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The evolving HER2+ metastatic breast cancer landscape: Novel agents and promising combination therapies
Recent therapeutic advances in HER2-positive metastatic breast cancer (MBC) have begun to reshape the treatment landscape for patients. Since late 2019, the U.S. Food and Drug Administration (FDA) has approved a handful of novel agents for HER2-positive MBC — most notably, the antibody-drug conjugate (ADC) trastuzumab deruxtecan in December 2019 and the tyrosine kinase inhibitors (TKIs) tucatinib and neratinib in 2020. According to the National Cancer Institute›s Surveillance, Epidemiology, and End Results (SEER) program, the 5-year survival rate for patients with advanced disease was already on the rise between 2004 and 2018, and
“I’ve been involved in the HER2 space for a long time and have watched the field evolve,” said Adam Brufsky, MD, PhD, associate chief in the division of hematology/oncology and co-director of the Comprehensive Breast Cancer Center at the University of Pittsburgh School of Medicine. “The fact that we’re now talking about fourth- and fifth-line therapies for HER2-positive MBC represents a major advance in the management of these patients.”
Oncologists are still building on this progress, focusing on designing more targeted therapies as well as studying different combinations of available agents. The main goal of treatment, experts say, is to prolong patients’ systemic response and prevent recurrences, especially in the brain. This news organization spoke to Dr. Brufksy and others about promising agents and therapeutic strategies on the horizon to treat HER2-positive MBC.
Inside emerging ADCs
Because many patients develop resistance to trastuzumab emtansine (T-DM1) — the first FDA-approved ADC in breast cancer — researchers have focused on developing the next generation of ADCs with more potent payloads, different linkers, and distinct mechanisms of action, according to Sayeh Lavasani, MD, MS, a medical oncologist at City of Hope, a comprehensive cancer center in Los Angeles County.
The second-generation ADC trastuzumab deruxtecan showed “really dramatic” results in HER2-positive MBC, demonstrating progression-free survival of 16 months, remarked Kevin 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. “These outcomes further changed how we treat patients with metastatic disease and prompted considerable excitement over the potential to develop novel ADCs to treat HER2-positive MBC.”
Most recently, two investigational ADCs — trastuzumab duocarmazine (SYD985) and ARX788 — have stood out. The FDA granted fast-track designations to trastuzumab duocarmazine in January 2018 and ARX788 in January 2021. Trastuzumab duocarmazine, the furthest along the pipeline, has shown promising results so far. In June 2021, Netherlands-based biopharmaceutical company Byondis reported preliminary phase 3 data from the TULIP trial. The open-label, randomized phase 3 study enrolled 436 patients with HER2-positive locally advanced or metastatic disease that had progressed on previous anti-HER2 regimens. The company shared early results that trastuzumab duocarmazine achieved its progression-free survival primary endpoint, marking a significant improvement over physician’s choice of chemotherapy, and promised more detailed results to come later this year.
Although only in early-phase trials, ARX788 has also shown robust anti-HER2 activity as well as low toxicity in HER2-positive tumors, according to recent data. The findings from two phase 1 studies, presented at the June 2021 virtual American Society for Clinical Oncology meeting (abstract 1038), revealed an overall response rate of 74% in the breast cancer cohort, but the investigators acknowledged it was too early to report median progression-free survival outcomes. Preclinical data also showed activity in HER2-low and T-DM1–resistant tumors.
Despite the encouraging initial findings, Dr. Kalinsky remains cautiously optimistic about long-term outcomes for both ADCs. “These data are hot off the press, but it’s too soon to know how these two ADCs and others in the pipeline will measure up to approved therapies,” he commented. As experts learn more about the efficacy of these novel ADCs, Dr. Brufsky would also like to better understand resistance mechanisms and how to integrate these agents into current treatment strategies. “The cellular biology of HER2-positive MBC is complicated, and many factors in these tumor cells affect where ADCs are released, how resistance develops, and whether or not resistance to one ADC applies to others,” Dr. Brufsky remarked. “As we gather more data, we’ll understand resistance mechanisms better and begin to figure out where to go with treatment sequencing.”
TKIs and beyond
In addition to ADCs, TKIs continue to make their mark in the targeted HER2 therapeutic space. The approvals of tucatinib and neratinib last year represented an important advance in treating HER2-positive MBC, particularly for patients with brain metastases. The HER2CLIMB trial, for instance, found that tucatinib combined with trastuzumab and capecitabine had a 4.5-month overall survival advantage compared with placebo (21.9 vs 17.4) and a median progression-free survival advantage of 5.4 months in patients with active brain metastases (9.5 vs 4.1) and 8.3 months in patients with stable metastases (13.9 vs 5.6).
Given this progress, experts are looking to add new TKIs to the armamentarium. In particular, pyrotinib — already approved in China for treating HER2-positive MBC — has demonstrated significantly longer progression-free survival compared with a standard TKI, lapatinib. The phase 3 PHOEBE trial results, published in The Lancet in early 2021, found a median progression-free survival of 12.5 months in patients randomly assigned to receive pyrotinib plus capecitabine compared with 6.8 months in those receiving lapatinib plus capecitabine. The investigators also reported “manageable toxicity”; diarrhea was the most common grade 3 adverse event, occurring in 31% of the pyrotinib group vs. 8% of the lapatinib group, and overall serious adverse events occurred in 10% of patients receiving pyrotinib vs. 8% of those receiving lapatinib.
More recent data on pyrotinib come from the phase 2 PERMEATE trial, which focused on the safety and efficacy of the agent in patients with advanced disease and brain metastases. The investigators, who presented their findings at the 2021 virtual ASCO meeting (abstract 1037), reported that radiation therapy–naive patients receiving pyrotinib plus capecitabine had an overall response rate of 74.6% in the central nervous system. Patients experiencing progression after whole-brain or stereotactic radiation therapy, however, had a comparatively lower overall response rate of 42.1%.
Similarly, median progression-free survival was much higher in the radiation therapy–naive patients (12.1 vs 5.6 months in the radiation therapy cohort). Similar to the PHOEBE trial, the most common grade 3 adverse event was diarrhea (23.1%), followed by decreased neutrophil and white blood cell counts (12.8% for both), anemia (9%), and hand-foot syndrome (7.7%). The main question for Dr. Kalinsky is how well pyrotinib will ultimately stack up to tucatinib and neratinib. “Pyrotinib — like neratinib — was shown to be superior to lapatinib plus capecitabine , but its role may be limited by its gastrointestinal toxicity,” he said. In addition to research focused on expanding the selection of novel ADCs and TKIs, researchers are also exploring new combinations of approved treatments and whether these combinations can be used earlier in treatment sequencing.
Take the CompassHER2 trials. The ongoing phase 3 trial in patients with high-risk HER2-positive breast cancer and residual disease will explore whether tucatinib plus T-DM1 compared with T-DM1 alone improves overall survival and recurrence-free survival and prevents brain metastases. Another possibility currently under investigation is pairing tucatinib and trastuzumab deruxtecan, instead of T-DM1. “Overall, it’s exciting that we are increasing the number of therapeutic options and combinations,” commented Debu Tripathy, MD, professor and chairman in the department of breast medical oncology at the University of Texas MD Anderson Cancer Center in Houston. “Having more choices allows us to tailor therapies to manage resistance and prolong patients’ responses.”
Curbing brain metastasis, according to Dr. Brufksy, is particularly important, and experts need to explore the extent to which ADCs can penetrate the blood-brain barrier. Already, a subgroup analysis of the DESTINY-Breast01 trial found that trastuzumab deruxtecan appeared to be active in patients with brain metastases. Investigators reported an overall response rate of 58.3% and a median progression-free survival of 18.1 months — results in line with those in the general study cohort — but the study population did not include patients with untreated or progressive brain metastases. A phase 2 study currently under way will examine whether patients with HER2-positive and HER2-low breast cancer who have untreated or progressive brain metastases respond to trastuzumab deruxtecan as well. Ultimately, Dr. Brufksy hopes the recent successes with preventing brain metastases in pediatric acute lymphoblastic leukemia (ALL) foreshadow what›s to come in HER2-positive MBC.
“When we figured out how to treat brain metastases prophylactically in childhood ALL, we saw a huge improvement in the cure rate, which is ultimately my vision for HER2-positive disease,” Dr. Brufsky remarked. “Are there cures for HER2-positive MBC on the horizon? We don’t know yet, but the field has really exploded in recent years.”
A version of this article first appeared on Medscape.com.
Recent therapeutic advances in HER2-positive metastatic breast cancer (MBC) have begun to reshape the treatment landscape for patients. Since late 2019, the U.S. Food and Drug Administration (FDA) has approved a handful of novel agents for HER2-positive MBC — most notably, the antibody-drug conjugate (ADC) trastuzumab deruxtecan in December 2019 and the tyrosine kinase inhibitors (TKIs) tucatinib and neratinib in 2020. According to the National Cancer Institute›s Surveillance, Epidemiology, and End Results (SEER) program, the 5-year survival rate for patients with advanced disease was already on the rise between 2004 and 2018, and
“I’ve been involved in the HER2 space for a long time and have watched the field evolve,” said Adam Brufsky, MD, PhD, associate chief in the division of hematology/oncology and co-director of the Comprehensive Breast Cancer Center at the University of Pittsburgh School of Medicine. “The fact that we’re now talking about fourth- and fifth-line therapies for HER2-positive MBC represents a major advance in the management of these patients.”
Oncologists are still building on this progress, focusing on designing more targeted therapies as well as studying different combinations of available agents. The main goal of treatment, experts say, is to prolong patients’ systemic response and prevent recurrences, especially in the brain. This news organization spoke to Dr. Brufksy and others about promising agents and therapeutic strategies on the horizon to treat HER2-positive MBC.
Inside emerging ADCs
Because many patients develop resistance to trastuzumab emtansine (T-DM1) — the first FDA-approved ADC in breast cancer — researchers have focused on developing the next generation of ADCs with more potent payloads, different linkers, and distinct mechanisms of action, according to Sayeh Lavasani, MD, MS, a medical oncologist at City of Hope, a comprehensive cancer center in Los Angeles County.
The second-generation ADC trastuzumab deruxtecan showed “really dramatic” results in HER2-positive MBC, demonstrating progression-free survival of 16 months, remarked Kevin 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. “These outcomes further changed how we treat patients with metastatic disease and prompted considerable excitement over the potential to develop novel ADCs to treat HER2-positive MBC.”
Most recently, two investigational ADCs — trastuzumab duocarmazine (SYD985) and ARX788 — have stood out. The FDA granted fast-track designations to trastuzumab duocarmazine in January 2018 and ARX788 in January 2021. Trastuzumab duocarmazine, the furthest along the pipeline, has shown promising results so far. In June 2021, Netherlands-based biopharmaceutical company Byondis reported preliminary phase 3 data from the TULIP trial. The open-label, randomized phase 3 study enrolled 436 patients with HER2-positive locally advanced or metastatic disease that had progressed on previous anti-HER2 regimens. The company shared early results that trastuzumab duocarmazine achieved its progression-free survival primary endpoint, marking a significant improvement over physician’s choice of chemotherapy, and promised more detailed results to come later this year.
Although only in early-phase trials, ARX788 has also shown robust anti-HER2 activity as well as low toxicity in HER2-positive tumors, according to recent data. The findings from two phase 1 studies, presented at the June 2021 virtual American Society for Clinical Oncology meeting (abstract 1038), revealed an overall response rate of 74% in the breast cancer cohort, but the investigators acknowledged it was too early to report median progression-free survival outcomes. Preclinical data also showed activity in HER2-low and T-DM1–resistant tumors.
Despite the encouraging initial findings, Dr. Kalinsky remains cautiously optimistic about long-term outcomes for both ADCs. “These data are hot off the press, but it’s too soon to know how these two ADCs and others in the pipeline will measure up to approved therapies,” he commented. As experts learn more about the efficacy of these novel ADCs, Dr. Brufsky would also like to better understand resistance mechanisms and how to integrate these agents into current treatment strategies. “The cellular biology of HER2-positive MBC is complicated, and many factors in these tumor cells affect where ADCs are released, how resistance develops, and whether or not resistance to one ADC applies to others,” Dr. Brufsky remarked. “As we gather more data, we’ll understand resistance mechanisms better and begin to figure out where to go with treatment sequencing.”
TKIs and beyond
In addition to ADCs, TKIs continue to make their mark in the targeted HER2 therapeutic space. The approvals of tucatinib and neratinib last year represented an important advance in treating HER2-positive MBC, particularly for patients with brain metastases. The HER2CLIMB trial, for instance, found that tucatinib combined with trastuzumab and capecitabine had a 4.5-month overall survival advantage compared with placebo (21.9 vs 17.4) and a median progression-free survival advantage of 5.4 months in patients with active brain metastases (9.5 vs 4.1) and 8.3 months in patients with stable metastases (13.9 vs 5.6).
Given this progress, experts are looking to add new TKIs to the armamentarium. In particular, pyrotinib — already approved in China for treating HER2-positive MBC — has demonstrated significantly longer progression-free survival compared with a standard TKI, lapatinib. The phase 3 PHOEBE trial results, published in The Lancet in early 2021, found a median progression-free survival of 12.5 months in patients randomly assigned to receive pyrotinib plus capecitabine compared with 6.8 months in those receiving lapatinib plus capecitabine. The investigators also reported “manageable toxicity”; diarrhea was the most common grade 3 adverse event, occurring in 31% of the pyrotinib group vs. 8% of the lapatinib group, and overall serious adverse events occurred in 10% of patients receiving pyrotinib vs. 8% of those receiving lapatinib.
More recent data on pyrotinib come from the phase 2 PERMEATE trial, which focused on the safety and efficacy of the agent in patients with advanced disease and brain metastases. The investigators, who presented their findings at the 2021 virtual ASCO meeting (abstract 1037), reported that radiation therapy–naive patients receiving pyrotinib plus capecitabine had an overall response rate of 74.6% in the central nervous system. Patients experiencing progression after whole-brain or stereotactic radiation therapy, however, had a comparatively lower overall response rate of 42.1%.
Similarly, median progression-free survival was much higher in the radiation therapy–naive patients (12.1 vs 5.6 months in the radiation therapy cohort). Similar to the PHOEBE trial, the most common grade 3 adverse event was diarrhea (23.1%), followed by decreased neutrophil and white blood cell counts (12.8% for both), anemia (9%), and hand-foot syndrome (7.7%). The main question for Dr. Kalinsky is how well pyrotinib will ultimately stack up to tucatinib and neratinib. “Pyrotinib — like neratinib — was shown to be superior to lapatinib plus capecitabine , but its role may be limited by its gastrointestinal toxicity,” he said. In addition to research focused on expanding the selection of novel ADCs and TKIs, researchers are also exploring new combinations of approved treatments and whether these combinations can be used earlier in treatment sequencing.
Take the CompassHER2 trials. The ongoing phase 3 trial in patients with high-risk HER2-positive breast cancer and residual disease will explore whether tucatinib plus T-DM1 compared with T-DM1 alone improves overall survival and recurrence-free survival and prevents brain metastases. Another possibility currently under investigation is pairing tucatinib and trastuzumab deruxtecan, instead of T-DM1. “Overall, it’s exciting that we are increasing the number of therapeutic options and combinations,” commented Debu Tripathy, MD, professor and chairman in the department of breast medical oncology at the University of Texas MD Anderson Cancer Center in Houston. “Having more choices allows us to tailor therapies to manage resistance and prolong patients’ responses.”
Curbing brain metastasis, according to Dr. Brufksy, is particularly important, and experts need to explore the extent to which ADCs can penetrate the blood-brain barrier. Already, a subgroup analysis of the DESTINY-Breast01 trial found that trastuzumab deruxtecan appeared to be active in patients with brain metastases. Investigators reported an overall response rate of 58.3% and a median progression-free survival of 18.1 months — results in line with those in the general study cohort — but the study population did not include patients with untreated or progressive brain metastases. A phase 2 study currently under way will examine whether patients with HER2-positive and HER2-low breast cancer who have untreated or progressive brain metastases respond to trastuzumab deruxtecan as well. Ultimately, Dr. Brufksy hopes the recent successes with preventing brain metastases in pediatric acute lymphoblastic leukemia (ALL) foreshadow what›s to come in HER2-positive MBC.
“When we figured out how to treat brain metastases prophylactically in childhood ALL, we saw a huge improvement in the cure rate, which is ultimately my vision for HER2-positive disease,” Dr. Brufsky remarked. “Are there cures for HER2-positive MBC on the horizon? We don’t know yet, but the field has really exploded in recent years.”
A version of this article first appeared on Medscape.com.
Recent therapeutic advances in HER2-positive metastatic breast cancer (MBC) have begun to reshape the treatment landscape for patients. Since late 2019, the U.S. Food and Drug Administration (FDA) has approved a handful of novel agents for HER2-positive MBC — most notably, the antibody-drug conjugate (ADC) trastuzumab deruxtecan in December 2019 and the tyrosine kinase inhibitors (TKIs) tucatinib and neratinib in 2020. According to the National Cancer Institute›s Surveillance, Epidemiology, and End Results (SEER) program, the 5-year survival rate for patients with advanced disease was already on the rise between 2004 and 2018, and
“I’ve been involved in the HER2 space for a long time and have watched the field evolve,” said Adam Brufsky, MD, PhD, associate chief in the division of hematology/oncology and co-director of the Comprehensive Breast Cancer Center at the University of Pittsburgh School of Medicine. “The fact that we’re now talking about fourth- and fifth-line therapies for HER2-positive MBC represents a major advance in the management of these patients.”
Oncologists are still building on this progress, focusing on designing more targeted therapies as well as studying different combinations of available agents. The main goal of treatment, experts say, is to prolong patients’ systemic response and prevent recurrences, especially in the brain. This news organization spoke to Dr. Brufksy and others about promising agents and therapeutic strategies on the horizon to treat HER2-positive MBC.
Inside emerging ADCs
Because many patients develop resistance to trastuzumab emtansine (T-DM1) — the first FDA-approved ADC in breast cancer — researchers have focused on developing the next generation of ADCs with more potent payloads, different linkers, and distinct mechanisms of action, according to Sayeh Lavasani, MD, MS, a medical oncologist at City of Hope, a comprehensive cancer center in Los Angeles County.
The second-generation ADC trastuzumab deruxtecan showed “really dramatic” results in HER2-positive MBC, demonstrating progression-free survival of 16 months, remarked Kevin 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. “These outcomes further changed how we treat patients with metastatic disease and prompted considerable excitement over the potential to develop novel ADCs to treat HER2-positive MBC.”
Most recently, two investigational ADCs — trastuzumab duocarmazine (SYD985) and ARX788 — have stood out. The FDA granted fast-track designations to trastuzumab duocarmazine in January 2018 and ARX788 in January 2021. Trastuzumab duocarmazine, the furthest along the pipeline, has shown promising results so far. In June 2021, Netherlands-based biopharmaceutical company Byondis reported preliminary phase 3 data from the TULIP trial. The open-label, randomized phase 3 study enrolled 436 patients with HER2-positive locally advanced or metastatic disease that had progressed on previous anti-HER2 regimens. The company shared early results that trastuzumab duocarmazine achieved its progression-free survival primary endpoint, marking a significant improvement over physician’s choice of chemotherapy, and promised more detailed results to come later this year.
Although only in early-phase trials, ARX788 has also shown robust anti-HER2 activity as well as low toxicity in HER2-positive tumors, according to recent data. The findings from two phase 1 studies, presented at the June 2021 virtual American Society for Clinical Oncology meeting (abstract 1038), revealed an overall response rate of 74% in the breast cancer cohort, but the investigators acknowledged it was too early to report median progression-free survival outcomes. Preclinical data also showed activity in HER2-low and T-DM1–resistant tumors.
Despite the encouraging initial findings, Dr. Kalinsky remains cautiously optimistic about long-term outcomes for both ADCs. “These data are hot off the press, but it’s too soon to know how these two ADCs and others in the pipeline will measure up to approved therapies,” he commented. As experts learn more about the efficacy of these novel ADCs, Dr. Brufsky would also like to better understand resistance mechanisms and how to integrate these agents into current treatment strategies. “The cellular biology of HER2-positive MBC is complicated, and many factors in these tumor cells affect where ADCs are released, how resistance develops, and whether or not resistance to one ADC applies to others,” Dr. Brufsky remarked. “As we gather more data, we’ll understand resistance mechanisms better and begin to figure out where to go with treatment sequencing.”
TKIs and beyond
In addition to ADCs, TKIs continue to make their mark in the targeted HER2 therapeutic space. The approvals of tucatinib and neratinib last year represented an important advance in treating HER2-positive MBC, particularly for patients with brain metastases. The HER2CLIMB trial, for instance, found that tucatinib combined with trastuzumab and capecitabine had a 4.5-month overall survival advantage compared with placebo (21.9 vs 17.4) and a median progression-free survival advantage of 5.4 months in patients with active brain metastases (9.5 vs 4.1) and 8.3 months in patients with stable metastases (13.9 vs 5.6).
Given this progress, experts are looking to add new TKIs to the armamentarium. In particular, pyrotinib — already approved in China for treating HER2-positive MBC — has demonstrated significantly longer progression-free survival compared with a standard TKI, lapatinib. The phase 3 PHOEBE trial results, published in The Lancet in early 2021, found a median progression-free survival of 12.5 months in patients randomly assigned to receive pyrotinib plus capecitabine compared with 6.8 months in those receiving lapatinib plus capecitabine. The investigators also reported “manageable toxicity”; diarrhea was the most common grade 3 adverse event, occurring in 31% of the pyrotinib group vs. 8% of the lapatinib group, and overall serious adverse events occurred in 10% of patients receiving pyrotinib vs. 8% of those receiving lapatinib.
More recent data on pyrotinib come from the phase 2 PERMEATE trial, which focused on the safety and efficacy of the agent in patients with advanced disease and brain metastases. The investigators, who presented their findings at the 2021 virtual ASCO meeting (abstract 1037), reported that radiation therapy–naive patients receiving pyrotinib plus capecitabine had an overall response rate of 74.6% in the central nervous system. Patients experiencing progression after whole-brain or stereotactic radiation therapy, however, had a comparatively lower overall response rate of 42.1%.
Similarly, median progression-free survival was much higher in the radiation therapy–naive patients (12.1 vs 5.6 months in the radiation therapy cohort). Similar to the PHOEBE trial, the most common grade 3 adverse event was diarrhea (23.1%), followed by decreased neutrophil and white blood cell counts (12.8% for both), anemia (9%), and hand-foot syndrome (7.7%). The main question for Dr. Kalinsky is how well pyrotinib will ultimately stack up to tucatinib and neratinib. “Pyrotinib — like neratinib — was shown to be superior to lapatinib plus capecitabine , but its role may be limited by its gastrointestinal toxicity,” he said. In addition to research focused on expanding the selection of novel ADCs and TKIs, researchers are also exploring new combinations of approved treatments and whether these combinations can be used earlier in treatment sequencing.
Take the CompassHER2 trials. The ongoing phase 3 trial in patients with high-risk HER2-positive breast cancer and residual disease will explore whether tucatinib plus T-DM1 compared with T-DM1 alone improves overall survival and recurrence-free survival and prevents brain metastases. Another possibility currently under investigation is pairing tucatinib and trastuzumab deruxtecan, instead of T-DM1. “Overall, it’s exciting that we are increasing the number of therapeutic options and combinations,” commented Debu Tripathy, MD, professor and chairman in the department of breast medical oncology at the University of Texas MD Anderson Cancer Center in Houston. “Having more choices allows us to tailor therapies to manage resistance and prolong patients’ responses.”
Curbing brain metastasis, according to Dr. Brufksy, is particularly important, and experts need to explore the extent to which ADCs can penetrate the blood-brain barrier. Already, a subgroup analysis of the DESTINY-Breast01 trial found that trastuzumab deruxtecan appeared to be active in patients with brain metastases. Investigators reported an overall response rate of 58.3% and a median progression-free survival of 18.1 months — results in line with those in the general study cohort — but the study population did not include patients with untreated or progressive brain metastases. A phase 2 study currently under way will examine whether patients with HER2-positive and HER2-low breast cancer who have untreated or progressive brain metastases respond to trastuzumab deruxtecan as well. Ultimately, Dr. Brufksy hopes the recent successes with preventing brain metastases in pediatric acute lymphoblastic leukemia (ALL) foreshadow what›s to come in HER2-positive MBC.
“When we figured out how to treat brain metastases prophylactically in childhood ALL, we saw a huge improvement in the cure rate, which is ultimately my vision for HER2-positive disease,” Dr. Brufsky remarked. “Are there cures for HER2-positive MBC on the horizon? We don’t know yet, but the field has really exploded in recent years.”
A version of this article first appeared on Medscape.com.
Genomic instability varies between breast cancer subtypes
More than 1,000 patients with TNBC, ER+ breast cancer, or ovarian cancer from five cohorts were examined for genomic instability scores (GIS) and the presence of BRCA deficiency, which showed that, while GIS was similar in BRCA-deficient TNBC and ovarian cancer, it was significantly different in ER+ breast cancer.
The analysis, presented at the San Antonio Breast Cancer Symposium, showed that the genomic instability scores threshold, which could be used to dictate a patient’s treatment, should be lower for ER+ breast cancer than for TNBC.
“This indicates that different GIS thresholds are appropriate for breast cancer subtypes, and that the GIS threshold developed for ovarian caner is not appropriate for ER+ breast cancer,” said lead author Kirsten Timms, PhD, from Myriad Genetics.
This, she noted, is “consistent with the fact that ovarian cancer and TNBC are known to have similar molecular signatures.”
The researchers suggest that the “more inclusive” thresholds assessed in the study should be examined in further studies “to determine whether these cutoffs are associated with a benefit from treatment with DNA-targeting agents,” such as poly (ADP-ribose) polymerase (PARP) inhibitors.
Thomas P. Slavin, MD, chief medical officer at Myriad Genetics, said in an interview that there is “not a one size fits all” for GIS thresholds.
“When you look at ER+ breast cancer you see we need a different cutoff because it’s probably not as driven by homologous recombination deficiency [HRD], as least as a whole, compared to the other two,” he said. “There’s a little less genomic instability.”
He continued that their results suggest around half of TNBC patients have a GIS score that indicates the presence of significant HRD, which is “spot on for what we see with ovarian cancer” and “those people should respond pretty well to PARP-inhibitor therapies,” which is currently being investigated in clinical trials.
“But even in the ER+ group, when we look at the thresholds we used in this research, still about a third have what looks like a substantial amount of HRD, so that’s a huge biomarker,” Dr. Slavin said.
He explained that the importance of their score is that, rather than looking for the causes of HRD, they are looking for the consequences.
“We don’t know all the causes of why, all of a sudden, a tumor cell looks like it can’t replicate through homologous combination [but] what this test does is it says: ‘We don’t really care what the cause is ... we can just look at the genomic scarring and the consequences.’ ”
Elena Provenzano, MD, CRUK Therapeutic Discovery Laboratories, Cambridge (England) University Hospitals NHS Foundation Trust, who was not involved in the study, said in an interview it is “interesting work.”
“We have a personalized breast cancer program here in Cambridge and we’re running trials where we use PARP inhibitors and platinum-based therapy, and what we’re using to make these sorts of decisions is COSMIC mutational signatures associated with genetic instability. And I guess we also look at the total mutational burden,” Dr. Provenzano said.
She continued that the GIS is one of several ways of measuring HRD. “So the question is how it compares with the other measures that are being used to assess whether or not patients are suitable for PARP inhibitor and platinum-based therapy.”
Dr. Provenzano underlined that it has been known since the “early 2000s” that breast cancer is a group of different diseases. “Even within those categories there’s quite a lot of tumor types,” so it “makes sense you need to adjust the threshold slightly for it to become relevant to types of breast cancer.”
She added that the “holy grail in oncology is this concept of personalized medicine, so all these tests help us make sure that the right patient is getting the right treatment.
“At the moment TNBC is often getting treated in a similar way, although we know that there are different biological subtypes, so while there’s a significant group that falls into this BRCA-deficient group that are going to respond to PARPs there are other types that don’t.
“So these sorts of tests help us decide which subset are going to help us the most, and for the others ones we potentially need to identify other treatments as being optimal,” Dr. Provenzano said.
Previous studies have shown that HR-deficient tumors may benefit from treatment with DNA-damaging agents, and that tools such as the three-biomarker GIS can be used to identify HR deficiency.
The Food and Drug Administration has already approved a GIS threshold for identifying HR deficiency in ovarian cancer of 42, which was set as the 5th percentile for BRCA-deficient tumors. However, a recent published in Molecular Cancer Research, and a second published on MDPI Open Access Journals, indicated that a lower, first percentile, cutoff of at least 33 was associated with improved outcomes after platinum-based treatment.
As TNBC is known to have a similar molecular profile to ovarian cancer, the researchers investigated whether it has a different GIS threshold to that in ER+ breast cancer, gathering data on patients newly diagnosed with ovarian cancer, TNBC, or ER+ breast cancer from across five cohorts.
They included 127 ovarian cancer patients from Nature, 434 ovarian cancer, 44 TNBC, and 213 ER+ breast cancer patients from The Cancer Genome Atlas, 55 TNBC and 112 ER+ breast cancer patients from Breast Cancer Research, 19 TNBC and 25 ER+ breast cancer patients from TBCRC 008, and 56 ER+ breast cancer patients from OlympiAD.
GIS was defined as a combination of loss of heterozygosity, telomeric-allellic imbalance, and large-scale state transitions, identified through next-generation sequencing, and GIS distributions were compared between cancer types and subtypes.
The team also determined the presence of BRCA deficiency, finding that, among BRCA deficient tumors, the GIS distribution among patients with ER+ breast cancer was significantly different from that seen in both ovarian cancer (P = 9.6 x 10–5) and TNBC (P = 2.1 x 10–4).
The first percentile of a normal distribution of BRCA-deficient ER+ breast cancers indicated a GIS threshold of 24, with 45.1% of all ER+ tumors at or above this threshold found to be GIS positive. This translated into 98.7% of BRCA-deficient tumors and 32.7% that were BRCA intact.
The results also showed, however, that the GIS distribution for TNBC was not significantly different from that seen in ovarian cancer (P = .72), with the threshold of at least 33 Identifying 64.4% of TNBC tumors as GIS positive. This equated to 100% of BRCA-deficient tumors and 41.7% that were BRCA intact.
Dr. Timms and Dr. Slavin are employed by Myriad Genetics, who funded the study.
More than 1,000 patients with TNBC, ER+ breast cancer, or ovarian cancer from five cohorts were examined for genomic instability scores (GIS) and the presence of BRCA deficiency, which showed that, while GIS was similar in BRCA-deficient TNBC and ovarian cancer, it was significantly different in ER+ breast cancer.
The analysis, presented at the San Antonio Breast Cancer Symposium, showed that the genomic instability scores threshold, which could be used to dictate a patient’s treatment, should be lower for ER+ breast cancer than for TNBC.
“This indicates that different GIS thresholds are appropriate for breast cancer subtypes, and that the GIS threshold developed for ovarian caner is not appropriate for ER+ breast cancer,” said lead author Kirsten Timms, PhD, from Myriad Genetics.
This, she noted, is “consistent with the fact that ovarian cancer and TNBC are known to have similar molecular signatures.”
The researchers suggest that the “more inclusive” thresholds assessed in the study should be examined in further studies “to determine whether these cutoffs are associated with a benefit from treatment with DNA-targeting agents,” such as poly (ADP-ribose) polymerase (PARP) inhibitors.
Thomas P. Slavin, MD, chief medical officer at Myriad Genetics, said in an interview that there is “not a one size fits all” for GIS thresholds.
“When you look at ER+ breast cancer you see we need a different cutoff because it’s probably not as driven by homologous recombination deficiency [HRD], as least as a whole, compared to the other two,” he said. “There’s a little less genomic instability.”
He continued that their results suggest around half of TNBC patients have a GIS score that indicates the presence of significant HRD, which is “spot on for what we see with ovarian cancer” and “those people should respond pretty well to PARP-inhibitor therapies,” which is currently being investigated in clinical trials.
“But even in the ER+ group, when we look at the thresholds we used in this research, still about a third have what looks like a substantial amount of HRD, so that’s a huge biomarker,” Dr. Slavin said.
He explained that the importance of their score is that, rather than looking for the causes of HRD, they are looking for the consequences.
“We don’t know all the causes of why, all of a sudden, a tumor cell looks like it can’t replicate through homologous combination [but] what this test does is it says: ‘We don’t really care what the cause is ... we can just look at the genomic scarring and the consequences.’ ”
Elena Provenzano, MD, CRUK Therapeutic Discovery Laboratories, Cambridge (England) University Hospitals NHS Foundation Trust, who was not involved in the study, said in an interview it is “interesting work.”
“We have a personalized breast cancer program here in Cambridge and we’re running trials where we use PARP inhibitors and platinum-based therapy, and what we’re using to make these sorts of decisions is COSMIC mutational signatures associated with genetic instability. And I guess we also look at the total mutational burden,” Dr. Provenzano said.
She continued that the GIS is one of several ways of measuring HRD. “So the question is how it compares with the other measures that are being used to assess whether or not patients are suitable for PARP inhibitor and platinum-based therapy.”
Dr. Provenzano underlined that it has been known since the “early 2000s” that breast cancer is a group of different diseases. “Even within those categories there’s quite a lot of tumor types,” so it “makes sense you need to adjust the threshold slightly for it to become relevant to types of breast cancer.”
She added that the “holy grail in oncology is this concept of personalized medicine, so all these tests help us make sure that the right patient is getting the right treatment.
“At the moment TNBC is often getting treated in a similar way, although we know that there are different biological subtypes, so while there’s a significant group that falls into this BRCA-deficient group that are going to respond to PARPs there are other types that don’t.
“So these sorts of tests help us decide which subset are going to help us the most, and for the others ones we potentially need to identify other treatments as being optimal,” Dr. Provenzano said.
Previous studies have shown that HR-deficient tumors may benefit from treatment with DNA-damaging agents, and that tools such as the three-biomarker GIS can be used to identify HR deficiency.
The Food and Drug Administration has already approved a GIS threshold for identifying HR deficiency in ovarian cancer of 42, which was set as the 5th percentile for BRCA-deficient tumors. However, a recent published in Molecular Cancer Research, and a second published on MDPI Open Access Journals, indicated that a lower, first percentile, cutoff of at least 33 was associated with improved outcomes after platinum-based treatment.
As TNBC is known to have a similar molecular profile to ovarian cancer, the researchers investigated whether it has a different GIS threshold to that in ER+ breast cancer, gathering data on patients newly diagnosed with ovarian cancer, TNBC, or ER+ breast cancer from across five cohorts.
They included 127 ovarian cancer patients from Nature, 434 ovarian cancer, 44 TNBC, and 213 ER+ breast cancer patients from The Cancer Genome Atlas, 55 TNBC and 112 ER+ breast cancer patients from Breast Cancer Research, 19 TNBC and 25 ER+ breast cancer patients from TBCRC 008, and 56 ER+ breast cancer patients from OlympiAD.
GIS was defined as a combination of loss of heterozygosity, telomeric-allellic imbalance, and large-scale state transitions, identified through next-generation sequencing, and GIS distributions were compared between cancer types and subtypes.
The team also determined the presence of BRCA deficiency, finding that, among BRCA deficient tumors, the GIS distribution among patients with ER+ breast cancer was significantly different from that seen in both ovarian cancer (P = 9.6 x 10–5) and TNBC (P = 2.1 x 10–4).
The first percentile of a normal distribution of BRCA-deficient ER+ breast cancers indicated a GIS threshold of 24, with 45.1% of all ER+ tumors at or above this threshold found to be GIS positive. This translated into 98.7% of BRCA-deficient tumors and 32.7% that were BRCA intact.
The results also showed, however, that the GIS distribution for TNBC was not significantly different from that seen in ovarian cancer (P = .72), with the threshold of at least 33 Identifying 64.4% of TNBC tumors as GIS positive. This equated to 100% of BRCA-deficient tumors and 41.7% that were BRCA intact.
Dr. Timms and Dr. Slavin are employed by Myriad Genetics, who funded the study.
More than 1,000 patients with TNBC, ER+ breast cancer, or ovarian cancer from five cohorts were examined for genomic instability scores (GIS) and the presence of BRCA deficiency, which showed that, while GIS was similar in BRCA-deficient TNBC and ovarian cancer, it was significantly different in ER+ breast cancer.
The analysis, presented at the San Antonio Breast Cancer Symposium, showed that the genomic instability scores threshold, which could be used to dictate a patient’s treatment, should be lower for ER+ breast cancer than for TNBC.
“This indicates that different GIS thresholds are appropriate for breast cancer subtypes, and that the GIS threshold developed for ovarian caner is not appropriate for ER+ breast cancer,” said lead author Kirsten Timms, PhD, from Myriad Genetics.
This, she noted, is “consistent with the fact that ovarian cancer and TNBC are known to have similar molecular signatures.”
The researchers suggest that the “more inclusive” thresholds assessed in the study should be examined in further studies “to determine whether these cutoffs are associated with a benefit from treatment with DNA-targeting agents,” such as poly (ADP-ribose) polymerase (PARP) inhibitors.
Thomas P. Slavin, MD, chief medical officer at Myriad Genetics, said in an interview that there is “not a one size fits all” for GIS thresholds.
“When you look at ER+ breast cancer you see we need a different cutoff because it’s probably not as driven by homologous recombination deficiency [HRD], as least as a whole, compared to the other two,” he said. “There’s a little less genomic instability.”
He continued that their results suggest around half of TNBC patients have a GIS score that indicates the presence of significant HRD, which is “spot on for what we see with ovarian cancer” and “those people should respond pretty well to PARP-inhibitor therapies,” which is currently being investigated in clinical trials.
“But even in the ER+ group, when we look at the thresholds we used in this research, still about a third have what looks like a substantial amount of HRD, so that’s a huge biomarker,” Dr. Slavin said.
He explained that the importance of their score is that, rather than looking for the causes of HRD, they are looking for the consequences.
“We don’t know all the causes of why, all of a sudden, a tumor cell looks like it can’t replicate through homologous combination [but] what this test does is it says: ‘We don’t really care what the cause is ... we can just look at the genomic scarring and the consequences.’ ”
Elena Provenzano, MD, CRUK Therapeutic Discovery Laboratories, Cambridge (England) University Hospitals NHS Foundation Trust, who was not involved in the study, said in an interview it is “interesting work.”
“We have a personalized breast cancer program here in Cambridge and we’re running trials where we use PARP inhibitors and platinum-based therapy, and what we’re using to make these sorts of decisions is COSMIC mutational signatures associated with genetic instability. And I guess we also look at the total mutational burden,” Dr. Provenzano said.
She continued that the GIS is one of several ways of measuring HRD. “So the question is how it compares with the other measures that are being used to assess whether or not patients are suitable for PARP inhibitor and platinum-based therapy.”
Dr. Provenzano underlined that it has been known since the “early 2000s” that breast cancer is a group of different diseases. “Even within those categories there’s quite a lot of tumor types,” so it “makes sense you need to adjust the threshold slightly for it to become relevant to types of breast cancer.”
She added that the “holy grail in oncology is this concept of personalized medicine, so all these tests help us make sure that the right patient is getting the right treatment.
“At the moment TNBC is often getting treated in a similar way, although we know that there are different biological subtypes, so while there’s a significant group that falls into this BRCA-deficient group that are going to respond to PARPs there are other types that don’t.
“So these sorts of tests help us decide which subset are going to help us the most, and for the others ones we potentially need to identify other treatments as being optimal,” Dr. Provenzano said.
Previous studies have shown that HR-deficient tumors may benefit from treatment with DNA-damaging agents, and that tools such as the three-biomarker GIS can be used to identify HR deficiency.
The Food and Drug Administration has already approved a GIS threshold for identifying HR deficiency in ovarian cancer of 42, which was set as the 5th percentile for BRCA-deficient tumors. However, a recent published in Molecular Cancer Research, and a second published on MDPI Open Access Journals, indicated that a lower, first percentile, cutoff of at least 33 was associated with improved outcomes after platinum-based treatment.
As TNBC is known to have a similar molecular profile to ovarian cancer, the researchers investigated whether it has a different GIS threshold to that in ER+ breast cancer, gathering data on patients newly diagnosed with ovarian cancer, TNBC, or ER+ breast cancer from across five cohorts.
They included 127 ovarian cancer patients from Nature, 434 ovarian cancer, 44 TNBC, and 213 ER+ breast cancer patients from The Cancer Genome Atlas, 55 TNBC and 112 ER+ breast cancer patients from Breast Cancer Research, 19 TNBC and 25 ER+ breast cancer patients from TBCRC 008, and 56 ER+ breast cancer patients from OlympiAD.
GIS was defined as a combination of loss of heterozygosity, telomeric-allellic imbalance, and large-scale state transitions, identified through next-generation sequencing, and GIS distributions were compared between cancer types and subtypes.
The team also determined the presence of BRCA deficiency, finding that, among BRCA deficient tumors, the GIS distribution among patients with ER+ breast cancer was significantly different from that seen in both ovarian cancer (P = 9.6 x 10–5) and TNBC (P = 2.1 x 10–4).
The first percentile of a normal distribution of BRCA-deficient ER+ breast cancers indicated a GIS threshold of 24, with 45.1% of all ER+ tumors at or above this threshold found to be GIS positive. This translated into 98.7% of BRCA-deficient tumors and 32.7% that were BRCA intact.
The results also showed, however, that the GIS distribution for TNBC was not significantly different from that seen in ovarian cancer (P = .72), with the threshold of at least 33 Identifying 64.4% of TNBC tumors as GIS positive. This equated to 100% of BRCA-deficient tumors and 41.7% that were BRCA intact.
Dr. Timms and Dr. Slavin are employed by Myriad Genetics, who funded the study.
FROM SABCS 2021
Ongoing HER2 breast cancer therapy may cost an additional $68,000 per patient
The current funding policy in British Columbia restricts patients to two lines of HER2-directed therapy for metastatic breast cancer, but accessing continued HER2 suppression has become more complex as novel agents have emerged, Emily Jackson, MD, and colleagues explained (in poster PD8-09) at the San Antonio Breast Cancer Symposium.
Continuing HER2 suppression has improved progression free survival (PFS) and overall survival (OS), but the financial implications of adapting funding policies to “reflect increasing lines of proven HER2 treatment” are unclear, they noted.
Drug funding is provided through the provincial government, but it can take months – and sometimes years – from when a drug is approved by Health Canada and when provincial protocols are approved and funding is made available, Dr. Jackson, co-chief resident (PGY5) at BC Cancer, Vancouver, said in an interview.
During that “lag time,” the province is negotiating drug prices with pharmaceutical companies and determining “which patients are eligible and under which circumstances,” she said.
To assess the potential costs, the investigators analyzed data from the BC Cancer outcomes unit, which collects clinical and outcome information on 85% of all patients diagnosed with breast cancer in the province. Information on therapy use was obtained from the BC Cancer pharmacy database.
Of 230 patients who received any HER2 treatment for metastatic breast cancer dispensed by BC Cancer between 2013 and 2018, 112 (49%) were eligible to continue beyond their second line of therapy.
“Of these, 86 patients accessed continued HER2-directed therapy, while 26 were eligible but unable to access continued HER2Rx,” they reported, noting that “the remaining 51% (n = 118) were not eligible for consideration of further HER2Rx due to either stable disease (n = 61) or deterioration precluding treatment (n = 57).”
At median follow-up of 42.2 months, the median number of lines of therapy in the entire study population was three. The median number of cycles in those who received HER2-directed therapy beyond second-line therapy was 33.
The median overall survival was 37.5 months for those who were eligible but did not continue HER2, compared with 57.9 months for those who did continue, they found.
The overall survival difference was not statistically significant (P = .13), but this was likely due to the small number of patients included in the initial analysis, Dr. Jackson said, noting that the finding is “hypothesis generating,” and should be further assessed.
Notably, most patients who continued HER2 therapy did so through pharmaceutical company compassionate access programs or clinical trials, she said.
The “conservative estimated cost per cycle of HER2Rx” was based on currently available trastuzumab biosimilars, and the potential financial implications were calculated based on the current cost of commonly used third-line therapies.
The findings demonstrate that most patients access continued treatment despite prohibitive funding policies, and suggest that significant increases in cost per patient can be expected if funding policies don’t evolve to meet treatment needs, they concluded, noting that “if these trends in survival continue we would expect an additional cost of $68,000 per patient over current costs.
“As the cost of novel therapies are likely to be higher than currently available biosimilars, there will be significant implications for both private payer and public payer healthcare systems,” they added.
A larger, more comprehensive analysis of the data is planned, said Dr. Jackson, who did not disclose any funding or other conflicts of interest associated with this study.
The current funding policy in British Columbia restricts patients to two lines of HER2-directed therapy for metastatic breast cancer, but accessing continued HER2 suppression has become more complex as novel agents have emerged, Emily Jackson, MD, and colleagues explained (in poster PD8-09) at the San Antonio Breast Cancer Symposium.
Continuing HER2 suppression has improved progression free survival (PFS) and overall survival (OS), but the financial implications of adapting funding policies to “reflect increasing lines of proven HER2 treatment” are unclear, they noted.
Drug funding is provided through the provincial government, but it can take months – and sometimes years – from when a drug is approved by Health Canada and when provincial protocols are approved and funding is made available, Dr. Jackson, co-chief resident (PGY5) at BC Cancer, Vancouver, said in an interview.
During that “lag time,” the province is negotiating drug prices with pharmaceutical companies and determining “which patients are eligible and under which circumstances,” she said.
To assess the potential costs, the investigators analyzed data from the BC Cancer outcomes unit, which collects clinical and outcome information on 85% of all patients diagnosed with breast cancer in the province. Information on therapy use was obtained from the BC Cancer pharmacy database.
Of 230 patients who received any HER2 treatment for metastatic breast cancer dispensed by BC Cancer between 2013 and 2018, 112 (49%) were eligible to continue beyond their second line of therapy.
“Of these, 86 patients accessed continued HER2-directed therapy, while 26 were eligible but unable to access continued HER2Rx,” they reported, noting that “the remaining 51% (n = 118) were not eligible for consideration of further HER2Rx due to either stable disease (n = 61) or deterioration precluding treatment (n = 57).”
At median follow-up of 42.2 months, the median number of lines of therapy in the entire study population was three. The median number of cycles in those who received HER2-directed therapy beyond second-line therapy was 33.
The median overall survival was 37.5 months for those who were eligible but did not continue HER2, compared with 57.9 months for those who did continue, they found.
The overall survival difference was not statistically significant (P = .13), but this was likely due to the small number of patients included in the initial analysis, Dr. Jackson said, noting that the finding is “hypothesis generating,” and should be further assessed.
Notably, most patients who continued HER2 therapy did so through pharmaceutical company compassionate access programs or clinical trials, she said.
The “conservative estimated cost per cycle of HER2Rx” was based on currently available trastuzumab biosimilars, and the potential financial implications were calculated based on the current cost of commonly used third-line therapies.
The findings demonstrate that most patients access continued treatment despite prohibitive funding policies, and suggest that significant increases in cost per patient can be expected if funding policies don’t evolve to meet treatment needs, they concluded, noting that “if these trends in survival continue we would expect an additional cost of $68,000 per patient over current costs.
“As the cost of novel therapies are likely to be higher than currently available biosimilars, there will be significant implications for both private payer and public payer healthcare systems,” they added.
A larger, more comprehensive analysis of the data is planned, said Dr. Jackson, who did not disclose any funding or other conflicts of interest associated with this study.
The current funding policy in British Columbia restricts patients to two lines of HER2-directed therapy for metastatic breast cancer, but accessing continued HER2 suppression has become more complex as novel agents have emerged, Emily Jackson, MD, and colleagues explained (in poster PD8-09) at the San Antonio Breast Cancer Symposium.
Continuing HER2 suppression has improved progression free survival (PFS) and overall survival (OS), but the financial implications of adapting funding policies to “reflect increasing lines of proven HER2 treatment” are unclear, they noted.
Drug funding is provided through the provincial government, but it can take months – and sometimes years – from when a drug is approved by Health Canada and when provincial protocols are approved and funding is made available, Dr. Jackson, co-chief resident (PGY5) at BC Cancer, Vancouver, said in an interview.
During that “lag time,” the province is negotiating drug prices with pharmaceutical companies and determining “which patients are eligible and under which circumstances,” she said.
To assess the potential costs, the investigators analyzed data from the BC Cancer outcomes unit, which collects clinical and outcome information on 85% of all patients diagnosed with breast cancer in the province. Information on therapy use was obtained from the BC Cancer pharmacy database.
Of 230 patients who received any HER2 treatment for metastatic breast cancer dispensed by BC Cancer between 2013 and 2018, 112 (49%) were eligible to continue beyond their second line of therapy.
“Of these, 86 patients accessed continued HER2-directed therapy, while 26 were eligible but unable to access continued HER2Rx,” they reported, noting that “the remaining 51% (n = 118) were not eligible for consideration of further HER2Rx due to either stable disease (n = 61) or deterioration precluding treatment (n = 57).”
At median follow-up of 42.2 months, the median number of lines of therapy in the entire study population was three. The median number of cycles in those who received HER2-directed therapy beyond second-line therapy was 33.
The median overall survival was 37.5 months for those who were eligible but did not continue HER2, compared with 57.9 months for those who did continue, they found.
The overall survival difference was not statistically significant (P = .13), but this was likely due to the small number of patients included in the initial analysis, Dr. Jackson said, noting that the finding is “hypothesis generating,” and should be further assessed.
Notably, most patients who continued HER2 therapy did so through pharmaceutical company compassionate access programs or clinical trials, she said.
The “conservative estimated cost per cycle of HER2Rx” was based on currently available trastuzumab biosimilars, and the potential financial implications were calculated based on the current cost of commonly used third-line therapies.
The findings demonstrate that most patients access continued treatment despite prohibitive funding policies, and suggest that significant increases in cost per patient can be expected if funding policies don’t evolve to meet treatment needs, they concluded, noting that “if these trends in survival continue we would expect an additional cost of $68,000 per patient over current costs.
“As the cost of novel therapies are likely to be higher than currently available biosimilars, there will be significant implications for both private payer and public payer healthcare systems,” they added.
A larger, more comprehensive analysis of the data is planned, said Dr. Jackson, who did not disclose any funding or other conflicts of interest associated with this study.
FROM SABCS 2021
1 in 7 breast cancers are overdiagnosed
A new model based on data from the Breast Cancer Surveillance Consortium (BCSC) suggests that overdiagnosis of screen-detected breast cancer is less frequent than estimates from excess-incidence studies, but the model also takes into account indolent tumors and produced a higher estimate than previous models that didn’t consider this factor.
“There is a pronounced lack of consensus of the true rate of overdiagnosis in the contemporary U.S. mammography practice. This uncertainty about the extent of overdiagnosis is a problem for the development of guidelines and policies. By overcoming shortcomings of previous studies, we produced a defensible estimate of overdiagnosis in contemporary U.S. mammography practice. About one in seven screen-detected cancers in women (between 50 and 74 years) undergoing biennial screening will be overdiagnosed, and about one in three overdiagnosed cancers are attributed to the detection of nonprogressive cancers,” said Marc D. Ryser, PhD, in an interview. Dr. Ryser is an expert in mathematical and statistical modeling in population health science at Duke University, Durham, N.C. He presented the results of the model at the 2021 San Antonio Breast Cancer Symposium.
Previous models have come up with estimates ranging from 0% to 54%, but the heterogeneity makes them difficult to compare. “They differ in study populations, estimation methods and their definitions of overdiagnosis,” Dr. Ryser said.
There are two general ways to estimate overdiagnosis. One is a model-based approach that works out the tumor latency using models of disease natural history and clinical data, and then uses that to predict overdiagnosis. But these models may not account or indolent tumors, or tumors that would not likely cause death during the patient’s lifetime, and the assumptions behind the models can be opaque. On the other hand, the excess-incidence strategy compares incidence in screened versus unscreened populations and assumes that excess cancers in the screened group is caused by overdiagnosis, but this can be affected by bias.
To get around these limitations, Dr. Ryser’s group used a model-based approach, but also allowed for indolent tumors. They ensured transparency of the underlying assumptions of the model, and took advantage of a contemporary, high-quality data source in the BCSC.
They used individual mammography screening and breast cancer diagnosis records from 35,986 women aged 50-74 years, who were first screened between 2000 and 2018. To estimate overdiagnosis caused by indolent tumors, they used the risk of non–breast cancer mortality from age cohort–adjusted annual mortality risks. There were a total 82,677 screens and 718 cases of breast cancer diagnosed. 3.6% of detected tumor were indolent (95% credible interval, 0.2%-13.8%). The predicted overdiagnosis rate for a biennial screening program was 15.3% (95% prediction interval, 9.7%-25.2%). 6.0% of overdiagnosis was projected to be caused by indolent tumors (95% PI, 0.2%-19.0%) that don’t progress at all, and 9.3% to tumors that would progress, but not fast enough to cause mortality during the individual’s lifetime. An annual screening program had a predicted overdiagnosis rate of 14.6% (95% PI, 9.4%-23.9%).
Dr. Ryser identified some specific studies that used the same definition of overdiagnosis as his group used, and compared them with the 15.3% incidence that his group determined. Excess-incidence studies produced higher estimates, while modeling studies produced lower estimates.
The model did not distinguish between ductal carcinoma in situ and invasive cancers, and it did not account for patient race and breast density.
The study was funded by the National Institutes of Health. Dr. Ryser has no relevant financial disclosures.
A new model based on data from the Breast Cancer Surveillance Consortium (BCSC) suggests that overdiagnosis of screen-detected breast cancer is less frequent than estimates from excess-incidence studies, but the model also takes into account indolent tumors and produced a higher estimate than previous models that didn’t consider this factor.
“There is a pronounced lack of consensus of the true rate of overdiagnosis in the contemporary U.S. mammography practice. This uncertainty about the extent of overdiagnosis is a problem for the development of guidelines and policies. By overcoming shortcomings of previous studies, we produced a defensible estimate of overdiagnosis in contemporary U.S. mammography practice. About one in seven screen-detected cancers in women (between 50 and 74 years) undergoing biennial screening will be overdiagnosed, and about one in three overdiagnosed cancers are attributed to the detection of nonprogressive cancers,” said Marc D. Ryser, PhD, in an interview. Dr. Ryser is an expert in mathematical and statistical modeling in population health science at Duke University, Durham, N.C. He presented the results of the model at the 2021 San Antonio Breast Cancer Symposium.
Previous models have come up with estimates ranging from 0% to 54%, but the heterogeneity makes them difficult to compare. “They differ in study populations, estimation methods and their definitions of overdiagnosis,” Dr. Ryser said.
There are two general ways to estimate overdiagnosis. One is a model-based approach that works out the tumor latency using models of disease natural history and clinical data, and then uses that to predict overdiagnosis. But these models may not account or indolent tumors, or tumors that would not likely cause death during the patient’s lifetime, and the assumptions behind the models can be opaque. On the other hand, the excess-incidence strategy compares incidence in screened versus unscreened populations and assumes that excess cancers in the screened group is caused by overdiagnosis, but this can be affected by bias.
To get around these limitations, Dr. Ryser’s group used a model-based approach, but also allowed for indolent tumors. They ensured transparency of the underlying assumptions of the model, and took advantage of a contemporary, high-quality data source in the BCSC.
They used individual mammography screening and breast cancer diagnosis records from 35,986 women aged 50-74 years, who were first screened between 2000 and 2018. To estimate overdiagnosis caused by indolent tumors, they used the risk of non–breast cancer mortality from age cohort–adjusted annual mortality risks. There were a total 82,677 screens and 718 cases of breast cancer diagnosed. 3.6% of detected tumor were indolent (95% credible interval, 0.2%-13.8%). The predicted overdiagnosis rate for a biennial screening program was 15.3% (95% prediction interval, 9.7%-25.2%). 6.0% of overdiagnosis was projected to be caused by indolent tumors (95% PI, 0.2%-19.0%) that don’t progress at all, and 9.3% to tumors that would progress, but not fast enough to cause mortality during the individual’s lifetime. An annual screening program had a predicted overdiagnosis rate of 14.6% (95% PI, 9.4%-23.9%).
Dr. Ryser identified some specific studies that used the same definition of overdiagnosis as his group used, and compared them with the 15.3% incidence that his group determined. Excess-incidence studies produced higher estimates, while modeling studies produced lower estimates.
The model did not distinguish between ductal carcinoma in situ and invasive cancers, and it did not account for patient race and breast density.
The study was funded by the National Institutes of Health. Dr. Ryser has no relevant financial disclosures.
A new model based on data from the Breast Cancer Surveillance Consortium (BCSC) suggests that overdiagnosis of screen-detected breast cancer is less frequent than estimates from excess-incidence studies, but the model also takes into account indolent tumors and produced a higher estimate than previous models that didn’t consider this factor.
“There is a pronounced lack of consensus of the true rate of overdiagnosis in the contemporary U.S. mammography practice. This uncertainty about the extent of overdiagnosis is a problem for the development of guidelines and policies. By overcoming shortcomings of previous studies, we produced a defensible estimate of overdiagnosis in contemporary U.S. mammography practice. About one in seven screen-detected cancers in women (between 50 and 74 years) undergoing biennial screening will be overdiagnosed, and about one in three overdiagnosed cancers are attributed to the detection of nonprogressive cancers,” said Marc D. Ryser, PhD, in an interview. Dr. Ryser is an expert in mathematical and statistical modeling in population health science at Duke University, Durham, N.C. He presented the results of the model at the 2021 San Antonio Breast Cancer Symposium.
Previous models have come up with estimates ranging from 0% to 54%, but the heterogeneity makes them difficult to compare. “They differ in study populations, estimation methods and their definitions of overdiagnosis,” Dr. Ryser said.
There are two general ways to estimate overdiagnosis. One is a model-based approach that works out the tumor latency using models of disease natural history and clinical data, and then uses that to predict overdiagnosis. But these models may not account or indolent tumors, or tumors that would not likely cause death during the patient’s lifetime, and the assumptions behind the models can be opaque. On the other hand, the excess-incidence strategy compares incidence in screened versus unscreened populations and assumes that excess cancers in the screened group is caused by overdiagnosis, but this can be affected by bias.
To get around these limitations, Dr. Ryser’s group used a model-based approach, but also allowed for indolent tumors. They ensured transparency of the underlying assumptions of the model, and took advantage of a contemporary, high-quality data source in the BCSC.
They used individual mammography screening and breast cancer diagnosis records from 35,986 women aged 50-74 years, who were first screened between 2000 and 2018. To estimate overdiagnosis caused by indolent tumors, they used the risk of non–breast cancer mortality from age cohort–adjusted annual mortality risks. There were a total 82,677 screens and 718 cases of breast cancer diagnosed. 3.6% of detected tumor were indolent (95% credible interval, 0.2%-13.8%). The predicted overdiagnosis rate for a biennial screening program was 15.3% (95% prediction interval, 9.7%-25.2%). 6.0% of overdiagnosis was projected to be caused by indolent tumors (95% PI, 0.2%-19.0%) that don’t progress at all, and 9.3% to tumors that would progress, but not fast enough to cause mortality during the individual’s lifetime. An annual screening program had a predicted overdiagnosis rate of 14.6% (95% PI, 9.4%-23.9%).
Dr. Ryser identified some specific studies that used the same definition of overdiagnosis as his group used, and compared them with the 15.3% incidence that his group determined. Excess-incidence studies produced higher estimates, while modeling studies produced lower estimates.
The model did not distinguish between ductal carcinoma in situ and invasive cancers, and it did not account for patient race and breast density.
The study was funded by the National Institutes of Health. Dr. Ryser has no relevant financial disclosures.
FROM SABCS 2021
Vitamin D counters bone density loss with aromatase inhibitors
Among women with breast cancer being treated with aromatase inhibitors (AI), supplementation with vitamin D and calcium protected against bone loss after 5 years, according to results from a prospective cohort study in Brazil. The study found no difference in bone mineral density outcomes at 5 years between women with hormone receptor–positive cancers treated with aromatase inhibitors (AIG) and triple negative or HER-2 positive patients who were treated with another therapy (CG).
About two-thirds of women with breast cancer have tumors that are positive for hormone receptors, and so are often treated with endocrine therapy such as selective estrogen receptor modulators or AI. However, there are concerns that AI treatment may lead to a loss of bone mineral density and impacts on quality of life. This loss is influenced by a range of factors, including body weight, physical activity, smoking, alcohol consumption, corticosteroid use, calcium in the diet, and circulating levels of vitamin D.
Vitamin D helps to regulate absorption of calcium and phosphorus, ensuring that their plasma concentrations are high enough for adequate bone health. But vitamin D deficiency is a common problem, even in tropical areas such as Brazil. “It is high in the general population and especially in postmenopausal breast cancer patients. Thus, vitamin D and calcium supplementation has an impact on these women’s lives,” said lead author Marcelo Antonini, MD, who presented the study (abstract P1-13-04) at the San Antonio Breast Cancer Symposium. He is a researcher at Hospital Servidor Publico Estadual in São Paulo, Brazil.
Although the findings are encouraging, more work needs to be done before it leads to a change in practice. “Larger studies must be carried out to prove this theory; however, in noncancer patients we have already well established the benefits of vitamin D and calcium supplementation,” Dr. Antonini said in an interview
The researchers examined women before the start of treatment, at 6 months, and at 5 years. Those with vitamin D levels below 30 ng/mL received 7,000 IU/day for 8 weeks, followed by a 1,000 IU/day maintenance dose. Subjects with osteopenia received a calcium supplement (500 mg calcium carbonate), and those with osteoporosis received 4 mg zoledronic acid (Zometa, Novartis).
There were 140 patients in both the AIG and CG groups. The average age was 65 years. Sixty-four percent of the AIG group and 71% of the CG group were vitamin D deficient at baseline. At 5 years, the frequencies were 17% and 16%, respectively. Both groups showed significant declines in bone mineral density in the femoral neck and femur at both 6 months and 5 years, but there was no significant difference between them. There was no significant difference between the two groups with respect to bone density loss in the spine.
The study is limited by the fact that it was conducted at a single center and had a small population size.
Another prospective observational study, published earlier this year, looked at vitamin D supplementation in 741 patients (mean age 61.9 years) being treated with aromatase inhibitors, whose baseline vitamin D levels were less 30 ng/mL. They received 16,000 IU dose of oral calcifediol every 2 weeks. At 3 months, individuals who achieved vitamin D levels of 40 ng/mL or higher were less likely to have joint pain (P < .05). At 12 months, data from 473 patients showed that for every 10-ng/mL increase in serum vitamin D at 3 months, there was a reduction in loss of bone marrow density in the lumbar spine (adjusted beta = +0.177%, P < .05), though there were no associations between vitamin D levels and BMD of the femur or total hip.
“Our results suggest that optimal levels of vitamin D are associated with a reduced risk of joint pain related to AI treatment. A target threshold (of vitamin D) levels was set at 40 ng/mL to significantly reduce the increase in joint pain. The authors noted that this threshold is well above the goal of 20 ng/mL recommended by the 2010 Institute of Medicine report.
The study did not receive external funding. Dr. Antonini has no relevant financial disclosures.
Among women with breast cancer being treated with aromatase inhibitors (AI), supplementation with vitamin D and calcium protected against bone loss after 5 years, according to results from a prospective cohort study in Brazil. The study found no difference in bone mineral density outcomes at 5 years between women with hormone receptor–positive cancers treated with aromatase inhibitors (AIG) and triple negative or HER-2 positive patients who were treated with another therapy (CG).
About two-thirds of women with breast cancer have tumors that are positive for hormone receptors, and so are often treated with endocrine therapy such as selective estrogen receptor modulators or AI. However, there are concerns that AI treatment may lead to a loss of bone mineral density and impacts on quality of life. This loss is influenced by a range of factors, including body weight, physical activity, smoking, alcohol consumption, corticosteroid use, calcium in the diet, and circulating levels of vitamin D.
Vitamin D helps to regulate absorption of calcium and phosphorus, ensuring that their plasma concentrations are high enough for adequate bone health. But vitamin D deficiency is a common problem, even in tropical areas such as Brazil. “It is high in the general population and especially in postmenopausal breast cancer patients. Thus, vitamin D and calcium supplementation has an impact on these women’s lives,” said lead author Marcelo Antonini, MD, who presented the study (abstract P1-13-04) at the San Antonio Breast Cancer Symposium. He is a researcher at Hospital Servidor Publico Estadual in São Paulo, Brazil.
Although the findings are encouraging, more work needs to be done before it leads to a change in practice. “Larger studies must be carried out to prove this theory; however, in noncancer patients we have already well established the benefits of vitamin D and calcium supplementation,” Dr. Antonini said in an interview
The researchers examined women before the start of treatment, at 6 months, and at 5 years. Those with vitamin D levels below 30 ng/mL received 7,000 IU/day for 8 weeks, followed by a 1,000 IU/day maintenance dose. Subjects with osteopenia received a calcium supplement (500 mg calcium carbonate), and those with osteoporosis received 4 mg zoledronic acid (Zometa, Novartis).
There were 140 patients in both the AIG and CG groups. The average age was 65 years. Sixty-four percent of the AIG group and 71% of the CG group were vitamin D deficient at baseline. At 5 years, the frequencies were 17% and 16%, respectively. Both groups showed significant declines in bone mineral density in the femoral neck and femur at both 6 months and 5 years, but there was no significant difference between them. There was no significant difference between the two groups with respect to bone density loss in the spine.
The study is limited by the fact that it was conducted at a single center and had a small population size.
Another prospective observational study, published earlier this year, looked at vitamin D supplementation in 741 patients (mean age 61.9 years) being treated with aromatase inhibitors, whose baseline vitamin D levels were less 30 ng/mL. They received 16,000 IU dose of oral calcifediol every 2 weeks. At 3 months, individuals who achieved vitamin D levels of 40 ng/mL or higher were less likely to have joint pain (P < .05). At 12 months, data from 473 patients showed that for every 10-ng/mL increase in serum vitamin D at 3 months, there was a reduction in loss of bone marrow density in the lumbar spine (adjusted beta = +0.177%, P < .05), though there were no associations between vitamin D levels and BMD of the femur or total hip.
“Our results suggest that optimal levels of vitamin D are associated with a reduced risk of joint pain related to AI treatment. A target threshold (of vitamin D) levels was set at 40 ng/mL to significantly reduce the increase in joint pain. The authors noted that this threshold is well above the goal of 20 ng/mL recommended by the 2010 Institute of Medicine report.
The study did not receive external funding. Dr. Antonini has no relevant financial disclosures.
Among women with breast cancer being treated with aromatase inhibitors (AI), supplementation with vitamin D and calcium protected against bone loss after 5 years, according to results from a prospective cohort study in Brazil. The study found no difference in bone mineral density outcomes at 5 years between women with hormone receptor–positive cancers treated with aromatase inhibitors (AIG) and triple negative or HER-2 positive patients who were treated with another therapy (CG).
About two-thirds of women with breast cancer have tumors that are positive for hormone receptors, and so are often treated with endocrine therapy such as selective estrogen receptor modulators or AI. However, there are concerns that AI treatment may lead to a loss of bone mineral density and impacts on quality of life. This loss is influenced by a range of factors, including body weight, physical activity, smoking, alcohol consumption, corticosteroid use, calcium in the diet, and circulating levels of vitamin D.
Vitamin D helps to regulate absorption of calcium and phosphorus, ensuring that their plasma concentrations are high enough for adequate bone health. But vitamin D deficiency is a common problem, even in tropical areas such as Brazil. “It is high in the general population and especially in postmenopausal breast cancer patients. Thus, vitamin D and calcium supplementation has an impact on these women’s lives,” said lead author Marcelo Antonini, MD, who presented the study (abstract P1-13-04) at the San Antonio Breast Cancer Symposium. He is a researcher at Hospital Servidor Publico Estadual in São Paulo, Brazil.
Although the findings are encouraging, more work needs to be done before it leads to a change in practice. “Larger studies must be carried out to prove this theory; however, in noncancer patients we have already well established the benefits of vitamin D and calcium supplementation,” Dr. Antonini said in an interview
The researchers examined women before the start of treatment, at 6 months, and at 5 years. Those with vitamin D levels below 30 ng/mL received 7,000 IU/day for 8 weeks, followed by a 1,000 IU/day maintenance dose. Subjects with osteopenia received a calcium supplement (500 mg calcium carbonate), and those with osteoporosis received 4 mg zoledronic acid (Zometa, Novartis).
There were 140 patients in both the AIG and CG groups. The average age was 65 years. Sixty-four percent of the AIG group and 71% of the CG group were vitamin D deficient at baseline. At 5 years, the frequencies were 17% and 16%, respectively. Both groups showed significant declines in bone mineral density in the femoral neck and femur at both 6 months and 5 years, but there was no significant difference between them. There was no significant difference between the two groups with respect to bone density loss in the spine.
The study is limited by the fact that it was conducted at a single center and had a small population size.
Another prospective observational study, published earlier this year, looked at vitamin D supplementation in 741 patients (mean age 61.9 years) being treated with aromatase inhibitors, whose baseline vitamin D levels were less 30 ng/mL. They received 16,000 IU dose of oral calcifediol every 2 weeks. At 3 months, individuals who achieved vitamin D levels of 40 ng/mL or higher were less likely to have joint pain (P < .05). At 12 months, data from 473 patients showed that for every 10-ng/mL increase in serum vitamin D at 3 months, there was a reduction in loss of bone marrow density in the lumbar spine (adjusted beta = +0.177%, P < .05), though there were no associations between vitamin D levels and BMD of the femur or total hip.
“Our results suggest that optimal levels of vitamin D are associated with a reduced risk of joint pain related to AI treatment. A target threshold (of vitamin D) levels was set at 40 ng/mL to significantly reduce the increase in joint pain. The authors noted that this threshold is well above the goal of 20 ng/mL recommended by the 2010 Institute of Medicine report.
The study did not receive external funding. Dr. Antonini has no relevant financial disclosures.
FROM SABCS 2021
Metformin does not improve outcomes in early breast cancer
In the primary analysis, the addition of metformin to standard therapy in moderate/high-risk hormone receptor positive or negative breast cancer did not improve invasive disease–free survival (IDFS), overall survival, or other breast outcomes, explained lead author Pamela J. Goodwin, MD, FRCPC, professor of medicine at the University of Toronto. “Metformin should not be used as breast cancer treatment in this population.”
However, an exploratory analysis suggested that metformin may have a beneficial effect in women with HER2-positive breast cancer, Dr. Goodwin noted.
In this subset, IDFS was improved in patients who received metformin (hazard ratio, 0.64; P = .03), as was overall survival (HR, 0.53; P = .04).
The findings were presented at the San Antonio Breast Cancer Symposium.
“This trial arose from the observation that obesity is associated with poor breast cancer outcomes, and insulin levels are higher in obesity and may be more strongly associated with breast cancer outcomes than obesity,” said Dr. Goodwin.
Metformin was used because of its ability to promote modest weight loss and lower insulin by about 15%-20% in nondiabetic breast cancer survivors. It has also shown anticancer effects in preclinical studies. “In some window of opportunity neoadjuvant studies, it has been shown to reduce Ki67 in breast cancer cells,” she said. “And in preclinical in vitro and in vivo research, it slows growth of breast cancer.”
In addition, emerging evidence from observational studies suggests that the use of metformin to treat diabetes in breast cancer patients may be associated with better outcomes, strengthening the rationale for the study.
The negative results in breast cancer follow recent reports of negative findings in lung cancer, when metformin was found to be ineffective when used alongside chemotherapy in locally advanced lung cancer, as reported by this news organization.
No benefit seen
Metformin was compared to placebo in the phase 3 CCTG MA.32 trial, conducted in 3,649 patients aged 18-74 years with T1-3 N0-3 M0 breast cancer. All patients were treated with standard therapy and were randomized to receive metformin 850 mg twice daily for 5 years or placebo.
In 2016, “futility was declared in ER/PR-negative patients” after a second interim analysis conducted at 29.6 months’ median follow-up, Dr. Goodwin noted. The intervention was stopped in that group, although blinding and follow-up continued.
After that, the study’s primary analysis focused on the 2,533 ER/PR-positive patients (mean age, 52.7 years; mean body mass index, 28.8; approx. 60% postmenopausal).
Just over half of these patients had T2 tumor stage, and most disease was grade 2 or 3.
In addition, 16.5% (of metformin) and 17.4% (of placebo) patients had HER2-positive disease, with the majority (97%) of all HER2 patients receiving trastuzumab.
There was no difference between the two groups in IDFS events, occurring in 18.5% of patients receiving metformin and 18.3% who received placebo, with most (75.6%) events due to breast cancer (HR, 1.01; P = .92).
There were 131 deaths in the metformin arm and 119 in the placebo arm, with most (75.8%) of the deaths related to breast cancer (HR, 1.10; P = .47).
Other breast cancer outcomes had similar results, including distant disease-free survival (HR, 0.99; P = .94) and breast cancer–free interval (HR, 0.98; P = .87), both of which showed no advantage for metformin.
Possible HER2 advantage
However, the exploratory analysis suggested there may be an advantage for patients with HER2-positive disease, but primarily those who had at least one C allele of a prespecified ATM associated rs11212617 SNP. These patients achieved a higher pathologic complete response rate with metformin than that of those without the allele.
There were 620 patients with HER2-positive disease analyzed, with 99.4% receiving chemotherapy and 96.5% receiving trastuzumab. There were 99 IDFS events, and 47 OS events.
In the entire HER2-positive cohort, patients who received metformin had fewer IDFS events (HR, 0.64; P = .026) compared with the placebo arm. Mortality was lower with metformin (HR for overall survival, 0.53; P = .038).
“Subjects with HER2-positive breast cancer, notably those with at least one C allele of the ATM-associated rs11212617 SNP, experienced improved IDFS and overall survival with metformin,” Dr. Goodwin concluded. “However, no P-value ‘spend’ was allocated to this comparison. As a result, it requires replication in a prospective trial focusing on the HER2-positive population.”
More research?
Stephanie Bernik, MD, chief of breast surgery, Mount Sinai West, and associate professor of breast surgery, Icahn School of Medicine at Mount Sinai, New York, was approached by this news organization for an independent comment.
“It has long been known that obesity, which often correlates with diabetes, increases a woman’s risk of breast cancer,” she said.
“This study tried to show that using a medication that helps control insulin levels, even in those without diabetes, might decrease one’s risk of breast cancer,” she said. “Unfortunately, using metformin had no effect on outcomes in this study, even though it has shown promise in other studies. Perhaps more research needs to be carried out to try to pinpoint which mechanisms of action, if any, might be helpful to combat cancer in those with and without diabetes.”
The study was funded by the Canadian Cancer Trials Group, Cancer Therapy Evaluation Program, Breast Cancer Researcher Foundation, Susan G. Komen for the Cure, Canadian Cancer Society, Apotex, Swiss Cancer Research, and the Canadian Breast Cancer Foundation. Dr. Goodwin has no disclosures.
A version of this article first appeared on Medscape.com.
In the primary analysis, the addition of metformin to standard therapy in moderate/high-risk hormone receptor positive or negative breast cancer did not improve invasive disease–free survival (IDFS), overall survival, or other breast outcomes, explained lead author Pamela J. Goodwin, MD, FRCPC, professor of medicine at the University of Toronto. “Metformin should not be used as breast cancer treatment in this population.”
However, an exploratory analysis suggested that metformin may have a beneficial effect in women with HER2-positive breast cancer, Dr. Goodwin noted.
In this subset, IDFS was improved in patients who received metformin (hazard ratio, 0.64; P = .03), as was overall survival (HR, 0.53; P = .04).
The findings were presented at the San Antonio Breast Cancer Symposium.
“This trial arose from the observation that obesity is associated with poor breast cancer outcomes, and insulin levels are higher in obesity and may be more strongly associated with breast cancer outcomes than obesity,” said Dr. Goodwin.
Metformin was used because of its ability to promote modest weight loss and lower insulin by about 15%-20% in nondiabetic breast cancer survivors. It has also shown anticancer effects in preclinical studies. “In some window of opportunity neoadjuvant studies, it has been shown to reduce Ki67 in breast cancer cells,” she said. “And in preclinical in vitro and in vivo research, it slows growth of breast cancer.”
In addition, emerging evidence from observational studies suggests that the use of metformin to treat diabetes in breast cancer patients may be associated with better outcomes, strengthening the rationale for the study.
The negative results in breast cancer follow recent reports of negative findings in lung cancer, when metformin was found to be ineffective when used alongside chemotherapy in locally advanced lung cancer, as reported by this news organization.
No benefit seen
Metformin was compared to placebo in the phase 3 CCTG MA.32 trial, conducted in 3,649 patients aged 18-74 years with T1-3 N0-3 M0 breast cancer. All patients were treated with standard therapy and were randomized to receive metformin 850 mg twice daily for 5 years or placebo.
In 2016, “futility was declared in ER/PR-negative patients” after a second interim analysis conducted at 29.6 months’ median follow-up, Dr. Goodwin noted. The intervention was stopped in that group, although blinding and follow-up continued.
After that, the study’s primary analysis focused on the 2,533 ER/PR-positive patients (mean age, 52.7 years; mean body mass index, 28.8; approx. 60% postmenopausal).
Just over half of these patients had T2 tumor stage, and most disease was grade 2 or 3.
In addition, 16.5% (of metformin) and 17.4% (of placebo) patients had HER2-positive disease, with the majority (97%) of all HER2 patients receiving trastuzumab.
There was no difference between the two groups in IDFS events, occurring in 18.5% of patients receiving metformin and 18.3% who received placebo, with most (75.6%) events due to breast cancer (HR, 1.01; P = .92).
There were 131 deaths in the metformin arm and 119 in the placebo arm, with most (75.8%) of the deaths related to breast cancer (HR, 1.10; P = .47).
Other breast cancer outcomes had similar results, including distant disease-free survival (HR, 0.99; P = .94) and breast cancer–free interval (HR, 0.98; P = .87), both of which showed no advantage for metformin.
Possible HER2 advantage
However, the exploratory analysis suggested there may be an advantage for patients with HER2-positive disease, but primarily those who had at least one C allele of a prespecified ATM associated rs11212617 SNP. These patients achieved a higher pathologic complete response rate with metformin than that of those without the allele.
There were 620 patients with HER2-positive disease analyzed, with 99.4% receiving chemotherapy and 96.5% receiving trastuzumab. There were 99 IDFS events, and 47 OS events.
In the entire HER2-positive cohort, patients who received metformin had fewer IDFS events (HR, 0.64; P = .026) compared with the placebo arm. Mortality was lower with metformin (HR for overall survival, 0.53; P = .038).
“Subjects with HER2-positive breast cancer, notably those with at least one C allele of the ATM-associated rs11212617 SNP, experienced improved IDFS and overall survival with metformin,” Dr. Goodwin concluded. “However, no P-value ‘spend’ was allocated to this comparison. As a result, it requires replication in a prospective trial focusing on the HER2-positive population.”
More research?
Stephanie Bernik, MD, chief of breast surgery, Mount Sinai West, and associate professor of breast surgery, Icahn School of Medicine at Mount Sinai, New York, was approached by this news organization for an independent comment.
“It has long been known that obesity, which often correlates with diabetes, increases a woman’s risk of breast cancer,” she said.
“This study tried to show that using a medication that helps control insulin levels, even in those without diabetes, might decrease one’s risk of breast cancer,” she said. “Unfortunately, using metformin had no effect on outcomes in this study, even though it has shown promise in other studies. Perhaps more research needs to be carried out to try to pinpoint which mechanisms of action, if any, might be helpful to combat cancer in those with and without diabetes.”
The study was funded by the Canadian Cancer Trials Group, Cancer Therapy Evaluation Program, Breast Cancer Researcher Foundation, Susan G. Komen for the Cure, Canadian Cancer Society, Apotex, Swiss Cancer Research, and the Canadian Breast Cancer Foundation. Dr. Goodwin has no disclosures.
A version of this article first appeared on Medscape.com.
In the primary analysis, the addition of metformin to standard therapy in moderate/high-risk hormone receptor positive or negative breast cancer did not improve invasive disease–free survival (IDFS), overall survival, or other breast outcomes, explained lead author Pamela J. Goodwin, MD, FRCPC, professor of medicine at the University of Toronto. “Metformin should not be used as breast cancer treatment in this population.”
However, an exploratory analysis suggested that metformin may have a beneficial effect in women with HER2-positive breast cancer, Dr. Goodwin noted.
In this subset, IDFS was improved in patients who received metformin (hazard ratio, 0.64; P = .03), as was overall survival (HR, 0.53; P = .04).
The findings were presented at the San Antonio Breast Cancer Symposium.
“This trial arose from the observation that obesity is associated with poor breast cancer outcomes, and insulin levels are higher in obesity and may be more strongly associated with breast cancer outcomes than obesity,” said Dr. Goodwin.
Metformin was used because of its ability to promote modest weight loss and lower insulin by about 15%-20% in nondiabetic breast cancer survivors. It has also shown anticancer effects in preclinical studies. “In some window of opportunity neoadjuvant studies, it has been shown to reduce Ki67 in breast cancer cells,” she said. “And in preclinical in vitro and in vivo research, it slows growth of breast cancer.”
In addition, emerging evidence from observational studies suggests that the use of metformin to treat diabetes in breast cancer patients may be associated with better outcomes, strengthening the rationale for the study.
The negative results in breast cancer follow recent reports of negative findings in lung cancer, when metformin was found to be ineffective when used alongside chemotherapy in locally advanced lung cancer, as reported by this news organization.
No benefit seen
Metformin was compared to placebo in the phase 3 CCTG MA.32 trial, conducted in 3,649 patients aged 18-74 years with T1-3 N0-3 M0 breast cancer. All patients were treated with standard therapy and were randomized to receive metformin 850 mg twice daily for 5 years or placebo.
In 2016, “futility was declared in ER/PR-negative patients” after a second interim analysis conducted at 29.6 months’ median follow-up, Dr. Goodwin noted. The intervention was stopped in that group, although blinding and follow-up continued.
After that, the study’s primary analysis focused on the 2,533 ER/PR-positive patients (mean age, 52.7 years; mean body mass index, 28.8; approx. 60% postmenopausal).
Just over half of these patients had T2 tumor stage, and most disease was grade 2 or 3.
In addition, 16.5% (of metformin) and 17.4% (of placebo) patients had HER2-positive disease, with the majority (97%) of all HER2 patients receiving trastuzumab.
There was no difference between the two groups in IDFS events, occurring in 18.5% of patients receiving metformin and 18.3% who received placebo, with most (75.6%) events due to breast cancer (HR, 1.01; P = .92).
There were 131 deaths in the metformin arm and 119 in the placebo arm, with most (75.8%) of the deaths related to breast cancer (HR, 1.10; P = .47).
Other breast cancer outcomes had similar results, including distant disease-free survival (HR, 0.99; P = .94) and breast cancer–free interval (HR, 0.98; P = .87), both of which showed no advantage for metformin.
Possible HER2 advantage
However, the exploratory analysis suggested there may be an advantage for patients with HER2-positive disease, but primarily those who had at least one C allele of a prespecified ATM associated rs11212617 SNP. These patients achieved a higher pathologic complete response rate with metformin than that of those without the allele.
There were 620 patients with HER2-positive disease analyzed, with 99.4% receiving chemotherapy and 96.5% receiving trastuzumab. There were 99 IDFS events, and 47 OS events.
In the entire HER2-positive cohort, patients who received metformin had fewer IDFS events (HR, 0.64; P = .026) compared with the placebo arm. Mortality was lower with metformin (HR for overall survival, 0.53; P = .038).
“Subjects with HER2-positive breast cancer, notably those with at least one C allele of the ATM-associated rs11212617 SNP, experienced improved IDFS and overall survival with metformin,” Dr. Goodwin concluded. “However, no P-value ‘spend’ was allocated to this comparison. As a result, it requires replication in a prospective trial focusing on the HER2-positive population.”
More research?
Stephanie Bernik, MD, chief of breast surgery, Mount Sinai West, and associate professor of breast surgery, Icahn School of Medicine at Mount Sinai, New York, was approached by this news organization for an independent comment.
“It has long been known that obesity, which often correlates with diabetes, increases a woman’s risk of breast cancer,” she said.
“This study tried to show that using a medication that helps control insulin levels, even in those without diabetes, might decrease one’s risk of breast cancer,” she said. “Unfortunately, using metformin had no effect on outcomes in this study, even though it has shown promise in other studies. Perhaps more research needs to be carried out to try to pinpoint which mechanisms of action, if any, might be helpful to combat cancer in those with and without diabetes.”
The study was funded by the Canadian Cancer Trials Group, Cancer Therapy Evaluation Program, Breast Cancer Researcher Foundation, Susan G. Komen for the Cure, Canadian Cancer Society, Apotex, Swiss Cancer Research, and the Canadian Breast Cancer Foundation. Dr. Goodwin has no disclosures.
A version of this article first appeared on Medscape.com.
FROM SABCS 2021
Genomic profiling can improve PFS in metastatic breast cancer
“The message is very simple,” lead study author Fabrice Andre, MD, PhD, research director, Gustave Roussy Cancer Campus, Villejuif, France, told this news organization during a virtual press briefing. “If a genomic alteration is validated, it is useful to give targeted therapy, but if the genomic alteration is not validated, we should not give a targeted therapy.”
The study, which pooled results from phase 2 randomized trials SAFIR02-BREAST and SAFIR-P13K, was presented Dec. 7 in a virtual press briefing at the San Antonio Breast Cancer Symposium (SABCS) 2021.
The new analysis explored two key questions: Is genomic testing of a cancer effective? And how should oncologists interpret a genomic report?
A total of 1,462 patients with metastatic HER2-negative breast cancer underwent next-generation sequencing. After receiving six to eight cycles of chemotherapy, 238 patients (16%) were randomized to one of nine targeted therapies matched to the genomic alteration identified on testing or to maintenance chemotherapy.
Genomic alterations in the patients’ tumors were classified using the ESMO Scale of Actionability of Molecular Targets (ESCAT). A tier I ranking indicates that the alteration-drug match is associated with improved outcomes in clinical trials, while a tier II ranking means that the alteration-drug match is associated with antitumor activity but the magnitude of benefit remains unknown.
In an analysis of the overall trial population, Dr. Andre and colleagues found an improvement in progression-free survival in the targeted therapy group (median of 5.5 months) in comparison with the maintenance chemotherapy group (2.9 months), but the difference was not significant (P = .109).
In a subgroup of 115 patients presenting with I- or II-tier genomic alterations, median progression-free survival was 59% longer, at 9.1 months, among patients receiving targeted therapy, compared with 2.8 months in the maintenance chemotherapy group (hazard ratio, 0.41; P < .001).
In addition, the team carried out single-nucleotide polymorphism (SNP) array analyses on 926 patients. They identified 21 genes that were altered more frequently in the metastases compared with the primary tumors, and they observed that a high homologous recombination deficiency score in patients with BCRA 1 or 2 mutations was associated with a longer progression-free survival in patients treated with olaparib.
“We also identified a subset of patients who are resistant to CDK4/6 inhibitors who presented with CDK4 amplification, and this amplification is associated with overexpression,” Dr. Andre explained.
When asked whether most oncologists were using genomic profiling to tailor treatment for breast cancer patients, Dr. Andre said that multigene sequencing is now widely used.
“The issue is not so much whether we should use or not use genomics; the issue here is to force everyone to put the genomic alteration in the right context in terms of its level of evidence,” Dr. Andre told this news organization.
Oncologists may overinterpret the genomic activation identified and give a targeted therapy that is not validated, but “oncologists should not use genomic information when the target has not been previously validated in a therapeutic trial,” he added.
Virginia Kaklamani, MD, professor of medicine at the University of Texas Health Sciences Center in San Antonio, said in an interview that approximately 5 years ago, Dr. Andre was part of the first debate at the SABCS discussing whether oncologists should be conducting next-generation sequencing for their patients with breast cancer.
“At the time, [Dr.] Andre’s comment was that we should not be doing it,” recalled Dr. Kaklamani, who is also leader of the breast cancer program at the Mays Cancer Center at the University of Texas Health San Antonio MD Anderson. “At that point, I think it was clear that we did not have the data we needed to be able to use next-generation sequencing to change our clinical management.”
However, the evidence has evolved. “Based on this clinical trial, I think we now do have the data,” she said. “I think that [next-generation sequencing] is something we will be using more and more in practice and treating our patients based on [validated] genomic alterations.”
Dr. Andre has received grants or advisory board/speaker honoraria from Daiichi Sankyo, Roche, Pfizer, AstraZeneca, Lily, and Novartis. Dr. Kaklamani has served as a consultant for Puma, AstraZeneca, Athenex, and Immunomedics, has received research funding from Eisai, and has served as a speaker for Pfizer, Celgene, Genentech, and Genomic Health, among other companies.
A version of this article first appeared on Medscape.com.
“The message is very simple,” lead study author Fabrice Andre, MD, PhD, research director, Gustave Roussy Cancer Campus, Villejuif, France, told this news organization during a virtual press briefing. “If a genomic alteration is validated, it is useful to give targeted therapy, but if the genomic alteration is not validated, we should not give a targeted therapy.”
The study, which pooled results from phase 2 randomized trials SAFIR02-BREAST and SAFIR-P13K, was presented Dec. 7 in a virtual press briefing at the San Antonio Breast Cancer Symposium (SABCS) 2021.
The new analysis explored two key questions: Is genomic testing of a cancer effective? And how should oncologists interpret a genomic report?
A total of 1,462 patients with metastatic HER2-negative breast cancer underwent next-generation sequencing. After receiving six to eight cycles of chemotherapy, 238 patients (16%) were randomized to one of nine targeted therapies matched to the genomic alteration identified on testing or to maintenance chemotherapy.
Genomic alterations in the patients’ tumors were classified using the ESMO Scale of Actionability of Molecular Targets (ESCAT). A tier I ranking indicates that the alteration-drug match is associated with improved outcomes in clinical trials, while a tier II ranking means that the alteration-drug match is associated with antitumor activity but the magnitude of benefit remains unknown.
In an analysis of the overall trial population, Dr. Andre and colleagues found an improvement in progression-free survival in the targeted therapy group (median of 5.5 months) in comparison with the maintenance chemotherapy group (2.9 months), but the difference was not significant (P = .109).
In a subgroup of 115 patients presenting with I- or II-tier genomic alterations, median progression-free survival was 59% longer, at 9.1 months, among patients receiving targeted therapy, compared with 2.8 months in the maintenance chemotherapy group (hazard ratio, 0.41; P < .001).
In addition, the team carried out single-nucleotide polymorphism (SNP) array analyses on 926 patients. They identified 21 genes that were altered more frequently in the metastases compared with the primary tumors, and they observed that a high homologous recombination deficiency score in patients with BCRA 1 or 2 mutations was associated with a longer progression-free survival in patients treated with olaparib.
“We also identified a subset of patients who are resistant to CDK4/6 inhibitors who presented with CDK4 amplification, and this amplification is associated with overexpression,” Dr. Andre explained.
When asked whether most oncologists were using genomic profiling to tailor treatment for breast cancer patients, Dr. Andre said that multigene sequencing is now widely used.
“The issue is not so much whether we should use or not use genomics; the issue here is to force everyone to put the genomic alteration in the right context in terms of its level of evidence,” Dr. Andre told this news organization.
Oncologists may overinterpret the genomic activation identified and give a targeted therapy that is not validated, but “oncologists should not use genomic information when the target has not been previously validated in a therapeutic trial,” he added.
Virginia Kaklamani, MD, professor of medicine at the University of Texas Health Sciences Center in San Antonio, said in an interview that approximately 5 years ago, Dr. Andre was part of the first debate at the SABCS discussing whether oncologists should be conducting next-generation sequencing for their patients with breast cancer.
“At the time, [Dr.] Andre’s comment was that we should not be doing it,” recalled Dr. Kaklamani, who is also leader of the breast cancer program at the Mays Cancer Center at the University of Texas Health San Antonio MD Anderson. “At that point, I think it was clear that we did not have the data we needed to be able to use next-generation sequencing to change our clinical management.”
However, the evidence has evolved. “Based on this clinical trial, I think we now do have the data,” she said. “I think that [next-generation sequencing] is something we will be using more and more in practice and treating our patients based on [validated] genomic alterations.”
Dr. Andre has received grants or advisory board/speaker honoraria from Daiichi Sankyo, Roche, Pfizer, AstraZeneca, Lily, and Novartis. Dr. Kaklamani has served as a consultant for Puma, AstraZeneca, Athenex, and Immunomedics, has received research funding from Eisai, and has served as a speaker for Pfizer, Celgene, Genentech, and Genomic Health, among other companies.
A version of this article first appeared on Medscape.com.
“The message is very simple,” lead study author Fabrice Andre, MD, PhD, research director, Gustave Roussy Cancer Campus, Villejuif, France, told this news organization during a virtual press briefing. “If a genomic alteration is validated, it is useful to give targeted therapy, but if the genomic alteration is not validated, we should not give a targeted therapy.”
The study, which pooled results from phase 2 randomized trials SAFIR02-BREAST and SAFIR-P13K, was presented Dec. 7 in a virtual press briefing at the San Antonio Breast Cancer Symposium (SABCS) 2021.
The new analysis explored two key questions: Is genomic testing of a cancer effective? And how should oncologists interpret a genomic report?
A total of 1,462 patients with metastatic HER2-negative breast cancer underwent next-generation sequencing. After receiving six to eight cycles of chemotherapy, 238 patients (16%) were randomized to one of nine targeted therapies matched to the genomic alteration identified on testing or to maintenance chemotherapy.
Genomic alterations in the patients’ tumors were classified using the ESMO Scale of Actionability of Molecular Targets (ESCAT). A tier I ranking indicates that the alteration-drug match is associated with improved outcomes in clinical trials, while a tier II ranking means that the alteration-drug match is associated with antitumor activity but the magnitude of benefit remains unknown.
In an analysis of the overall trial population, Dr. Andre and colleagues found an improvement in progression-free survival in the targeted therapy group (median of 5.5 months) in comparison with the maintenance chemotherapy group (2.9 months), but the difference was not significant (P = .109).
In a subgroup of 115 patients presenting with I- or II-tier genomic alterations, median progression-free survival was 59% longer, at 9.1 months, among patients receiving targeted therapy, compared with 2.8 months in the maintenance chemotherapy group (hazard ratio, 0.41; P < .001).
In addition, the team carried out single-nucleotide polymorphism (SNP) array analyses on 926 patients. They identified 21 genes that were altered more frequently in the metastases compared with the primary tumors, and they observed that a high homologous recombination deficiency score in patients with BCRA 1 or 2 mutations was associated with a longer progression-free survival in patients treated with olaparib.
“We also identified a subset of patients who are resistant to CDK4/6 inhibitors who presented with CDK4 amplification, and this amplification is associated with overexpression,” Dr. Andre explained.
When asked whether most oncologists were using genomic profiling to tailor treatment for breast cancer patients, Dr. Andre said that multigene sequencing is now widely used.
“The issue is not so much whether we should use or not use genomics; the issue here is to force everyone to put the genomic alteration in the right context in terms of its level of evidence,” Dr. Andre told this news organization.
Oncologists may overinterpret the genomic activation identified and give a targeted therapy that is not validated, but “oncologists should not use genomic information when the target has not been previously validated in a therapeutic trial,” he added.
Virginia Kaklamani, MD, professor of medicine at the University of Texas Health Sciences Center in San Antonio, said in an interview that approximately 5 years ago, Dr. Andre was part of the first debate at the SABCS discussing whether oncologists should be conducting next-generation sequencing for their patients with breast cancer.
“At the time, [Dr.] Andre’s comment was that we should not be doing it,” recalled Dr. Kaklamani, who is also leader of the breast cancer program at the Mays Cancer Center at the University of Texas Health San Antonio MD Anderson. “At that point, I think it was clear that we did not have the data we needed to be able to use next-generation sequencing to change our clinical management.”
However, the evidence has evolved. “Based on this clinical trial, I think we now do have the data,” she said. “I think that [next-generation sequencing] is something we will be using more and more in practice and treating our patients based on [validated] genomic alterations.”
Dr. Andre has received grants or advisory board/speaker honoraria from Daiichi Sankyo, Roche, Pfizer, AstraZeneca, Lily, and Novartis. Dr. Kaklamani has served as a consultant for Puma, AstraZeneca, Athenex, and Immunomedics, has received research funding from Eisai, and has served as a speaker for Pfizer, Celgene, Genentech, and Genomic Health, among other companies.
A version of this article first appeared on Medscape.com.
CDK4/6 inhibitors: Should they be stopped in the face of COVID-19?
The treatment interruptions occurred during the COVID-19 pandemic, out of concern that myelosuppression from the drugs might make patients more vulnerable to COVID-19 infection, and that other side effects might be confused with symptoms of COVID-19 infection.
The finding comes from a multicenter study presented by Sophie Martin, PhD, at the San Antonio Breast Cancer Symposium. Dr. Martin is a researcher at ICANS Institut de cancérologie Strasbourg Europe. The patient population had a complete or partial response, or stable disease complete for at least 6 months.
Although CDK4/6i combined with endocrine therapy has led to significant improvements in outcomes among metastatic HR-positive, HER-2-negative patients, the treatment can lead to chronic toxicities that may affect quality of life.
In its 2020 guidance on management of cancer patients during the COVID-19 pandemic, the European Society for Medical Oncology noted that cancer patients are at higher risk of severe symptoms and worse outcomes. However, it points out that there is no direct evidence that neutropenia caused CDK4/6i or poly-adenosine diphosphate ribose polymer inhibitors leads to an increase risk of COVID-19 infection.
The American Society for Clinical Oncology guidance for managing treatment of cancer patients in the context of COVID-19 also says there is little direct evidence to guide practice regarding therapies that may lead to immunosuppression. Therefore, the society recommends against changing or withholding those drugs. “The balance of potential harms that may result from delaying or interrupting treatment versus the potential benefits of possibly preventing or delaying COVID-19 infection is very uncertain,” the authors wrote.
There were 60 patients in the study, and the median age was 64 years. The average interruption period was 8 weeks. Twenty-two patients (37%) experienced radiological and/or clinical disease progression. Sixteen of the 22 (73%) restarted on CDK4/6I, while the remaining 4 patients initiated chemotherapy or targeted therapy. Two patients died during CDK4/6i treatment interruption. A univariate analysis found that the presence of liver metastases was associated with increased risk of progression during CDK4/6I withdrawal (odds ratio, 5.50; 95% confidence interval, 1.14-26.41).
There was also a trend toward greater likelihood of disease progression when the withdrawal period was 2 or more months (OR, 2.38), but the finding was not statistically significant. Although the study looked at treatment interruption due to the COVID-19 pandemic, the authors noted that the findings likely apply to other reasons for interruption, such as analgesic radiotherapy or programmed surgery.
Although the study authors advise against stopping CDK4/6i inhibitors, another small study conducted at a single German center suggested that treatment interruption might be an option in patients with stable disease. The authors examined elective CDK4/6i discontinuation among 22 patients with advanced, hormone receptor–positive, HER-2-negative breast cancer who had stable disease for at least 6 months with treatment regimens of CDK4/6i plus aromatase inhibitors or fulvestrant. After discontinuation of CDK4/6i but maintenance of endocrine therapy, 13 patients had stable disease, 8 had a partial response, and 1 had a complete response. After withdrawal, 5 patients had a local relapse and 1 experienced systemic progression. The patients restabilized with chemotherapy or retreatment with CDK4/6i.
“Discontinuation of CDK4/6 inhibitors seems to be safe in selected patients with metastatic HR-positive HER-2-negative breast cancer and prolonged disease control,” the authors wrote, although they noted that the results need to be backed up with prospective clinical trials.
Both studies had small sample sizes and were retrospective in nature.
One author on the COVID-19 study has received consulting fees from Lilly, Novartis, Pfizer, Daïchi, Seagen, and AstraZeneca. Authors of the German study have received honoraria from Iomedico, Novartis, Roche, AstraZeneca, Boehringer Ingelheim, Merck, Sanofi, and BMS.
The treatment interruptions occurred during the COVID-19 pandemic, out of concern that myelosuppression from the drugs might make patients more vulnerable to COVID-19 infection, and that other side effects might be confused with symptoms of COVID-19 infection.
The finding comes from a multicenter study presented by Sophie Martin, PhD, at the San Antonio Breast Cancer Symposium. Dr. Martin is a researcher at ICANS Institut de cancérologie Strasbourg Europe. The patient population had a complete or partial response, or stable disease complete for at least 6 months.
Although CDK4/6i combined with endocrine therapy has led to significant improvements in outcomes among metastatic HR-positive, HER-2-negative patients, the treatment can lead to chronic toxicities that may affect quality of life.
In its 2020 guidance on management of cancer patients during the COVID-19 pandemic, the European Society for Medical Oncology noted that cancer patients are at higher risk of severe symptoms and worse outcomes. However, it points out that there is no direct evidence that neutropenia caused CDK4/6i or poly-adenosine diphosphate ribose polymer inhibitors leads to an increase risk of COVID-19 infection.
The American Society for Clinical Oncology guidance for managing treatment of cancer patients in the context of COVID-19 also says there is little direct evidence to guide practice regarding therapies that may lead to immunosuppression. Therefore, the society recommends against changing or withholding those drugs. “The balance of potential harms that may result from delaying or interrupting treatment versus the potential benefits of possibly preventing or delaying COVID-19 infection is very uncertain,” the authors wrote.
There were 60 patients in the study, and the median age was 64 years. The average interruption period was 8 weeks. Twenty-two patients (37%) experienced radiological and/or clinical disease progression. Sixteen of the 22 (73%) restarted on CDK4/6I, while the remaining 4 patients initiated chemotherapy or targeted therapy. Two patients died during CDK4/6i treatment interruption. A univariate analysis found that the presence of liver metastases was associated with increased risk of progression during CDK4/6I withdrawal (odds ratio, 5.50; 95% confidence interval, 1.14-26.41).
There was also a trend toward greater likelihood of disease progression when the withdrawal period was 2 or more months (OR, 2.38), but the finding was not statistically significant. Although the study looked at treatment interruption due to the COVID-19 pandemic, the authors noted that the findings likely apply to other reasons for interruption, such as analgesic radiotherapy or programmed surgery.
Although the study authors advise against stopping CDK4/6i inhibitors, another small study conducted at a single German center suggested that treatment interruption might be an option in patients with stable disease. The authors examined elective CDK4/6i discontinuation among 22 patients with advanced, hormone receptor–positive, HER-2-negative breast cancer who had stable disease for at least 6 months with treatment regimens of CDK4/6i plus aromatase inhibitors or fulvestrant. After discontinuation of CDK4/6i but maintenance of endocrine therapy, 13 patients had stable disease, 8 had a partial response, and 1 had a complete response. After withdrawal, 5 patients had a local relapse and 1 experienced systemic progression. The patients restabilized with chemotherapy or retreatment with CDK4/6i.
“Discontinuation of CDK4/6 inhibitors seems to be safe in selected patients with metastatic HR-positive HER-2-negative breast cancer and prolonged disease control,” the authors wrote, although they noted that the results need to be backed up with prospective clinical trials.
Both studies had small sample sizes and were retrospective in nature.
One author on the COVID-19 study has received consulting fees from Lilly, Novartis, Pfizer, Daïchi, Seagen, and AstraZeneca. Authors of the German study have received honoraria from Iomedico, Novartis, Roche, AstraZeneca, Boehringer Ingelheim, Merck, Sanofi, and BMS.
The treatment interruptions occurred during the COVID-19 pandemic, out of concern that myelosuppression from the drugs might make patients more vulnerable to COVID-19 infection, and that other side effects might be confused with symptoms of COVID-19 infection.
The finding comes from a multicenter study presented by Sophie Martin, PhD, at the San Antonio Breast Cancer Symposium. Dr. Martin is a researcher at ICANS Institut de cancérologie Strasbourg Europe. The patient population had a complete or partial response, or stable disease complete for at least 6 months.
Although CDK4/6i combined with endocrine therapy has led to significant improvements in outcomes among metastatic HR-positive, HER-2-negative patients, the treatment can lead to chronic toxicities that may affect quality of life.
In its 2020 guidance on management of cancer patients during the COVID-19 pandemic, the European Society for Medical Oncology noted that cancer patients are at higher risk of severe symptoms and worse outcomes. However, it points out that there is no direct evidence that neutropenia caused CDK4/6i or poly-adenosine diphosphate ribose polymer inhibitors leads to an increase risk of COVID-19 infection.
The American Society for Clinical Oncology guidance for managing treatment of cancer patients in the context of COVID-19 also says there is little direct evidence to guide practice regarding therapies that may lead to immunosuppression. Therefore, the society recommends against changing or withholding those drugs. “The balance of potential harms that may result from delaying or interrupting treatment versus the potential benefits of possibly preventing or delaying COVID-19 infection is very uncertain,” the authors wrote.
There were 60 patients in the study, and the median age was 64 years. The average interruption period was 8 weeks. Twenty-two patients (37%) experienced radiological and/or clinical disease progression. Sixteen of the 22 (73%) restarted on CDK4/6I, while the remaining 4 patients initiated chemotherapy or targeted therapy. Two patients died during CDK4/6i treatment interruption. A univariate analysis found that the presence of liver metastases was associated with increased risk of progression during CDK4/6I withdrawal (odds ratio, 5.50; 95% confidence interval, 1.14-26.41).
There was also a trend toward greater likelihood of disease progression when the withdrawal period was 2 or more months (OR, 2.38), but the finding was not statistically significant. Although the study looked at treatment interruption due to the COVID-19 pandemic, the authors noted that the findings likely apply to other reasons for interruption, such as analgesic radiotherapy or programmed surgery.
Although the study authors advise against stopping CDK4/6i inhibitors, another small study conducted at a single German center suggested that treatment interruption might be an option in patients with stable disease. The authors examined elective CDK4/6i discontinuation among 22 patients with advanced, hormone receptor–positive, HER-2-negative breast cancer who had stable disease for at least 6 months with treatment regimens of CDK4/6i plus aromatase inhibitors or fulvestrant. After discontinuation of CDK4/6i but maintenance of endocrine therapy, 13 patients had stable disease, 8 had a partial response, and 1 had a complete response. After withdrawal, 5 patients had a local relapse and 1 experienced systemic progression. The patients restabilized with chemotherapy or retreatment with CDK4/6i.
“Discontinuation of CDK4/6 inhibitors seems to be safe in selected patients with metastatic HR-positive HER-2-negative breast cancer and prolonged disease control,” the authors wrote, although they noted that the results need to be backed up with prospective clinical trials.
Both studies had small sample sizes and were retrospective in nature.
One author on the COVID-19 study has received consulting fees from Lilly, Novartis, Pfizer, Daïchi, Seagen, and AstraZeneca. Authors of the German study have received honoraria from Iomedico, Novartis, Roche, AstraZeneca, Boehringer Ingelheim, Merck, Sanofi, and BMS.
FROM SABCS 2021
Novel SERD reduces risk of death by 30% in HR+ breast cancer
Findings from the phase 3 EMERALD trial, presented at the San Antonio Breast Cancer Symposium, revealed that the effects of elacestrant (Menarini and Radius Health) were even more pronounced in women with ESR1 mutations. Women in the elacestrant arm had a 45% reduced risk of death or disease progression in comparison with those who received standard of care.
This new agent is the “first oral SERD to demonstrate a statistically significant and clinically meaningful improvement of progression-free survival in patients with ER-positive/HER2-negative metastatic breast cancer in the second- and third-line settings,” said lead author Aditya Bardia, MD, MPH, director of the breast cancer research program at Mass General Cancer Center and associate professor at Harvard Medical School, both in Boston. “Clinically, elacestrant has the potential to become the new standard of care in the study population.”
Endocrine therapy and CDK4/6 inhibitors remain the mainstay for the management of ER-positive/HER2 metastatic breast cancer. However, most patients will eventually develop resistance to these agents, often caused by the development of ESR1 mutations.
At the current time, fulvestrant is the only SERD available on the U.S. market, which means there is an urgent unmet need for new, effective SERDs in this setting, especially for patients harboring ESR1 mutations, Dr. Bardia explained.
In an early phase 1 trial, Dr. Bardia and his team evaluated elacestrant for safety and antitumor activity and found it had an acceptable safety profile and demonstrated single-agent activity with confirmed partial responses in heavily pretreated patients with ER-positive metastatic breast cancer.
This trial provided the rationale for investigating elacestrant in a phase 3 setting, Dr. Bardia said.
The multicenter, randomized, controlled phase 3 EMERALD trial included 477 postmenopausal women with ER-positive/HER2-negative metastatic breast cancer who had received one or two prior lines of endocrine therapy and no more than one line of chemotherapy in the metastatic setting. Patients had also progressed on prior treatment with a CDK4/6 inhibitor.
Patients were randomized to elacestrant 400 mg orally daily (n = 239) or standard of care (investigator’s choice of fulvestrant or an aromatase inhibitor, n = 238). The cohorts were further stratified by ESR1 mutation status, prior fulvestrant exposure, and presence of visceral disease.
The coprimary endpoints were progression-free survival in patients with tumors harboring ESR1 mutations and in the entire cohort. Secondary endpoints included overall survival, safety, tolerability, and quality of life.
“This was a positive study as it met both primary endpoints,” said Dr. Bardia.
The team found a 30% reduction in the risk of progression or death in the elacestrant arm for all patients (hazard ratio, 0.697; P = .0018) and a 45% (HR, 0.546; P =.0005) reduction in the risk of progression or death among those with ESR1 mutations.
At 12 months, the progression-free survival rate was 22.32% with elacestrant versus 9.42% for those receiving the standard of care. Among the ESR1 mutation group, those rates were slightly more pronounced: 26.76% with elacestrant versus 8.19% with standard of care.
Overall survival data were not yet mature but trended in favor of elacestrant in all patients (HR, 0.751; P = .0821) as well as those with ESR1 mutations (HR, 0.592; P = .0325). The final overall survival analysis is expected next year, Dr. Bardia said.
Common treatment-related adverse events with elacestrant versus standard of care included mostly grade 1 or 2 nausea (25.3% vs. 8.7%), vomiting (11% vs. 2.6%), and fatigue (11% vs. 7.9%). The rate of grade 3 or higher adverse events was 7.2% in the elacestrant arm versus 3.1% in the standard of care group and was mainly driven by nausea. Treatment-emergent adverse events leading to discontinuation of elacestrant or standard of care were infrequent in both arms (6.3% and 4.4%, respectively). No treatment-related deaths occurred in either group.
Dr. Bardia added that further studies are planned and assess the efficacy of elacestrant during earlier lines of treatment and in combination with other therapies, such as CDK4/6 inhibitors.
Weighing in on the recent findings, Carlos Arteaga, MD, who was not involved in the research, said this represents an important study evaluating a therapeutic priority.
“The data suggest that [elacestrant] may be a new option, not only as monotherapy but in combination with other therapies,” Dr. Arteaga, director of Simmons Comprehensive Cancer Center at the University of Texas Southwestern Medical Center, Dallas, and cochair of SABCS, said in an interview.
Coral Omene, MD, PhD, a medical oncologist at Rutgers Cancer Institute of New Jersey and assistant professor of medicine at Robert Wood Johnson Medical School, both in New Brunswick, also commented on the importance of the EMERALD results.
“I would think that this is practice changing,” said Dr. Omene, who was also not involved in the research. The new oral SERD “demonstrates a significant advantage in progression-free survival over either fulvestrant or an aromatase inhibitor.”
An oral drug could also potentially save patients from painful injections that can occasionally result in injection-site abscesses from long-term administration, she explained. “It’s also more convenient to take oral pills at home. It saves on transportation and omits waiting in treatment rooms for administrations.”
Although the overall survival data are not yet mature and the rate of adverse events was higher with elacestrant, “progression-free survival is a surrogate endpoint widely used for overall survival and is reasonable to consider a treatment regimen based on this while awaiting mature survival data,” Dr. Omene added. “The increase in nausea and vomiting seen in oral SERD arm is likely manageable, as there were no significant differences in discontinuation in both arms of treatment.”
The study was supported by Radius Health. Dr. Bardia has served as a consultant or on an advisory board for Radius Health, Pfizer, Novartis, Genentech, Merck, Immunomedics/Gilead, Sanofi, Daiichi Sankyo/AstraZeneca, Phillips, Eli Lilly, and Foundation Medicine. He has conducted contracted research or received grants from Genentech, Novartis, Pfizer, Merck, Sanofi, Radius Health, Immunomedics/Gilead, Daiichi Sankyo/AstraZeneca, Natera, and Eli Lilly.
A version of this article first appeared on Medscape.com.
Findings from the phase 3 EMERALD trial, presented at the San Antonio Breast Cancer Symposium, revealed that the effects of elacestrant (Menarini and Radius Health) were even more pronounced in women with ESR1 mutations. Women in the elacestrant arm had a 45% reduced risk of death or disease progression in comparison with those who received standard of care.
This new agent is the “first oral SERD to demonstrate a statistically significant and clinically meaningful improvement of progression-free survival in patients with ER-positive/HER2-negative metastatic breast cancer in the second- and third-line settings,” said lead author Aditya Bardia, MD, MPH, director of the breast cancer research program at Mass General Cancer Center and associate professor at Harvard Medical School, both in Boston. “Clinically, elacestrant has the potential to become the new standard of care in the study population.”
Endocrine therapy and CDK4/6 inhibitors remain the mainstay for the management of ER-positive/HER2 metastatic breast cancer. However, most patients will eventually develop resistance to these agents, often caused by the development of ESR1 mutations.
At the current time, fulvestrant is the only SERD available on the U.S. market, which means there is an urgent unmet need for new, effective SERDs in this setting, especially for patients harboring ESR1 mutations, Dr. Bardia explained.
In an early phase 1 trial, Dr. Bardia and his team evaluated elacestrant for safety and antitumor activity and found it had an acceptable safety profile and demonstrated single-agent activity with confirmed partial responses in heavily pretreated patients with ER-positive metastatic breast cancer.
This trial provided the rationale for investigating elacestrant in a phase 3 setting, Dr. Bardia said.
The multicenter, randomized, controlled phase 3 EMERALD trial included 477 postmenopausal women with ER-positive/HER2-negative metastatic breast cancer who had received one or two prior lines of endocrine therapy and no more than one line of chemotherapy in the metastatic setting. Patients had also progressed on prior treatment with a CDK4/6 inhibitor.
Patients were randomized to elacestrant 400 mg orally daily (n = 239) or standard of care (investigator’s choice of fulvestrant or an aromatase inhibitor, n = 238). The cohorts were further stratified by ESR1 mutation status, prior fulvestrant exposure, and presence of visceral disease.
The coprimary endpoints were progression-free survival in patients with tumors harboring ESR1 mutations and in the entire cohort. Secondary endpoints included overall survival, safety, tolerability, and quality of life.
“This was a positive study as it met both primary endpoints,” said Dr. Bardia.
The team found a 30% reduction in the risk of progression or death in the elacestrant arm for all patients (hazard ratio, 0.697; P = .0018) and a 45% (HR, 0.546; P =.0005) reduction in the risk of progression or death among those with ESR1 mutations.
At 12 months, the progression-free survival rate was 22.32% with elacestrant versus 9.42% for those receiving the standard of care. Among the ESR1 mutation group, those rates were slightly more pronounced: 26.76% with elacestrant versus 8.19% with standard of care.
Overall survival data were not yet mature but trended in favor of elacestrant in all patients (HR, 0.751; P = .0821) as well as those with ESR1 mutations (HR, 0.592; P = .0325). The final overall survival analysis is expected next year, Dr. Bardia said.
Common treatment-related adverse events with elacestrant versus standard of care included mostly grade 1 or 2 nausea (25.3% vs. 8.7%), vomiting (11% vs. 2.6%), and fatigue (11% vs. 7.9%). The rate of grade 3 or higher adverse events was 7.2% in the elacestrant arm versus 3.1% in the standard of care group and was mainly driven by nausea. Treatment-emergent adverse events leading to discontinuation of elacestrant or standard of care were infrequent in both arms (6.3% and 4.4%, respectively). No treatment-related deaths occurred in either group.
Dr. Bardia added that further studies are planned and assess the efficacy of elacestrant during earlier lines of treatment and in combination with other therapies, such as CDK4/6 inhibitors.
Weighing in on the recent findings, Carlos Arteaga, MD, who was not involved in the research, said this represents an important study evaluating a therapeutic priority.
“The data suggest that [elacestrant] may be a new option, not only as monotherapy but in combination with other therapies,” Dr. Arteaga, director of Simmons Comprehensive Cancer Center at the University of Texas Southwestern Medical Center, Dallas, and cochair of SABCS, said in an interview.
Coral Omene, MD, PhD, a medical oncologist at Rutgers Cancer Institute of New Jersey and assistant professor of medicine at Robert Wood Johnson Medical School, both in New Brunswick, also commented on the importance of the EMERALD results.
“I would think that this is practice changing,” said Dr. Omene, who was also not involved in the research. The new oral SERD “demonstrates a significant advantage in progression-free survival over either fulvestrant or an aromatase inhibitor.”
An oral drug could also potentially save patients from painful injections that can occasionally result in injection-site abscesses from long-term administration, she explained. “It’s also more convenient to take oral pills at home. It saves on transportation and omits waiting in treatment rooms for administrations.”
Although the overall survival data are not yet mature and the rate of adverse events was higher with elacestrant, “progression-free survival is a surrogate endpoint widely used for overall survival and is reasonable to consider a treatment regimen based on this while awaiting mature survival data,” Dr. Omene added. “The increase in nausea and vomiting seen in oral SERD arm is likely manageable, as there were no significant differences in discontinuation in both arms of treatment.”
The study was supported by Radius Health. Dr. Bardia has served as a consultant or on an advisory board for Radius Health, Pfizer, Novartis, Genentech, Merck, Immunomedics/Gilead, Sanofi, Daiichi Sankyo/AstraZeneca, Phillips, Eli Lilly, and Foundation Medicine. He has conducted contracted research or received grants from Genentech, Novartis, Pfizer, Merck, Sanofi, Radius Health, Immunomedics/Gilead, Daiichi Sankyo/AstraZeneca, Natera, and Eli Lilly.
A version of this article first appeared on Medscape.com.
Findings from the phase 3 EMERALD trial, presented at the San Antonio Breast Cancer Symposium, revealed that the effects of elacestrant (Menarini and Radius Health) were even more pronounced in women with ESR1 mutations. Women in the elacestrant arm had a 45% reduced risk of death or disease progression in comparison with those who received standard of care.
This new agent is the “first oral SERD to demonstrate a statistically significant and clinically meaningful improvement of progression-free survival in patients with ER-positive/HER2-negative metastatic breast cancer in the second- and third-line settings,” said lead author Aditya Bardia, MD, MPH, director of the breast cancer research program at Mass General Cancer Center and associate professor at Harvard Medical School, both in Boston. “Clinically, elacestrant has the potential to become the new standard of care in the study population.”
Endocrine therapy and CDK4/6 inhibitors remain the mainstay for the management of ER-positive/HER2 metastatic breast cancer. However, most patients will eventually develop resistance to these agents, often caused by the development of ESR1 mutations.
At the current time, fulvestrant is the only SERD available on the U.S. market, which means there is an urgent unmet need for new, effective SERDs in this setting, especially for patients harboring ESR1 mutations, Dr. Bardia explained.
In an early phase 1 trial, Dr. Bardia and his team evaluated elacestrant for safety and antitumor activity and found it had an acceptable safety profile and demonstrated single-agent activity with confirmed partial responses in heavily pretreated patients with ER-positive metastatic breast cancer.
This trial provided the rationale for investigating elacestrant in a phase 3 setting, Dr. Bardia said.
The multicenter, randomized, controlled phase 3 EMERALD trial included 477 postmenopausal women with ER-positive/HER2-negative metastatic breast cancer who had received one or two prior lines of endocrine therapy and no more than one line of chemotherapy in the metastatic setting. Patients had also progressed on prior treatment with a CDK4/6 inhibitor.
Patients were randomized to elacestrant 400 mg orally daily (n = 239) or standard of care (investigator’s choice of fulvestrant or an aromatase inhibitor, n = 238). The cohorts were further stratified by ESR1 mutation status, prior fulvestrant exposure, and presence of visceral disease.
The coprimary endpoints were progression-free survival in patients with tumors harboring ESR1 mutations and in the entire cohort. Secondary endpoints included overall survival, safety, tolerability, and quality of life.
“This was a positive study as it met both primary endpoints,” said Dr. Bardia.
The team found a 30% reduction in the risk of progression or death in the elacestrant arm for all patients (hazard ratio, 0.697; P = .0018) and a 45% (HR, 0.546; P =.0005) reduction in the risk of progression or death among those with ESR1 mutations.
At 12 months, the progression-free survival rate was 22.32% with elacestrant versus 9.42% for those receiving the standard of care. Among the ESR1 mutation group, those rates were slightly more pronounced: 26.76% with elacestrant versus 8.19% with standard of care.
Overall survival data were not yet mature but trended in favor of elacestrant in all patients (HR, 0.751; P = .0821) as well as those with ESR1 mutations (HR, 0.592; P = .0325). The final overall survival analysis is expected next year, Dr. Bardia said.
Common treatment-related adverse events with elacestrant versus standard of care included mostly grade 1 or 2 nausea (25.3% vs. 8.7%), vomiting (11% vs. 2.6%), and fatigue (11% vs. 7.9%). The rate of grade 3 or higher adverse events was 7.2% in the elacestrant arm versus 3.1% in the standard of care group and was mainly driven by nausea. Treatment-emergent adverse events leading to discontinuation of elacestrant or standard of care were infrequent in both arms (6.3% and 4.4%, respectively). No treatment-related deaths occurred in either group.
Dr. Bardia added that further studies are planned and assess the efficacy of elacestrant during earlier lines of treatment and in combination with other therapies, such as CDK4/6 inhibitors.
Weighing in on the recent findings, Carlos Arteaga, MD, who was not involved in the research, said this represents an important study evaluating a therapeutic priority.
“The data suggest that [elacestrant] may be a new option, not only as monotherapy but in combination with other therapies,” Dr. Arteaga, director of Simmons Comprehensive Cancer Center at the University of Texas Southwestern Medical Center, Dallas, and cochair of SABCS, said in an interview.
Coral Omene, MD, PhD, a medical oncologist at Rutgers Cancer Institute of New Jersey and assistant professor of medicine at Robert Wood Johnson Medical School, both in New Brunswick, also commented on the importance of the EMERALD results.
“I would think that this is practice changing,” said Dr. Omene, who was also not involved in the research. The new oral SERD “demonstrates a significant advantage in progression-free survival over either fulvestrant or an aromatase inhibitor.”
An oral drug could also potentially save patients from painful injections that can occasionally result in injection-site abscesses from long-term administration, she explained. “It’s also more convenient to take oral pills at home. It saves on transportation and omits waiting in treatment rooms for administrations.”
Although the overall survival data are not yet mature and the rate of adverse events was higher with elacestrant, “progression-free survival is a surrogate endpoint widely used for overall survival and is reasonable to consider a treatment regimen based on this while awaiting mature survival data,” Dr. Omene added. “The increase in nausea and vomiting seen in oral SERD arm is likely manageable, as there were no significant differences in discontinuation in both arms of treatment.”
The study was supported by Radius Health. Dr. Bardia has served as a consultant or on an advisory board for Radius Health, Pfizer, Novartis, Genentech, Merck, Immunomedics/Gilead, Sanofi, Daiichi Sankyo/AstraZeneca, Phillips, Eli Lilly, and Foundation Medicine. He has conducted contracted research or received grants from Genentech, Novartis, Pfizer, Merck, Sanofi, Radius Health, Immunomedics/Gilead, Daiichi Sankyo/AstraZeneca, Natera, and Eli Lilly.
A version of this article first appeared on Medscape.com.
FROM SABCS 2021
Black women most at risk for lymphedema after ALND
“Axillary lymph node dissection remains the main risk factor for the development of lymphedema,” Andrea Barrio, MD, associate attending physician, Memorial Sloan Kettering Cancer Center, New York, said at a virtual press briefing at the San Antonio Breast Cancer Symposium (SABCS) 2021.
“We observed a higher incidence of lymphedema in Black women treated with ALND and RT [radiotherapy] after adjustment for other variables,” Dr. Barrio added. “While the etiology for this increased incidence is largely unknown, future studies should address the biologic mechanisms behind racial disparities in lymphedema development.”
Dr. Barrio and colleagues included 276 patients in the analysis – 60% were White, 20% Black, 11% Asian, and 6% Hispanic. The remaining 3% did not report race or ethnicity. Patients’ median age at baseline was 48 years, and the median body mass index was 26.4 kg/m2. Slightly over-two thirds of participants had hormone receptor (HR)–positive/HER2-negative breast cancer.
All patients underwent unilateral ALND. About 70% received neoadjuvant chemotherapy (NAC), and the remainder had upfront surgery followed by adjuvant chemotherapy. Ninety-five percent of patients received radiotherapy, and almost all underwent nodal radiotherapy as well.
The median number of lymph nodes removed was 18, and the median number of positive lymph nodes was two. Using a perometer, arm volume was measured at baseline, postoperatively, and every 6 months for a total of 2 years. Lymphedema was defined as a relative increase in arm volume of greater than or equal to 10% from baseline.
At 24 months, almost 25% of the group had lymphedema, but the incidence differed significantly by race and ethnicity. The highest incidence was observed among Black women, at 39.4%, compared to 27.7% of Hispanic women, 23.4% of Asian women, and 20.5% of White women in the study.
The incidence of lymphedema also varied significantly by treatment group. The incidence was twofold greater among women treated with NAC in comparison with those who underwent upfront surgery (30.9% vs. 11.1%), Dr. Barrio noted.
On multivariate analysis, Black race was the strongest predictor of lymphedema. Compared to White women, Black women had a 3.5-fold greater risk of lymphedema. Hispanic women also had a threefold increased risk compared to White women, but Dr. Barrio cautioned that there were only 16 Hispanic patients in the study.
Older age and increasing time from surgery were also both modestly associated with an increased risk of lymphedema. Among women who ultimately developed lymphedema, “severity did not vary across race or ethnicity with similar relative volume changes observed,” Dr. Barrio said.
Given that the study found that NAC was an independent predictor of lymphedema, should alternatives to NAC be favored?
Although oncologists provide NAC for a variety of reasons, women with HR-positive/HER2-negative disease – which represent the majority of patients in the current analysis – are most likely to have residual disease after NAC, Dr. Barrio noted. This suggests that oncologists need to start looking at surgical de-escalation trials in this group of patients to help them avoid ALND.
Asked whether oncologists still underestimate the impact that lymphedema has on patients’ quality of life, Virginia Kaklamani, MD, professor of medicine, UT Health San Antonio MD Anderson Cancer Center, Texas, said the oncology community has come a long way.
“Any surgeon or medical oncologist will tell you that in the 1960s and 70s, women were having much higher rates of lymphedema than they are now, so this is something that we do recognize and we are a lot more careful about,” she told this news organization.
Surgical techniques are also better now, and the number of lymph nodes that are being removed is much reduced. Nevertheless, when physicians add ALND and radiation to the axilla, “rates of lymphedema go up,” Dr. Kaklamani acknowledged. “We need these women to have physical therapy before they develop lymphedema.”
Dr. Barrio agreed, adding that if oncologists could identify earlier thresholds for lymphedema, before patients develop arm swelling, “we may be able to intervene and see a reduction in its development.”
In the meantime, Dr. Barrio and colleagues are testing the protective value of offering immediate lymphatic reconstruction following ALND versus no reconstruction. In addition, they will be studying banked tissue from Black women to better understand any racial differences in inflammatory responses, the risk of fibrosis, and the reaction to radiotherapy.
“I think we see that inflammation is a key driver of lymphedema development, and so maybe Black women are predisposed to a different inflammatory reaction to treatment or perhaps have higher levels of inflammation at baseline,” Dr. Barrio speculated.
“I think it’s also important to stratify a woman’s risk for lymphedema, and once we can tailor that risk, we can start to identify which patients might benefit from preventative strategies,” she added.
Dr. Barrio has disclosed no relevant financial relationships. Dr. Kaklamani has served as a consultant for Puma, AstraZeneca, Athenex, and Immunomedics and as a speaker for Pfizer, Celgene, Genentech, Genomic Health, Puma, Eisai, Novartis, AstraZeneca, Daiichi Sankyo, and Seattle Genetics. She has also received research funding from Eisai.
A version of this article first appeared on Medscape.com.
“Axillary lymph node dissection remains the main risk factor for the development of lymphedema,” Andrea Barrio, MD, associate attending physician, Memorial Sloan Kettering Cancer Center, New York, said at a virtual press briefing at the San Antonio Breast Cancer Symposium (SABCS) 2021.
“We observed a higher incidence of lymphedema in Black women treated with ALND and RT [radiotherapy] after adjustment for other variables,” Dr. Barrio added. “While the etiology for this increased incidence is largely unknown, future studies should address the biologic mechanisms behind racial disparities in lymphedema development.”
Dr. Barrio and colleagues included 276 patients in the analysis – 60% were White, 20% Black, 11% Asian, and 6% Hispanic. The remaining 3% did not report race or ethnicity. Patients’ median age at baseline was 48 years, and the median body mass index was 26.4 kg/m2. Slightly over-two thirds of participants had hormone receptor (HR)–positive/HER2-negative breast cancer.
All patients underwent unilateral ALND. About 70% received neoadjuvant chemotherapy (NAC), and the remainder had upfront surgery followed by adjuvant chemotherapy. Ninety-five percent of patients received radiotherapy, and almost all underwent nodal radiotherapy as well.
The median number of lymph nodes removed was 18, and the median number of positive lymph nodes was two. Using a perometer, arm volume was measured at baseline, postoperatively, and every 6 months for a total of 2 years. Lymphedema was defined as a relative increase in arm volume of greater than or equal to 10% from baseline.
At 24 months, almost 25% of the group had lymphedema, but the incidence differed significantly by race and ethnicity. The highest incidence was observed among Black women, at 39.4%, compared to 27.7% of Hispanic women, 23.4% of Asian women, and 20.5% of White women in the study.
The incidence of lymphedema also varied significantly by treatment group. The incidence was twofold greater among women treated with NAC in comparison with those who underwent upfront surgery (30.9% vs. 11.1%), Dr. Barrio noted.
On multivariate analysis, Black race was the strongest predictor of lymphedema. Compared to White women, Black women had a 3.5-fold greater risk of lymphedema. Hispanic women also had a threefold increased risk compared to White women, but Dr. Barrio cautioned that there were only 16 Hispanic patients in the study.
Older age and increasing time from surgery were also both modestly associated with an increased risk of lymphedema. Among women who ultimately developed lymphedema, “severity did not vary across race or ethnicity with similar relative volume changes observed,” Dr. Barrio said.
Given that the study found that NAC was an independent predictor of lymphedema, should alternatives to NAC be favored?
Although oncologists provide NAC for a variety of reasons, women with HR-positive/HER2-negative disease – which represent the majority of patients in the current analysis – are most likely to have residual disease after NAC, Dr. Barrio noted. This suggests that oncologists need to start looking at surgical de-escalation trials in this group of patients to help them avoid ALND.
Asked whether oncologists still underestimate the impact that lymphedema has on patients’ quality of life, Virginia Kaklamani, MD, professor of medicine, UT Health San Antonio MD Anderson Cancer Center, Texas, said the oncology community has come a long way.
“Any surgeon or medical oncologist will tell you that in the 1960s and 70s, women were having much higher rates of lymphedema than they are now, so this is something that we do recognize and we are a lot more careful about,” she told this news organization.
Surgical techniques are also better now, and the number of lymph nodes that are being removed is much reduced. Nevertheless, when physicians add ALND and radiation to the axilla, “rates of lymphedema go up,” Dr. Kaklamani acknowledged. “We need these women to have physical therapy before they develop lymphedema.”
Dr. Barrio agreed, adding that if oncologists could identify earlier thresholds for lymphedema, before patients develop arm swelling, “we may be able to intervene and see a reduction in its development.”
In the meantime, Dr. Barrio and colleagues are testing the protective value of offering immediate lymphatic reconstruction following ALND versus no reconstruction. In addition, they will be studying banked tissue from Black women to better understand any racial differences in inflammatory responses, the risk of fibrosis, and the reaction to radiotherapy.
“I think we see that inflammation is a key driver of lymphedema development, and so maybe Black women are predisposed to a different inflammatory reaction to treatment or perhaps have higher levels of inflammation at baseline,” Dr. Barrio speculated.
“I think it’s also important to stratify a woman’s risk for lymphedema, and once we can tailor that risk, we can start to identify which patients might benefit from preventative strategies,” she added.
Dr. Barrio has disclosed no relevant financial relationships. Dr. Kaklamani has served as a consultant for Puma, AstraZeneca, Athenex, and Immunomedics and as a speaker for Pfizer, Celgene, Genentech, Genomic Health, Puma, Eisai, Novartis, AstraZeneca, Daiichi Sankyo, and Seattle Genetics. She has also received research funding from Eisai.
A version of this article first appeared on Medscape.com.
“Axillary lymph node dissection remains the main risk factor for the development of lymphedema,” Andrea Barrio, MD, associate attending physician, Memorial Sloan Kettering Cancer Center, New York, said at a virtual press briefing at the San Antonio Breast Cancer Symposium (SABCS) 2021.
“We observed a higher incidence of lymphedema in Black women treated with ALND and RT [radiotherapy] after adjustment for other variables,” Dr. Barrio added. “While the etiology for this increased incidence is largely unknown, future studies should address the biologic mechanisms behind racial disparities in lymphedema development.”
Dr. Barrio and colleagues included 276 patients in the analysis – 60% were White, 20% Black, 11% Asian, and 6% Hispanic. The remaining 3% did not report race or ethnicity. Patients’ median age at baseline was 48 years, and the median body mass index was 26.4 kg/m2. Slightly over-two thirds of participants had hormone receptor (HR)–positive/HER2-negative breast cancer.
All patients underwent unilateral ALND. About 70% received neoadjuvant chemotherapy (NAC), and the remainder had upfront surgery followed by adjuvant chemotherapy. Ninety-five percent of patients received radiotherapy, and almost all underwent nodal radiotherapy as well.
The median number of lymph nodes removed was 18, and the median number of positive lymph nodes was two. Using a perometer, arm volume was measured at baseline, postoperatively, and every 6 months for a total of 2 years. Lymphedema was defined as a relative increase in arm volume of greater than or equal to 10% from baseline.
At 24 months, almost 25% of the group had lymphedema, but the incidence differed significantly by race and ethnicity. The highest incidence was observed among Black women, at 39.4%, compared to 27.7% of Hispanic women, 23.4% of Asian women, and 20.5% of White women in the study.
The incidence of lymphedema also varied significantly by treatment group. The incidence was twofold greater among women treated with NAC in comparison with those who underwent upfront surgery (30.9% vs. 11.1%), Dr. Barrio noted.
On multivariate analysis, Black race was the strongest predictor of lymphedema. Compared to White women, Black women had a 3.5-fold greater risk of lymphedema. Hispanic women also had a threefold increased risk compared to White women, but Dr. Barrio cautioned that there were only 16 Hispanic patients in the study.
Older age and increasing time from surgery were also both modestly associated with an increased risk of lymphedema. Among women who ultimately developed lymphedema, “severity did not vary across race or ethnicity with similar relative volume changes observed,” Dr. Barrio said.
Given that the study found that NAC was an independent predictor of lymphedema, should alternatives to NAC be favored?
Although oncologists provide NAC for a variety of reasons, women with HR-positive/HER2-negative disease – which represent the majority of patients in the current analysis – are most likely to have residual disease after NAC, Dr. Barrio noted. This suggests that oncologists need to start looking at surgical de-escalation trials in this group of patients to help them avoid ALND.
Asked whether oncologists still underestimate the impact that lymphedema has on patients’ quality of life, Virginia Kaklamani, MD, professor of medicine, UT Health San Antonio MD Anderson Cancer Center, Texas, said the oncology community has come a long way.
“Any surgeon or medical oncologist will tell you that in the 1960s and 70s, women were having much higher rates of lymphedema than they are now, so this is something that we do recognize and we are a lot more careful about,” she told this news organization.
Surgical techniques are also better now, and the number of lymph nodes that are being removed is much reduced. Nevertheless, when physicians add ALND and radiation to the axilla, “rates of lymphedema go up,” Dr. Kaklamani acknowledged. “We need these women to have physical therapy before they develop lymphedema.”
Dr. Barrio agreed, adding that if oncologists could identify earlier thresholds for lymphedema, before patients develop arm swelling, “we may be able to intervene and see a reduction in its development.”
In the meantime, Dr. Barrio and colleagues are testing the protective value of offering immediate lymphatic reconstruction following ALND versus no reconstruction. In addition, they will be studying banked tissue from Black women to better understand any racial differences in inflammatory responses, the risk of fibrosis, and the reaction to radiotherapy.
“I think we see that inflammation is a key driver of lymphedema development, and so maybe Black women are predisposed to a different inflammatory reaction to treatment or perhaps have higher levels of inflammation at baseline,” Dr. Barrio speculated.
“I think it’s also important to stratify a woman’s risk for lymphedema, and once we can tailor that risk, we can start to identify which patients might benefit from preventative strategies,” she added.
Dr. Barrio has disclosed no relevant financial relationships. Dr. Kaklamani has served as a consultant for Puma, AstraZeneca, Athenex, and Immunomedics and as a speaker for Pfizer, Celgene, Genentech, Genomic Health, Puma, Eisai, Novartis, AstraZeneca, Daiichi Sankyo, and Seattle Genetics. She has also received research funding from Eisai.
A version of this article first appeared on Medscape.com.