme revolved around fear of consequences resulting from prescribing practices, including fears of violent repercussions.
“You may not know, but pain specialists have been shot in this country for [refusing to prescribe opioids],” one pain management specialist said during the interview. “There’s been a number of shootings of pain specialists who would not prescribe opioids. So, I mean, there’s real issues of violence.”
Meanwhile, a palliative care provider described legal pressure from the opposite direction:
“I think there’s a lot of fear of litigiousness … and loss of licenses. That sort of makes them pressure us into not prescribing opioids or sticking with a certain number per day that might not be therapeutic for a patient.”
Reflecting on these themes, the investigators identified “a fundamental uncertainty in survivorship pain management.”
What Strategies Might Improve Opioid Prescribing Practices for Chronic Cancer Pain?
After sharing their attitudes about prescribing opioids for chronic cancer pain, the clinicians were asked for suggestions to improve the situation.
They offered four main suggestions: create relevant guidelines, increase education and access to pain management options for clinicians, increase interdisciplinary communication across medical subspecialties, and promote multidisciplinary care in the survivorship setting.
Dr. Bulls and colleagues supported these strategies in their concluding remarks and called for more research.
This study was supported by the National Institute of Drug Abuse, the National Institutes of Health, the National Center for Advancing Translational Sciences, and the National Cancer Institute. The investigators disclosed relationships with Arcadia Health Solutions and Biomotivate.
from legal concerns to threats of violence, say the authors of new research.
These findings suggest that evidence-based, systematic guidance is needed to steer opioid usage in cancer survivorship, wrote lead author Hailey W. Bulls, PhD, of the University of Pittsburgh, and colleagues.
“Prescription opioids are considered the standard of care to treat moderate to severe cancer pain during active treatment, yet guidance in the posttreatment survivorship phase is much less clear,” the investigators wrote. “Existing clinical resources recognize that opioid prescribing in survivorship is complex and nuanced and that the relative benefits and risks in this population are not fully understood.”
Who Should Manage Chronic Cancer Pain?
Despite the knowledge gap, survivors are typically excluded from long-term opioid use studies, leaving providers in a largely data-free zone. Simultaneously, patients who had been receiving focused care during their cancer treatment find themselves with an ill-defined health care team.
“Without a clear transition of care, survivors may seek pain management services from a variety of specialties, including oncologists, palliative care clinicians, primary care clinicians, and pain management specialists,” the investigators wrote. “However, many clinicians may view pain management to be outside of their skill set and may not be well equipped to handle opioid continuation or deprescribing [or] to manage the potential consequences of long‐term opioid use like side effects, misuse, and/or opioid use disorder.”
What Factors Guide Opioid Prescribing Practices for Chronic Cancer Pain?
To learn more about prescribing practices in this setting, Dr. Bulls and colleagues conducted qualitative interviews with 20 providers representing four specialties: oncology (n = 5), palliative care (n = 8), primary care (n = 5), and pain management (n = 2). Eighteen of these participants were physicians and two were advanced practice providers. Average time in clinical practice was about 16 years.
These interviews yielded three themes.
First, no “medical home” exists for chronic pain management in cancer survivors.
“Although clinicians generally agreed that minimizing the role of opioids in chronic pain management in cancer survivors was desirable, they described a lack of common treatment protocols to guide pain management in survivorship,” the investigators wrote.
Second, the interviews revealed that prescribing strategies are partly driven by peer pressure, sometimes leading to tension between providers and feelings of self-doubt.
“I feel like there’s been this weird judgment thing that’s happened [to] the prescribers,” one primary care provider said during the interview. “Because, when I trained … pain was a vital sign, and we were supposed to treat pain, and now I feel like we’re all being judged for that.”
The third theme revolved around fear of consequences resulting from prescribing practices, including fears of violent repercussions.
“You may not know, but pain specialists have been shot in this country for [refusing to prescribe opioids],” one pain management specialist said during the interview. “There’s been a number of shootings of pain specialists who would not prescribe opioids. So, I mean, there’s real issues of violence.”
Meanwhile, a palliative care provider described legal pressure from the opposite direction:
“I think there’s a lot of fear of litigiousness … and loss of licenses. That sort of makes them pressure us into not prescribing opioids or sticking with a certain number per day that might not be therapeutic for a patient.”
Reflecting on these themes, the investigators identified “a fundamental uncertainty in survivorship pain management.”
What Strategies Might Improve Opioid Prescribing Practices for Chronic Cancer Pain?
After sharing their attitudes about prescribing opioids for chronic cancer pain, the clinicians were asked for suggestions to improve the situation.
They offered four main suggestions: create relevant guidelines, increase education and access to pain management options for clinicians, increase interdisciplinary communication across medical subspecialties, and promote multidisciplinary care in the survivorship setting.
Dr. Bulls and colleagues supported these strategies in their concluding remarks and called for more research.
This study was supported by the National Institute of Drug Abuse, the National Institutes of Health, the National Center for Advancing Translational Sciences, and the National Cancer Institute. The investigators disclosed relationships with Arcadia Health Solutions and Biomotivate.
from legal concerns to threats of violence, say the authors of new research.
These findings suggest that evidence-based, systematic guidance is needed to steer opioid usage in cancer survivorship, wrote lead author Hailey W. Bulls, PhD, of the University of Pittsburgh, and colleagues.
“Prescription opioids are considered the standard of care to treat moderate to severe cancer pain during active treatment, yet guidance in the posttreatment survivorship phase is much less clear,” the investigators wrote. “Existing clinical resources recognize that opioid prescribing in survivorship is complex and nuanced and that the relative benefits and risks in this population are not fully understood.”
Who Should Manage Chronic Cancer Pain?
Despite the knowledge gap, survivors are typically excluded from long-term opioid use studies, leaving providers in a largely data-free zone. Simultaneously, patients who had been receiving focused care during their cancer treatment find themselves with an ill-defined health care team.
“Without a clear transition of care, survivors may seek pain management services from a variety of specialties, including oncologists, palliative care clinicians, primary care clinicians, and pain management specialists,” the investigators wrote. “However, many clinicians may view pain management to be outside of their skill set and may not be well equipped to handle opioid continuation or deprescribing [or] to manage the potential consequences of long‐term opioid use like side effects, misuse, and/or opioid use disorder.”
What Factors Guide Opioid Prescribing Practices for Chronic Cancer Pain?
To learn more about prescribing practices in this setting, Dr. Bulls and colleagues conducted qualitative interviews with 20 providers representing four specialties: oncology (n = 5), palliative care (n = 8), primary care (n = 5), and pain management (n = 2). Eighteen of these participants were physicians and two were advanced practice providers. Average time in clinical practice was about 16 years.
These interviews yielded three themes.
First, no “medical home” exists for chronic pain management in cancer survivors.
“Although clinicians generally agreed that minimizing the role of opioids in chronic pain management in cancer survivors was desirable, they described a lack of common treatment protocols to guide pain management in survivorship,” the investigators wrote.
Second, the interviews revealed that prescribing strategies are partly driven by peer pressure, sometimes leading to tension between providers and feelings of self-doubt.
“I feel like there’s been this weird judgment thing that’s happened [to] the prescribers,” one primary care provider said during the interview. “Because, when I trained … pain was a vital sign, and we were supposed to treat pain, and now I feel like we’re all being judged for that.”
The third theme revolved around fear of consequences resulting from prescribing practices, including fears of violent repercussions.
“You may not know, but pain specialists have been shot in this country for [refusing to prescribe opioids],” one pain management specialist said during the interview. “There’s been a number of shootings of pain specialists who would not prescribe opioids. So, I mean, there’s real issues of violence.”
Meanwhile, a palliative care provider described legal pressure from the opposite direction:
“I think there’s a lot of fear of litigiousness … and loss of licenses. That sort of makes them pressure us into not prescribing opioids or sticking with a certain number per day that might not be therapeutic for a patient.”
Reflecting on these themes, the investigators identified “a fundamental uncertainty in survivorship pain management.”
What Strategies Might Improve Opioid Prescribing Practices for Chronic Cancer Pain?
After sharing their attitudes about prescribing opioids for chronic cancer pain, the clinicians were asked for suggestions to improve the situation.
They offered four main suggestions: create relevant guidelines, increase education and access to pain management options for clinicians, increase interdisciplinary communication across medical subspecialties, and promote multidisciplinary care in the survivorship setting.
Dr. Bulls and colleagues supported these strategies in their concluding remarks and called for more research.
This study was supported by the National Institute of Drug Abuse, the National Institutes of Health, the National Center for Advancing Translational Sciences, and the National Cancer Institute. The investigators disclosed relationships with Arcadia Health Solutions and Biomotivate.
FROM CANCER
A Banned Chemical That Is Still Causing Cancer
This transcript has been edited for clarity.
These types of stories usually end with a call for regulation — to ban said chemical or substance, or to regulate it — but in this case, that has already happened. This new carcinogen I’m telling you about is actually an old chemical. And it has not been manufactured or legally imported in the US since 2013.
So, why bother? Because in this case, the chemical — or, really, a group of chemicals called polybrominated diphenyl ethers (PBDEs) — are still around: in our soil, in our food, and in our blood.
PBDEs are a group of compounds that confer flame-retardant properties to plastics, and they were used extensively in the latter part of the 20th century in electronic enclosures, business equipment, and foam cushioning in upholstery.
But there was a problem. They don’t chemically bond to plastics; they are just sort of mixed in, which means they can leach out. They are hydrophobic, meaning they don’t get washed out of soil, and, when ingested or inhaled by humans, they dissolve in our fat stores, making it difficult for our normal excretory systems to excrete them.
PBDEs biomagnify. Small animals can take them up from contaminated soil or water, and those animals are eaten by larger animals, which accumulate higher concentrations of the chemicals. This bioaccumulation increases as you move up the food web until you get to an apex predator — like you and me.
This is true of lots of chemicals, of course. The concern arises when these chemicals are toxic. To date, the toxicity data for PBDEs were pretty limited. There were some animal studies where rats were exposed to extremely high doses and they developed liver lesions — but I am always very wary of extrapolating high-dose rat toxicity studies to humans. There was also some suggestion that the chemicals could be endocrine disruptors, affecting breast and thyroid tissue.
What about cancer? In 2016, the International Agency for Research on Cancer concluded there was “inadequate evidence in humans for the carcinogencity of” PBDEs.
In the same report, though, they suggested PBDEs are “probably carcinogenic to humans” based on mechanistic studies.
In other words, we can’t prove they’re cancerous — but come on, they probably are.
Finally, we have some evidence that really pushes us toward the carcinogenic conclusion, in the form of this study, appearing in JAMA Network Open. It’s a nice bit of epidemiology leveraging the population-based National Health and Nutrition Examination Survey (NHANES).
Researchers measured PBDE levels in blood samples from 1100 people enrolled in NHANES in 2003 and 2004 and linked them to death records collected over the next 20 years or so.
The first thing to note is that the researchers were able to measure PBDEs in the blood samples. They were in there. They were detectable. And they were variable. Dividing the 1100 participants into low, medium, and high PBDE tertiles, you can see a nearly 10-fold difference across the population.
Importantly, not many baseline variables correlated with PBDE levels. People in the highest group were a bit younger but had a fairly similar sex distribution, race, ethnicity, education, income, physical activity, smoking status, and body mass index.
This is not a randomized trial, of course — but at least based on these data, exposure levels do seem fairly random, which is what you would expect from an environmental toxin that percolates up through the food chain. They are often somewhat indiscriminate.
This similarity in baseline characteristics between people with low or high blood levels of PBDE also allows us to make some stronger inferences about the observed outcomes. Let’s take a look at them.
After adjustment for baseline factors, individuals in the highest PBDE group had a 43% higher rate of death from any cause over the follow-up period. This was not enough to achieve statistical significance, but it was close.
But the key finding is deaths due to cancer. After adjustment, cancer deaths occurred four times as frequently among those in the high PBDE group, and that is a statistically significant difference.
To be fair, cancer deaths were rare in this cohort. The vast majority of people did not die of anything during the follow-up period regardless of PBDE level. But the data are strongly suggestive of the carcinogenicity of these chemicals.
I should also point out that the researchers are linking the PBDE level at a single time point to all these future events. If PBDE levels remain relatively stable within an individual over time, that’s fine, but if they tend to vary with intake of different foods for example, this would not be captured and would actually lead to an underestimation of the cancer risk.
The researchers also didn’t have granular enough data to determine the type of cancer, but they do show that rates are similar between men and women, which might point away from the more sex-specific cancer etiologies. Clearly, some more work is needed.
Of course, I started this piece by telling you that these chemicals are already pretty much banned in the United States. What are we supposed to do about these findings? Studies have examined the primary ongoing sources of PBDE in our environment and it seems like most of our exposure will be coming from the food we eat due to that biomagnification thing: high-fat fish, meat and dairy products, and fish oil supplements. It may be worth some investigation into the relative adulteration of these products with this new old carcinogen.
Dr. F. Perry Wilson is associate professor of medicine and public health and director of the Clinical and Translational Research Accelerator at Yale University, New Haven, Conn. He has disclosed no relevant financial relationships.
A version of this article appeared on Medscape.com.
This transcript has been edited for clarity.
These types of stories usually end with a call for regulation — to ban said chemical or substance, or to regulate it — but in this case, that has already happened. This new carcinogen I’m telling you about is actually an old chemical. And it has not been manufactured or legally imported in the US since 2013.
So, why bother? Because in this case, the chemical — or, really, a group of chemicals called polybrominated diphenyl ethers (PBDEs) — are still around: in our soil, in our food, and in our blood.
PBDEs are a group of compounds that confer flame-retardant properties to plastics, and they were used extensively in the latter part of the 20th century in electronic enclosures, business equipment, and foam cushioning in upholstery.
But there was a problem. They don’t chemically bond to plastics; they are just sort of mixed in, which means they can leach out. They are hydrophobic, meaning they don’t get washed out of soil, and, when ingested or inhaled by humans, they dissolve in our fat stores, making it difficult for our normal excretory systems to excrete them.
PBDEs biomagnify. Small animals can take them up from contaminated soil or water, and those animals are eaten by larger animals, which accumulate higher concentrations of the chemicals. This bioaccumulation increases as you move up the food web until you get to an apex predator — like you and me.
This is true of lots of chemicals, of course. The concern arises when these chemicals are toxic. To date, the toxicity data for PBDEs were pretty limited. There were some animal studies where rats were exposed to extremely high doses and they developed liver lesions — but I am always very wary of extrapolating high-dose rat toxicity studies to humans. There was also some suggestion that the chemicals could be endocrine disruptors, affecting breast and thyroid tissue.
What about cancer? In 2016, the International Agency for Research on Cancer concluded there was “inadequate evidence in humans for the carcinogencity of” PBDEs.
In the same report, though, they suggested PBDEs are “probably carcinogenic to humans” based on mechanistic studies.
In other words, we can’t prove they’re cancerous — but come on, they probably are.
Finally, we have some evidence that really pushes us toward the carcinogenic conclusion, in the form of this study, appearing in JAMA Network Open. It’s a nice bit of epidemiology leveraging the population-based National Health and Nutrition Examination Survey (NHANES).
Researchers measured PBDE levels in blood samples from 1100 people enrolled in NHANES in 2003 and 2004 and linked them to death records collected over the next 20 years or so.
The first thing to note is that the researchers were able to measure PBDEs in the blood samples. They were in there. They were detectable. And they were variable. Dividing the 1100 participants into low, medium, and high PBDE tertiles, you can see a nearly 10-fold difference across the population.
Importantly, not many baseline variables correlated with PBDE levels. People in the highest group were a bit younger but had a fairly similar sex distribution, race, ethnicity, education, income, physical activity, smoking status, and body mass index.
This is not a randomized trial, of course — but at least based on these data, exposure levels do seem fairly random, which is what you would expect from an environmental toxin that percolates up through the food chain. They are often somewhat indiscriminate.
This similarity in baseline characteristics between people with low or high blood levels of PBDE also allows us to make some stronger inferences about the observed outcomes. Let’s take a look at them.
After adjustment for baseline factors, individuals in the highest PBDE group had a 43% higher rate of death from any cause over the follow-up period. This was not enough to achieve statistical significance, but it was close.
But the key finding is deaths due to cancer. After adjustment, cancer deaths occurred four times as frequently among those in the high PBDE group, and that is a statistically significant difference.
To be fair, cancer deaths were rare in this cohort. The vast majority of people did not die of anything during the follow-up period regardless of PBDE level. But the data are strongly suggestive of the carcinogenicity of these chemicals.
I should also point out that the researchers are linking the PBDE level at a single time point to all these future events. If PBDE levels remain relatively stable within an individual over time, that’s fine, but if they tend to vary with intake of different foods for example, this would not be captured and would actually lead to an underestimation of the cancer risk.
The researchers also didn’t have granular enough data to determine the type of cancer, but they do show that rates are similar between men and women, which might point away from the more sex-specific cancer etiologies. Clearly, some more work is needed.
Of course, I started this piece by telling you that these chemicals are already pretty much banned in the United States. What are we supposed to do about these findings? Studies have examined the primary ongoing sources of PBDE in our environment and it seems like most of our exposure will be coming from the food we eat due to that biomagnification thing: high-fat fish, meat and dairy products, and fish oil supplements. It may be worth some investigation into the relative adulteration of these products with this new old carcinogen.
Dr. F. Perry Wilson is associate professor of medicine and public health and director of the Clinical and Translational Research Accelerator at Yale University, New Haven, Conn. He has disclosed no relevant financial relationships.
A version of this article appeared on Medscape.com.
This transcript has been edited for clarity.
These types of stories usually end with a call for regulation — to ban said chemical or substance, or to regulate it — but in this case, that has already happened. This new carcinogen I’m telling you about is actually an old chemical. And it has not been manufactured or legally imported in the US since 2013.
So, why bother? Because in this case, the chemical — or, really, a group of chemicals called polybrominated diphenyl ethers (PBDEs) — are still around: in our soil, in our food, and in our blood.
PBDEs are a group of compounds that confer flame-retardant properties to plastics, and they were used extensively in the latter part of the 20th century in electronic enclosures, business equipment, and foam cushioning in upholstery.
But there was a problem. They don’t chemically bond to plastics; they are just sort of mixed in, which means they can leach out. They are hydrophobic, meaning they don’t get washed out of soil, and, when ingested or inhaled by humans, they dissolve in our fat stores, making it difficult for our normal excretory systems to excrete them.
PBDEs biomagnify. Small animals can take them up from contaminated soil or water, and those animals are eaten by larger animals, which accumulate higher concentrations of the chemicals. This bioaccumulation increases as you move up the food web until you get to an apex predator — like you and me.
This is true of lots of chemicals, of course. The concern arises when these chemicals are toxic. To date, the toxicity data for PBDEs were pretty limited. There were some animal studies where rats were exposed to extremely high doses and they developed liver lesions — but I am always very wary of extrapolating high-dose rat toxicity studies to humans. There was also some suggestion that the chemicals could be endocrine disruptors, affecting breast and thyroid tissue.
What about cancer? In 2016, the International Agency for Research on Cancer concluded there was “inadequate evidence in humans for the carcinogencity of” PBDEs.
In the same report, though, they suggested PBDEs are “probably carcinogenic to humans” based on mechanistic studies.
In other words, we can’t prove they’re cancerous — but come on, they probably are.
Finally, we have some evidence that really pushes us toward the carcinogenic conclusion, in the form of this study, appearing in JAMA Network Open. It’s a nice bit of epidemiology leveraging the population-based National Health and Nutrition Examination Survey (NHANES).
Researchers measured PBDE levels in blood samples from 1100 people enrolled in NHANES in 2003 and 2004 and linked them to death records collected over the next 20 years or so.
The first thing to note is that the researchers were able to measure PBDEs in the blood samples. They were in there. They were detectable. And they were variable. Dividing the 1100 participants into low, medium, and high PBDE tertiles, you can see a nearly 10-fold difference across the population.
Importantly, not many baseline variables correlated with PBDE levels. People in the highest group were a bit younger but had a fairly similar sex distribution, race, ethnicity, education, income, physical activity, smoking status, and body mass index.
This is not a randomized trial, of course — but at least based on these data, exposure levels do seem fairly random, which is what you would expect from an environmental toxin that percolates up through the food chain. They are often somewhat indiscriminate.
This similarity in baseline characteristics between people with low or high blood levels of PBDE also allows us to make some stronger inferences about the observed outcomes. Let’s take a look at them.
After adjustment for baseline factors, individuals in the highest PBDE group had a 43% higher rate of death from any cause over the follow-up period. This was not enough to achieve statistical significance, but it was close.
But the key finding is deaths due to cancer. After adjustment, cancer deaths occurred four times as frequently among those in the high PBDE group, and that is a statistically significant difference.
To be fair, cancer deaths were rare in this cohort. The vast majority of people did not die of anything during the follow-up period regardless of PBDE level. But the data are strongly suggestive of the carcinogenicity of these chemicals.
I should also point out that the researchers are linking the PBDE level at a single time point to all these future events. If PBDE levels remain relatively stable within an individual over time, that’s fine, but if they tend to vary with intake of different foods for example, this would not be captured and would actually lead to an underestimation of the cancer risk.
The researchers also didn’t have granular enough data to determine the type of cancer, but they do show that rates are similar between men and women, which might point away from the more sex-specific cancer etiologies. Clearly, some more work is needed.
Of course, I started this piece by telling you that these chemicals are already pretty much banned in the United States. What are we supposed to do about these findings? Studies have examined the primary ongoing sources of PBDE in our environment and it seems like most of our exposure will be coming from the food we eat due to that biomagnification thing: high-fat fish, meat and dairy products, and fish oil supplements. It may be worth some investigation into the relative adulteration of these products with this new old carcinogen.
Dr. F. Perry Wilson is associate professor of medicine and public health and director of the Clinical and Translational Research Accelerator at Yale University, New Haven, Conn. He has disclosed no relevant financial relationships.
A version of this article appeared on Medscape.com.
Active Surveillance for Cancer Doesn’t Increase Malpractice Risk
TOPLINE:
METHODOLOGY:
- Although practice guidelines from the National Comprehensive Cancer Network consider active surveillance an effective strategy for managing low-risk cancers, some physicians have been hesitant to incorporate it into their practice because of concerns about potential litigation.
- Researchers used Westlaw Edge and LexisNexis Advance databases to identify malpractice trends involving active surveillance related to thyroid, prostate, kidney, and or from 1990 to 2022.
- Data included unpublished cases, trial orders, jury verdicts, and administrative decisions.
- Researchers identified 201 malpractice cases across all low-risk cancers in the initial screening. Out of these, only five cases, all , involved active surveillance as the point of allegation.
TAKEAWAY:
- Out of the five prostate cancer cases, two involved incarcerated patients with Gleason 6 very-low-risk prostate adenocarcinoma that was managed with active surveillance by their urologists.
- In these two cases, the patients claimed that active surveillance violated their 8th Amendment right to be free from cruel or unusual punishment. In both cases, there was no metastasis or spread detected and the court determined active surveillance management was performed under national standards.
- The other three cases involved litigation claiming that active surveillance was not explicitly recommended as a treatment option for patients who all had very-low-risk prostate adenocarcinoma and had reported negligence from an intervention ( or cryoablation). However, all cases had documented informed consent for active surveillance.
- No relevant cases were found relating to active surveillance in any other type of cancer, whether in an initial diagnosis or recurrence.
IN PRACTICE:
“This data should bolster physicians’ confidence in recommending active surveillance for their patients when it is an appropriate option,” study coauthor Timothy Daskivich, MD, assistant professor of surgery at Cedars-Sinai Medical Center, Los Angeles, said in a statement . “Active surveillance maximizes quality of life and avoids unnecessary overtreatment, and it does not increase medicolegal liability to physicians, as detailed in the case dismissals identified in this study.”
SOURCE:
This study, led by Samuel Chang, JD, with Athene Law LLP, San Francisco, was recently published in Annals of Surgery.
LIMITATIONS:
The Westlaw and Lexis databases may not contain all cases or decisions issued by a state regulatory agency, like a medical board. Federal and state decisions from lower courts may not be published and available. Also, settlements outside of court or suits filed and not pursued were not included in the data.
DISCLOSURES:
The researchers did not provide any disclosures.
A version of this article appeared on Medscape.com.
TOPLINE:
METHODOLOGY:
- Although practice guidelines from the National Comprehensive Cancer Network consider active surveillance an effective strategy for managing low-risk cancers, some physicians have been hesitant to incorporate it into their practice because of concerns about potential litigation.
- Researchers used Westlaw Edge and LexisNexis Advance databases to identify malpractice trends involving active surveillance related to thyroid, prostate, kidney, and or from 1990 to 2022.
- Data included unpublished cases, trial orders, jury verdicts, and administrative decisions.
- Researchers identified 201 malpractice cases across all low-risk cancers in the initial screening. Out of these, only five cases, all , involved active surveillance as the point of allegation.
TAKEAWAY:
- Out of the five prostate cancer cases, two involved incarcerated patients with Gleason 6 very-low-risk prostate adenocarcinoma that was managed with active surveillance by their urologists.
- In these two cases, the patients claimed that active surveillance violated their 8th Amendment right to be free from cruel or unusual punishment. In both cases, there was no metastasis or spread detected and the court determined active surveillance management was performed under national standards.
- The other three cases involved litigation claiming that active surveillance was not explicitly recommended as a treatment option for patients who all had very-low-risk prostate adenocarcinoma and had reported negligence from an intervention ( or cryoablation). However, all cases had documented informed consent for active surveillance.
- No relevant cases were found relating to active surveillance in any other type of cancer, whether in an initial diagnosis or recurrence.
IN PRACTICE:
“This data should bolster physicians’ confidence in recommending active surveillance for their patients when it is an appropriate option,” study coauthor Timothy Daskivich, MD, assistant professor of surgery at Cedars-Sinai Medical Center, Los Angeles, said in a statement . “Active surveillance maximizes quality of life and avoids unnecessary overtreatment, and it does not increase medicolegal liability to physicians, as detailed in the case dismissals identified in this study.”
SOURCE:
This study, led by Samuel Chang, JD, with Athene Law LLP, San Francisco, was recently published in Annals of Surgery.
LIMITATIONS:
The Westlaw and Lexis databases may not contain all cases or decisions issued by a state regulatory agency, like a medical board. Federal and state decisions from lower courts may not be published and available. Also, settlements outside of court or suits filed and not pursued were not included in the data.
DISCLOSURES:
The researchers did not provide any disclosures.
A version of this article appeared on Medscape.com.
TOPLINE:
METHODOLOGY:
- Although practice guidelines from the National Comprehensive Cancer Network consider active surveillance an effective strategy for managing low-risk cancers, some physicians have been hesitant to incorporate it into their practice because of concerns about potential litigation.
- Researchers used Westlaw Edge and LexisNexis Advance databases to identify malpractice trends involving active surveillance related to thyroid, prostate, kidney, and or from 1990 to 2022.
- Data included unpublished cases, trial orders, jury verdicts, and administrative decisions.
- Researchers identified 201 malpractice cases across all low-risk cancers in the initial screening. Out of these, only five cases, all , involved active surveillance as the point of allegation.
TAKEAWAY:
- Out of the five prostate cancer cases, two involved incarcerated patients with Gleason 6 very-low-risk prostate adenocarcinoma that was managed with active surveillance by their urologists.
- In these two cases, the patients claimed that active surveillance violated their 8th Amendment right to be free from cruel or unusual punishment. In both cases, there was no metastasis or spread detected and the court determined active surveillance management was performed under national standards.
- The other three cases involved litigation claiming that active surveillance was not explicitly recommended as a treatment option for patients who all had very-low-risk prostate adenocarcinoma and had reported negligence from an intervention ( or cryoablation). However, all cases had documented informed consent for active surveillance.
- No relevant cases were found relating to active surveillance in any other type of cancer, whether in an initial diagnosis or recurrence.
IN PRACTICE:
“This data should bolster physicians’ confidence in recommending active surveillance for their patients when it is an appropriate option,” study coauthor Timothy Daskivich, MD, assistant professor of surgery at Cedars-Sinai Medical Center, Los Angeles, said in a statement . “Active surveillance maximizes quality of life and avoids unnecessary overtreatment, and it does not increase medicolegal liability to physicians, as detailed in the case dismissals identified in this study.”
SOURCE:
This study, led by Samuel Chang, JD, with Athene Law LLP, San Francisco, was recently published in Annals of Surgery.
LIMITATIONS:
The Westlaw and Lexis databases may not contain all cases or decisions issued by a state regulatory agency, like a medical board. Federal and state decisions from lower courts may not be published and available. Also, settlements outside of court or suits filed and not pursued were not included in the data.
DISCLOSURES:
The researchers did not provide any disclosures.
A version of this article appeared on Medscape.com.
New Guidance for the Treatment of Metastatic Breast Cancer
The Advanced Breast Cancer (ABC) 7th International Consensus Conference Guidelines for Advanced Breast Cancer will soon be released. This news organization discussed the new guidelines with Fatima Cardoso, MD, director of the Breast Unit at Champalimaud Clinical Center, Lisbon, Portugal. Dr. Cardoso is president of the ABC Global Alliance and chair of the guidelines committee. The interview has been edited for length and clarity.
Where do the ABC International Consensus Guidelines come from?
The 7th International Consensus Conference for Advanced Breast Cancer was held in November 2023. This is an international conference that takes place every 2 years. At the conference, we discuss new data that have come out in the past 2 years regarding advanced and metastatic breast cancer, and whether they should impact the guidelines or not. We look at whether there is any new treatment that is ready for clinical practice that wasn’t available 2 years ago. We look at whether there is anything else that has changed in the past 2 years.
How do the ABC International Consensus Guidelines differ from other guidelines, such as those from the National Comprehensive Cancer Network (NCCN), American Society of Clinical Oncology (ASCO), or the European Society for Medical Oncology (ESMO)?
Patients and patient advocates are members of the consensus panel where we discuss important issues around this disease and how to manage it. We also do not discuss drugs exclusively because there are other needs for patients with advanced breast cancer, and we issue recommendations regarding the global care of these patients.
Can you tell me about the other issues discussed in the guidelines besides drugs?
For example, in the more general recommendations, we revisited the proper definition of endocrine resistance. A lot of clinical trials are based on selecting a population that is considered to be endocrine sensitive or endocrine resistant, but the definition is very heterogeneous. We have updated the definition because there have been quite a few advances in this particular subtype of cancer. This [new] definition of endocrine resistance and sensitivity will be used and implemented in the different clinical trials, allowing for a better interpretation of the results, with clear impact on clinical practice.
What subtype of metastatic breast cancer had the biggest advances in terms of drugs in the guidelines?
The subtype that had the biggest advances in the new guidelines is the hormonal-dependent breast cancer, the ER-positive, HER2-negative. For that particular subtype, we have new drugs either already approved or in the process of being evaluated. Some of them have been approved in the United States but not yet in Europe by the European Medicines Agency (EMA). We are starting to discuss whether these drugs should be approved, and if they are, how we should use them. It is relevant to know what the cost-effectiveness is of each new treatment, as well and the balance between efficacy and toxicity. Sometimes data are too preliminary and we need longer follow-up or more important endpoints, such as survival.
Elacestrant is one of the drugs that has been approved by the US Food and Drug Administration (FDA), and it is very controversial because the benefit it provides on progression-free survival is modest and we still lack data on survival. So, there was a discussion on whether to consider this drug as an option or wait until we have survival data. The majority on the panel thought we could consider elacestrant as a potential new option, when we do not have other endocrine options available.
We issued a recommendation on a drug that is not FDA approved because we think the FDA is going to approve it quite soon. The drug is capivasertib and it blocks the PIK3CA pathway. [Editor’s note: The drug has since been approved by the FDA.] We have a drug that targets this pathway, alpelisib, but it is quite toxic so it is not widely used. Capivasertib has a better toxicity profile so we believe it could be a good addition to our armamentarium for this particular subtype of breast cancer.
We have lots of new data about the antibody-drug conjugates, the ADCs. Initially, we had more data for HER2-positive and triple-negative disease, but now studies have been done to show the value of the ADCs also in the ER-positive, HER2-negative subtype, and so they are now options. In particular, we have trastuzumab deruxtecan for patients with HER2-low disease. Most of the HER2-low tumors are also hormone receptor–positive.
The ABC Guidelines discuss tough clinical situations. Can you explain?
The guidelines also discuss issues that in clinical practice are quite difficult because we don’t have strong data. There are certain tough clinical situations. One example is how to treat a woman who has metastatic disease and is pregnant. We discuss the possibilities of treatment in that situation and also what other support these patients need. We discussed that the only available therapy we can use is chemotherapy. We cannot use endocrine therapy, nor biological agents such as anti-HER2 agents and immunotherapy. So, this raises a lot of concerns for how to treat these women without hurting the fetus. But in these guidelines, we discuss other needs of these patients. It’s a hot topic in the US and we did issue a recommendation: that in some situations where the life of the mother may be at risk because we are not able to provide the most adequate treatment, then they should be free to choose to terminate the pregnancy.
It is important to realize that you can’t give most of the new treatments — and ones that have an impact on survival — to a woman when she is pregnant.
What other tough clinical situations do you discuss in the new guidelines?
We discuss someone who has metastatic disease and is HIV-positive. Can we use CDK4/6 inhibitors? Can we use immunotherapy? What are the recent data? We have very little data to show that we can possibly use immunotherapy, but we do not have any safety data regarding the CDK4/6 inhibitors.
It’s important to note that people who are HIV-positive tend to have a worse mortality rate from cancer and also suffer from more toxicity. Very often, there is a need to reduce the doses of the treatments we are going to give. The guidelines provide guidance on these issues so that in clinical practice, doctors can have some help managing these difficult situations.
Another example of a tough clinical situation is how to treat an elderly, frail patient who has metastatic disease. We discuss what geriatric evaluations you need to perform before deciding the treatment. We discuss the need very often to reduce the starting dose and then adapt according to what the patient can tolerate.
We have discussed quite a lot of topics that are really patient-oriented and clinically oriented. The aim is to help everyone in clinical practice to provide the best available care.
Do you want to expand a bit on the elderly, frail patient and what you have in the guidelines about that?
A very important message is that it doesn’t matter what age your ID card says; it’s the biological age that is important. There are some people who are in their 80s, but they are very fit and they have a very active, normal life. There are other people who are in their 50s and they struggle. It’s important to perform a geriatric evaluation to determine the probability of tolerating a cancer treatment, and we normally use a simple tool called G8. If this tool shows fragility, then it is crucial to have a full geriatric assessment and a full physical exam.
It’s also very important to look for drug-drug interactions in the elderly because these patients often take many different therapies for other diseases.
Another issue is chronic undertreatment in the elderly. If you look just at chronological age and you don’t provide the optimal treatment, there will be increased mortality.
We also recommend starting elderly patients on a lower dose. There are not strong data for that, but we think it is clinical common sense to start at a lower dose. Then, if there is good tolerance, you can move to the usual dose.
Often, the elderly are excluded from clinical trials. Some of the clinical trials for some of the newer agents have included elderly patients. For example, there were some elderly patients in the CDK4/6 inhibitor trials. We know that these patients can receive these treatments with a reduction in dose.
Very frail elderly patients are often excluded from clinical trials. If we continue to do that, we will never know how to treat them.
Is there anything you would like to add about the ABC Guidelines that we haven’t talked about?
In the general statement of the guidelines, we mention two things that I think are important for people to know. The first is that during the COVID-19 pandemic, a lot of cancer patients, particularly those with advanced disease, were not offered access to ventilators. Remember, we didn’t have enough ventilators for everyone, so there were exclusion criteria, and one of the exclusion criteria was having cancer. Cancer patients shouldn’t be excluded from having life-saving treatment based solely on the cancer diagnosis. There are many different cancers and many different stages of the disease.
Access to intensive care units is sometimes needed temporarily for a patient with advanced breast cancer. The new treatments, such as immunotherapies and ADCs, can have significant and life-threatening toxicities. You can die from some of these side effects. All over the world, this is a difficult situation because of the bias among many healthcare providers regarding access to intensive care units for cancer patients. It’s a bias we are fighting against.
The second thing we discuss in the beginning of the new guidelines is what is happening to cancer patients during periods of war or conflict. For example, in Ukraine, many of the patients were able to run away and go to another country, but all their health information was lost because the hospitals were destroyed. Patients arrive in a new country and they don’t have any information on the type of cancer they have nor the type of treatment they were undergoing. It was very difficult, for example, for the doctors in Poland to know how to continue to treat the Ukrainian patients. So, in the guidelines, we discuss how we can find a way to ensure that a patient has a copy of their important health data.
Dr. Cardoso, MD, has disclosed the following relevant financial relationships:Personal financial interest in form of consultancy role for: Amgen; Astellas/Medivation; AstraZeneca; Celgene; Daiichi-Sankyo; Eisai; GE Oncology; Genentech; Gilead; GlaxoSmithKline; Iqvia; Macrogenics; Medscape; Merck-Sharp; Merus BV; Mylan; Mundipharma; Novartis; Pfizer; Pierre-Fabre; prIME Oncology; Roche; Sanofi; Samsung Bioepis; Seagen; Teva; Touchime.
Institutional financial support for clinical trials from: Amgen; AstraZeneca; Bayer; Boehringer Ingelheim; Bristol Myers Squibb; Bayer; Daiichi; Eisai; Fresenius GmbH; Genentech; GlaxoSmithKline; Ipsen; Incyte; Nektar Therapeutics; Nerviano; Novartis; Macrogenics; Medigene; MedImmune; Merck; Millennium; Pfizer; Pierre-Fabre; Roche; Sanofi-Aventis; Sonus; Tesaro; Tigris; Wilex; Wyeth.
A version of this article appeared on Medscape.com.
The Advanced Breast Cancer (ABC) 7th International Consensus Conference Guidelines for Advanced Breast Cancer will soon be released. This news organization discussed the new guidelines with Fatima Cardoso, MD, director of the Breast Unit at Champalimaud Clinical Center, Lisbon, Portugal. Dr. Cardoso is president of the ABC Global Alliance and chair of the guidelines committee. The interview has been edited for length and clarity.
Where do the ABC International Consensus Guidelines come from?
The 7th International Consensus Conference for Advanced Breast Cancer was held in November 2023. This is an international conference that takes place every 2 years. At the conference, we discuss new data that have come out in the past 2 years regarding advanced and metastatic breast cancer, and whether they should impact the guidelines or not. We look at whether there is any new treatment that is ready for clinical practice that wasn’t available 2 years ago. We look at whether there is anything else that has changed in the past 2 years.
How do the ABC International Consensus Guidelines differ from other guidelines, such as those from the National Comprehensive Cancer Network (NCCN), American Society of Clinical Oncology (ASCO), or the European Society for Medical Oncology (ESMO)?
Patients and patient advocates are members of the consensus panel where we discuss important issues around this disease and how to manage it. We also do not discuss drugs exclusively because there are other needs for patients with advanced breast cancer, and we issue recommendations regarding the global care of these patients.
Can you tell me about the other issues discussed in the guidelines besides drugs?
For example, in the more general recommendations, we revisited the proper definition of endocrine resistance. A lot of clinical trials are based on selecting a population that is considered to be endocrine sensitive or endocrine resistant, but the definition is very heterogeneous. We have updated the definition because there have been quite a few advances in this particular subtype of cancer. This [new] definition of endocrine resistance and sensitivity will be used and implemented in the different clinical trials, allowing for a better interpretation of the results, with clear impact on clinical practice.
What subtype of metastatic breast cancer had the biggest advances in terms of drugs in the guidelines?
The subtype that had the biggest advances in the new guidelines is the hormonal-dependent breast cancer, the ER-positive, HER2-negative. For that particular subtype, we have new drugs either already approved or in the process of being evaluated. Some of them have been approved in the United States but not yet in Europe by the European Medicines Agency (EMA). We are starting to discuss whether these drugs should be approved, and if they are, how we should use them. It is relevant to know what the cost-effectiveness is of each new treatment, as well and the balance between efficacy and toxicity. Sometimes data are too preliminary and we need longer follow-up or more important endpoints, such as survival.
Elacestrant is one of the drugs that has been approved by the US Food and Drug Administration (FDA), and it is very controversial because the benefit it provides on progression-free survival is modest and we still lack data on survival. So, there was a discussion on whether to consider this drug as an option or wait until we have survival data. The majority on the panel thought we could consider elacestrant as a potential new option, when we do not have other endocrine options available.
We issued a recommendation on a drug that is not FDA approved because we think the FDA is going to approve it quite soon. The drug is capivasertib and it blocks the PIK3CA pathway. [Editor’s note: The drug has since been approved by the FDA.] We have a drug that targets this pathway, alpelisib, but it is quite toxic so it is not widely used. Capivasertib has a better toxicity profile so we believe it could be a good addition to our armamentarium for this particular subtype of breast cancer.
We have lots of new data about the antibody-drug conjugates, the ADCs. Initially, we had more data for HER2-positive and triple-negative disease, but now studies have been done to show the value of the ADCs also in the ER-positive, HER2-negative subtype, and so they are now options. In particular, we have trastuzumab deruxtecan for patients with HER2-low disease. Most of the HER2-low tumors are also hormone receptor–positive.
The ABC Guidelines discuss tough clinical situations. Can you explain?
The guidelines also discuss issues that in clinical practice are quite difficult because we don’t have strong data. There are certain tough clinical situations. One example is how to treat a woman who has metastatic disease and is pregnant. We discuss the possibilities of treatment in that situation and also what other support these patients need. We discussed that the only available therapy we can use is chemotherapy. We cannot use endocrine therapy, nor biological agents such as anti-HER2 agents and immunotherapy. So, this raises a lot of concerns for how to treat these women without hurting the fetus. But in these guidelines, we discuss other needs of these patients. It’s a hot topic in the US and we did issue a recommendation: that in some situations where the life of the mother may be at risk because we are not able to provide the most adequate treatment, then they should be free to choose to terminate the pregnancy.
It is important to realize that you can’t give most of the new treatments — and ones that have an impact on survival — to a woman when she is pregnant.
What other tough clinical situations do you discuss in the new guidelines?
We discuss someone who has metastatic disease and is HIV-positive. Can we use CDK4/6 inhibitors? Can we use immunotherapy? What are the recent data? We have very little data to show that we can possibly use immunotherapy, but we do not have any safety data regarding the CDK4/6 inhibitors.
It’s important to note that people who are HIV-positive tend to have a worse mortality rate from cancer and also suffer from more toxicity. Very often, there is a need to reduce the doses of the treatments we are going to give. The guidelines provide guidance on these issues so that in clinical practice, doctors can have some help managing these difficult situations.
Another example of a tough clinical situation is how to treat an elderly, frail patient who has metastatic disease. We discuss what geriatric evaluations you need to perform before deciding the treatment. We discuss the need very often to reduce the starting dose and then adapt according to what the patient can tolerate.
We have discussed quite a lot of topics that are really patient-oriented and clinically oriented. The aim is to help everyone in clinical practice to provide the best available care.
Do you want to expand a bit on the elderly, frail patient and what you have in the guidelines about that?
A very important message is that it doesn’t matter what age your ID card says; it’s the biological age that is important. There are some people who are in their 80s, but they are very fit and they have a very active, normal life. There are other people who are in their 50s and they struggle. It’s important to perform a geriatric evaluation to determine the probability of tolerating a cancer treatment, and we normally use a simple tool called G8. If this tool shows fragility, then it is crucial to have a full geriatric assessment and a full physical exam.
It’s also very important to look for drug-drug interactions in the elderly because these patients often take many different therapies for other diseases.
Another issue is chronic undertreatment in the elderly. If you look just at chronological age and you don’t provide the optimal treatment, there will be increased mortality.
We also recommend starting elderly patients on a lower dose. There are not strong data for that, but we think it is clinical common sense to start at a lower dose. Then, if there is good tolerance, you can move to the usual dose.
Often, the elderly are excluded from clinical trials. Some of the clinical trials for some of the newer agents have included elderly patients. For example, there were some elderly patients in the CDK4/6 inhibitor trials. We know that these patients can receive these treatments with a reduction in dose.
Very frail elderly patients are often excluded from clinical trials. If we continue to do that, we will never know how to treat them.
Is there anything you would like to add about the ABC Guidelines that we haven’t talked about?
In the general statement of the guidelines, we mention two things that I think are important for people to know. The first is that during the COVID-19 pandemic, a lot of cancer patients, particularly those with advanced disease, were not offered access to ventilators. Remember, we didn’t have enough ventilators for everyone, so there were exclusion criteria, and one of the exclusion criteria was having cancer. Cancer patients shouldn’t be excluded from having life-saving treatment based solely on the cancer diagnosis. There are many different cancers and many different stages of the disease.
Access to intensive care units is sometimes needed temporarily for a patient with advanced breast cancer. The new treatments, such as immunotherapies and ADCs, can have significant and life-threatening toxicities. You can die from some of these side effects. All over the world, this is a difficult situation because of the bias among many healthcare providers regarding access to intensive care units for cancer patients. It’s a bias we are fighting against.
The second thing we discuss in the beginning of the new guidelines is what is happening to cancer patients during periods of war or conflict. For example, in Ukraine, many of the patients were able to run away and go to another country, but all their health information was lost because the hospitals were destroyed. Patients arrive in a new country and they don’t have any information on the type of cancer they have nor the type of treatment they were undergoing. It was very difficult, for example, for the doctors in Poland to know how to continue to treat the Ukrainian patients. So, in the guidelines, we discuss how we can find a way to ensure that a patient has a copy of their important health data.
Dr. Cardoso, MD, has disclosed the following relevant financial relationships:Personal financial interest in form of consultancy role for: Amgen; Astellas/Medivation; AstraZeneca; Celgene; Daiichi-Sankyo; Eisai; GE Oncology; Genentech; Gilead; GlaxoSmithKline; Iqvia; Macrogenics; Medscape; Merck-Sharp; Merus BV; Mylan; Mundipharma; Novartis; Pfizer; Pierre-Fabre; prIME Oncology; Roche; Sanofi; Samsung Bioepis; Seagen; Teva; Touchime.
Institutional financial support for clinical trials from: Amgen; AstraZeneca; Bayer; Boehringer Ingelheim; Bristol Myers Squibb; Bayer; Daiichi; Eisai; Fresenius GmbH; Genentech; GlaxoSmithKline; Ipsen; Incyte; Nektar Therapeutics; Nerviano; Novartis; Macrogenics; Medigene; MedImmune; Merck; Millennium; Pfizer; Pierre-Fabre; Roche; Sanofi-Aventis; Sonus; Tesaro; Tigris; Wilex; Wyeth.
A version of this article appeared on Medscape.com.
The Advanced Breast Cancer (ABC) 7th International Consensus Conference Guidelines for Advanced Breast Cancer will soon be released. This news organization discussed the new guidelines with Fatima Cardoso, MD, director of the Breast Unit at Champalimaud Clinical Center, Lisbon, Portugal. Dr. Cardoso is president of the ABC Global Alliance and chair of the guidelines committee. The interview has been edited for length and clarity.
Where do the ABC International Consensus Guidelines come from?
The 7th International Consensus Conference for Advanced Breast Cancer was held in November 2023. This is an international conference that takes place every 2 years. At the conference, we discuss new data that have come out in the past 2 years regarding advanced and metastatic breast cancer, and whether they should impact the guidelines or not. We look at whether there is any new treatment that is ready for clinical practice that wasn’t available 2 years ago. We look at whether there is anything else that has changed in the past 2 years.
How do the ABC International Consensus Guidelines differ from other guidelines, such as those from the National Comprehensive Cancer Network (NCCN), American Society of Clinical Oncology (ASCO), or the European Society for Medical Oncology (ESMO)?
Patients and patient advocates are members of the consensus panel where we discuss important issues around this disease and how to manage it. We also do not discuss drugs exclusively because there are other needs for patients with advanced breast cancer, and we issue recommendations regarding the global care of these patients.
Can you tell me about the other issues discussed in the guidelines besides drugs?
For example, in the more general recommendations, we revisited the proper definition of endocrine resistance. A lot of clinical trials are based on selecting a population that is considered to be endocrine sensitive or endocrine resistant, but the definition is very heterogeneous. We have updated the definition because there have been quite a few advances in this particular subtype of cancer. This [new] definition of endocrine resistance and sensitivity will be used and implemented in the different clinical trials, allowing for a better interpretation of the results, with clear impact on clinical practice.
What subtype of metastatic breast cancer had the biggest advances in terms of drugs in the guidelines?
The subtype that had the biggest advances in the new guidelines is the hormonal-dependent breast cancer, the ER-positive, HER2-negative. For that particular subtype, we have new drugs either already approved or in the process of being evaluated. Some of them have been approved in the United States but not yet in Europe by the European Medicines Agency (EMA). We are starting to discuss whether these drugs should be approved, and if they are, how we should use them. It is relevant to know what the cost-effectiveness is of each new treatment, as well and the balance between efficacy and toxicity. Sometimes data are too preliminary and we need longer follow-up or more important endpoints, such as survival.
Elacestrant is one of the drugs that has been approved by the US Food and Drug Administration (FDA), and it is very controversial because the benefit it provides on progression-free survival is modest and we still lack data on survival. So, there was a discussion on whether to consider this drug as an option or wait until we have survival data. The majority on the panel thought we could consider elacestrant as a potential new option, when we do not have other endocrine options available.
We issued a recommendation on a drug that is not FDA approved because we think the FDA is going to approve it quite soon. The drug is capivasertib and it blocks the PIK3CA pathway. [Editor’s note: The drug has since been approved by the FDA.] We have a drug that targets this pathway, alpelisib, but it is quite toxic so it is not widely used. Capivasertib has a better toxicity profile so we believe it could be a good addition to our armamentarium for this particular subtype of breast cancer.
We have lots of new data about the antibody-drug conjugates, the ADCs. Initially, we had more data for HER2-positive and triple-negative disease, but now studies have been done to show the value of the ADCs also in the ER-positive, HER2-negative subtype, and so they are now options. In particular, we have trastuzumab deruxtecan for patients with HER2-low disease. Most of the HER2-low tumors are also hormone receptor–positive.
The ABC Guidelines discuss tough clinical situations. Can you explain?
The guidelines also discuss issues that in clinical practice are quite difficult because we don’t have strong data. There are certain tough clinical situations. One example is how to treat a woman who has metastatic disease and is pregnant. We discuss the possibilities of treatment in that situation and also what other support these patients need. We discussed that the only available therapy we can use is chemotherapy. We cannot use endocrine therapy, nor biological agents such as anti-HER2 agents and immunotherapy. So, this raises a lot of concerns for how to treat these women without hurting the fetus. But in these guidelines, we discuss other needs of these patients. It’s a hot topic in the US and we did issue a recommendation: that in some situations where the life of the mother may be at risk because we are not able to provide the most adequate treatment, then they should be free to choose to terminate the pregnancy.
It is important to realize that you can’t give most of the new treatments — and ones that have an impact on survival — to a woman when she is pregnant.
What other tough clinical situations do you discuss in the new guidelines?
We discuss someone who has metastatic disease and is HIV-positive. Can we use CDK4/6 inhibitors? Can we use immunotherapy? What are the recent data? We have very little data to show that we can possibly use immunotherapy, but we do not have any safety data regarding the CDK4/6 inhibitors.
It’s important to note that people who are HIV-positive tend to have a worse mortality rate from cancer and also suffer from more toxicity. Very often, there is a need to reduce the doses of the treatments we are going to give. The guidelines provide guidance on these issues so that in clinical practice, doctors can have some help managing these difficult situations.
Another example of a tough clinical situation is how to treat an elderly, frail patient who has metastatic disease. We discuss what geriatric evaluations you need to perform before deciding the treatment. We discuss the need very often to reduce the starting dose and then adapt according to what the patient can tolerate.
We have discussed quite a lot of topics that are really patient-oriented and clinically oriented. The aim is to help everyone in clinical practice to provide the best available care.
Do you want to expand a bit on the elderly, frail patient and what you have in the guidelines about that?
A very important message is that it doesn’t matter what age your ID card says; it’s the biological age that is important. There are some people who are in their 80s, but they are very fit and they have a very active, normal life. There are other people who are in their 50s and they struggle. It’s important to perform a geriatric evaluation to determine the probability of tolerating a cancer treatment, and we normally use a simple tool called G8. If this tool shows fragility, then it is crucial to have a full geriatric assessment and a full physical exam.
It’s also very important to look for drug-drug interactions in the elderly because these patients often take many different therapies for other diseases.
Another issue is chronic undertreatment in the elderly. If you look just at chronological age and you don’t provide the optimal treatment, there will be increased mortality.
We also recommend starting elderly patients on a lower dose. There are not strong data for that, but we think it is clinical common sense to start at a lower dose. Then, if there is good tolerance, you can move to the usual dose.
Often, the elderly are excluded from clinical trials. Some of the clinical trials for some of the newer agents have included elderly patients. For example, there were some elderly patients in the CDK4/6 inhibitor trials. We know that these patients can receive these treatments with a reduction in dose.
Very frail elderly patients are often excluded from clinical trials. If we continue to do that, we will never know how to treat them.
Is there anything you would like to add about the ABC Guidelines that we haven’t talked about?
In the general statement of the guidelines, we mention two things that I think are important for people to know. The first is that during the COVID-19 pandemic, a lot of cancer patients, particularly those with advanced disease, were not offered access to ventilators. Remember, we didn’t have enough ventilators for everyone, so there were exclusion criteria, and one of the exclusion criteria was having cancer. Cancer patients shouldn’t be excluded from having life-saving treatment based solely on the cancer diagnosis. There are many different cancers and many different stages of the disease.
Access to intensive care units is sometimes needed temporarily for a patient with advanced breast cancer. The new treatments, such as immunotherapies and ADCs, can have significant and life-threatening toxicities. You can die from some of these side effects. All over the world, this is a difficult situation because of the bias among many healthcare providers regarding access to intensive care units for cancer patients. It’s a bias we are fighting against.
The second thing we discuss in the beginning of the new guidelines is what is happening to cancer patients during periods of war or conflict. For example, in Ukraine, many of the patients were able to run away and go to another country, but all their health information was lost because the hospitals were destroyed. Patients arrive in a new country and they don’t have any information on the type of cancer they have nor the type of treatment they were undergoing. It was very difficult, for example, for the doctors in Poland to know how to continue to treat the Ukrainian patients. So, in the guidelines, we discuss how we can find a way to ensure that a patient has a copy of their important health data.
Dr. Cardoso, MD, has disclosed the following relevant financial relationships:Personal financial interest in form of consultancy role for: Amgen; Astellas/Medivation; AstraZeneca; Celgene; Daiichi-Sankyo; Eisai; GE Oncology; Genentech; Gilead; GlaxoSmithKline; Iqvia; Macrogenics; Medscape; Merck-Sharp; Merus BV; Mylan; Mundipharma; Novartis; Pfizer; Pierre-Fabre; prIME Oncology; Roche; Sanofi; Samsung Bioepis; Seagen; Teva; Touchime.
Institutional financial support for clinical trials from: Amgen; AstraZeneca; Bayer; Boehringer Ingelheim; Bristol Myers Squibb; Bayer; Daiichi; Eisai; Fresenius GmbH; Genentech; GlaxoSmithKline; Ipsen; Incyte; Nektar Therapeutics; Nerviano; Novartis; Macrogenics; Medigene; MedImmune; Merck; Millennium; Pfizer; Pierre-Fabre; Roche; Sanofi-Aventis; Sonus; Tesaro; Tigris; Wilex; Wyeth.
A version of this article appeared on Medscape.com.