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Most community-based oncologists skip biomarker testing
A recent survey shows that fewer than half of community oncologists use biomarker testing to guide patient discussions about treatment, which compares with 73% of academic clinicians.
The findings, reported at the 2020 World Conference on Lung Cancer, which was rescheduled for January 2021, highlight the potential for unequal application of the latest advances in cancer genomics and targeted therapies throughout the health care system, which could worsen existing disparities in underserved populations, according to Leigh Boehmer, PharmD, medical director for the Association of Community Cancer Centers, Rockville, Md.
The survey – a mixed-methods approach for assessing practice patterns, attitudes, barriers, and resource needs related to biomarker testing among clinicians – was developed by the ACCC in partnership with the LUNGevity Foundation and administered to clinicians caring for patients with non–small cell lung cancer who are uninsured or covered by Medicaid.
Of 99 respondents, more than 85% were physicians and 68% worked in a community setting. Only 40% indicated they were very familiar or extremely familiar with 2018 Molecular Testing Guidelines for Lung Cancer from the College of American Pathologists, the International Association for the Study of Lung Cancer, and the Association for Molecular Pathology.
Clinicians were most confident about selecting appropriate tests to use, interpreting test results, and prognosticating based on test results, with 77%, 74%, and 74%, respectively, saying they are very confident or extremely confident in those areas. They were less confident about determining when to order testing and in coordinating care across the multidisciplinary team, with 59% and 64%, respectively, saying they were very confident or extremely confident in those areas, Dr. Boehmer reported at the conference.
The shortcomings with respect to communication across teams were echoed in two focus groups convened to further validate the survey results, he noted.
As for the reasons why clinicians ordered biomarker testing, 88% and 82% of community and academic clinicians, respectively, said they did so to help make targeted treatment decisions.
“Only 48% of community clinicians indicated that they use biomarker testing to guide patient discussions, compared to 73% of academic clinicians,” he said. “That finding was considered statistically significant.”
With respect to decision-making about biomarker testing, 41% said they prefer to share the responsibility with patients, whereas 52% said they prefer to make the final decision.
“Shedding further light on this situation, focus group participants expressed that patients lacked comprehension and interest about what testing entails and what testing means for their treatment options,” Dr. Boehmer noted.
In order to make more informed decisions about biomarker testing, respondents said they need more information on financial resources for patient assistance (26%) and education around both published guidelines and practical implications of the clinical data (21%).
When asked about patients’ information needs, 23% said their patients need psychosocial support, 22% said they need financial assistance, and 9% said their patients have no additional resource needs.
However, only 27% said they provide patients with resources related to psychosocial support services, and only 44% share financial assistance information, he said.
Further, the fact that 9% said their patients need no additional resources represents “a disconnect” from the findings of the survey and focus groups, he added.
“We believe that this study identifies key areas of ongoing clinician need related to biomarker testing, including things like increased guideline familiarity, practical applications of guideline-concordant testing, and … how to optimally coordinate multidisciplinary care delivery,” Dr. Boehmer said. “Professional organizations … in partnership with patient advocacy organizations or groups should focus on developing those patient education materials … and tools for improving patient-clinician discussions about biomarker testing.”
The ACCC will be working with the LUNGevity Foundation and the Center for Business Models in Healthcare to develop an intervention to ensure that such discussions are “easily integrated into the care process for every patient,” he noted.
Such efforts are important for ensuring that clinicians are informed about the value of biomarker testing and about guidelines for testing so that patients receive the best possible care, said invited discussant Joshua Sabari, MD, of New York University Langone Health’s Perlmutter Cancer Center.
“I know that, in clinic, when meeting a new patient with non–small cell lung cancer, it’s critical to understand the driver alteration, not only for prognosis, but also for goals-of-care discussion, as well as potential treatment option,” Dr. Sabari said.
Dr. Boehmer reported consulting for Pfizer. Dr. Sabari reported consulting and advisory board membership for multiple pharmaceutical companies.
A recent survey shows that fewer than half of community oncologists use biomarker testing to guide patient discussions about treatment, which compares with 73% of academic clinicians.
The findings, reported at the 2020 World Conference on Lung Cancer, which was rescheduled for January 2021, highlight the potential for unequal application of the latest advances in cancer genomics and targeted therapies throughout the health care system, which could worsen existing disparities in underserved populations, according to Leigh Boehmer, PharmD, medical director for the Association of Community Cancer Centers, Rockville, Md.
The survey – a mixed-methods approach for assessing practice patterns, attitudes, barriers, and resource needs related to biomarker testing among clinicians – was developed by the ACCC in partnership with the LUNGevity Foundation and administered to clinicians caring for patients with non–small cell lung cancer who are uninsured or covered by Medicaid.
Of 99 respondents, more than 85% were physicians and 68% worked in a community setting. Only 40% indicated they were very familiar or extremely familiar with 2018 Molecular Testing Guidelines for Lung Cancer from the College of American Pathologists, the International Association for the Study of Lung Cancer, and the Association for Molecular Pathology.
Clinicians were most confident about selecting appropriate tests to use, interpreting test results, and prognosticating based on test results, with 77%, 74%, and 74%, respectively, saying they are very confident or extremely confident in those areas. They were less confident about determining when to order testing and in coordinating care across the multidisciplinary team, with 59% and 64%, respectively, saying they were very confident or extremely confident in those areas, Dr. Boehmer reported at the conference.
The shortcomings with respect to communication across teams were echoed in two focus groups convened to further validate the survey results, he noted.
As for the reasons why clinicians ordered biomarker testing, 88% and 82% of community and academic clinicians, respectively, said they did so to help make targeted treatment decisions.
“Only 48% of community clinicians indicated that they use biomarker testing to guide patient discussions, compared to 73% of academic clinicians,” he said. “That finding was considered statistically significant.”
With respect to decision-making about biomarker testing, 41% said they prefer to share the responsibility with patients, whereas 52% said they prefer to make the final decision.
“Shedding further light on this situation, focus group participants expressed that patients lacked comprehension and interest about what testing entails and what testing means for their treatment options,” Dr. Boehmer noted.
In order to make more informed decisions about biomarker testing, respondents said they need more information on financial resources for patient assistance (26%) and education around both published guidelines and practical implications of the clinical data (21%).
When asked about patients’ information needs, 23% said their patients need psychosocial support, 22% said they need financial assistance, and 9% said their patients have no additional resource needs.
However, only 27% said they provide patients with resources related to psychosocial support services, and only 44% share financial assistance information, he said.
Further, the fact that 9% said their patients need no additional resources represents “a disconnect” from the findings of the survey and focus groups, he added.
“We believe that this study identifies key areas of ongoing clinician need related to biomarker testing, including things like increased guideline familiarity, practical applications of guideline-concordant testing, and … how to optimally coordinate multidisciplinary care delivery,” Dr. Boehmer said. “Professional organizations … in partnership with patient advocacy organizations or groups should focus on developing those patient education materials … and tools for improving patient-clinician discussions about biomarker testing.”
The ACCC will be working with the LUNGevity Foundation and the Center for Business Models in Healthcare to develop an intervention to ensure that such discussions are “easily integrated into the care process for every patient,” he noted.
Such efforts are important for ensuring that clinicians are informed about the value of biomarker testing and about guidelines for testing so that patients receive the best possible care, said invited discussant Joshua Sabari, MD, of New York University Langone Health’s Perlmutter Cancer Center.
“I know that, in clinic, when meeting a new patient with non–small cell lung cancer, it’s critical to understand the driver alteration, not only for prognosis, but also for goals-of-care discussion, as well as potential treatment option,” Dr. Sabari said.
Dr. Boehmer reported consulting for Pfizer. Dr. Sabari reported consulting and advisory board membership for multiple pharmaceutical companies.
A recent survey shows that fewer than half of community oncologists use biomarker testing to guide patient discussions about treatment, which compares with 73% of academic clinicians.
The findings, reported at the 2020 World Conference on Lung Cancer, which was rescheduled for January 2021, highlight the potential for unequal application of the latest advances in cancer genomics and targeted therapies throughout the health care system, which could worsen existing disparities in underserved populations, according to Leigh Boehmer, PharmD, medical director for the Association of Community Cancer Centers, Rockville, Md.
The survey – a mixed-methods approach for assessing practice patterns, attitudes, barriers, and resource needs related to biomarker testing among clinicians – was developed by the ACCC in partnership with the LUNGevity Foundation and administered to clinicians caring for patients with non–small cell lung cancer who are uninsured or covered by Medicaid.
Of 99 respondents, more than 85% were physicians and 68% worked in a community setting. Only 40% indicated they were very familiar or extremely familiar with 2018 Molecular Testing Guidelines for Lung Cancer from the College of American Pathologists, the International Association for the Study of Lung Cancer, and the Association for Molecular Pathology.
Clinicians were most confident about selecting appropriate tests to use, interpreting test results, and prognosticating based on test results, with 77%, 74%, and 74%, respectively, saying they are very confident or extremely confident in those areas. They were less confident about determining when to order testing and in coordinating care across the multidisciplinary team, with 59% and 64%, respectively, saying they were very confident or extremely confident in those areas, Dr. Boehmer reported at the conference.
The shortcomings with respect to communication across teams were echoed in two focus groups convened to further validate the survey results, he noted.
As for the reasons why clinicians ordered biomarker testing, 88% and 82% of community and academic clinicians, respectively, said they did so to help make targeted treatment decisions.
“Only 48% of community clinicians indicated that they use biomarker testing to guide patient discussions, compared to 73% of academic clinicians,” he said. “That finding was considered statistically significant.”
With respect to decision-making about biomarker testing, 41% said they prefer to share the responsibility with patients, whereas 52% said they prefer to make the final decision.
“Shedding further light on this situation, focus group participants expressed that patients lacked comprehension and interest about what testing entails and what testing means for their treatment options,” Dr. Boehmer noted.
In order to make more informed decisions about biomarker testing, respondents said they need more information on financial resources for patient assistance (26%) and education around both published guidelines and practical implications of the clinical data (21%).
When asked about patients’ information needs, 23% said their patients need psychosocial support, 22% said they need financial assistance, and 9% said their patients have no additional resource needs.
However, only 27% said they provide patients with resources related to psychosocial support services, and only 44% share financial assistance information, he said.
Further, the fact that 9% said their patients need no additional resources represents “a disconnect” from the findings of the survey and focus groups, he added.
“We believe that this study identifies key areas of ongoing clinician need related to biomarker testing, including things like increased guideline familiarity, practical applications of guideline-concordant testing, and … how to optimally coordinate multidisciplinary care delivery,” Dr. Boehmer said. “Professional organizations … in partnership with patient advocacy organizations or groups should focus on developing those patient education materials … and tools for improving patient-clinician discussions about biomarker testing.”
The ACCC will be working with the LUNGevity Foundation and the Center for Business Models in Healthcare to develop an intervention to ensure that such discussions are “easily integrated into the care process for every patient,” he noted.
Such efforts are important for ensuring that clinicians are informed about the value of biomarker testing and about guidelines for testing so that patients receive the best possible care, said invited discussant Joshua Sabari, MD, of New York University Langone Health’s Perlmutter Cancer Center.
“I know that, in clinic, when meeting a new patient with non–small cell lung cancer, it’s critical to understand the driver alteration, not only for prognosis, but also for goals-of-care discussion, as well as potential treatment option,” Dr. Sabari said.
Dr. Boehmer reported consulting for Pfizer. Dr. Sabari reported consulting and advisory board membership for multiple pharmaceutical companies.
REPORTING FROM WCLC 2020
Twelve-month overall survival benefit with ribociclib for metastatic breast cancer
“Based on these results, ribociclib and letrozole should be considered the preferred treatment option,” said lead investigator Gabriel N. Hortobagyi, MD, a breast cancer medical oncologist at the University of Texas MD Anderson Cancer Center, Houston.
He presented the definitive overall survival results from MONALESSA-2 which randomized 668 patients equally and in the first line to either ribociclib or placebo on a background of standard dose letrozole.
At a median follow up of 6.6 years, median overall survival with ribociclib was 63.9 months versus 51.4 months in the placebo arm, a 24% reduction in the relative risk of death (P = .004).
It was the first report of a median overall survival (OS) exceeding 5 years in a phase 3 trial for advanced breast cancer. The estimated 6-year OS rate was 44.2% for ribociclib versus 32.0% with placebo.
“These are really impressive results” and support the use of CDK 4/6 inhibitors in the front-line setting,” said study discussant Gonzalo Gomez Abuin, MD, a medical oncologist at Hospital Alemán in Bueno Aires.
Ribociclib and other CDK 4/6 inhibitors have shown consistent progression-free survival benefit for metastatic disease, but ribociclib is the first of the major phase 3 trials with definitive overall survival results. They have “been long awaited,” Dr. Abuin said.
The overall survival benefit in MONALESSA-2 began to emerge at around 20 months and continued to increase over time.
Women had no prior CDK4/6 inhibitor treatment, chemotherapy, or endocrine therapy for metastatic disease. “They represented a pure first-line population,” Dr. Hortobagyi said.
Among other benefits, the time to first chemotherapy was a median of 50.6 months with ribociclib versus 38.9 months with placebo, so patients “had an extra year of delay before chemotherapy was utilized,” he said.
In general, Dr. Abuin said, we “see a consistent benefit with CDK 4/6 inhibitors in metastatic breast cancer across different settings.”
However, “it’s a little intriguing” that in a subgroup analysis of non–de novo disease, the overall survival benefit with ribociclib had a hazard ratio of 0.91, whereas the progression-free survival benefit was robust and statistically significant in an earlier report.
“This has been an important question, but I would caution all of us not to make too much out of the forest plot,” Dr. Hortobagyi said.
“There are a number of hypotheses one could come up with that could explain why the de novo and non–de novo populations faired differently in overall survival as opposed to progression-free survival, but there is also the simple possibility that this is a statistical fluke,” he said.
“We are in the process of analyzing this particular observation. In the meantime, I think we should just take the overall survival results of the entire population as the lead answer, and not follow the subgroup analysis until further information is available,” Dr. Hortobagyi said.
No new ribociclib safety signals were observed in the trial. The most common adverse events were neutropenia and liver function abnormalities, but they were “largely asymptomatic laboratory findings and completely reversible,” he said.
Twice as many patients treated with ribociclib developed prolonged QT intervals, but again, “no clinical consequences of this EKG finding were detected,” Dr. Hortobagyi said.
Less than 1% of patients in the ribociclib arm developed interstitial lung disease. The majority of safety events occurred in the first 12 months of treatment.
The work was funded by Novartis, maker of both ribociclib and letrozole. Dr. Hortobagyi reported receiving an institutional grant from the company and personal fees related to the trial. Other investigators disclosed ties to Novartis. Dr. Abuin reported relationships with many companies, including Novartis.
This article was updated 9/24/21.
“Based on these results, ribociclib and letrozole should be considered the preferred treatment option,” said lead investigator Gabriel N. Hortobagyi, MD, a breast cancer medical oncologist at the University of Texas MD Anderson Cancer Center, Houston.
He presented the definitive overall survival results from MONALESSA-2 which randomized 668 patients equally and in the first line to either ribociclib or placebo on a background of standard dose letrozole.
At a median follow up of 6.6 years, median overall survival with ribociclib was 63.9 months versus 51.4 months in the placebo arm, a 24% reduction in the relative risk of death (P = .004).
It was the first report of a median overall survival (OS) exceeding 5 years in a phase 3 trial for advanced breast cancer. The estimated 6-year OS rate was 44.2% for ribociclib versus 32.0% with placebo.
“These are really impressive results” and support the use of CDK 4/6 inhibitors in the front-line setting,” said study discussant Gonzalo Gomez Abuin, MD, a medical oncologist at Hospital Alemán in Bueno Aires.
Ribociclib and other CDK 4/6 inhibitors have shown consistent progression-free survival benefit for metastatic disease, but ribociclib is the first of the major phase 3 trials with definitive overall survival results. They have “been long awaited,” Dr. Abuin said.
The overall survival benefit in MONALESSA-2 began to emerge at around 20 months and continued to increase over time.
Women had no prior CDK4/6 inhibitor treatment, chemotherapy, or endocrine therapy for metastatic disease. “They represented a pure first-line population,” Dr. Hortobagyi said.
Among other benefits, the time to first chemotherapy was a median of 50.6 months with ribociclib versus 38.9 months with placebo, so patients “had an extra year of delay before chemotherapy was utilized,” he said.
In general, Dr. Abuin said, we “see a consistent benefit with CDK 4/6 inhibitors in metastatic breast cancer across different settings.”
However, “it’s a little intriguing” that in a subgroup analysis of non–de novo disease, the overall survival benefit with ribociclib had a hazard ratio of 0.91, whereas the progression-free survival benefit was robust and statistically significant in an earlier report.
“This has been an important question, but I would caution all of us not to make too much out of the forest plot,” Dr. Hortobagyi said.
“There are a number of hypotheses one could come up with that could explain why the de novo and non–de novo populations faired differently in overall survival as opposed to progression-free survival, but there is also the simple possibility that this is a statistical fluke,” he said.
“We are in the process of analyzing this particular observation. In the meantime, I think we should just take the overall survival results of the entire population as the lead answer, and not follow the subgroup analysis until further information is available,” Dr. Hortobagyi said.
No new ribociclib safety signals were observed in the trial. The most common adverse events were neutropenia and liver function abnormalities, but they were “largely asymptomatic laboratory findings and completely reversible,” he said.
Twice as many patients treated with ribociclib developed prolonged QT intervals, but again, “no clinical consequences of this EKG finding were detected,” Dr. Hortobagyi said.
Less than 1% of patients in the ribociclib arm developed interstitial lung disease. The majority of safety events occurred in the first 12 months of treatment.
The work was funded by Novartis, maker of both ribociclib and letrozole. Dr. Hortobagyi reported receiving an institutional grant from the company and personal fees related to the trial. Other investigators disclosed ties to Novartis. Dr. Abuin reported relationships with many companies, including Novartis.
This article was updated 9/24/21.
“Based on these results, ribociclib and letrozole should be considered the preferred treatment option,” said lead investigator Gabriel N. Hortobagyi, MD, a breast cancer medical oncologist at the University of Texas MD Anderson Cancer Center, Houston.
He presented the definitive overall survival results from MONALESSA-2 which randomized 668 patients equally and in the first line to either ribociclib or placebo on a background of standard dose letrozole.
At a median follow up of 6.6 years, median overall survival with ribociclib was 63.9 months versus 51.4 months in the placebo arm, a 24% reduction in the relative risk of death (P = .004).
It was the first report of a median overall survival (OS) exceeding 5 years in a phase 3 trial for advanced breast cancer. The estimated 6-year OS rate was 44.2% for ribociclib versus 32.0% with placebo.
“These are really impressive results” and support the use of CDK 4/6 inhibitors in the front-line setting,” said study discussant Gonzalo Gomez Abuin, MD, a medical oncologist at Hospital Alemán in Bueno Aires.
Ribociclib and other CDK 4/6 inhibitors have shown consistent progression-free survival benefit for metastatic disease, but ribociclib is the first of the major phase 3 trials with definitive overall survival results. They have “been long awaited,” Dr. Abuin said.
The overall survival benefit in MONALESSA-2 began to emerge at around 20 months and continued to increase over time.
Women had no prior CDK4/6 inhibitor treatment, chemotherapy, or endocrine therapy for metastatic disease. “They represented a pure first-line population,” Dr. Hortobagyi said.
Among other benefits, the time to first chemotherapy was a median of 50.6 months with ribociclib versus 38.9 months with placebo, so patients “had an extra year of delay before chemotherapy was utilized,” he said.
In general, Dr. Abuin said, we “see a consistent benefit with CDK 4/6 inhibitors in metastatic breast cancer across different settings.”
However, “it’s a little intriguing” that in a subgroup analysis of non–de novo disease, the overall survival benefit with ribociclib had a hazard ratio of 0.91, whereas the progression-free survival benefit was robust and statistically significant in an earlier report.
“This has been an important question, but I would caution all of us not to make too much out of the forest plot,” Dr. Hortobagyi said.
“There are a number of hypotheses one could come up with that could explain why the de novo and non–de novo populations faired differently in overall survival as opposed to progression-free survival, but there is also the simple possibility that this is a statistical fluke,” he said.
“We are in the process of analyzing this particular observation. In the meantime, I think we should just take the overall survival results of the entire population as the lead answer, and not follow the subgroup analysis until further information is available,” Dr. Hortobagyi said.
No new ribociclib safety signals were observed in the trial. The most common adverse events were neutropenia and liver function abnormalities, but they were “largely asymptomatic laboratory findings and completely reversible,” he said.
Twice as many patients treated with ribociclib developed prolonged QT intervals, but again, “no clinical consequences of this EKG finding were detected,” Dr. Hortobagyi said.
Less than 1% of patients in the ribociclib arm developed interstitial lung disease. The majority of safety events occurred in the first 12 months of treatment.
The work was funded by Novartis, maker of both ribociclib and letrozole. Dr. Hortobagyi reported receiving an institutional grant from the company and personal fees related to the trial. Other investigators disclosed ties to Novartis. Dr. Abuin reported relationships with many companies, including Novartis.
This article was updated 9/24/21.
FROM ESMO 2021
Flurry of cancer drug endorsements from EU panel
The CHMP recommended the granting of a conditional marketing authorization for pralsetinib (Gavreto) for the treatment of non–small cell lung cancer (NSCLC).
Specifically, pralsetinib is indicated as monotherapy for the treatment of adult patients with rearranged during transfection (RET) fusion-positive advanced NSCLC not previously treated with a RET inhibitor.
Available as 100 mg capsules, pralsetinib is a RET-receptor tyrosine kinase inhibitor, targeting oncogenic RET fusion proteins (KIF5B-RET and CCDC6-RET).
Pralsetinib’s benefits are its objective response rate and response duration in patients with RET-fusion positive NSCLC, as observed in a pivotal phase 1/2, open-label, multi-cohort, single-arm study.
The most common side effects are anemia, increased aspartate aminotransferase, neutropenia, constipation, musculoskeletal pain, fatigue, leukopenia, increased alanine aminotransferase, and hypertension.
CHMP also recommended ripretinib (Qinlock) for the treatment of adult patients with advanced gastrointestinal stromal tumor (GIST) who have received prior treatment with three or more kinase inhibitors, including imatinib (Gleevec).
Available as 50 mg tablets, ripretinib is a protein kinase inhibitor designed to selectively block the oncogenic KIT and PDGFRA kinases by inhibiting their active conformation.
Ripretinib improved progression-free survival in patients with GIST.
The most common side effects are fatigue, alopecia, nausea, myalgia, constipation, diarrhea, palmar-plantar erythrodysesthesia syndrome, weight loss, and vomiting.
The third drug recommended for approval was zanubrutinib (Brukinsa) for the treatment of adult patients with Waldenström’s macroglobulinemia who have received at least one prior therapy or who are to receive the drug as first-line treatment (and are unsuitable for chemo-immunotherapy).
Available as 80 mg capsules, zanubrutinib is a Bruton’s tyrosine kinase inhibitor that blocks the activity of BTK, inactivating the pathways necessary for B-cell proliferation, trafficking, chemotaxis, and adhesion.
Zanubrutinib has demonstrated a clinically meaningful rate of very good partial response and/or complete response.
The most common side effects are neutropenia, thrombocytopenia, upper respiratory tract infection, hemorrhage/hematoma, rash, bruising, anemia, musculoskeletal pain, diarrhea, pneumonia, and cough.
Two new indications for already marketed drugs
CHMP also recommended an extension of the indications for two immunotherapies.
Pembrolizumab (Keytruda) will now also have an indication for use in combination with chemotherapy for the treatment of locally recurrent unresectable or metastatic triple negative breast cancer in adults whose tumors express PD-L1 with a CPS greater than or equal to 10 and who have not received prior chemotherapy for metastatic disease
Nivolumab (Opdivo) received an extension of indication to include use, in combination with fluoropyrimidine- and platinum-based combination chemotherapy, in the firstline treatment of adult patients with HER2 negative advanced or metastatic gastric, gastroesophageal junction, or esophageal adenocarcinoma whose tumors express PD-L1 with a combined positive score (CPS) greater than or equal to 5.
A version of this article first appeared on Medscape.com.
The CHMP recommended the granting of a conditional marketing authorization for pralsetinib (Gavreto) for the treatment of non–small cell lung cancer (NSCLC).
Specifically, pralsetinib is indicated as monotherapy for the treatment of adult patients with rearranged during transfection (RET) fusion-positive advanced NSCLC not previously treated with a RET inhibitor.
Available as 100 mg capsules, pralsetinib is a RET-receptor tyrosine kinase inhibitor, targeting oncogenic RET fusion proteins (KIF5B-RET and CCDC6-RET).
Pralsetinib’s benefits are its objective response rate and response duration in patients with RET-fusion positive NSCLC, as observed in a pivotal phase 1/2, open-label, multi-cohort, single-arm study.
The most common side effects are anemia, increased aspartate aminotransferase, neutropenia, constipation, musculoskeletal pain, fatigue, leukopenia, increased alanine aminotransferase, and hypertension.
CHMP also recommended ripretinib (Qinlock) for the treatment of adult patients with advanced gastrointestinal stromal tumor (GIST) who have received prior treatment with three or more kinase inhibitors, including imatinib (Gleevec).
Available as 50 mg tablets, ripretinib is a protein kinase inhibitor designed to selectively block the oncogenic KIT and PDGFRA kinases by inhibiting their active conformation.
Ripretinib improved progression-free survival in patients with GIST.
The most common side effects are fatigue, alopecia, nausea, myalgia, constipation, diarrhea, palmar-plantar erythrodysesthesia syndrome, weight loss, and vomiting.
The third drug recommended for approval was zanubrutinib (Brukinsa) for the treatment of adult patients with Waldenström’s macroglobulinemia who have received at least one prior therapy or who are to receive the drug as first-line treatment (and are unsuitable for chemo-immunotherapy).
Available as 80 mg capsules, zanubrutinib is a Bruton’s tyrosine kinase inhibitor that blocks the activity of BTK, inactivating the pathways necessary for B-cell proliferation, trafficking, chemotaxis, and adhesion.
Zanubrutinib has demonstrated a clinically meaningful rate of very good partial response and/or complete response.
The most common side effects are neutropenia, thrombocytopenia, upper respiratory tract infection, hemorrhage/hematoma, rash, bruising, anemia, musculoskeletal pain, diarrhea, pneumonia, and cough.
Two new indications for already marketed drugs
CHMP also recommended an extension of the indications for two immunotherapies.
Pembrolizumab (Keytruda) will now also have an indication for use in combination with chemotherapy for the treatment of locally recurrent unresectable or metastatic triple negative breast cancer in adults whose tumors express PD-L1 with a CPS greater than or equal to 10 and who have not received prior chemotherapy for metastatic disease
Nivolumab (Opdivo) received an extension of indication to include use, in combination with fluoropyrimidine- and platinum-based combination chemotherapy, in the firstline treatment of adult patients with HER2 negative advanced or metastatic gastric, gastroesophageal junction, or esophageal adenocarcinoma whose tumors express PD-L1 with a combined positive score (CPS) greater than or equal to 5.
A version of this article first appeared on Medscape.com.
The CHMP recommended the granting of a conditional marketing authorization for pralsetinib (Gavreto) for the treatment of non–small cell lung cancer (NSCLC).
Specifically, pralsetinib is indicated as monotherapy for the treatment of adult patients with rearranged during transfection (RET) fusion-positive advanced NSCLC not previously treated with a RET inhibitor.
Available as 100 mg capsules, pralsetinib is a RET-receptor tyrosine kinase inhibitor, targeting oncogenic RET fusion proteins (KIF5B-RET and CCDC6-RET).
Pralsetinib’s benefits are its objective response rate and response duration in patients with RET-fusion positive NSCLC, as observed in a pivotal phase 1/2, open-label, multi-cohort, single-arm study.
The most common side effects are anemia, increased aspartate aminotransferase, neutropenia, constipation, musculoskeletal pain, fatigue, leukopenia, increased alanine aminotransferase, and hypertension.
CHMP also recommended ripretinib (Qinlock) for the treatment of adult patients with advanced gastrointestinal stromal tumor (GIST) who have received prior treatment with three or more kinase inhibitors, including imatinib (Gleevec).
Available as 50 mg tablets, ripretinib is a protein kinase inhibitor designed to selectively block the oncogenic KIT and PDGFRA kinases by inhibiting their active conformation.
Ripretinib improved progression-free survival in patients with GIST.
The most common side effects are fatigue, alopecia, nausea, myalgia, constipation, diarrhea, palmar-plantar erythrodysesthesia syndrome, weight loss, and vomiting.
The third drug recommended for approval was zanubrutinib (Brukinsa) for the treatment of adult patients with Waldenström’s macroglobulinemia who have received at least one prior therapy or who are to receive the drug as first-line treatment (and are unsuitable for chemo-immunotherapy).
Available as 80 mg capsules, zanubrutinib is a Bruton’s tyrosine kinase inhibitor that blocks the activity of BTK, inactivating the pathways necessary for B-cell proliferation, trafficking, chemotaxis, and adhesion.
Zanubrutinib has demonstrated a clinically meaningful rate of very good partial response and/or complete response.
The most common side effects are neutropenia, thrombocytopenia, upper respiratory tract infection, hemorrhage/hematoma, rash, bruising, anemia, musculoskeletal pain, diarrhea, pneumonia, and cough.
Two new indications for already marketed drugs
CHMP also recommended an extension of the indications for two immunotherapies.
Pembrolizumab (Keytruda) will now also have an indication for use in combination with chemotherapy for the treatment of locally recurrent unresectable or metastatic triple negative breast cancer in adults whose tumors express PD-L1 with a CPS greater than or equal to 10 and who have not received prior chemotherapy for metastatic disease
Nivolumab (Opdivo) received an extension of indication to include use, in combination with fluoropyrimidine- and platinum-based combination chemotherapy, in the firstline treatment of adult patients with HER2 negative advanced or metastatic gastric, gastroesophageal junction, or esophageal adenocarcinoma whose tumors express PD-L1 with a combined positive score (CPS) greater than or equal to 5.
A version of this article first appeared on Medscape.com.
Immunotherapy for cancer patients with poor PS needs a rethink
The findings have prompted an expert to argue against the use of immunotherapy for such patients, who may have little time left and very little chance of benefiting.
“It is quite clear from clinical practice that most patients with limited PS do very poorly and do not benefit from immune check point inhibitors (ICI),” Jason Luke, MD, UPMC Hillman Cancer Center and the University of Pittsburgh, said in an email.
“So, my strong opinion is that patients should not be getting an immunotherapy just because it might not cause as many side effects as chemotherapy,” he added.
“Instead of giving an immunotherapy with little chance of success, patients and families deserve to have a direct conversation about what realistic expectations [might be] and how we as the oncology community can support them to achieve whatever their personal goals are in the time that they have left,” he emphasized.
Dr. Luke was the lead author of an editorial in which he commented on the study. Both the study and the editorial were published online in JCO Oncology Practice.
Variety of cancers
The study was conducted by Mridula Krishnan, MD, Nebraska Medicine Fred and Pamela Buffett Cancer Center, Omaha, Nebraska, and colleagues.
The team reviewed 257 patients who had been treated with either a programmed cell death protein–1 inhibitor or programmed cell death–ligand-1 inhibitor for a variety of advanced cancers. The drugs included pembrolizumab (Keytruda), nivolumab (Opdivo), atezolizumab (Tecentique), durvalumab (Imfinzi), and avelumab (Bavencio).
Most of the patients (71%) had good PS, with an Eastern Cooperative Oncology Group (ECOG) PS of 0-1 on initiation of immunotherapy; 29% of patients had poor PS, with an ECOG PS of greater than or equal to 2.
“The primary outcome was OS stratified by ECOG PS 0-1 versus ≥2,” note the authors. Across all tumor types, OS was superior for patients in the ECOG 0-1 PS group, the investigators note. The median OS was 12.6 months, compared with only 3.1 months for patients in the ECOG greater than or equal to 2 group (P < .001).
Moreover, overall response rates for patients with a poor PS were low. Only 8%, or 6 of 75 patients with an ECOG PS of greater than or equal to 2, achieved an objective response by RECIST criteria.
This compared to an overall response rate of 23% for patients with an ECOG PS of 0-1, the investigators note (P = .005).
Interestingly, the hospice referral rate for patients with a poor PS (67%) was similar to that of patients with a PS of 1-2 (61.9%), Dr. Krishnan and colleagues observe.
Those with a poor PS were more like to die in-hospital (28.6%) than were patients with a good PS (15.1%; P = .035). The authors point out that it is well known that outcomes with chemotherapy are worse among patients who experience a decline in functional reserve, owing to increased susceptibility to toxicity and complications.
“Regardless of age, patients with ECOG PS >2 usually have poor tolerability to chemotherapy, and this correlates with worse survival outcome,” they emphasize. There is as yet no clear guidance regarding the impact of PS on ICI treatment response, although “there should be,” Dr. Luke believes.
“In a patient with declining performance status, especially ECOG PS 3-4 but potentially 2 as well, there is little likelihood that the functional and immune reserve of the patient will be adequate to mount a robust antitumor response,” he elaborated.
“It’s not impossible, but trying for it should not come at the expense of engaging about end-of-life care and maximizing the palliative opportunities that many only have a short window of time in which to pursue,” he added.
Again, Dr. Luke strongly believes that just giving an ICI without engaging in a frank conversation with the patient and their families – which happens all too often, he feels – is absolutely not the way to go when treating patients with a poor PS and little time left.
“Patients and families might be better served by having a more direct and frank conversation about what the likelihood [is] that ICI therapy will actually do,” Dr. Luke stressed.
In their editorial, Dr. Luke and colleagues write: “Overall, we as an oncology community need to improve our communication with patients regarding goals of care and end-of-life considerations as opposed to reflexive treatment initiation,” he writes.
“Our duty, first and foremost, should focus on the person sitting in front of us – taking a step back may be the best way to move forward with compassionate care,” they add.
The authors and editorialists have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
The findings have prompted an expert to argue against the use of immunotherapy for such patients, who may have little time left and very little chance of benefiting.
“It is quite clear from clinical practice that most patients with limited PS do very poorly and do not benefit from immune check point inhibitors (ICI),” Jason Luke, MD, UPMC Hillman Cancer Center and the University of Pittsburgh, said in an email.
“So, my strong opinion is that patients should not be getting an immunotherapy just because it might not cause as many side effects as chemotherapy,” he added.
“Instead of giving an immunotherapy with little chance of success, patients and families deserve to have a direct conversation about what realistic expectations [might be] and how we as the oncology community can support them to achieve whatever their personal goals are in the time that they have left,” he emphasized.
Dr. Luke was the lead author of an editorial in which he commented on the study. Both the study and the editorial were published online in JCO Oncology Practice.
Variety of cancers
The study was conducted by Mridula Krishnan, MD, Nebraska Medicine Fred and Pamela Buffett Cancer Center, Omaha, Nebraska, and colleagues.
The team reviewed 257 patients who had been treated with either a programmed cell death protein–1 inhibitor or programmed cell death–ligand-1 inhibitor for a variety of advanced cancers. The drugs included pembrolizumab (Keytruda), nivolumab (Opdivo), atezolizumab (Tecentique), durvalumab (Imfinzi), and avelumab (Bavencio).
Most of the patients (71%) had good PS, with an Eastern Cooperative Oncology Group (ECOG) PS of 0-1 on initiation of immunotherapy; 29% of patients had poor PS, with an ECOG PS of greater than or equal to 2.
“The primary outcome was OS stratified by ECOG PS 0-1 versus ≥2,” note the authors. Across all tumor types, OS was superior for patients in the ECOG 0-1 PS group, the investigators note. The median OS was 12.6 months, compared with only 3.1 months for patients in the ECOG greater than or equal to 2 group (P < .001).
Moreover, overall response rates for patients with a poor PS were low. Only 8%, or 6 of 75 patients with an ECOG PS of greater than or equal to 2, achieved an objective response by RECIST criteria.
This compared to an overall response rate of 23% for patients with an ECOG PS of 0-1, the investigators note (P = .005).
Interestingly, the hospice referral rate for patients with a poor PS (67%) was similar to that of patients with a PS of 1-2 (61.9%), Dr. Krishnan and colleagues observe.
Those with a poor PS were more like to die in-hospital (28.6%) than were patients with a good PS (15.1%; P = .035). The authors point out that it is well known that outcomes with chemotherapy are worse among patients who experience a decline in functional reserve, owing to increased susceptibility to toxicity and complications.
“Regardless of age, patients with ECOG PS >2 usually have poor tolerability to chemotherapy, and this correlates with worse survival outcome,” they emphasize. There is as yet no clear guidance regarding the impact of PS on ICI treatment response, although “there should be,” Dr. Luke believes.
“In a patient with declining performance status, especially ECOG PS 3-4 but potentially 2 as well, there is little likelihood that the functional and immune reserve of the patient will be adequate to mount a robust antitumor response,” he elaborated.
“It’s not impossible, but trying for it should not come at the expense of engaging about end-of-life care and maximizing the palliative opportunities that many only have a short window of time in which to pursue,” he added.
Again, Dr. Luke strongly believes that just giving an ICI without engaging in a frank conversation with the patient and their families – which happens all too often, he feels – is absolutely not the way to go when treating patients with a poor PS and little time left.
“Patients and families might be better served by having a more direct and frank conversation about what the likelihood [is] that ICI therapy will actually do,” Dr. Luke stressed.
In their editorial, Dr. Luke and colleagues write: “Overall, we as an oncology community need to improve our communication with patients regarding goals of care and end-of-life considerations as opposed to reflexive treatment initiation,” he writes.
“Our duty, first and foremost, should focus on the person sitting in front of us – taking a step back may be the best way to move forward with compassionate care,” they add.
The authors and editorialists have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
The findings have prompted an expert to argue against the use of immunotherapy for such patients, who may have little time left and very little chance of benefiting.
“It is quite clear from clinical practice that most patients with limited PS do very poorly and do not benefit from immune check point inhibitors (ICI),” Jason Luke, MD, UPMC Hillman Cancer Center and the University of Pittsburgh, said in an email.
“So, my strong opinion is that patients should not be getting an immunotherapy just because it might not cause as many side effects as chemotherapy,” he added.
“Instead of giving an immunotherapy with little chance of success, patients and families deserve to have a direct conversation about what realistic expectations [might be] and how we as the oncology community can support them to achieve whatever their personal goals are in the time that they have left,” he emphasized.
Dr. Luke was the lead author of an editorial in which he commented on the study. Both the study and the editorial were published online in JCO Oncology Practice.
Variety of cancers
The study was conducted by Mridula Krishnan, MD, Nebraska Medicine Fred and Pamela Buffett Cancer Center, Omaha, Nebraska, and colleagues.
The team reviewed 257 patients who had been treated with either a programmed cell death protein–1 inhibitor or programmed cell death–ligand-1 inhibitor for a variety of advanced cancers. The drugs included pembrolizumab (Keytruda), nivolumab (Opdivo), atezolizumab (Tecentique), durvalumab (Imfinzi), and avelumab (Bavencio).
Most of the patients (71%) had good PS, with an Eastern Cooperative Oncology Group (ECOG) PS of 0-1 on initiation of immunotherapy; 29% of patients had poor PS, with an ECOG PS of greater than or equal to 2.
“The primary outcome was OS stratified by ECOG PS 0-1 versus ≥2,” note the authors. Across all tumor types, OS was superior for patients in the ECOG 0-1 PS group, the investigators note. The median OS was 12.6 months, compared with only 3.1 months for patients in the ECOG greater than or equal to 2 group (P < .001).
Moreover, overall response rates for patients with a poor PS were low. Only 8%, or 6 of 75 patients with an ECOG PS of greater than or equal to 2, achieved an objective response by RECIST criteria.
This compared to an overall response rate of 23% for patients with an ECOG PS of 0-1, the investigators note (P = .005).
Interestingly, the hospice referral rate for patients with a poor PS (67%) was similar to that of patients with a PS of 1-2 (61.9%), Dr. Krishnan and colleagues observe.
Those with a poor PS were more like to die in-hospital (28.6%) than were patients with a good PS (15.1%; P = .035). The authors point out that it is well known that outcomes with chemotherapy are worse among patients who experience a decline in functional reserve, owing to increased susceptibility to toxicity and complications.
“Regardless of age, patients with ECOG PS >2 usually have poor tolerability to chemotherapy, and this correlates with worse survival outcome,” they emphasize. There is as yet no clear guidance regarding the impact of PS on ICI treatment response, although “there should be,” Dr. Luke believes.
“In a patient with declining performance status, especially ECOG PS 3-4 but potentially 2 as well, there is little likelihood that the functional and immune reserve of the patient will be adequate to mount a robust antitumor response,” he elaborated.
“It’s not impossible, but trying for it should not come at the expense of engaging about end-of-life care and maximizing the palliative opportunities that many only have a short window of time in which to pursue,” he added.
Again, Dr. Luke strongly believes that just giving an ICI without engaging in a frank conversation with the patient and their families – which happens all too often, he feels – is absolutely not the way to go when treating patients with a poor PS and little time left.
“Patients and families might be better served by having a more direct and frank conversation about what the likelihood [is] that ICI therapy will actually do,” Dr. Luke stressed.
In their editorial, Dr. Luke and colleagues write: “Overall, we as an oncology community need to improve our communication with patients regarding goals of care and end-of-life considerations as opposed to reflexive treatment initiation,” he writes.
“Our duty, first and foremost, should focus on the person sitting in front of us – taking a step back may be the best way to move forward with compassionate care,” they add.
The authors and editorialists have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
A case is building for personalized, genome-based radiation dosing
A team of researchers from the Cleveland Clinic, the Moffitt Cancer Center in Tampa, and Case Western Reserve University in Cleveland is zeroing in on a way to personalize radiation therapy for cancer patients based on genomic profile, much as genomics is used to tailor oncologic drug therapy.
It’s called “genomic-adjusted radiation dose” (GARD), a dose tailored to a person’s radiosensitivity as determined by the expression of 10 genes, known as the radiosensitivity index (RSI), combined with a linear quadratic model to yield GARD, a prediction of risk and benefit at various radiation doses for a particular patient.
A recent report in The Lancet Oncology validated GARD in 1,615 patients with seven cancer types from 11 study cohorts. If it holds up in clinical trials set to start later this year, GARD should “allow us to predict the benefit of radiation for an individual patient and adjust their treatment strategy,” wrote the authors of an editorial that accompanied the study. “The efforts need to be applauded worldwide, because radiotherapy is considerably lagging, compared with the enormous progress done in the field of personalized medicine,” Orit Kaidar-Person, MD, a radiation oncologist at Sheba Medical Center in Ramat Gan, Israel, and colleagues wrote.
GARD was associated with time to first recurrence and overall survival for patients receiving radiotherapy and predicted radiotherapy benefit, while physical dose did not. The team found a relative 2% reduction in risk of first recurrence for each unit increase of GARD (P = .0017) and a relative 3% increase in overall survival for each unit increase in GARD (P = .0007), among those who got radiotherapy. Values of GARD run from 0 to over 100, with higher scores meaning more radiation benefit.
The radiosensitivity index, which was derived from genomic studies of cancer cell lines exposed to radiation, was previously validated by the team and other groups across several tumor types.
Currently, radiation dosing is generally uniform for a given disease site and stage, based on the assumption that a given dose of radiation results in the same clinical effect across patients. In fact, the biological effect of a given dose varies widely between individual patients. “Patients we treat uniformly do not have a uniform response” which is why a more personalized approach would help, said lead investigator and Cleveland Clinic radiation oncologist Jacob Scott, MD, DPhil.
One patient with a given tumor might benefit from 2 extra fractions, while the next might need an extra 15 for the same benefit. “You need to know about [a patient’s] tumor genomics to know how hard you have to work,” he said.
Dr. Scott and colleagues are working with a genomics company to commercialize the approach. The vision for now is that physicians would ship in biopsy samples to be analyzed; RSI and GARD would be calculated, and then a decision support report would be sent back to the treatment team outlining the risks and benefits of various doses for the patient.
Dr. Scott, who holds proprietary rights on the approach, is bullish. When asked if he anticipates GARD dosing to be standard of care in 10 years, he said that “I can’t imagine another world. Everything else in cancer is personalized. Why aren’t we? It just makes sense. I know there’s a better way” to prescribe radiation, “and I’m excited for the future when I can use it.”
When asked for comment, Brian Marples, PhD, a radiation oncology professor at the University of Rochester (N.Y.), said the data so far for GARD “seem very solid. I’m very excited by the concept.”
It’s been “the holy grail” of radiation researchers to find a biologic marker that predicts what dosages patients need and what can be given safely. “This strategy is a good way of doing that. Other groups are proposing similar strategies, but I think this group is ahead. I can see [GARD] being readily applied to the clinic because patients are [already] getting their tumors genomically characterized as part of care,” Dr. Marples said.
But many questions remain. For instance, the editorial writers questioned how GARD is “affected by tumor heterogeneity, response to systemic therapy, and changes in the tumor microenvironment.” Also, the approach is based on conventional 2 Gy fractions, but other fractionation regimens are becoming more common.
For Dr. Marples, the big caveat is that most cancer patients are treated with both radiation and chemotherapy. He said he would like to see GARD validated in patients who receive both.
They seven tumor types in the study included breast cancer, head and neck cancer, non–small cell lung cancer, pancreatic cancer, endometrial cancer, melanoma, and glioma. The majority of the subjects were treated with radiation, and each had the genomic data needed to calculate GARD.
Dr. Scott, senior author and Moffitt Center radiation oncologist Javier Torres-Roca, MD, and a third author hold intellectual property rights on RSI, GARD, and prescription dose base on RSI, plus equity in Cvergenx, a company that seeks to commercialize the approach. Dr. Torres-Roca and another author are cofounders. The editorial writers and Dr. Marples did not have any relevant disclosures.
A team of researchers from the Cleveland Clinic, the Moffitt Cancer Center in Tampa, and Case Western Reserve University in Cleveland is zeroing in on a way to personalize radiation therapy for cancer patients based on genomic profile, much as genomics is used to tailor oncologic drug therapy.
It’s called “genomic-adjusted radiation dose” (GARD), a dose tailored to a person’s radiosensitivity as determined by the expression of 10 genes, known as the radiosensitivity index (RSI), combined with a linear quadratic model to yield GARD, a prediction of risk and benefit at various radiation doses for a particular patient.
A recent report in The Lancet Oncology validated GARD in 1,615 patients with seven cancer types from 11 study cohorts. If it holds up in clinical trials set to start later this year, GARD should “allow us to predict the benefit of radiation for an individual patient and adjust their treatment strategy,” wrote the authors of an editorial that accompanied the study. “The efforts need to be applauded worldwide, because radiotherapy is considerably lagging, compared with the enormous progress done in the field of personalized medicine,” Orit Kaidar-Person, MD, a radiation oncologist at Sheba Medical Center in Ramat Gan, Israel, and colleagues wrote.
GARD was associated with time to first recurrence and overall survival for patients receiving radiotherapy and predicted radiotherapy benefit, while physical dose did not. The team found a relative 2% reduction in risk of first recurrence for each unit increase of GARD (P = .0017) and a relative 3% increase in overall survival for each unit increase in GARD (P = .0007), among those who got radiotherapy. Values of GARD run from 0 to over 100, with higher scores meaning more radiation benefit.
The radiosensitivity index, which was derived from genomic studies of cancer cell lines exposed to radiation, was previously validated by the team and other groups across several tumor types.
Currently, radiation dosing is generally uniform for a given disease site and stage, based on the assumption that a given dose of radiation results in the same clinical effect across patients. In fact, the biological effect of a given dose varies widely between individual patients. “Patients we treat uniformly do not have a uniform response” which is why a more personalized approach would help, said lead investigator and Cleveland Clinic radiation oncologist Jacob Scott, MD, DPhil.
One patient with a given tumor might benefit from 2 extra fractions, while the next might need an extra 15 for the same benefit. “You need to know about [a patient’s] tumor genomics to know how hard you have to work,” he said.
Dr. Scott and colleagues are working with a genomics company to commercialize the approach. The vision for now is that physicians would ship in biopsy samples to be analyzed; RSI and GARD would be calculated, and then a decision support report would be sent back to the treatment team outlining the risks and benefits of various doses for the patient.
Dr. Scott, who holds proprietary rights on the approach, is bullish. When asked if he anticipates GARD dosing to be standard of care in 10 years, he said that “I can’t imagine another world. Everything else in cancer is personalized. Why aren’t we? It just makes sense. I know there’s a better way” to prescribe radiation, “and I’m excited for the future when I can use it.”
When asked for comment, Brian Marples, PhD, a radiation oncology professor at the University of Rochester (N.Y.), said the data so far for GARD “seem very solid. I’m very excited by the concept.”
It’s been “the holy grail” of radiation researchers to find a biologic marker that predicts what dosages patients need and what can be given safely. “This strategy is a good way of doing that. Other groups are proposing similar strategies, but I think this group is ahead. I can see [GARD] being readily applied to the clinic because patients are [already] getting their tumors genomically characterized as part of care,” Dr. Marples said.
But many questions remain. For instance, the editorial writers questioned how GARD is “affected by tumor heterogeneity, response to systemic therapy, and changes in the tumor microenvironment.” Also, the approach is based on conventional 2 Gy fractions, but other fractionation regimens are becoming more common.
For Dr. Marples, the big caveat is that most cancer patients are treated with both radiation and chemotherapy. He said he would like to see GARD validated in patients who receive both.
They seven tumor types in the study included breast cancer, head and neck cancer, non–small cell lung cancer, pancreatic cancer, endometrial cancer, melanoma, and glioma. The majority of the subjects were treated with radiation, and each had the genomic data needed to calculate GARD.
Dr. Scott, senior author and Moffitt Center radiation oncologist Javier Torres-Roca, MD, and a third author hold intellectual property rights on RSI, GARD, and prescription dose base on RSI, plus equity in Cvergenx, a company that seeks to commercialize the approach. Dr. Torres-Roca and another author are cofounders. The editorial writers and Dr. Marples did not have any relevant disclosures.
A team of researchers from the Cleveland Clinic, the Moffitt Cancer Center in Tampa, and Case Western Reserve University in Cleveland is zeroing in on a way to personalize radiation therapy for cancer patients based on genomic profile, much as genomics is used to tailor oncologic drug therapy.
It’s called “genomic-adjusted radiation dose” (GARD), a dose tailored to a person’s radiosensitivity as determined by the expression of 10 genes, known as the radiosensitivity index (RSI), combined with a linear quadratic model to yield GARD, a prediction of risk and benefit at various radiation doses for a particular patient.
A recent report in The Lancet Oncology validated GARD in 1,615 patients with seven cancer types from 11 study cohorts. If it holds up in clinical trials set to start later this year, GARD should “allow us to predict the benefit of radiation for an individual patient and adjust their treatment strategy,” wrote the authors of an editorial that accompanied the study. “The efforts need to be applauded worldwide, because radiotherapy is considerably lagging, compared with the enormous progress done in the field of personalized medicine,” Orit Kaidar-Person, MD, a radiation oncologist at Sheba Medical Center in Ramat Gan, Israel, and colleagues wrote.
GARD was associated with time to first recurrence and overall survival for patients receiving radiotherapy and predicted radiotherapy benefit, while physical dose did not. The team found a relative 2% reduction in risk of first recurrence for each unit increase of GARD (P = .0017) and a relative 3% increase in overall survival for each unit increase in GARD (P = .0007), among those who got radiotherapy. Values of GARD run from 0 to over 100, with higher scores meaning more radiation benefit.
The radiosensitivity index, which was derived from genomic studies of cancer cell lines exposed to radiation, was previously validated by the team and other groups across several tumor types.
Currently, radiation dosing is generally uniform for a given disease site and stage, based on the assumption that a given dose of radiation results in the same clinical effect across patients. In fact, the biological effect of a given dose varies widely between individual patients. “Patients we treat uniformly do not have a uniform response” which is why a more personalized approach would help, said lead investigator and Cleveland Clinic radiation oncologist Jacob Scott, MD, DPhil.
One patient with a given tumor might benefit from 2 extra fractions, while the next might need an extra 15 for the same benefit. “You need to know about [a patient’s] tumor genomics to know how hard you have to work,” he said.
Dr. Scott and colleagues are working with a genomics company to commercialize the approach. The vision for now is that physicians would ship in biopsy samples to be analyzed; RSI and GARD would be calculated, and then a decision support report would be sent back to the treatment team outlining the risks and benefits of various doses for the patient.
Dr. Scott, who holds proprietary rights on the approach, is bullish. When asked if he anticipates GARD dosing to be standard of care in 10 years, he said that “I can’t imagine another world. Everything else in cancer is personalized. Why aren’t we? It just makes sense. I know there’s a better way” to prescribe radiation, “and I’m excited for the future when I can use it.”
When asked for comment, Brian Marples, PhD, a radiation oncology professor at the University of Rochester (N.Y.), said the data so far for GARD “seem very solid. I’m very excited by the concept.”
It’s been “the holy grail” of radiation researchers to find a biologic marker that predicts what dosages patients need and what can be given safely. “This strategy is a good way of doing that. Other groups are proposing similar strategies, but I think this group is ahead. I can see [GARD] being readily applied to the clinic because patients are [already] getting their tumors genomically characterized as part of care,” Dr. Marples said.
But many questions remain. For instance, the editorial writers questioned how GARD is “affected by tumor heterogeneity, response to systemic therapy, and changes in the tumor microenvironment.” Also, the approach is based on conventional 2 Gy fractions, but other fractionation regimens are becoming more common.
For Dr. Marples, the big caveat is that most cancer patients are treated with both radiation and chemotherapy. He said he would like to see GARD validated in patients who receive both.
They seven tumor types in the study included breast cancer, head and neck cancer, non–small cell lung cancer, pancreatic cancer, endometrial cancer, melanoma, and glioma. The majority of the subjects were treated with radiation, and each had the genomic data needed to calculate GARD.
Dr. Scott, senior author and Moffitt Center radiation oncologist Javier Torres-Roca, MD, and a third author hold intellectual property rights on RSI, GARD, and prescription dose base on RSI, plus equity in Cvergenx, a company that seeks to commercialize the approach. Dr. Torres-Roca and another author are cofounders. The editorial writers and Dr. Marples did not have any relevant disclosures.
FROM LANCET ONCOLOGY
Polygenic breast cancer risk scores strive to overcome racial bias
The potential of polygenic risk scores (PRSs) to become key components in the assessment of individual risk for disease in the clinical setting is inching closer to fruition; however, the technology is plagued by one glaring omission of most existing PRSs – the lack of applicability to those of non-European ancestry.
Polygenic risk scores predict an individual’s risk of disease based on common genetic variants identified in large genomewide association studies (GWASs). They have gained ground in research, as well as in the unregulated realm of the direct-to-consumer market where they are sold as add-ons to DNA ancestry kits such as 23andMe and MyHeritage.com.
While the risk scores show strong validation in estimating risk among people of European descent, their striking caveat is the lack of applicability to other ancestries, particularly African, and their use in practice outside of clinical trials is discouraged in National Comprehensive Cancer Network guidelines.
Study underscores need for ethnically diverse datasets
In a recent study published in JAMA Network Open, researchers evaluated the use of polygenic risk scores’ models in a clinical setting. Researchers tested 7 PRSs models for breast cancer risk against the medical records data of 39,591 women of European, African, and Latinx ancestry.
The PRSs models – all used only for research purposes – included three models involving European ancestry cohorts, two from Latinx cohorts, and two from women African descent.
After adjusting for factors including age, breast cancer family history, and ancestry, the PRSs from women with European ancestry highly corresponded to breast cancer risk, with a mean odds ratio of 1.46 per standard deviation increase in the score.
PRSs were also generalized relatively well among women of Latinx ancestry with a mean OR of 1.31. The authors noted that association is likely caused by Latinx individuals in the United States having a greater proportion of European ancestry than individuals with African ancestry. Importantly, however, the effect size was lower for women of African ancestry with a highest OR of 1.19 per standard deviation.
In the highest percentiles of breast cancer risk, women of European descent had odds ratio as high as 2.19-2.48, suggesting a statistically significant association with overall breast cancer risk. No statistically significant associations were found among women of Latinx and African-ancestry.
The PRSs models were smaller for women of non-European ancestry and included fewer genetic variants for women of non-European ancestry were notably smaller and hence reflected fewer genetic variants. Of the two risk scores involving African ancestry, the Women’s Health Initiative for Women with African ancestry risk score had just 75 variants, while the African diaspora study (ROOT) had 34 variants, compared with 3,820 and 5,218 in the two largest European ancestry PRSs, the Breast Cancer Association Consortium and the UK Biobank, respectively.
“These results highlight the need to improve representation of diverse population groups, particularly women with African ancestry, in genomic research cohorts,” the authors wrote.
First author, Cong Liu, PhD, of Columbia University Irving Medical Center, New York, said that efforts are underway to improve the inclusivity in the Electronic Medical Records and Genomics network data set used in this study.
“Until well-developed and validated PRSs for women with non-European ancestry become available, the current PRSs based on cohorts with European ancestry could be adapted for Latinx women, but not women with African ancestry until additional data sets become available in this important and high-risk group,” Dr. Liu and colleagues wrote.
In a commentary published with the study, Payal D. Shah, MD, of the Basser Center for BRCA at the University of Pennsylvania, Philadelphia, said that PRSs are “disproportionately applicable to patients with European ancestry and are insufficiently vetted and developed in other populations. If an instrument exists that has clinical utility in informing effective cancer risk mitigation strategies, then we must strive to ensure that it is available and applicable to all.”
Higher morality among African American women
While American Cancer Society data shows women with African ancestry generally have incidence rates of breast cancer similar to White women, they have significantly higher mortality from the disease in part because of later-stage diagnosis and health care barriers.
Anne Marie McCarthy, PhD, of the University of Pennsylvania, and Katrina Armstrong, MD, of Harvard Medical School, Boston, wrote in the Journal of the National Cancer Institute that African American women “have 42% higher breast cancer mortality than white women, despite having lower disease incidence, and are more likely to be diagnosed with triple-negative breast cancer, which has poorer prognosis than other molecular subtypes.”
Dr. McCarthy and Dr. Armstrong wrote that African American women are chronically underrepresented in breast cancer studies. And as such, it is impossible to know the extent of the prevalence of mutations and risk.
Failing to address the lack of diversity in genomic studies may worsen health disparities for women with African ancestry, Dr. Liu and colleagues wrote. The higher mortality “underscores the urgent need to increase diversity in genomic studies so that future clinical applications of the PRS do not exacerbate existing health disparities. These results highlight the need to improve representation of diverse population groups, particularly women with African ancestry, in genomic research cohorts.”
Potential PRS benefits underscore need to eliminate bias
The potentially important benefits of PRSs as risk prediction tools used in combination with family history, reproductive history and other factors, should provide strong incentive to push for improvement, Dr. Shah wrote.
For instance, if an individual is estrogen receptor positive and shows elevations in breast cancer risk on a reliable PRS, “this may inform antiestrogen chemoprevention strategies,” she wrote.
A risk score could furthermore influence the age at which breast cancer screening should begin or factor into whether a patient should also receive surveillance breast MRI.
Importantly, PRSs could also add to other risk factors to provide more precise risk estimates and inform management of women with a pathogenic variant in a breast cancer risk predisposition gene, Dr. Shah wrote.
Confluence project
Among the most promising developments in research is the National Cancer Institute’s Confluence Project, a large research resource aiming to include approximately 300,000 breast cancer cases and 300,000 controls of different races/ethnicities, utilizing the confluence of existing GWAS and new genomewide genotyping data.
Having started enrollment in 2018, the project is approaching implementation, said Montserrat García-Closas, MD, MPH, DrPH, deputy director of cancer epidemiology and genetics with the National Cancer Institute.
“We expect genotyping to be completed by the end of 2022 and for the data to be made available to the research community soon after that,” she said.
Among the project’s key objectives are the development of PRSs to be integrated with known risk factors to provide a personalized risk assessment for breast cancer, overall and by ancestral subtype.
“We plan to apply novel methods to derive multiancestry PRS that will account for differences and similarities in genetic architecture across ethnic/racial groups to develop breast cancer PRSs that can be applied in multiethnic/racial populations,” she said.
NCI is working with investigators in Africa, Central and South America, and Asia, and reaching out to non-European organizations such as AORTIC for studies of African populations.
Direct-to-consumer global PRS
In the commercial PRS market, efforts to address diversity shortcomings are also gaining momentum, with Myriad Genetics touting a first-of-its kind “global PRS.”
The PRS, a recalibrated version the company’s riskScore PRS, sold as part of its Myriad myRisk Hereditary Cancer test, will reportedly apply to all ethnicities in estimating an individual’s 5-year and lifetime risk of breast cancer.
A study presented in June at the American Society of Clinical Oncology meeting, describes the development of the model with the use of three large ancestry-specific PRSs based on African American, Asian, and European cohorts, with the system including a total of 149 single-nucleotide polymorphisms, including 93 well established for breast cancer and 56 that are ancestry specific.
In validation of the data in an independent cohort of 62,707 individuals, the global PRS was strongly associated with breast cancer in the full combined validation cohort as well as in all three of the ancestry subcohorts.
However, the effect size among women with African ancestry was still the lowest of all of the groups, with a mean OR of 1.24 per standard deviation, versus the highest rate of mixed ancestry (OR, 1.59).
According to senior author Holly Pederson, MD, director of medical breast services at the Cleveland Clinic, the applicability of the PRS to women with African ancestry is expected to further improve as additional data become available.
“The discriminatory power in women of African descent was significantly improved but still suboptimal,” she said. “The need for more data, particularly in Black women, is challenging not only because there is likely more diversity in the genomic landscape of women of African descent, but also because the barriers created by historical, cultural, institutional and interpersonal dynamics result in the paucity of this data.”
“We must be committed to ending bias resulting in health care disparities,” Dr. Pederson said. She noted that the global PRS is nevertheless “still clinically useful in Black women,” and recommended that clinicians be up front with patients on the status of the research challenges.
“As with any clinical shared decision-making conversation between a patient and her provider, it is important for Black women to know that data is limited in the African American population, particularly given the vast genomic diversity of the African continent,” she said. “This model, as models that have gone before it, will improve with additional data, particularly in this population.”
Commercial PRSs may benefit research
While the commercial marketing of PRSs in a direct-to-consumer fashion have raised some concerns, such as how individuals respond to their risk scores, there could be important benefits as well, commented Megan C. Roberts, PhD.
“There may be an opportunity to learn from these companies about how to engage diverse communities in genomic testing,” said Dr. Roberts, an assistant professor and director of implementation science in precision health and society at the University of North Carolina at Chapel Hill. “Moreover, the data they collect from their customers often can be used for research purposes as well.”
In a recent perspective, Dr. Roberts and colleagues addressed the role of health disparities in PRSs. She’ll be joining international precision public health researchers in October in hosting a free virtual conference at UNC on the topic.
“There is a huge need to improve racial and ethnic diversity in our genomic datasets,” Dr. Roberts said. “Without this, we will not be able to return on the promise of precision medicine and prevention for improving the health of our whole population.”
Dr. Pederson disclosed that she is a consultant for Myriad Genetics.
The potential of polygenic risk scores (PRSs) to become key components in the assessment of individual risk for disease in the clinical setting is inching closer to fruition; however, the technology is plagued by one glaring omission of most existing PRSs – the lack of applicability to those of non-European ancestry.
Polygenic risk scores predict an individual’s risk of disease based on common genetic variants identified in large genomewide association studies (GWASs). They have gained ground in research, as well as in the unregulated realm of the direct-to-consumer market where they are sold as add-ons to DNA ancestry kits such as 23andMe and MyHeritage.com.
While the risk scores show strong validation in estimating risk among people of European descent, their striking caveat is the lack of applicability to other ancestries, particularly African, and their use in practice outside of clinical trials is discouraged in National Comprehensive Cancer Network guidelines.
Study underscores need for ethnically diverse datasets
In a recent study published in JAMA Network Open, researchers evaluated the use of polygenic risk scores’ models in a clinical setting. Researchers tested 7 PRSs models for breast cancer risk against the medical records data of 39,591 women of European, African, and Latinx ancestry.
The PRSs models – all used only for research purposes – included three models involving European ancestry cohorts, two from Latinx cohorts, and two from women African descent.
After adjusting for factors including age, breast cancer family history, and ancestry, the PRSs from women with European ancestry highly corresponded to breast cancer risk, with a mean odds ratio of 1.46 per standard deviation increase in the score.
PRSs were also generalized relatively well among women of Latinx ancestry with a mean OR of 1.31. The authors noted that association is likely caused by Latinx individuals in the United States having a greater proportion of European ancestry than individuals with African ancestry. Importantly, however, the effect size was lower for women of African ancestry with a highest OR of 1.19 per standard deviation.
In the highest percentiles of breast cancer risk, women of European descent had odds ratio as high as 2.19-2.48, suggesting a statistically significant association with overall breast cancer risk. No statistically significant associations were found among women of Latinx and African-ancestry.
The PRSs models were smaller for women of non-European ancestry and included fewer genetic variants for women of non-European ancestry were notably smaller and hence reflected fewer genetic variants. Of the two risk scores involving African ancestry, the Women’s Health Initiative for Women with African ancestry risk score had just 75 variants, while the African diaspora study (ROOT) had 34 variants, compared with 3,820 and 5,218 in the two largest European ancestry PRSs, the Breast Cancer Association Consortium and the UK Biobank, respectively.
“These results highlight the need to improve representation of diverse population groups, particularly women with African ancestry, in genomic research cohorts,” the authors wrote.
First author, Cong Liu, PhD, of Columbia University Irving Medical Center, New York, said that efforts are underway to improve the inclusivity in the Electronic Medical Records and Genomics network data set used in this study.
“Until well-developed and validated PRSs for women with non-European ancestry become available, the current PRSs based on cohorts with European ancestry could be adapted for Latinx women, but not women with African ancestry until additional data sets become available in this important and high-risk group,” Dr. Liu and colleagues wrote.
In a commentary published with the study, Payal D. Shah, MD, of the Basser Center for BRCA at the University of Pennsylvania, Philadelphia, said that PRSs are “disproportionately applicable to patients with European ancestry and are insufficiently vetted and developed in other populations. If an instrument exists that has clinical utility in informing effective cancer risk mitigation strategies, then we must strive to ensure that it is available and applicable to all.”
Higher morality among African American women
While American Cancer Society data shows women with African ancestry generally have incidence rates of breast cancer similar to White women, they have significantly higher mortality from the disease in part because of later-stage diagnosis and health care barriers.
Anne Marie McCarthy, PhD, of the University of Pennsylvania, and Katrina Armstrong, MD, of Harvard Medical School, Boston, wrote in the Journal of the National Cancer Institute that African American women “have 42% higher breast cancer mortality than white women, despite having lower disease incidence, and are more likely to be diagnosed with triple-negative breast cancer, which has poorer prognosis than other molecular subtypes.”
Dr. McCarthy and Dr. Armstrong wrote that African American women are chronically underrepresented in breast cancer studies. And as such, it is impossible to know the extent of the prevalence of mutations and risk.
Failing to address the lack of diversity in genomic studies may worsen health disparities for women with African ancestry, Dr. Liu and colleagues wrote. The higher mortality “underscores the urgent need to increase diversity in genomic studies so that future clinical applications of the PRS do not exacerbate existing health disparities. These results highlight the need to improve representation of diverse population groups, particularly women with African ancestry, in genomic research cohorts.”
Potential PRS benefits underscore need to eliminate bias
The potentially important benefits of PRSs as risk prediction tools used in combination with family history, reproductive history and other factors, should provide strong incentive to push for improvement, Dr. Shah wrote.
For instance, if an individual is estrogen receptor positive and shows elevations in breast cancer risk on a reliable PRS, “this may inform antiestrogen chemoprevention strategies,” she wrote.
A risk score could furthermore influence the age at which breast cancer screening should begin or factor into whether a patient should also receive surveillance breast MRI.
Importantly, PRSs could also add to other risk factors to provide more precise risk estimates and inform management of women with a pathogenic variant in a breast cancer risk predisposition gene, Dr. Shah wrote.
Confluence project
Among the most promising developments in research is the National Cancer Institute’s Confluence Project, a large research resource aiming to include approximately 300,000 breast cancer cases and 300,000 controls of different races/ethnicities, utilizing the confluence of existing GWAS and new genomewide genotyping data.
Having started enrollment in 2018, the project is approaching implementation, said Montserrat García-Closas, MD, MPH, DrPH, deputy director of cancer epidemiology and genetics with the National Cancer Institute.
“We expect genotyping to be completed by the end of 2022 and for the data to be made available to the research community soon after that,” she said.
Among the project’s key objectives are the development of PRSs to be integrated with known risk factors to provide a personalized risk assessment for breast cancer, overall and by ancestral subtype.
“We plan to apply novel methods to derive multiancestry PRS that will account for differences and similarities in genetic architecture across ethnic/racial groups to develop breast cancer PRSs that can be applied in multiethnic/racial populations,” she said.
NCI is working with investigators in Africa, Central and South America, and Asia, and reaching out to non-European organizations such as AORTIC for studies of African populations.
Direct-to-consumer global PRS
In the commercial PRS market, efforts to address diversity shortcomings are also gaining momentum, with Myriad Genetics touting a first-of-its kind “global PRS.”
The PRS, a recalibrated version the company’s riskScore PRS, sold as part of its Myriad myRisk Hereditary Cancer test, will reportedly apply to all ethnicities in estimating an individual’s 5-year and lifetime risk of breast cancer.
A study presented in June at the American Society of Clinical Oncology meeting, describes the development of the model with the use of three large ancestry-specific PRSs based on African American, Asian, and European cohorts, with the system including a total of 149 single-nucleotide polymorphisms, including 93 well established for breast cancer and 56 that are ancestry specific.
In validation of the data in an independent cohort of 62,707 individuals, the global PRS was strongly associated with breast cancer in the full combined validation cohort as well as in all three of the ancestry subcohorts.
However, the effect size among women with African ancestry was still the lowest of all of the groups, with a mean OR of 1.24 per standard deviation, versus the highest rate of mixed ancestry (OR, 1.59).
According to senior author Holly Pederson, MD, director of medical breast services at the Cleveland Clinic, the applicability of the PRS to women with African ancestry is expected to further improve as additional data become available.
“The discriminatory power in women of African descent was significantly improved but still suboptimal,” she said. “The need for more data, particularly in Black women, is challenging not only because there is likely more diversity in the genomic landscape of women of African descent, but also because the barriers created by historical, cultural, institutional and interpersonal dynamics result in the paucity of this data.”
“We must be committed to ending bias resulting in health care disparities,” Dr. Pederson said. She noted that the global PRS is nevertheless “still clinically useful in Black women,” and recommended that clinicians be up front with patients on the status of the research challenges.
“As with any clinical shared decision-making conversation between a patient and her provider, it is important for Black women to know that data is limited in the African American population, particularly given the vast genomic diversity of the African continent,” she said. “This model, as models that have gone before it, will improve with additional data, particularly in this population.”
Commercial PRSs may benefit research
While the commercial marketing of PRSs in a direct-to-consumer fashion have raised some concerns, such as how individuals respond to their risk scores, there could be important benefits as well, commented Megan C. Roberts, PhD.
“There may be an opportunity to learn from these companies about how to engage diverse communities in genomic testing,” said Dr. Roberts, an assistant professor and director of implementation science in precision health and society at the University of North Carolina at Chapel Hill. “Moreover, the data they collect from their customers often can be used for research purposes as well.”
In a recent perspective, Dr. Roberts and colleagues addressed the role of health disparities in PRSs. She’ll be joining international precision public health researchers in October in hosting a free virtual conference at UNC on the topic.
“There is a huge need to improve racial and ethnic diversity in our genomic datasets,” Dr. Roberts said. “Without this, we will not be able to return on the promise of precision medicine and prevention for improving the health of our whole population.”
Dr. Pederson disclosed that she is a consultant for Myriad Genetics.
The potential of polygenic risk scores (PRSs) to become key components in the assessment of individual risk for disease in the clinical setting is inching closer to fruition; however, the technology is plagued by one glaring omission of most existing PRSs – the lack of applicability to those of non-European ancestry.
Polygenic risk scores predict an individual’s risk of disease based on common genetic variants identified in large genomewide association studies (GWASs). They have gained ground in research, as well as in the unregulated realm of the direct-to-consumer market where they are sold as add-ons to DNA ancestry kits such as 23andMe and MyHeritage.com.
While the risk scores show strong validation in estimating risk among people of European descent, their striking caveat is the lack of applicability to other ancestries, particularly African, and their use in practice outside of clinical trials is discouraged in National Comprehensive Cancer Network guidelines.
Study underscores need for ethnically diverse datasets
In a recent study published in JAMA Network Open, researchers evaluated the use of polygenic risk scores’ models in a clinical setting. Researchers tested 7 PRSs models for breast cancer risk against the medical records data of 39,591 women of European, African, and Latinx ancestry.
The PRSs models – all used only for research purposes – included three models involving European ancestry cohorts, two from Latinx cohorts, and two from women African descent.
After adjusting for factors including age, breast cancer family history, and ancestry, the PRSs from women with European ancestry highly corresponded to breast cancer risk, with a mean odds ratio of 1.46 per standard deviation increase in the score.
PRSs were also generalized relatively well among women of Latinx ancestry with a mean OR of 1.31. The authors noted that association is likely caused by Latinx individuals in the United States having a greater proportion of European ancestry than individuals with African ancestry. Importantly, however, the effect size was lower for women of African ancestry with a highest OR of 1.19 per standard deviation.
In the highest percentiles of breast cancer risk, women of European descent had odds ratio as high as 2.19-2.48, suggesting a statistically significant association with overall breast cancer risk. No statistically significant associations were found among women of Latinx and African-ancestry.
The PRSs models were smaller for women of non-European ancestry and included fewer genetic variants for women of non-European ancestry were notably smaller and hence reflected fewer genetic variants. Of the two risk scores involving African ancestry, the Women’s Health Initiative for Women with African ancestry risk score had just 75 variants, while the African diaspora study (ROOT) had 34 variants, compared with 3,820 and 5,218 in the two largest European ancestry PRSs, the Breast Cancer Association Consortium and the UK Biobank, respectively.
“These results highlight the need to improve representation of diverse population groups, particularly women with African ancestry, in genomic research cohorts,” the authors wrote.
First author, Cong Liu, PhD, of Columbia University Irving Medical Center, New York, said that efforts are underway to improve the inclusivity in the Electronic Medical Records and Genomics network data set used in this study.
“Until well-developed and validated PRSs for women with non-European ancestry become available, the current PRSs based on cohorts with European ancestry could be adapted for Latinx women, but not women with African ancestry until additional data sets become available in this important and high-risk group,” Dr. Liu and colleagues wrote.
In a commentary published with the study, Payal D. Shah, MD, of the Basser Center for BRCA at the University of Pennsylvania, Philadelphia, said that PRSs are “disproportionately applicable to patients with European ancestry and are insufficiently vetted and developed in other populations. If an instrument exists that has clinical utility in informing effective cancer risk mitigation strategies, then we must strive to ensure that it is available and applicable to all.”
Higher morality among African American women
While American Cancer Society data shows women with African ancestry generally have incidence rates of breast cancer similar to White women, they have significantly higher mortality from the disease in part because of later-stage diagnosis and health care barriers.
Anne Marie McCarthy, PhD, of the University of Pennsylvania, and Katrina Armstrong, MD, of Harvard Medical School, Boston, wrote in the Journal of the National Cancer Institute that African American women “have 42% higher breast cancer mortality than white women, despite having lower disease incidence, and are more likely to be diagnosed with triple-negative breast cancer, which has poorer prognosis than other molecular subtypes.”
Dr. McCarthy and Dr. Armstrong wrote that African American women are chronically underrepresented in breast cancer studies. And as such, it is impossible to know the extent of the prevalence of mutations and risk.
Failing to address the lack of diversity in genomic studies may worsen health disparities for women with African ancestry, Dr. Liu and colleagues wrote. The higher mortality “underscores the urgent need to increase diversity in genomic studies so that future clinical applications of the PRS do not exacerbate existing health disparities. These results highlight the need to improve representation of diverse population groups, particularly women with African ancestry, in genomic research cohorts.”
Potential PRS benefits underscore need to eliminate bias
The potentially important benefits of PRSs as risk prediction tools used in combination with family history, reproductive history and other factors, should provide strong incentive to push for improvement, Dr. Shah wrote.
For instance, if an individual is estrogen receptor positive and shows elevations in breast cancer risk on a reliable PRS, “this may inform antiestrogen chemoprevention strategies,” she wrote.
A risk score could furthermore influence the age at which breast cancer screening should begin or factor into whether a patient should also receive surveillance breast MRI.
Importantly, PRSs could also add to other risk factors to provide more precise risk estimates and inform management of women with a pathogenic variant in a breast cancer risk predisposition gene, Dr. Shah wrote.
Confluence project
Among the most promising developments in research is the National Cancer Institute’s Confluence Project, a large research resource aiming to include approximately 300,000 breast cancer cases and 300,000 controls of different races/ethnicities, utilizing the confluence of existing GWAS and new genomewide genotyping data.
Having started enrollment in 2018, the project is approaching implementation, said Montserrat García-Closas, MD, MPH, DrPH, deputy director of cancer epidemiology and genetics with the National Cancer Institute.
“We expect genotyping to be completed by the end of 2022 and for the data to be made available to the research community soon after that,” she said.
Among the project’s key objectives are the development of PRSs to be integrated with known risk factors to provide a personalized risk assessment for breast cancer, overall and by ancestral subtype.
“We plan to apply novel methods to derive multiancestry PRS that will account for differences and similarities in genetic architecture across ethnic/racial groups to develop breast cancer PRSs that can be applied in multiethnic/racial populations,” she said.
NCI is working with investigators in Africa, Central and South America, and Asia, and reaching out to non-European organizations such as AORTIC for studies of African populations.
Direct-to-consumer global PRS
In the commercial PRS market, efforts to address diversity shortcomings are also gaining momentum, with Myriad Genetics touting a first-of-its kind “global PRS.”
The PRS, a recalibrated version the company’s riskScore PRS, sold as part of its Myriad myRisk Hereditary Cancer test, will reportedly apply to all ethnicities in estimating an individual’s 5-year and lifetime risk of breast cancer.
A study presented in June at the American Society of Clinical Oncology meeting, describes the development of the model with the use of three large ancestry-specific PRSs based on African American, Asian, and European cohorts, with the system including a total of 149 single-nucleotide polymorphisms, including 93 well established for breast cancer and 56 that are ancestry specific.
In validation of the data in an independent cohort of 62,707 individuals, the global PRS was strongly associated with breast cancer in the full combined validation cohort as well as in all three of the ancestry subcohorts.
However, the effect size among women with African ancestry was still the lowest of all of the groups, with a mean OR of 1.24 per standard deviation, versus the highest rate of mixed ancestry (OR, 1.59).
According to senior author Holly Pederson, MD, director of medical breast services at the Cleveland Clinic, the applicability of the PRS to women with African ancestry is expected to further improve as additional data become available.
“The discriminatory power in women of African descent was significantly improved but still suboptimal,” she said. “The need for more data, particularly in Black women, is challenging not only because there is likely more diversity in the genomic landscape of women of African descent, but also because the barriers created by historical, cultural, institutional and interpersonal dynamics result in the paucity of this data.”
“We must be committed to ending bias resulting in health care disparities,” Dr. Pederson said. She noted that the global PRS is nevertheless “still clinically useful in Black women,” and recommended that clinicians be up front with patients on the status of the research challenges.
“As with any clinical shared decision-making conversation between a patient and her provider, it is important for Black women to know that data is limited in the African American population, particularly given the vast genomic diversity of the African continent,” she said. “This model, as models that have gone before it, will improve with additional data, particularly in this population.”
Commercial PRSs may benefit research
While the commercial marketing of PRSs in a direct-to-consumer fashion have raised some concerns, such as how individuals respond to their risk scores, there could be important benefits as well, commented Megan C. Roberts, PhD.
“There may be an opportunity to learn from these companies about how to engage diverse communities in genomic testing,” said Dr. Roberts, an assistant professor and director of implementation science in precision health and society at the University of North Carolina at Chapel Hill. “Moreover, the data they collect from their customers often can be used for research purposes as well.”
In a recent perspective, Dr. Roberts and colleagues addressed the role of health disparities in PRSs. She’ll be joining international precision public health researchers in October in hosting a free virtual conference at UNC on the topic.
“There is a huge need to improve racial and ethnic diversity in our genomic datasets,” Dr. Roberts said. “Without this, we will not be able to return on the promise of precision medicine and prevention for improving the health of our whole population.”
Dr. Pederson disclosed that she is a consultant for Myriad Genetics.
FROM JAMA NETWORK OPEN
Therapeutic Approaches in Advanced Breast Cancer
More than 280,000 women in the United States will be diagnosed with invasive breast cancer this year. For those with metastatic breast cancer with distant spread, the 5-year survival rate is approximately 28%. Whether advanced disease is discovered at initial diagnosis or in relapsed disease, it is imperative to understand the molecular characteristics of the metastatic tumor.
Dr Susan Domchek, from the University of Pennsylvania, discusses the importance of retesting for estrogen receptor, progesterone receptor, and HER2/neu on a metastatic tumor focus in order to identify potential discordance between the primary cancer and metastatic disease.
Additionally, Dr Domchek discusses the importance of molecular testing for targetable mutations, including P13K and germline BRCA1/2, for which approved therapies have shown survival benefit.
The list of targetable mutations in breast cancer continues to expand. In the tumor-agnostic studies, pembrolizumab has shown survival benefit in tumors that have mismatch repair deficiency and microsatellite instability, and TRK inhibitors have shown efficacy in tumors positive for NTRK fusions. Numerous clinical trials are available looking at additional molecular-based therapies.
--
Susan M. Domchek, MD, Basser Professor, Department of Oncology; Executive Director, Basser Center for BRCA, Abramson Cancer Center, University of Pennsylvania, Philadelphia.
Susan M. Domchek, MD, has disclosed the following relevant financial relationships: Received income in an amount equal to or greater than $250 from: AstraZeneca; Clovis; Bristol Myers Squibb.
More than 280,000 women in the United States will be diagnosed with invasive breast cancer this year. For those with metastatic breast cancer with distant spread, the 5-year survival rate is approximately 28%. Whether advanced disease is discovered at initial diagnosis or in relapsed disease, it is imperative to understand the molecular characteristics of the metastatic tumor.
Dr Susan Domchek, from the University of Pennsylvania, discusses the importance of retesting for estrogen receptor, progesterone receptor, and HER2/neu on a metastatic tumor focus in order to identify potential discordance between the primary cancer and metastatic disease.
Additionally, Dr Domchek discusses the importance of molecular testing for targetable mutations, including P13K and germline BRCA1/2, for which approved therapies have shown survival benefit.
The list of targetable mutations in breast cancer continues to expand. In the tumor-agnostic studies, pembrolizumab has shown survival benefit in tumors that have mismatch repair deficiency and microsatellite instability, and TRK inhibitors have shown efficacy in tumors positive for NTRK fusions. Numerous clinical trials are available looking at additional molecular-based therapies.
--
Susan M. Domchek, MD, Basser Professor, Department of Oncology; Executive Director, Basser Center for BRCA, Abramson Cancer Center, University of Pennsylvania, Philadelphia.
Susan M. Domchek, MD, has disclosed the following relevant financial relationships: Received income in an amount equal to or greater than $250 from: AstraZeneca; Clovis; Bristol Myers Squibb.
More than 280,000 women in the United States will be diagnosed with invasive breast cancer this year. For those with metastatic breast cancer with distant spread, the 5-year survival rate is approximately 28%. Whether advanced disease is discovered at initial diagnosis or in relapsed disease, it is imperative to understand the molecular characteristics of the metastatic tumor.
Dr Susan Domchek, from the University of Pennsylvania, discusses the importance of retesting for estrogen receptor, progesterone receptor, and HER2/neu on a metastatic tumor focus in order to identify potential discordance between the primary cancer and metastatic disease.
Additionally, Dr Domchek discusses the importance of molecular testing for targetable mutations, including P13K and germline BRCA1/2, for which approved therapies have shown survival benefit.
The list of targetable mutations in breast cancer continues to expand. In the tumor-agnostic studies, pembrolizumab has shown survival benefit in tumors that have mismatch repair deficiency and microsatellite instability, and TRK inhibitors have shown efficacy in tumors positive for NTRK fusions. Numerous clinical trials are available looking at additional molecular-based therapies.
--
Susan M. Domchek, MD, Basser Professor, Department of Oncology; Executive Director, Basser Center for BRCA, Abramson Cancer Center, University of Pennsylvania, Philadelphia.
Susan M. Domchek, MD, has disclosed the following relevant financial relationships: Received income in an amount equal to or greater than $250 from: AstraZeneca; Clovis; Bristol Myers Squibb.
Key strategies for managing breast cancer brain metastases
Brain metastases remain a frequent and often fatal consequence of metastatic breast cancer (MBC). MBC carries a median survival of about 3 years, but that rate drops significantly when cancer cells move to the brain. A recent analysis estimates median survival in patients with brain metastases ranges from 6 months in triple-negative breast cancer (TNBC) to 21 months in human epidermal growth factor receptor 2 (HER2)–positive disease.
This news organization spoke to Kevin M. Kalinsky, MD, acting associate professor in the department of hematology and medical oncology at Emory University School of Medicine in Atlanta and director of the Glenn Family Breast Center at the Winship Cancer Institute of Emory University, about the risk for brain metastases in patients with MBC, strategies for screening and treatment, and the work being done to achieve a better understanding of the disease.
Question: Before we dig into strategies to manage MBC brain metastasis, let’s talk about the risks. When and how often do brain metastases present in patients with MBC? What factors increase the likelihood of developing brain metastasis?
Dr. Kalinsky: The biggest risk factor for MBC spreading to the central nervous system (CNS), which includes the brain and spine, is breast cancer subtype. For patients with metastatic TNBC, the risk for brain metastasis can be more than 50%. For patients with HER2-positive disease, the risk may be slightly lower, with estimates in the range of 25%-50%, whereas the likelihood of brain metastasis in patients with hormone receptor–positive MBC is significantly lower at close to 14%. In addition, patients with metastatic TNBC may have brain metastases a little earlier in their disease progression compared with patients with HER2-positive or estrogen receptor–positive breast cancers, where brain metastases generally develop a little later in the disease course.
At what point is it recommended to screen patients with MBC for brain metastasis?
Current guidelines suggest that we scan for brain metastasis in the presence of new neurologic symptoms, such as headache, dizziness, or weakness in the arms or legs. MRI, in particular, is useful for evaluating brain metastasis, especially for smaller lesions, but lesions are sometimes detected through CT imaging of the head, too.
That’s where the guidelines are now. But as our systemic agents improve, there’s always the possibility these recommendations will be revisited and potentially include imaging as screening tools in asymptomatic patients, as well.
How do you assess which patients with MBC should receive local therapy?
Increasingly, because our systemic therapies in breast cancer are getting better in terms of crossing the blood-brain barrier, we think about local therapy on a case-by-case basis. We think about it with the question of whether we delay surgery or radiation — whole brain radiation, in particular — given concerns surrounding the side effects of these modalities, namely cognitive dysfunction for radiation and increased risk of bleeding and infection for surgery.
Giving a patient-directed local therapy, such as Gamma Knife radiosurgery or whole-brain radiotherapy, ultimately depends on the burden of brain metastasis, the status of systemic disease outside of the brain, and the number and size of the lesions seen on imaging. If, for instance, a patient has a large lesion that will immediately impact their neurologic status, we may opt to resect the lesion. If there are innumerable lesions, some of which are large, we may do whole-brain radiotherapy. If, however, a patient has systemic disease that is largely under control but is experiencing local progression in the brain, we may use local radiotherapy while continuing systemic therapy.
What about systemic therapies that cross the blood-brain barrier? What’s available now and how do you choose among the options?The subtype of breast cancer informs treatment with systemic therapies. For instance, patients with HER2-positive disease may receive oral tyrosine kinase inhibitors, such as tucatinib, neratinib, and lapatinib, which have strong CNS penetration. For patients with estrogen receptor–positive, HER2-negative MBC, estrogen therapies including aromatase inhibitors, as well as targeted therapies such as the mTOR inhibitor everolimus, have good CNS penetration. For patients with metastatic TNBC, we have chemotherapies that cross the blood-brain barrier, such as capecitabine and platinum-based chemotherapy.
Evidence suggests that tumors in the brain may harbor different genetic abnormalities from tumors in the breast. How do you consider the potential genetic heterogeneity in CNS tumors vs. the primary breast tumor?When a patient’s disease has spread to the brain, we may preferentially use agents we know cross the blood-brain barrier, so we can obtain systemic control both intracranially and extracranially. If we have already resected or biopsied cancerous brain tissue, it’s good to check the tumor’s estrogen receptor, progesterone receptor, and HER2 status and do next-generation sequencing to see if the tumor has any other targetable mutations, such as PIK3CA mutations.
But when a patient has multiple lesions, we don’t go in and biopsy all of them to check for heterogeneity. We have to make decisions based on samples we have. In cases where we start systemic therapy and notice one lesion is not responding to these agents while others are, the nonresponsive lesion may be an outlier in terms of its biologic characteristics. It may be worth targeting that lesion for biopsy and further sequencing to determine the next best systemic approach.
How do quality of life considerations factor into the management of patients with MBC brain metastases?
We use a multidisciplinary approach when treating patients. This means patient care involves a team of experts, which can include medical oncologists, radiation oncologists, and neuro-oncologists who help determine a treatment plan that takes factors such as survival and quality of life into account.
This is why, for example, we try to delay whole brain radiotherapy when we can. The HER2CLIMB study, which led to the approval of tucatinib as a treatment option for patients with HER2-positive MBC, showed us that patients with treated or untreated brain metastases receiving systemic therapy before local therapy could benefit from the combination of tucatinib, trastuzumab, and capecitabine. These patients exhibited a median progression-free survival of 7.6 months compared with 5.4 months in the placebo group.
HER2CLIMB has been practice changing because it showed us that tucatinib has good CNS activity in patients with brain metastases. The HER2CLIMB findings raise an important question: As our systemic therapies improve, how aggressive do we need to be with local therapy? Can we push off modalities like whole-brain radiotherapy, which are associated with toxicity?
This study also highlights how important it is for patients with metastatic disease to seek clinical trials. Although some trials exclude patients with brain metastases and others may have criteria that require the stability of brain metastasis for a certain amount of time, the knowledge gained can be invaluable.
Where are some of the main gaps in our understanding of brain metastases in patients with MBC?
One issue is our understanding of tropism to the brain. In other words, why does MBC spread to the brain? Once we understand this key piece, we can work on developing more effective therapies and therapeutic combinations to block brain metastasis.
For hormone receptor–positive disease, in particular, a central question is whether the current antiestrogen therapies — such as selective estrogen receptor degraders like fulvestrant, as well as targeted AKT inhibitors — have the potential to affect brain tumor activity. The same holds true for TNBC, where antibody drug conjugates and immunotherapies are being evaluated for treatment of brain tumors. For patients with HER2-positive MBC that has spread to the brain, understanding the continued role for tyrosine kinase inhibitors, such as tucatinib and neratinib, as well as whether antibody drug conjugates, including trastuzumab deruxtecan and trastuzumab emtansine, have CNS activity are important areas to explore further.
The CompassHER2 trial, going on now, is randomizing patients with residual HER2-positive disease after neoadjuvant chemotherapy and HER2-targeted therapy to receive trastuzumab emtansine with or without tucatinib. One of the core questions of this study is whether trastuzumab emtansine/tucatinib lowers the rate of brain metastasis and the incidence of systemic metastasis.
Another area in MBC that requires greater scrutiny is patients who develop leptomeningeal disease, which is when cancer cells spread to the cerebrospinal fluid. These patients have a particularly poor prognosis, and it would be helpful to evaluate the efficacy of existing therapies, but these patients are often excluded from clinical trials.
Overall, the ultimate goal in these endeavors is to decrease the rate of metastasis to the brain and improve survival and quality of life in patients with MBC who do experience brain metastases.
A version of this article first appeared on Medscape.com.
Brain metastases remain a frequent and often fatal consequence of metastatic breast cancer (MBC). MBC carries a median survival of about 3 years, but that rate drops significantly when cancer cells move to the brain. A recent analysis estimates median survival in patients with brain metastases ranges from 6 months in triple-negative breast cancer (TNBC) to 21 months in human epidermal growth factor receptor 2 (HER2)–positive disease.
This news organization spoke to Kevin M. Kalinsky, MD, acting associate professor in the department of hematology and medical oncology at Emory University School of Medicine in Atlanta and director of the Glenn Family Breast Center at the Winship Cancer Institute of Emory University, about the risk for brain metastases in patients with MBC, strategies for screening and treatment, and the work being done to achieve a better understanding of the disease.
Question: Before we dig into strategies to manage MBC brain metastasis, let’s talk about the risks. When and how often do brain metastases present in patients with MBC? What factors increase the likelihood of developing brain metastasis?
Dr. Kalinsky: The biggest risk factor for MBC spreading to the central nervous system (CNS), which includes the brain and spine, is breast cancer subtype. For patients with metastatic TNBC, the risk for brain metastasis can be more than 50%. For patients with HER2-positive disease, the risk may be slightly lower, with estimates in the range of 25%-50%, whereas the likelihood of brain metastasis in patients with hormone receptor–positive MBC is significantly lower at close to 14%. In addition, patients with metastatic TNBC may have brain metastases a little earlier in their disease progression compared with patients with HER2-positive or estrogen receptor–positive breast cancers, where brain metastases generally develop a little later in the disease course.
At what point is it recommended to screen patients with MBC for brain metastasis?
Current guidelines suggest that we scan for brain metastasis in the presence of new neurologic symptoms, such as headache, dizziness, or weakness in the arms or legs. MRI, in particular, is useful for evaluating brain metastasis, especially for smaller lesions, but lesions are sometimes detected through CT imaging of the head, too.
That’s where the guidelines are now. But as our systemic agents improve, there’s always the possibility these recommendations will be revisited and potentially include imaging as screening tools in asymptomatic patients, as well.
How do you assess which patients with MBC should receive local therapy?
Increasingly, because our systemic therapies in breast cancer are getting better in terms of crossing the blood-brain barrier, we think about local therapy on a case-by-case basis. We think about it with the question of whether we delay surgery or radiation — whole brain radiation, in particular — given concerns surrounding the side effects of these modalities, namely cognitive dysfunction for radiation and increased risk of bleeding and infection for surgery.
Giving a patient-directed local therapy, such as Gamma Knife radiosurgery or whole-brain radiotherapy, ultimately depends on the burden of brain metastasis, the status of systemic disease outside of the brain, and the number and size of the lesions seen on imaging. If, for instance, a patient has a large lesion that will immediately impact their neurologic status, we may opt to resect the lesion. If there are innumerable lesions, some of which are large, we may do whole-brain radiotherapy. If, however, a patient has systemic disease that is largely under control but is experiencing local progression in the brain, we may use local radiotherapy while continuing systemic therapy.
What about systemic therapies that cross the blood-brain barrier? What’s available now and how do you choose among the options?The subtype of breast cancer informs treatment with systemic therapies. For instance, patients with HER2-positive disease may receive oral tyrosine kinase inhibitors, such as tucatinib, neratinib, and lapatinib, which have strong CNS penetration. For patients with estrogen receptor–positive, HER2-negative MBC, estrogen therapies including aromatase inhibitors, as well as targeted therapies such as the mTOR inhibitor everolimus, have good CNS penetration. For patients with metastatic TNBC, we have chemotherapies that cross the blood-brain barrier, such as capecitabine and platinum-based chemotherapy.
Evidence suggests that tumors in the brain may harbor different genetic abnormalities from tumors in the breast. How do you consider the potential genetic heterogeneity in CNS tumors vs. the primary breast tumor?When a patient’s disease has spread to the brain, we may preferentially use agents we know cross the blood-brain barrier, so we can obtain systemic control both intracranially and extracranially. If we have already resected or biopsied cancerous brain tissue, it’s good to check the tumor’s estrogen receptor, progesterone receptor, and HER2 status and do next-generation sequencing to see if the tumor has any other targetable mutations, such as PIK3CA mutations.
But when a patient has multiple lesions, we don’t go in and biopsy all of them to check for heterogeneity. We have to make decisions based on samples we have. In cases where we start systemic therapy and notice one lesion is not responding to these agents while others are, the nonresponsive lesion may be an outlier in terms of its biologic characteristics. It may be worth targeting that lesion for biopsy and further sequencing to determine the next best systemic approach.
How do quality of life considerations factor into the management of patients with MBC brain metastases?
We use a multidisciplinary approach when treating patients. This means patient care involves a team of experts, which can include medical oncologists, radiation oncologists, and neuro-oncologists who help determine a treatment plan that takes factors such as survival and quality of life into account.
This is why, for example, we try to delay whole brain radiotherapy when we can. The HER2CLIMB study, which led to the approval of tucatinib as a treatment option for patients with HER2-positive MBC, showed us that patients with treated or untreated brain metastases receiving systemic therapy before local therapy could benefit from the combination of tucatinib, trastuzumab, and capecitabine. These patients exhibited a median progression-free survival of 7.6 months compared with 5.4 months in the placebo group.
HER2CLIMB has been practice changing because it showed us that tucatinib has good CNS activity in patients with brain metastases. The HER2CLIMB findings raise an important question: As our systemic therapies improve, how aggressive do we need to be with local therapy? Can we push off modalities like whole-brain radiotherapy, which are associated with toxicity?
This study also highlights how important it is for patients with metastatic disease to seek clinical trials. Although some trials exclude patients with brain metastases and others may have criteria that require the stability of brain metastasis for a certain amount of time, the knowledge gained can be invaluable.
Where are some of the main gaps in our understanding of brain metastases in patients with MBC?
One issue is our understanding of tropism to the brain. In other words, why does MBC spread to the brain? Once we understand this key piece, we can work on developing more effective therapies and therapeutic combinations to block brain metastasis.
For hormone receptor–positive disease, in particular, a central question is whether the current antiestrogen therapies — such as selective estrogen receptor degraders like fulvestrant, as well as targeted AKT inhibitors — have the potential to affect brain tumor activity. The same holds true for TNBC, where antibody drug conjugates and immunotherapies are being evaluated for treatment of brain tumors. For patients with HER2-positive MBC that has spread to the brain, understanding the continued role for tyrosine kinase inhibitors, such as tucatinib and neratinib, as well as whether antibody drug conjugates, including trastuzumab deruxtecan and trastuzumab emtansine, have CNS activity are important areas to explore further.
The CompassHER2 trial, going on now, is randomizing patients with residual HER2-positive disease after neoadjuvant chemotherapy and HER2-targeted therapy to receive trastuzumab emtansine with or without tucatinib. One of the core questions of this study is whether trastuzumab emtansine/tucatinib lowers the rate of brain metastasis and the incidence of systemic metastasis.
Another area in MBC that requires greater scrutiny is patients who develop leptomeningeal disease, which is when cancer cells spread to the cerebrospinal fluid. These patients have a particularly poor prognosis, and it would be helpful to evaluate the efficacy of existing therapies, but these patients are often excluded from clinical trials.
Overall, the ultimate goal in these endeavors is to decrease the rate of metastasis to the brain and improve survival and quality of life in patients with MBC who do experience brain metastases.
A version of this article first appeared on Medscape.com.
Brain metastases remain a frequent and often fatal consequence of metastatic breast cancer (MBC). MBC carries a median survival of about 3 years, but that rate drops significantly when cancer cells move to the brain. A recent analysis estimates median survival in patients with brain metastases ranges from 6 months in triple-negative breast cancer (TNBC) to 21 months in human epidermal growth factor receptor 2 (HER2)–positive disease.
This news organization spoke to Kevin M. Kalinsky, MD, acting associate professor in the department of hematology and medical oncology at Emory University School of Medicine in Atlanta and director of the Glenn Family Breast Center at the Winship Cancer Institute of Emory University, about the risk for brain metastases in patients with MBC, strategies for screening and treatment, and the work being done to achieve a better understanding of the disease.
Question: Before we dig into strategies to manage MBC brain metastasis, let’s talk about the risks. When and how often do brain metastases present in patients with MBC? What factors increase the likelihood of developing brain metastasis?
Dr. Kalinsky: The biggest risk factor for MBC spreading to the central nervous system (CNS), which includes the brain and spine, is breast cancer subtype. For patients with metastatic TNBC, the risk for brain metastasis can be more than 50%. For patients with HER2-positive disease, the risk may be slightly lower, with estimates in the range of 25%-50%, whereas the likelihood of brain metastasis in patients with hormone receptor–positive MBC is significantly lower at close to 14%. In addition, patients with metastatic TNBC may have brain metastases a little earlier in their disease progression compared with patients with HER2-positive or estrogen receptor–positive breast cancers, where brain metastases generally develop a little later in the disease course.
At what point is it recommended to screen patients with MBC for brain metastasis?
Current guidelines suggest that we scan for brain metastasis in the presence of new neurologic symptoms, such as headache, dizziness, or weakness in the arms or legs. MRI, in particular, is useful for evaluating brain metastasis, especially for smaller lesions, but lesions are sometimes detected through CT imaging of the head, too.
That’s where the guidelines are now. But as our systemic agents improve, there’s always the possibility these recommendations will be revisited and potentially include imaging as screening tools in asymptomatic patients, as well.
How do you assess which patients with MBC should receive local therapy?
Increasingly, because our systemic therapies in breast cancer are getting better in terms of crossing the blood-brain barrier, we think about local therapy on a case-by-case basis. We think about it with the question of whether we delay surgery or radiation — whole brain radiation, in particular — given concerns surrounding the side effects of these modalities, namely cognitive dysfunction for radiation and increased risk of bleeding and infection for surgery.
Giving a patient-directed local therapy, such as Gamma Knife radiosurgery or whole-brain radiotherapy, ultimately depends on the burden of brain metastasis, the status of systemic disease outside of the brain, and the number and size of the lesions seen on imaging. If, for instance, a patient has a large lesion that will immediately impact their neurologic status, we may opt to resect the lesion. If there are innumerable lesions, some of which are large, we may do whole-brain radiotherapy. If, however, a patient has systemic disease that is largely under control but is experiencing local progression in the brain, we may use local radiotherapy while continuing systemic therapy.
What about systemic therapies that cross the blood-brain barrier? What’s available now and how do you choose among the options?The subtype of breast cancer informs treatment with systemic therapies. For instance, patients with HER2-positive disease may receive oral tyrosine kinase inhibitors, such as tucatinib, neratinib, and lapatinib, which have strong CNS penetration. For patients with estrogen receptor–positive, HER2-negative MBC, estrogen therapies including aromatase inhibitors, as well as targeted therapies such as the mTOR inhibitor everolimus, have good CNS penetration. For patients with metastatic TNBC, we have chemotherapies that cross the blood-brain barrier, such as capecitabine and platinum-based chemotherapy.
Evidence suggests that tumors in the brain may harbor different genetic abnormalities from tumors in the breast. How do you consider the potential genetic heterogeneity in CNS tumors vs. the primary breast tumor?When a patient’s disease has spread to the brain, we may preferentially use agents we know cross the blood-brain barrier, so we can obtain systemic control both intracranially and extracranially. If we have already resected or biopsied cancerous brain tissue, it’s good to check the tumor’s estrogen receptor, progesterone receptor, and HER2 status and do next-generation sequencing to see if the tumor has any other targetable mutations, such as PIK3CA mutations.
But when a patient has multiple lesions, we don’t go in and biopsy all of them to check for heterogeneity. We have to make decisions based on samples we have. In cases where we start systemic therapy and notice one lesion is not responding to these agents while others are, the nonresponsive lesion may be an outlier in terms of its biologic characteristics. It may be worth targeting that lesion for biopsy and further sequencing to determine the next best systemic approach.
How do quality of life considerations factor into the management of patients with MBC brain metastases?
We use a multidisciplinary approach when treating patients. This means patient care involves a team of experts, which can include medical oncologists, radiation oncologists, and neuro-oncologists who help determine a treatment plan that takes factors such as survival and quality of life into account.
This is why, for example, we try to delay whole brain radiotherapy when we can. The HER2CLIMB study, which led to the approval of tucatinib as a treatment option for patients with HER2-positive MBC, showed us that patients with treated or untreated brain metastases receiving systemic therapy before local therapy could benefit from the combination of tucatinib, trastuzumab, and capecitabine. These patients exhibited a median progression-free survival of 7.6 months compared with 5.4 months in the placebo group.
HER2CLIMB has been practice changing because it showed us that tucatinib has good CNS activity in patients with brain metastases. The HER2CLIMB findings raise an important question: As our systemic therapies improve, how aggressive do we need to be with local therapy? Can we push off modalities like whole-brain radiotherapy, which are associated with toxicity?
This study also highlights how important it is for patients with metastatic disease to seek clinical trials. Although some trials exclude patients with brain metastases and others may have criteria that require the stability of brain metastasis for a certain amount of time, the knowledge gained can be invaluable.
Where are some of the main gaps in our understanding of brain metastases in patients with MBC?
One issue is our understanding of tropism to the brain. In other words, why does MBC spread to the brain? Once we understand this key piece, we can work on developing more effective therapies and therapeutic combinations to block brain metastasis.
For hormone receptor–positive disease, in particular, a central question is whether the current antiestrogen therapies — such as selective estrogen receptor degraders like fulvestrant, as well as targeted AKT inhibitors — have the potential to affect brain tumor activity. The same holds true for TNBC, where antibody drug conjugates and immunotherapies are being evaluated for treatment of brain tumors. For patients with HER2-positive MBC that has spread to the brain, understanding the continued role for tyrosine kinase inhibitors, such as tucatinib and neratinib, as well as whether antibody drug conjugates, including trastuzumab deruxtecan and trastuzumab emtansine, have CNS activity are important areas to explore further.
The CompassHER2 trial, going on now, is randomizing patients with residual HER2-positive disease after neoadjuvant chemotherapy and HER2-targeted therapy to receive trastuzumab emtansine with or without tucatinib. One of the core questions of this study is whether trastuzumab emtansine/tucatinib lowers the rate of brain metastasis and the incidence of systemic metastasis.
Another area in MBC that requires greater scrutiny is patients who develop leptomeningeal disease, which is when cancer cells spread to the cerebrospinal fluid. These patients have a particularly poor prognosis, and it would be helpful to evaluate the efficacy of existing therapies, but these patients are often excluded from clinical trials.
Overall, the ultimate goal in these endeavors is to decrease the rate of metastasis to the brain and improve survival and quality of life in patients with MBC who do experience brain metastases.
A version of this article first appeared on Medscape.com.
CONCERT: Better QoL but not survival with cabazitaxel in metastatic HER2– breast cancer
For patients with HER2-negative metastatic breast cancer, first line chemotherapy with cabazitaxel (Jevtana) every 3 weeks offers efficacy comparable to that of once-weekly paclitaxel, but with lower risk for peripheral neuropathy and better patient-reported quality of life, investigators in the multicenter CONCERT trial found.
In an open-label clinical trial of 158 patients from 14 hospitals in the United Kingdom, there was no difference in the primary endpoint of progression-free survival (PFS) or a secondary overall survival endpoint between patients randomly assigned to initial chemotherapy with cabazitaxel every 3 weeks or weekly paclitaxel, reported Amit Bahl, MD, of University Hospital Bristol, England, and colleagues.
“Cabazitaxel is safe and well tolerated for metastatic breast cancer and requires fewer hospital visits than weekly paclitaxel, which is very important for patients and health care providers, but more so in the current situation,” he said in an oral abstract session at the American Society of Clinical Oncology annual meeting (Abstract 1008).
Cabazitaxel is currently approved in the United States and Europe in combination with prednisone for treatment of patients with metastatic castration-resistant prostate cancer previously treated with a docetaxel-containing treatment regimen. It is not currently approved for the treatment of metastatic breast cancer, but has been explored for this indication in clinical trials.
“In the metastatic setting, where patients continue on treatment pretty much indefinitely until disease progression or unacceptable toxicity, the use of an every-3-week regimen could be attractive, because it means less visits for the patients, and it appears that this drug has lower toxicity in terms of peripheral neuropathy,” said breast cancer specialist Aditya Bardia, MD, MPH, who was not involved in the study.
Dr. Bardia, of Mass General Cancer Center in Boston, commented on the study in an interview.
Although paclitaxel is commonly used as first-line chemotherapy for HER2-negative metastatic breast cancer, it is associated with only modest response rates, ranging from 21.5% to 53.7% and carries significant risk of peripheral neuropathy, Dr. Bahl and colleagues noted.
“There is an unmet need for an alternative first-line cytotoxic chemotherapy agent, and cabazitaxel is a taxoid agent which has showed promising results in phase 2 trial of metastatic breast cancer patients in the second-line setting, even those with taxane resistance,” he said.
Open-label trial
To see whether cabazitaxel could meet those requirements, the investigators conducted a phase 2 randomized trial in which patients with HER2-negative metastatic breast cancer not previously treated with cytotoxic chemotherapy were assigned, 79 in each arm, to receive cabazitaxel 25 mg/m2 every 3 weeks, or paclitaxel 80 mg/m2 weekly.
The median patient age was 56 years in the cabazitaxel group and 61 years in the paclitaxel group. Roughly two-thirds of patients in each arm had Eastern Cooperative Oncology Group performance status 0, and the remainder had ECOG performance status 1.
In each arm, the median time on treatment was 15 weeks, but treatment delays and dose reductions were more common among patients on paclitaxel than cabazitaxel (61% vs. 39%, and 37% vs. 24%, respectively).
There were 149 PFS events at the time of the analysis. The median PFS with cabazitaxel was 6.7 months vs. 5.8 months with paclitaxel. This difference was not statistically significant. Median overall survival was 20.6 months in the cabazitaxel arm, vs. 18.2 months 20.0 months, respectively.
Similarly, there were no significant differences in either the overall response rates (42% vs. 37%), or time to response.
There were no complete responses with cabazitaxel vs. two (2.5%) with paclitaxel. The respective partial response rates were 41.8% vs. 34.2%.
In a subgroup analysis of PFS, there were no significant between-arm differences, except for an improved PFS in patients 65 and older with cabazitaxel (hazard ratio 0.45, 95% confidence interval, 0.25-0.80).
Quality of life favors cabazitaxel
Grade 3 or greater adverse events occurred in 42% of patients on cabazitaxel vs. 51% on paclitaxel. Diarrhea, febrile neutropenia, and nausea were the most common grade 3 or greater events in the cabazitaxel arm, whereas grade 3 or greater lung infection and peripheral neuropathy were more common with paclitaxel.
Sensory peripheral neuropathy of any grade occurred in 16% of patients assigned to cabazitaxel, compared with 54% assigned to paclitaxel. The respective rates of alopecia were 27% and 42%.
Over the course of treatment, the mean EuroQuol EQ-5D-5L single index utility score and visual analogue scale score were higher with cabazitaxel arm compared to paclitaxel, suggesting better patient quality of life with cabazitaxel.
In addition, throughout treatment patients in the cabazitaxel arm reported significantly better scores on The Functional Assessment of Cancer Therapy – Breast (FACT-B) breast cancer subscale, Dr. Bahl said.
Second-line may be better
ASCO invited discussant Marleen Kok, MD, PhD, from the Netherlands Cancer Institute in Amsterdam, pointed out that in the phase 2 GENEVIEVE trial comparing the efficacy and safety of cabazitaxel versus weekly paclitaxel as neoadjuvant treatment in patients with triple negative or luminal B/HER2 normal breast cancer the pathologic complete response rate with cabazitaxel was 1.2%, compared with 11% with paclitaxel.
“This GENEVIEVE trial, together with the CONCERT trial, suggests that there is not a big role for cabazitaxel to be used upfront before other taxanes,” she said.
However, in a phase 2 study of cabazitaxel as second-line therapy in patients with HER2-negative metastatic breast cancer who had previously been treated with taxanes, the overall response rate was 23%, “which is still of interest and importance for our patients,” she added.
Dr. Kok did not address quality of life differences between the regimens, however.
In a side note, Dr. Bardia said that “if there were an oral form of paclitaxel, that would certainly be very welcome, in that an oral drug is more convenient for patients, and would require fewer visits to the hospital.”
The CONCERT trial was funded by an investigator-sponsored study grant from Sanofi. Dr. Bahl disclosed honoraria and institutional research funding from Sanofi/Aventis and others, and travel expenses from Bayer and Roche. Dr. Kok disclosed a consulting or advisory role for Bristol Myers Squibb/Medarex, and institutional research funding from that company and others. Dr. Bardia disclosed a consulting or advisory role and research funding to his institution from multiple companies.
For patients with HER2-negative metastatic breast cancer, first line chemotherapy with cabazitaxel (Jevtana) every 3 weeks offers efficacy comparable to that of once-weekly paclitaxel, but with lower risk for peripheral neuropathy and better patient-reported quality of life, investigators in the multicenter CONCERT trial found.
In an open-label clinical trial of 158 patients from 14 hospitals in the United Kingdom, there was no difference in the primary endpoint of progression-free survival (PFS) or a secondary overall survival endpoint between patients randomly assigned to initial chemotherapy with cabazitaxel every 3 weeks or weekly paclitaxel, reported Amit Bahl, MD, of University Hospital Bristol, England, and colleagues.
“Cabazitaxel is safe and well tolerated for metastatic breast cancer and requires fewer hospital visits than weekly paclitaxel, which is very important for patients and health care providers, but more so in the current situation,” he said in an oral abstract session at the American Society of Clinical Oncology annual meeting (Abstract 1008).
Cabazitaxel is currently approved in the United States and Europe in combination with prednisone for treatment of patients with metastatic castration-resistant prostate cancer previously treated with a docetaxel-containing treatment regimen. It is not currently approved for the treatment of metastatic breast cancer, but has been explored for this indication in clinical trials.
“In the metastatic setting, where patients continue on treatment pretty much indefinitely until disease progression or unacceptable toxicity, the use of an every-3-week regimen could be attractive, because it means less visits for the patients, and it appears that this drug has lower toxicity in terms of peripheral neuropathy,” said breast cancer specialist Aditya Bardia, MD, MPH, who was not involved in the study.
Dr. Bardia, of Mass General Cancer Center in Boston, commented on the study in an interview.
Although paclitaxel is commonly used as first-line chemotherapy for HER2-negative metastatic breast cancer, it is associated with only modest response rates, ranging from 21.5% to 53.7% and carries significant risk of peripheral neuropathy, Dr. Bahl and colleagues noted.
“There is an unmet need for an alternative first-line cytotoxic chemotherapy agent, and cabazitaxel is a taxoid agent which has showed promising results in phase 2 trial of metastatic breast cancer patients in the second-line setting, even those with taxane resistance,” he said.
Open-label trial
To see whether cabazitaxel could meet those requirements, the investigators conducted a phase 2 randomized trial in which patients with HER2-negative metastatic breast cancer not previously treated with cytotoxic chemotherapy were assigned, 79 in each arm, to receive cabazitaxel 25 mg/m2 every 3 weeks, or paclitaxel 80 mg/m2 weekly.
The median patient age was 56 years in the cabazitaxel group and 61 years in the paclitaxel group. Roughly two-thirds of patients in each arm had Eastern Cooperative Oncology Group performance status 0, and the remainder had ECOG performance status 1.
In each arm, the median time on treatment was 15 weeks, but treatment delays and dose reductions were more common among patients on paclitaxel than cabazitaxel (61% vs. 39%, and 37% vs. 24%, respectively).
There were 149 PFS events at the time of the analysis. The median PFS with cabazitaxel was 6.7 months vs. 5.8 months with paclitaxel. This difference was not statistically significant. Median overall survival was 20.6 months in the cabazitaxel arm, vs. 18.2 months 20.0 months, respectively.
Similarly, there were no significant differences in either the overall response rates (42% vs. 37%), or time to response.
There were no complete responses with cabazitaxel vs. two (2.5%) with paclitaxel. The respective partial response rates were 41.8% vs. 34.2%.
In a subgroup analysis of PFS, there were no significant between-arm differences, except for an improved PFS in patients 65 and older with cabazitaxel (hazard ratio 0.45, 95% confidence interval, 0.25-0.80).
Quality of life favors cabazitaxel
Grade 3 or greater adverse events occurred in 42% of patients on cabazitaxel vs. 51% on paclitaxel. Diarrhea, febrile neutropenia, and nausea were the most common grade 3 or greater events in the cabazitaxel arm, whereas grade 3 or greater lung infection and peripheral neuropathy were more common with paclitaxel.
Sensory peripheral neuropathy of any grade occurred in 16% of patients assigned to cabazitaxel, compared with 54% assigned to paclitaxel. The respective rates of alopecia were 27% and 42%.
Over the course of treatment, the mean EuroQuol EQ-5D-5L single index utility score and visual analogue scale score were higher with cabazitaxel arm compared to paclitaxel, suggesting better patient quality of life with cabazitaxel.
In addition, throughout treatment patients in the cabazitaxel arm reported significantly better scores on The Functional Assessment of Cancer Therapy – Breast (FACT-B) breast cancer subscale, Dr. Bahl said.
Second-line may be better
ASCO invited discussant Marleen Kok, MD, PhD, from the Netherlands Cancer Institute in Amsterdam, pointed out that in the phase 2 GENEVIEVE trial comparing the efficacy and safety of cabazitaxel versus weekly paclitaxel as neoadjuvant treatment in patients with triple negative or luminal B/HER2 normal breast cancer the pathologic complete response rate with cabazitaxel was 1.2%, compared with 11% with paclitaxel.
“This GENEVIEVE trial, together with the CONCERT trial, suggests that there is not a big role for cabazitaxel to be used upfront before other taxanes,” she said.
However, in a phase 2 study of cabazitaxel as second-line therapy in patients with HER2-negative metastatic breast cancer who had previously been treated with taxanes, the overall response rate was 23%, “which is still of interest and importance for our patients,” she added.
Dr. Kok did not address quality of life differences between the regimens, however.
In a side note, Dr. Bardia said that “if there were an oral form of paclitaxel, that would certainly be very welcome, in that an oral drug is more convenient for patients, and would require fewer visits to the hospital.”
The CONCERT trial was funded by an investigator-sponsored study grant from Sanofi. Dr. Bahl disclosed honoraria and institutional research funding from Sanofi/Aventis and others, and travel expenses from Bayer and Roche. Dr. Kok disclosed a consulting or advisory role for Bristol Myers Squibb/Medarex, and institutional research funding from that company and others. Dr. Bardia disclosed a consulting or advisory role and research funding to his institution from multiple companies.
For patients with HER2-negative metastatic breast cancer, first line chemotherapy with cabazitaxel (Jevtana) every 3 weeks offers efficacy comparable to that of once-weekly paclitaxel, but with lower risk for peripheral neuropathy and better patient-reported quality of life, investigators in the multicenter CONCERT trial found.
In an open-label clinical trial of 158 patients from 14 hospitals in the United Kingdom, there was no difference in the primary endpoint of progression-free survival (PFS) or a secondary overall survival endpoint between patients randomly assigned to initial chemotherapy with cabazitaxel every 3 weeks or weekly paclitaxel, reported Amit Bahl, MD, of University Hospital Bristol, England, and colleagues.
“Cabazitaxel is safe and well tolerated for metastatic breast cancer and requires fewer hospital visits than weekly paclitaxel, which is very important for patients and health care providers, but more so in the current situation,” he said in an oral abstract session at the American Society of Clinical Oncology annual meeting (Abstract 1008).
Cabazitaxel is currently approved in the United States and Europe in combination with prednisone for treatment of patients with metastatic castration-resistant prostate cancer previously treated with a docetaxel-containing treatment regimen. It is not currently approved for the treatment of metastatic breast cancer, but has been explored for this indication in clinical trials.
“In the metastatic setting, where patients continue on treatment pretty much indefinitely until disease progression or unacceptable toxicity, the use of an every-3-week regimen could be attractive, because it means less visits for the patients, and it appears that this drug has lower toxicity in terms of peripheral neuropathy,” said breast cancer specialist Aditya Bardia, MD, MPH, who was not involved in the study.
Dr. Bardia, of Mass General Cancer Center in Boston, commented on the study in an interview.
Although paclitaxel is commonly used as first-line chemotherapy for HER2-negative metastatic breast cancer, it is associated with only modest response rates, ranging from 21.5% to 53.7% and carries significant risk of peripheral neuropathy, Dr. Bahl and colleagues noted.
“There is an unmet need for an alternative first-line cytotoxic chemotherapy agent, and cabazitaxel is a taxoid agent which has showed promising results in phase 2 trial of metastatic breast cancer patients in the second-line setting, even those with taxane resistance,” he said.
Open-label trial
To see whether cabazitaxel could meet those requirements, the investigators conducted a phase 2 randomized trial in which patients with HER2-negative metastatic breast cancer not previously treated with cytotoxic chemotherapy were assigned, 79 in each arm, to receive cabazitaxel 25 mg/m2 every 3 weeks, or paclitaxel 80 mg/m2 weekly.
The median patient age was 56 years in the cabazitaxel group and 61 years in the paclitaxel group. Roughly two-thirds of patients in each arm had Eastern Cooperative Oncology Group performance status 0, and the remainder had ECOG performance status 1.
In each arm, the median time on treatment was 15 weeks, but treatment delays and dose reductions were more common among patients on paclitaxel than cabazitaxel (61% vs. 39%, and 37% vs. 24%, respectively).
There were 149 PFS events at the time of the analysis. The median PFS with cabazitaxel was 6.7 months vs. 5.8 months with paclitaxel. This difference was not statistically significant. Median overall survival was 20.6 months in the cabazitaxel arm, vs. 18.2 months 20.0 months, respectively.
Similarly, there were no significant differences in either the overall response rates (42% vs. 37%), or time to response.
There were no complete responses with cabazitaxel vs. two (2.5%) with paclitaxel. The respective partial response rates were 41.8% vs. 34.2%.
In a subgroup analysis of PFS, there were no significant between-arm differences, except for an improved PFS in patients 65 and older with cabazitaxel (hazard ratio 0.45, 95% confidence interval, 0.25-0.80).
Quality of life favors cabazitaxel
Grade 3 or greater adverse events occurred in 42% of patients on cabazitaxel vs. 51% on paclitaxel. Diarrhea, febrile neutropenia, and nausea were the most common grade 3 or greater events in the cabazitaxel arm, whereas grade 3 or greater lung infection and peripheral neuropathy were more common with paclitaxel.
Sensory peripheral neuropathy of any grade occurred in 16% of patients assigned to cabazitaxel, compared with 54% assigned to paclitaxel. The respective rates of alopecia were 27% and 42%.
Over the course of treatment, the mean EuroQuol EQ-5D-5L single index utility score and visual analogue scale score were higher with cabazitaxel arm compared to paclitaxel, suggesting better patient quality of life with cabazitaxel.
In addition, throughout treatment patients in the cabazitaxel arm reported significantly better scores on The Functional Assessment of Cancer Therapy – Breast (FACT-B) breast cancer subscale, Dr. Bahl said.
Second-line may be better
ASCO invited discussant Marleen Kok, MD, PhD, from the Netherlands Cancer Institute in Amsterdam, pointed out that in the phase 2 GENEVIEVE trial comparing the efficacy and safety of cabazitaxel versus weekly paclitaxel as neoadjuvant treatment in patients with triple negative or luminal B/HER2 normal breast cancer the pathologic complete response rate with cabazitaxel was 1.2%, compared with 11% with paclitaxel.
“This GENEVIEVE trial, together with the CONCERT trial, suggests that there is not a big role for cabazitaxel to be used upfront before other taxanes,” she said.
However, in a phase 2 study of cabazitaxel as second-line therapy in patients with HER2-negative metastatic breast cancer who had previously been treated with taxanes, the overall response rate was 23%, “which is still of interest and importance for our patients,” she added.
Dr. Kok did not address quality of life differences between the regimens, however.
In a side note, Dr. Bardia said that “if there were an oral form of paclitaxel, that would certainly be very welcome, in that an oral drug is more convenient for patients, and would require fewer visits to the hospital.”
The CONCERT trial was funded by an investigator-sponsored study grant from Sanofi. Dr. Bahl disclosed honoraria and institutional research funding from Sanofi/Aventis and others, and travel expenses from Bayer and Roche. Dr. Kok disclosed a consulting or advisory role for Bristol Myers Squibb/Medarex, and institutional research funding from that company and others. Dr. Bardia disclosed a consulting or advisory role and research funding to his institution from multiple companies.
FROM ASCO 2021
ASCO 2021: Breast cancer sessions not to miss
This transcript has been edited for clarity.
Hello. It’s Dr. Kathy Miller from Indiana University.
I have to admit that time has snuck up on me this year. It is already time for the American Society of Clinical Oncology Annual Meeting.
I found it hard to keep track of time this year with the pandemic. Many of the things that help mark the passage of time haven’t happened, have happened at different times of the year than is typical, or have happened in different ways that just haven’t had the same impact in my brain.
Just recently, I was taking a look through the breast cancer program at ASCO and there is a special clinical science symposium that I want to make sure you know about and tune into. It’s the sort of session that might not otherwise reach you.
This has been a year of incredible turmoil and critical thinking about issues of race, ethnicity, justice, and how we can make sure that the medical care we’re providing is inclusive and equitable. How we can make sure we are giving the best outcome to all of our patients.
This special clinical science symposium this year includes several presentations that will delve into how genetically determined ancestry and socially determined race might impact the outcome of our patients. This is a tangled web that is difficult to unpack and separate, but there are clear distinctions here: The genes we inherit do affect how we metabolize drugs, what side effects we might have from drugs, and what drugs might be the best choices for us.
Our socially determined race affects how the world interacts with us. Those biases, be they conscious or unconscious, can affect where we live, where we go to school, how people treat us, what opportunities we have, and how the medical system treats us. They’re related, but they’re not the same. Tune into that clinical science symposium to begin thinking about those differences and how we can make sure we give our patients the best care.
There are other high-profile presentations that you’re going to want to see as well, looking at how we can optimize therapy in patients with HER2-positive disease and beginning to think about who might not need chemotherapy to have an excellent outcome in early-stage disease.
Also, we will be thinking about those patients with triple-negative disease who have residual disease after neoadjuvant chemotherapy. We were all caught off guard with the results of the CREATE-X trial, quite frankly, several years ago.
This year we will hear the results of a postneoadjuvant trial coordinated by the Eastern Cooperative Oncology Group comparing platinum therapy with capecitabine. Tune in to think more about whether capecitabine really should be the standard of care in this population.
As always, I’m interested in your thoughts before or after ASCO. What stood out for you this year in breast cancer? Drop us a comment and let us know about these sessions and what else you found worthwhile.
Dr. Miller is associate director of clinical research and codirector of the breast cancer program at the Melvin and Bren Simon Cancer Center at Indiana University, Indianapolis. Her career has combined both laboratory and clinical research in breast cancer.
A version of this article first appeared on Medscape.com.
This transcript has been edited for clarity.
Hello. It’s Dr. Kathy Miller from Indiana University.
I have to admit that time has snuck up on me this year. It is already time for the American Society of Clinical Oncology Annual Meeting.
I found it hard to keep track of time this year with the pandemic. Many of the things that help mark the passage of time haven’t happened, have happened at different times of the year than is typical, or have happened in different ways that just haven’t had the same impact in my brain.
Just recently, I was taking a look through the breast cancer program at ASCO and there is a special clinical science symposium that I want to make sure you know about and tune into. It’s the sort of session that might not otherwise reach you.
This has been a year of incredible turmoil and critical thinking about issues of race, ethnicity, justice, and how we can make sure that the medical care we’re providing is inclusive and equitable. How we can make sure we are giving the best outcome to all of our patients.
This special clinical science symposium this year includes several presentations that will delve into how genetically determined ancestry and socially determined race might impact the outcome of our patients. This is a tangled web that is difficult to unpack and separate, but there are clear distinctions here: The genes we inherit do affect how we metabolize drugs, what side effects we might have from drugs, and what drugs might be the best choices for us.
Our socially determined race affects how the world interacts with us. Those biases, be they conscious or unconscious, can affect where we live, where we go to school, how people treat us, what opportunities we have, and how the medical system treats us. They’re related, but they’re not the same. Tune into that clinical science symposium to begin thinking about those differences and how we can make sure we give our patients the best care.
There are other high-profile presentations that you’re going to want to see as well, looking at how we can optimize therapy in patients with HER2-positive disease and beginning to think about who might not need chemotherapy to have an excellent outcome in early-stage disease.
Also, we will be thinking about those patients with triple-negative disease who have residual disease after neoadjuvant chemotherapy. We were all caught off guard with the results of the CREATE-X trial, quite frankly, several years ago.
This year we will hear the results of a postneoadjuvant trial coordinated by the Eastern Cooperative Oncology Group comparing platinum therapy with capecitabine. Tune in to think more about whether capecitabine really should be the standard of care in this population.
As always, I’m interested in your thoughts before or after ASCO. What stood out for you this year in breast cancer? Drop us a comment and let us know about these sessions and what else you found worthwhile.
Dr. Miller is associate director of clinical research and codirector of the breast cancer program at the Melvin and Bren Simon Cancer Center at Indiana University, Indianapolis. Her career has combined both laboratory and clinical research in breast cancer.
A version of this article first appeared on Medscape.com.
This transcript has been edited for clarity.
Hello. It’s Dr. Kathy Miller from Indiana University.
I have to admit that time has snuck up on me this year. It is already time for the American Society of Clinical Oncology Annual Meeting.
I found it hard to keep track of time this year with the pandemic. Many of the things that help mark the passage of time haven’t happened, have happened at different times of the year than is typical, or have happened in different ways that just haven’t had the same impact in my brain.
Just recently, I was taking a look through the breast cancer program at ASCO and there is a special clinical science symposium that I want to make sure you know about and tune into. It’s the sort of session that might not otherwise reach you.
This has been a year of incredible turmoil and critical thinking about issues of race, ethnicity, justice, and how we can make sure that the medical care we’re providing is inclusive and equitable. How we can make sure we are giving the best outcome to all of our patients.
This special clinical science symposium this year includes several presentations that will delve into how genetically determined ancestry and socially determined race might impact the outcome of our patients. This is a tangled web that is difficult to unpack and separate, but there are clear distinctions here: The genes we inherit do affect how we metabolize drugs, what side effects we might have from drugs, and what drugs might be the best choices for us.
Our socially determined race affects how the world interacts with us. Those biases, be they conscious or unconscious, can affect where we live, where we go to school, how people treat us, what opportunities we have, and how the medical system treats us. They’re related, but they’re not the same. Tune into that clinical science symposium to begin thinking about those differences and how we can make sure we give our patients the best care.
There are other high-profile presentations that you’re going to want to see as well, looking at how we can optimize therapy in patients with HER2-positive disease and beginning to think about who might not need chemotherapy to have an excellent outcome in early-stage disease.
Also, we will be thinking about those patients with triple-negative disease who have residual disease after neoadjuvant chemotherapy. We were all caught off guard with the results of the CREATE-X trial, quite frankly, several years ago.
This year we will hear the results of a postneoadjuvant trial coordinated by the Eastern Cooperative Oncology Group comparing platinum therapy with capecitabine. Tune in to think more about whether capecitabine really should be the standard of care in this population.
As always, I’m interested in your thoughts before or after ASCO. What stood out for you this year in breast cancer? Drop us a comment and let us know about these sessions and what else you found worthwhile.
Dr. Miller is associate director of clinical research and codirector of the breast cancer program at the Melvin and Bren Simon Cancer Center at Indiana University, Indianapolis. Her career has combined both laboratory and clinical research in breast cancer.
A version of this article first appeared on Medscape.com.
