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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.
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
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.
Cancer risk-reducing strategies: Focus on chemoprevention
In her presentation at The North American Menopause Society (NAMS) 2021 annual meeting (September 22–25, 2021, in Washington, DC), Dr. Holly J. Pederson offered her expert perspectives on breast cancer prevention in at-risk women in “Chemoprevention for risk reduction: Women’s health clinicians have a role.”
Which patients would benefit from chemoprevention?
Holly J. Pederson, MD: Obviously, women with significant family history are at risk. And approximately 10% of biopsies that are done for other reasons incidentally show atypical hyperplasia (AH) or lobular carcinoma in situ (LCIS)—which are not precancers or cancers but are markers for the development of the disease—and they markedly increase risk. Atypical hyperplasia confers a 30% risk for developing breast cancer over the next 25 years, and LCIS is associated with up to a 2% per year risk. In this setting, preventive medication has been shown to cut risk by 56% to 86%; this is a targeted population that is often overlooked.
Mathematical risk models can be used to assess risk by assessing women’s risk factors. The United States Preventive Services Task Force (USPSTF) has set forth a threshold at which they believe the benefits outweigh the risks of preventive medications. That threshold is 3% or greater over the next 5 years using the Gail breast cancer risk assessment tool.1 The American Society of Clinical Oncology (ASCO) uses the Tyrer-Cuzick breast cancer risk evaluation model with a threshold of 5% over the next 10 years.2 In general, those are the situations in which chemoprevention is a no-brainer.
Certain genetic mutations also predispose to estrogen-sensitive breast cancer. While preventive medications specifically have not been studied in large groups of gene carriers, chemoprevention makes sense because these medications prevent estrogen-sensitive breast cancers that those patients are prone to. Examples would be patients with ATM and CHEK2 gene mutations, which are very common, and patients with BRCA2 and even BRCA1 variants in the postmenopausal years. Those are the big targets.
Risk assessment models
Dr. Pederson: Yes, I almost exclusively use the Tyrer-Cuzick risk model, version 8, which incorporates breast density. This model is intimidating to some practitioners initially, but once you get used to it, you can complete it very quickly.
The Gail model is very limited. It assesses only first-degree relatives, so you don’t get the paternal information at all, and you don’t use age at diagnosis, family structure, genetic testing, results of breast density, or body mass index (BMI). There are many limitations of the Gail model, but most people use it because it is so easy and they are familiar with it.
Possibly the best model is the CanRisk tool, which incorporates the Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm (BOADICEA), but it takes too much time to use in clinic; it’s too complicated. The Tyrer-Cuzick model is easy to use once you get used to it.
Dr. Pederson: Risk doesn’t always need to be formally calculated, which can be time-consuming. It’s one of those situations where most practitioners know it when they see it. Benign atypical biopsies, a strong family history, or, obviously, the presence of a genetic mutation are huge red flags.
If a practitioner has a nearby high-risk center where they can refer patients, that can be so useful, even for a one-time consultation to guide management. For example, with the virtual world now, I do a lot of consultations for patients and outline a plan, and then the referring practitioner can carry out the plan with confidence and then send the patient back periodically. There are so many more options now that previously did not exist for the busy ObGyn or primary care provider to rely on.
Continue to: Chemoprevention uptake in at-risk women...
Chemoprevention uptake in at-risk women
Dr. Pederson: We really never practice medicine using numbers. We use clinical judgment, and we use relationships with patients in terms of developing confidence and trust. I think that the uptake that we exhibit in our center probably is more based on the patients’ perception that we are confident in our recommendations. I think that many practitioners simply are not comfortable with explaining medications, explaining and managing adverse effects, and using alternative medications. While the modeling helps, I think the personal expertise really makes the difference.
Going forward, the addition of the polygenic risk score to the mathematical risk models is going to make a big difference. Right now, the mathematical risk model is simply that: it takes the traditional risk factors that a patient has and spits out a number. But adding the patient’s genomic data—that is, a weighted summation of SNPs, or single nucleotide polymorphisms, now numbering over 300 for breast cancer—can explain more about their personalized risk, which is going to be more powerful in influencing a woman to take medication or not to take medication, in my opinion. Knowing their actual genomic risk will be a big step forward in individualized risk stratification and increased medication uptake as well as vigilance with high risk screening and attention to diet, exercise, and drinking alcohol in moderation.
Dr. Pederson: The only drug that can be used in the premenopausal setting is tamoxifen (TABLE 1). Women can’t take it if they are pregnant, planning to become pregnant, or if they don’t use a reliable form of birth control because it is teratogenic. Women also cannot take tamoxifen if they have had a history of blood clots, stroke, or transient ischemic attack; if they are on warfarin or estrogen preparations; or if they have had atypical endometrial biopsies or endometrial cancer. Those are the absolute contraindications for tamoxifen use.
Tamoxifen is generally very well tolerated in most women; some women experience hot flashes and night sweats that often will subside (or become tolerable) over the first 90 days. In addition, some women experience vaginal discharge rather than dryness, but it is not as bothersome to patients as dryness can be.
Tamoxifen can be used in the pre- or postmenopausal setting. In healthy premenopausal women, there’s no increased risk of the serious adverse effects that are seen with tamoxifen use in postmenopausal women, such as the 1% risk of blood clots and the 1% risk of endometrial cancer.
In postmenopausal women who still have their uterus, I’ll preferentially use raloxifene over tamoxifen. If they don’t have their uterus, tamoxifen is slightly more effective than the raloxifene, and I’ll use that.
Tamoxifen and raloxifene are both selective estrogen receptor modulators, or SERMs, which means that they stimulate receptors in some tissues, like bone, keeping bones strong, and block the receptors in other tissues, like the breast, reducing risk. And so you get kind of a two-for-one in terms of breast cancer risk reduction and osteoporosis prevention.
Another class of preventive drugs is the aromatase inhibitors (AIs). They block the enzyme aromatase, which converts androgens to estrogens peripherally; that is, the androgens that are produced primarily in the adrenal gland, but in part in postmenopausal ovaries.
In general, AIs are less well tolerated. There are generally more hot flashes and night sweats, and more vaginal dryness than with the SERMs. Anastrozole use is associated with arthralgias; and with exemestane use, there can be some hair loss (TABLE 2). Relative contraindications to SERMs become more important in the postmenopausal setting because of the increased frequency of both blood clots and uterine cancer in the postmenopausal years. I won’t give it to smokers. I won’t give tamoxifen to smokers in the premenopausal period either. With obese women, care must be taken because of the risk of blood clots with the SERMS, so then I’ll resort to the AIs. In the postmenopausal setting, you have to think a lot harder about the choices you use for preventive medication. Preferentially, I’ll use the SERMS if possible as they have fewer adverse effects.
Dr. Pederson: All of them are recommended to be given for 5 years, but the MAP.3 trial, which studied exemestane compared with placebo, showed a 65% risk reduction with 3 years of therapy.3 So occasionally, we’ll use 3 years of therapy. Why the treatment recommendation is universally 5 years is unclear, given that the trial with that particular drug was done in 3 years. And with low-dose tamoxifen, the recommended duration is 3 years. That study was done in Italy with 5 mg daily for 3 years.4 In the United States we use 10 mg every other day for 3 years because the 5-mg tablet is not available here.
Continue to: Counseling points...
Counseling points
Dr. Pederson: Patients’ fears about adverse effects are often worse than the adverse effects themselves. Women will fester over, Should I take it? Should I take it possibly for years? And then they take the medication and they tell me, “I don’t even notice that I’m taking it, and I know I’m being proactive.” The majority of patients who take these medications don’t have a lot of significant adverse effects.
Severe hot flashes can be managed in a number of ways, primarily and most effectively with certain antidepressants. Oxybutynin use is another good way to manage vasomotor symptoms. Sometimes we use local vaginal estrogen if a patient has vaginal dryness. In general, however, I would say at least 80% of my patients who take preventive medications do not require management of adverse side effects, that they are tolerable.
I counsel women this way, “Don’t think of this as a 5-year course of medication. Think of it as a 90-day trial, and let’s see how you do. If you hate it, then we don’t do it.” They often are pleasantly surprised that the medication is much easier to tolerate than they thought it would be.
Dr. Pederson: It would be neat if a trial would directly compare lifestyle interventions with medications, because probably lifestyle change is as effective as medication is—but we don’t know that and probably will never have that data. We do know that alcohol consumption, every drink per day, increases risk by 10%. We know that obesity is responsible for 30% of breast cancers in this country, and that hormone replacement probably is overrated as a significant risk factor. Updated data from the Women’s Health Initiative study suggest that hormone replacement may actually reduce both breast cancer and cardiovascular risk in women in their 50s, but that’s in average-risk women and not in high-risk women, so we can’t generalize. We do recommend lifestyle measures including weight loss, exercise, and limiting alcohol consumption for all of our patients and certainly for our high-risk patients.
The only 2 things a woman can do to reduce the risk of triple negative breast cancer are to achieve and maintain ideal body weight and to breastfeed. The medications that I have mentioned don’t reduce the risk of triple negative breast cancer. Staying thin and breastfeeding do. It’s a problem in this country because at least 35% of all women and 58% of Black women are obese in America, and Black women tend to be prone to triple-negative breast cancer. That’s a real public health issue that we need to address. If we were going to focus on one thing, it would be focusing on obesity in terms of risk reduction.
Final thoughts
Dr. Pederson: I would like to direct attention to the American Heart Association scientific statement published at the end of 2020 that reported that hormone replacement in average-risk women reduced both cardiovascular events and overall mortality in women in their 50s by 30%.5 While that’s not directly related to what we are talking about, we need to weigh the pros and cons of estrogen versus estrogen blockade in women in terms of breast cancer risk management discussions. Part of shared decision making now needs to include cardiovascular risk factors and how estrogen is going to play into that.
In women with atypical hyperplasia or LCIS, they may benefit from the preventive medications we discussed. But in women with family history or in women with genetic mutations who have not had benign atypical biopsies, they may choose to consider estrogen during their 50s and perhaps take tamoxifen either beforehand or raloxifene afterward.
We need to look at patients holistically and consider all their risk factors together. We can’t look at one dimension alone.
- US Preventive Services Task Force. Medication use to reduce risk of breast cancer: US Preventive Services Task Force Recommendation Statement. JAMA. 2019;322:857-867.
- Visvanathan K, Fabian CJ, Bantug E, et al. Use of endocrine therapy for breast cancer risk reduction: ASCO clinical practice guideline update. J Clin Oncol. 2019;37:3152-3165.
- Goss PE, Ingle JN, Alex-Martinez JE, et al. Exemestane for breast-cancer prevention in postmenopausal women. N Engl J Med. 2011;364:2381-2391.
- DeCensi A, Puntoni M, Guerrieri-Gonzaga A, et al. Randomized placebo controlled trial of low-dose tamoxifen to prevent local and contralateral recurrence in breast intraepithelial neoplasia. J Clin Oncol. 2019;37:1629-1637.
- El Khoudary SR, Aggarwal B, Beckie TM, et al; American Heart Association Prevention Science Committee of the Council on Epidemiology and Prevention, and Council on Cardiovascular and Stroke Nursing. Menopause transition and cardiovascular disease risk: implications for timing of early prevention: a scientific statement from the American Heart Association. Circulation. 2020;142:e506-e532.
In her presentation at The North American Menopause Society (NAMS) 2021 annual meeting (September 22–25, 2021, in Washington, DC), Dr. Holly J. Pederson offered her expert perspectives on breast cancer prevention in at-risk women in “Chemoprevention for risk reduction: Women’s health clinicians have a role.”
Which patients would benefit from chemoprevention?
Holly J. Pederson, MD: Obviously, women with significant family history are at risk. And approximately 10% of biopsies that are done for other reasons incidentally show atypical hyperplasia (AH) or lobular carcinoma in situ (LCIS)—which are not precancers or cancers but are markers for the development of the disease—and they markedly increase risk. Atypical hyperplasia confers a 30% risk for developing breast cancer over the next 25 years, and LCIS is associated with up to a 2% per year risk. In this setting, preventive medication has been shown to cut risk by 56% to 86%; this is a targeted population that is often overlooked.
Mathematical risk models can be used to assess risk by assessing women’s risk factors. The United States Preventive Services Task Force (USPSTF) has set forth a threshold at which they believe the benefits outweigh the risks of preventive medications. That threshold is 3% or greater over the next 5 years using the Gail breast cancer risk assessment tool.1 The American Society of Clinical Oncology (ASCO) uses the Tyrer-Cuzick breast cancer risk evaluation model with a threshold of 5% over the next 10 years.2 In general, those are the situations in which chemoprevention is a no-brainer.
Certain genetic mutations also predispose to estrogen-sensitive breast cancer. While preventive medications specifically have not been studied in large groups of gene carriers, chemoprevention makes sense because these medications prevent estrogen-sensitive breast cancers that those patients are prone to. Examples would be patients with ATM and CHEK2 gene mutations, which are very common, and patients with BRCA2 and even BRCA1 variants in the postmenopausal years. Those are the big targets.
Risk assessment models
Dr. Pederson: Yes, I almost exclusively use the Tyrer-Cuzick risk model, version 8, which incorporates breast density. This model is intimidating to some practitioners initially, but once you get used to it, you can complete it very quickly.
The Gail model is very limited. It assesses only first-degree relatives, so you don’t get the paternal information at all, and you don’t use age at diagnosis, family structure, genetic testing, results of breast density, or body mass index (BMI). There are many limitations of the Gail model, but most people use it because it is so easy and they are familiar with it.
Possibly the best model is the CanRisk tool, which incorporates the Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm (BOADICEA), but it takes too much time to use in clinic; it’s too complicated. The Tyrer-Cuzick model is easy to use once you get used to it.
Dr. Pederson: Risk doesn’t always need to be formally calculated, which can be time-consuming. It’s one of those situations where most practitioners know it when they see it. Benign atypical biopsies, a strong family history, or, obviously, the presence of a genetic mutation are huge red flags.
If a practitioner has a nearby high-risk center where they can refer patients, that can be so useful, even for a one-time consultation to guide management. For example, with the virtual world now, I do a lot of consultations for patients and outline a plan, and then the referring practitioner can carry out the plan with confidence and then send the patient back periodically. There are so many more options now that previously did not exist for the busy ObGyn or primary care provider to rely on.
Continue to: Chemoprevention uptake in at-risk women...
Chemoprevention uptake in at-risk women
Dr. Pederson: We really never practice medicine using numbers. We use clinical judgment, and we use relationships with patients in terms of developing confidence and trust. I think that the uptake that we exhibit in our center probably is more based on the patients’ perception that we are confident in our recommendations. I think that many practitioners simply are not comfortable with explaining medications, explaining and managing adverse effects, and using alternative medications. While the modeling helps, I think the personal expertise really makes the difference.
Going forward, the addition of the polygenic risk score to the mathematical risk models is going to make a big difference. Right now, the mathematical risk model is simply that: it takes the traditional risk factors that a patient has and spits out a number. But adding the patient’s genomic data—that is, a weighted summation of SNPs, or single nucleotide polymorphisms, now numbering over 300 for breast cancer—can explain more about their personalized risk, which is going to be more powerful in influencing a woman to take medication or not to take medication, in my opinion. Knowing their actual genomic risk will be a big step forward in individualized risk stratification and increased medication uptake as well as vigilance with high risk screening and attention to diet, exercise, and drinking alcohol in moderation.
Dr. Pederson: The only drug that can be used in the premenopausal setting is tamoxifen (TABLE 1). Women can’t take it if they are pregnant, planning to become pregnant, or if they don’t use a reliable form of birth control because it is teratogenic. Women also cannot take tamoxifen if they have had a history of blood clots, stroke, or transient ischemic attack; if they are on warfarin or estrogen preparations; or if they have had atypical endometrial biopsies or endometrial cancer. Those are the absolute contraindications for tamoxifen use.
Tamoxifen is generally very well tolerated in most women; some women experience hot flashes and night sweats that often will subside (or become tolerable) over the first 90 days. In addition, some women experience vaginal discharge rather than dryness, but it is not as bothersome to patients as dryness can be.
Tamoxifen can be used in the pre- or postmenopausal setting. In healthy premenopausal women, there’s no increased risk of the serious adverse effects that are seen with tamoxifen use in postmenopausal women, such as the 1% risk of blood clots and the 1% risk of endometrial cancer.
In postmenopausal women who still have their uterus, I’ll preferentially use raloxifene over tamoxifen. If they don’t have their uterus, tamoxifen is slightly more effective than the raloxifene, and I’ll use that.
Tamoxifen and raloxifene are both selective estrogen receptor modulators, or SERMs, which means that they stimulate receptors in some tissues, like bone, keeping bones strong, and block the receptors in other tissues, like the breast, reducing risk. And so you get kind of a two-for-one in terms of breast cancer risk reduction and osteoporosis prevention.
Another class of preventive drugs is the aromatase inhibitors (AIs). They block the enzyme aromatase, which converts androgens to estrogens peripherally; that is, the androgens that are produced primarily in the adrenal gland, but in part in postmenopausal ovaries.
In general, AIs are less well tolerated. There are generally more hot flashes and night sweats, and more vaginal dryness than with the SERMs. Anastrozole use is associated with arthralgias; and with exemestane use, there can be some hair loss (TABLE 2). Relative contraindications to SERMs become more important in the postmenopausal setting because of the increased frequency of both blood clots and uterine cancer in the postmenopausal years. I won’t give it to smokers. I won’t give tamoxifen to smokers in the premenopausal period either. With obese women, care must be taken because of the risk of blood clots with the SERMS, so then I’ll resort to the AIs. In the postmenopausal setting, you have to think a lot harder about the choices you use for preventive medication. Preferentially, I’ll use the SERMS if possible as they have fewer adverse effects.
Dr. Pederson: All of them are recommended to be given for 5 years, but the MAP.3 trial, which studied exemestane compared with placebo, showed a 65% risk reduction with 3 years of therapy.3 So occasionally, we’ll use 3 years of therapy. Why the treatment recommendation is universally 5 years is unclear, given that the trial with that particular drug was done in 3 years. And with low-dose tamoxifen, the recommended duration is 3 years. That study was done in Italy with 5 mg daily for 3 years.4 In the United States we use 10 mg every other day for 3 years because the 5-mg tablet is not available here.
Continue to: Counseling points...
Counseling points
Dr. Pederson: Patients’ fears about adverse effects are often worse than the adverse effects themselves. Women will fester over, Should I take it? Should I take it possibly for years? And then they take the medication and they tell me, “I don’t even notice that I’m taking it, and I know I’m being proactive.” The majority of patients who take these medications don’t have a lot of significant adverse effects.
Severe hot flashes can be managed in a number of ways, primarily and most effectively with certain antidepressants. Oxybutynin use is another good way to manage vasomotor symptoms. Sometimes we use local vaginal estrogen if a patient has vaginal dryness. In general, however, I would say at least 80% of my patients who take preventive medications do not require management of adverse side effects, that they are tolerable.
I counsel women this way, “Don’t think of this as a 5-year course of medication. Think of it as a 90-day trial, and let’s see how you do. If you hate it, then we don’t do it.” They often are pleasantly surprised that the medication is much easier to tolerate than they thought it would be.
Dr. Pederson: It would be neat if a trial would directly compare lifestyle interventions with medications, because probably lifestyle change is as effective as medication is—but we don’t know that and probably will never have that data. We do know that alcohol consumption, every drink per day, increases risk by 10%. We know that obesity is responsible for 30% of breast cancers in this country, and that hormone replacement probably is overrated as a significant risk factor. Updated data from the Women’s Health Initiative study suggest that hormone replacement may actually reduce both breast cancer and cardiovascular risk in women in their 50s, but that’s in average-risk women and not in high-risk women, so we can’t generalize. We do recommend lifestyle measures including weight loss, exercise, and limiting alcohol consumption for all of our patients and certainly for our high-risk patients.
The only 2 things a woman can do to reduce the risk of triple negative breast cancer are to achieve and maintain ideal body weight and to breastfeed. The medications that I have mentioned don’t reduce the risk of triple negative breast cancer. Staying thin and breastfeeding do. It’s a problem in this country because at least 35% of all women and 58% of Black women are obese in America, and Black women tend to be prone to triple-negative breast cancer. That’s a real public health issue that we need to address. If we were going to focus on one thing, it would be focusing on obesity in terms of risk reduction.
Final thoughts
Dr. Pederson: I would like to direct attention to the American Heart Association scientific statement published at the end of 2020 that reported that hormone replacement in average-risk women reduced both cardiovascular events and overall mortality in women in their 50s by 30%.5 While that’s not directly related to what we are talking about, we need to weigh the pros and cons of estrogen versus estrogen blockade in women in terms of breast cancer risk management discussions. Part of shared decision making now needs to include cardiovascular risk factors and how estrogen is going to play into that.
In women with atypical hyperplasia or LCIS, they may benefit from the preventive medications we discussed. But in women with family history or in women with genetic mutations who have not had benign atypical biopsies, they may choose to consider estrogen during their 50s and perhaps take tamoxifen either beforehand or raloxifene afterward.
We need to look at patients holistically and consider all their risk factors together. We can’t look at one dimension alone.
In her presentation at The North American Menopause Society (NAMS) 2021 annual meeting (September 22–25, 2021, in Washington, DC), Dr. Holly J. Pederson offered her expert perspectives on breast cancer prevention in at-risk women in “Chemoprevention for risk reduction: Women’s health clinicians have a role.”
Which patients would benefit from chemoprevention?
Holly J. Pederson, MD: Obviously, women with significant family history are at risk. And approximately 10% of biopsies that are done for other reasons incidentally show atypical hyperplasia (AH) or lobular carcinoma in situ (LCIS)—which are not precancers or cancers but are markers for the development of the disease—and they markedly increase risk. Atypical hyperplasia confers a 30% risk for developing breast cancer over the next 25 years, and LCIS is associated with up to a 2% per year risk. In this setting, preventive medication has been shown to cut risk by 56% to 86%; this is a targeted population that is often overlooked.
Mathematical risk models can be used to assess risk by assessing women’s risk factors. The United States Preventive Services Task Force (USPSTF) has set forth a threshold at which they believe the benefits outweigh the risks of preventive medications. That threshold is 3% or greater over the next 5 years using the Gail breast cancer risk assessment tool.1 The American Society of Clinical Oncology (ASCO) uses the Tyrer-Cuzick breast cancer risk evaluation model with a threshold of 5% over the next 10 years.2 In general, those are the situations in which chemoprevention is a no-brainer.
Certain genetic mutations also predispose to estrogen-sensitive breast cancer. While preventive medications specifically have not been studied in large groups of gene carriers, chemoprevention makes sense because these medications prevent estrogen-sensitive breast cancers that those patients are prone to. Examples would be patients with ATM and CHEK2 gene mutations, which are very common, and patients with BRCA2 and even BRCA1 variants in the postmenopausal years. Those are the big targets.
Risk assessment models
Dr. Pederson: Yes, I almost exclusively use the Tyrer-Cuzick risk model, version 8, which incorporates breast density. This model is intimidating to some practitioners initially, but once you get used to it, you can complete it very quickly.
The Gail model is very limited. It assesses only first-degree relatives, so you don’t get the paternal information at all, and you don’t use age at diagnosis, family structure, genetic testing, results of breast density, or body mass index (BMI). There are many limitations of the Gail model, but most people use it because it is so easy and they are familiar with it.
Possibly the best model is the CanRisk tool, which incorporates the Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm (BOADICEA), but it takes too much time to use in clinic; it’s too complicated. The Tyrer-Cuzick model is easy to use once you get used to it.
Dr. Pederson: Risk doesn’t always need to be formally calculated, which can be time-consuming. It’s one of those situations where most practitioners know it when they see it. Benign atypical biopsies, a strong family history, or, obviously, the presence of a genetic mutation are huge red flags.
If a practitioner has a nearby high-risk center where they can refer patients, that can be so useful, even for a one-time consultation to guide management. For example, with the virtual world now, I do a lot of consultations for patients and outline a plan, and then the referring practitioner can carry out the plan with confidence and then send the patient back periodically. There are so many more options now that previously did not exist for the busy ObGyn or primary care provider to rely on.
Continue to: Chemoprevention uptake in at-risk women...
Chemoprevention uptake in at-risk women
Dr. Pederson: We really never practice medicine using numbers. We use clinical judgment, and we use relationships with patients in terms of developing confidence and trust. I think that the uptake that we exhibit in our center probably is more based on the patients’ perception that we are confident in our recommendations. I think that many practitioners simply are not comfortable with explaining medications, explaining and managing adverse effects, and using alternative medications. While the modeling helps, I think the personal expertise really makes the difference.
Going forward, the addition of the polygenic risk score to the mathematical risk models is going to make a big difference. Right now, the mathematical risk model is simply that: it takes the traditional risk factors that a patient has and spits out a number. But adding the patient’s genomic data—that is, a weighted summation of SNPs, or single nucleotide polymorphisms, now numbering over 300 for breast cancer—can explain more about their personalized risk, which is going to be more powerful in influencing a woman to take medication or not to take medication, in my opinion. Knowing their actual genomic risk will be a big step forward in individualized risk stratification and increased medication uptake as well as vigilance with high risk screening and attention to diet, exercise, and drinking alcohol in moderation.
Dr. Pederson: The only drug that can be used in the premenopausal setting is tamoxifen (TABLE 1). Women can’t take it if they are pregnant, planning to become pregnant, or if they don’t use a reliable form of birth control because it is teratogenic. Women also cannot take tamoxifen if they have had a history of blood clots, stroke, or transient ischemic attack; if they are on warfarin or estrogen preparations; or if they have had atypical endometrial biopsies or endometrial cancer. Those are the absolute contraindications for tamoxifen use.
Tamoxifen is generally very well tolerated in most women; some women experience hot flashes and night sweats that often will subside (or become tolerable) over the first 90 days. In addition, some women experience vaginal discharge rather than dryness, but it is not as bothersome to patients as dryness can be.
Tamoxifen can be used in the pre- or postmenopausal setting. In healthy premenopausal women, there’s no increased risk of the serious adverse effects that are seen with tamoxifen use in postmenopausal women, such as the 1% risk of blood clots and the 1% risk of endometrial cancer.
In postmenopausal women who still have their uterus, I’ll preferentially use raloxifene over tamoxifen. If they don’t have their uterus, tamoxifen is slightly more effective than the raloxifene, and I’ll use that.
Tamoxifen and raloxifene are both selective estrogen receptor modulators, or SERMs, which means that they stimulate receptors in some tissues, like bone, keeping bones strong, and block the receptors in other tissues, like the breast, reducing risk. And so you get kind of a two-for-one in terms of breast cancer risk reduction and osteoporosis prevention.
Another class of preventive drugs is the aromatase inhibitors (AIs). They block the enzyme aromatase, which converts androgens to estrogens peripherally; that is, the androgens that are produced primarily in the adrenal gland, but in part in postmenopausal ovaries.
In general, AIs are less well tolerated. There are generally more hot flashes and night sweats, and more vaginal dryness than with the SERMs. Anastrozole use is associated with arthralgias; and with exemestane use, there can be some hair loss (TABLE 2). Relative contraindications to SERMs become more important in the postmenopausal setting because of the increased frequency of both blood clots and uterine cancer in the postmenopausal years. I won’t give it to smokers. I won’t give tamoxifen to smokers in the premenopausal period either. With obese women, care must be taken because of the risk of blood clots with the SERMS, so then I’ll resort to the AIs. In the postmenopausal setting, you have to think a lot harder about the choices you use for preventive medication. Preferentially, I’ll use the SERMS if possible as they have fewer adverse effects.
Dr. Pederson: All of them are recommended to be given for 5 years, but the MAP.3 trial, which studied exemestane compared with placebo, showed a 65% risk reduction with 3 years of therapy.3 So occasionally, we’ll use 3 years of therapy. Why the treatment recommendation is universally 5 years is unclear, given that the trial with that particular drug was done in 3 years. And with low-dose tamoxifen, the recommended duration is 3 years. That study was done in Italy with 5 mg daily for 3 years.4 In the United States we use 10 mg every other day for 3 years because the 5-mg tablet is not available here.
Continue to: Counseling points...
Counseling points
Dr. Pederson: Patients’ fears about adverse effects are often worse than the adverse effects themselves. Women will fester over, Should I take it? Should I take it possibly for years? And then they take the medication and they tell me, “I don’t even notice that I’m taking it, and I know I’m being proactive.” The majority of patients who take these medications don’t have a lot of significant adverse effects.
Severe hot flashes can be managed in a number of ways, primarily and most effectively with certain antidepressants. Oxybutynin use is another good way to manage vasomotor symptoms. Sometimes we use local vaginal estrogen if a patient has vaginal dryness. In general, however, I would say at least 80% of my patients who take preventive medications do not require management of adverse side effects, that they are tolerable.
I counsel women this way, “Don’t think of this as a 5-year course of medication. Think of it as a 90-day trial, and let’s see how you do. If you hate it, then we don’t do it.” They often are pleasantly surprised that the medication is much easier to tolerate than they thought it would be.
Dr. Pederson: It would be neat if a trial would directly compare lifestyle interventions with medications, because probably lifestyle change is as effective as medication is—but we don’t know that and probably will never have that data. We do know that alcohol consumption, every drink per day, increases risk by 10%. We know that obesity is responsible for 30% of breast cancers in this country, and that hormone replacement probably is overrated as a significant risk factor. Updated data from the Women’s Health Initiative study suggest that hormone replacement may actually reduce both breast cancer and cardiovascular risk in women in their 50s, but that’s in average-risk women and not in high-risk women, so we can’t generalize. We do recommend lifestyle measures including weight loss, exercise, and limiting alcohol consumption for all of our patients and certainly for our high-risk patients.
The only 2 things a woman can do to reduce the risk of triple negative breast cancer are to achieve and maintain ideal body weight and to breastfeed. The medications that I have mentioned don’t reduce the risk of triple negative breast cancer. Staying thin and breastfeeding do. It’s a problem in this country because at least 35% of all women and 58% of Black women are obese in America, and Black women tend to be prone to triple-negative breast cancer. That’s a real public health issue that we need to address. If we were going to focus on one thing, it would be focusing on obesity in terms of risk reduction.
Final thoughts
Dr. Pederson: I would like to direct attention to the American Heart Association scientific statement published at the end of 2020 that reported that hormone replacement in average-risk women reduced both cardiovascular events and overall mortality in women in their 50s by 30%.5 While that’s not directly related to what we are talking about, we need to weigh the pros and cons of estrogen versus estrogen blockade in women in terms of breast cancer risk management discussions. Part of shared decision making now needs to include cardiovascular risk factors and how estrogen is going to play into that.
In women with atypical hyperplasia or LCIS, they may benefit from the preventive medications we discussed. But in women with family history or in women with genetic mutations who have not had benign atypical biopsies, they may choose to consider estrogen during their 50s and perhaps take tamoxifen either beforehand or raloxifene afterward.
We need to look at patients holistically and consider all their risk factors together. We can’t look at one dimension alone.
- US Preventive Services Task Force. Medication use to reduce risk of breast cancer: US Preventive Services Task Force Recommendation Statement. JAMA. 2019;322:857-867.
- Visvanathan K, Fabian CJ, Bantug E, et al. Use of endocrine therapy for breast cancer risk reduction: ASCO clinical practice guideline update. J Clin Oncol. 2019;37:3152-3165.
- Goss PE, Ingle JN, Alex-Martinez JE, et al. Exemestane for breast-cancer prevention in postmenopausal women. N Engl J Med. 2011;364:2381-2391.
- DeCensi A, Puntoni M, Guerrieri-Gonzaga A, et al. Randomized placebo controlled trial of low-dose tamoxifen to prevent local and contralateral recurrence in breast intraepithelial neoplasia. J Clin Oncol. 2019;37:1629-1637.
- El Khoudary SR, Aggarwal B, Beckie TM, et al; American Heart Association Prevention Science Committee of the Council on Epidemiology and Prevention, and Council on Cardiovascular and Stroke Nursing. Menopause transition and cardiovascular disease risk: implications for timing of early prevention: a scientific statement from the American Heart Association. Circulation. 2020;142:e506-e532.
- US Preventive Services Task Force. Medication use to reduce risk of breast cancer: US Preventive Services Task Force Recommendation Statement. JAMA. 2019;322:857-867.
- Visvanathan K, Fabian CJ, Bantug E, et al. Use of endocrine therapy for breast cancer risk reduction: ASCO clinical practice guideline update. J Clin Oncol. 2019;37:3152-3165.
- Goss PE, Ingle JN, Alex-Martinez JE, et al. Exemestane for breast-cancer prevention in postmenopausal women. N Engl J Med. 2011;364:2381-2391.
- DeCensi A, Puntoni M, Guerrieri-Gonzaga A, et al. Randomized placebo controlled trial of low-dose tamoxifen to prevent local and contralateral recurrence in breast intraepithelial neoplasia. J Clin Oncol. 2019;37:1629-1637.
- El Khoudary SR, Aggarwal B, Beckie TM, et al; American Heart Association Prevention Science Committee of the Council on Epidemiology and Prevention, and Council on Cardiovascular and Stroke Nursing. Menopause transition and cardiovascular disease risk: implications for timing of early prevention: a scientific statement from the American Heart Association. Circulation. 2020;142:e506-e532.
Cancer prevention through cascade genetic testing: A review of the current practice guidelines, barriers to testing and proposed solutions
CASE Woman with BRCA2 mutation
An 80-year-old woman presents for evaluation of newly diagnosed metastatic pancreatic adenocarcinoma. Her medical history is notable for breast cancer. Genetic testing of pancreatic tumor tissue detected a pathogenic variant in BRCA2. Family history revealed a history of melanoma as well as bladder, prostate, breast, and colon cancer. The patient subsequently underwent germline genetic testing with an 86-gene panel and a pathogenic mutation in BRCA2 was identified.
Watch a video of this patient and her clinician, Dr. Andrea Hagemann: https://www.youtube.com/watch?
Methods of genetic testing
It is estimated that 1 in 300 to 1 in 500 women in the United States carry a deleterious mutation in BRCA1 or BRCA2. This equates to between 250,000 and 415,000 women who are at high risk for breast and ovarian cancer.1 Looking at all women with cancer, 20% with ovarian,2 10% with breast,3 2% to 3% with endometrial,4 and 5% with colon cancer5 will have a germline mutation predisposing them to cancer. Identification of germline or somatic (tumor) mutations now inform treatment for patients with cancer. An equally important goal of germline genetic testing is cancer prevention. Cancer prevention strategies include risk-based screening for breast, colon, melanoma, and pancreatic cancer and prophylactic surgeries to reduce the risk of breast and ovarian cancer based on mutation type. Evidence-based screening guidelines by mutation type and absolute risk of associated cancers can be found on the National Comprehensive Cancer Network (NCCN).6,7
Multiple strategies have been proposed to identify patients for germline genetic testing. Patients can be identified based on a detailed multigenerational family history. This strategy requires clinicians or genetic counselors to take and update family histories, to recognize when a patient requires referral for testing, and for such testing to be completed. Even then the generation of a detailed pedigree is not very sensitive or specific. Population-based screening for high-penetrance breast and ovarian cancer susceptibility genes, regardless of family history, also has been proposed.8 Such a strategy has become increasingly realistic with decreasing cost and increasing availability of genetic testing. However, it would require increased genetic counseling resources to feasibly and equitably reach the target population and to explain the results to those patients and their relatives.
An alternative is to test the enriched population of family members of a patient with cancer who has been found to carry a pathogenic variant in a clinically relevant cancer susceptibility gene. This type of testing is termed cascade genetic testing. Cascade testing in first-degree family members carries a 50% probability of detecting the same pathogenic mutation. A related testing model is traceback testing where genetic testing is performed on pathology or tumor registry specimens from deceased patients with cancer.9 This genetic testing information is then provided to the family. Traceback models of genetic testing are an active area of research but can introduce ethical dilemmas. The more widely accepted cascade testing starts with the testing of a living patient affected with cancer. A recent article demonstrated the feasibility of a cascade testing model. Using a multiple linear regression model, the authors determined that all carriers of pathogenic mutations in 18 clinically relevant cancer susceptibility genes in the United States could be identified in 9.9 years if there was a 70% cascade testing rate of first-, second- and third-degree relatives, compared to 59.5 years with no cascade testing.10
Gaps in practice
Identification of mutation carriers, either through screening triggered by family history or through testing of patients affected with cancer, represents a gap between guidelines and clinical practice. Current NCCN guidelines outline genetic testing criteria for hereditary breast and ovarian cancer syndrome and for hereditary colorectal cancer. Despite well-established criteria, a survey in the United States revealed that only 19% of primary care providers were able to accurately assess family history for BRCA1 and 2 testing.11 Looking at patients who meet criteria for testing for Lynch syndrome, only 1 in 4 individuals have undergone genetic testing.12 Among patients diagnosed with breast and ovarian cancer, current NCCN guidelines recommend germline genetic testing for all patients with epithelial ovarian cancer; emerging evidence suggests all patients with breast cancer should be offered germline genetic testing.7,13 Large population-based studies have repeatedly demonstrated that testing rates fall short of this goal, with only 10% to 30% of patients undergoing genetic testing.9,14
Among families with a known hereditary mutation, rates of cascade genetic testing are also low, ranging from 17% to 50%.15-18 Evidence-based management guidelines, for both hereditary breast and ovarian cancer as well as Lynch syndrome, have been shown to reduce mortality.19,20 Failure to identify patients who carry these genetic mutations equates to increased mortality for our patients.
Barriers to cascade genetic testing
Cascade genetic testing ideally would be performed on entire families. Actual practice is far from ideal, and barriers to cascade testing exist. Barriers encompass resistance on the part of the family and provider as well as environmental or system factors.
Family factors
Because of privacy laws, the responsibility of disclosure of genetic testing results to family members falls primarily to the patient. Proband education is critical to ensure disclosure amongst family members. Family dynamics and geographic distribution of family members can further complicate disclosure. Following disclosure, family member gender, education, and demographics as well as personal views, attitudes, and emotions affect whether a family member decides to undergo testing.21 Furthermore, insurance status and awareness of and access to specialty-specific care for the proband’s family members may influence cascade genetic testing rates.
Provider factors
Provider factors that affect cascade genetic testing include awareness of testing guidelines, interpretation of genetic testing results, and education and knowledge of specific mutations. For instance, providers must recognize that cascade testing is not appropriate for variants of uncertain significance. This can lead to unnecessary surveillance testing and prophylactic surgeries. Providers, however, must continue to follow patients and periodically update testing results as variants may be reclassified over time. Additionally, providers must be knowledgeable about the complex and nuanced nature of the screening guidelines for each mutation. The NCCN provides detailed recommendations by mutation.7 Patients may benefit from care with cancer specialists who are aware of the guidelines, particularly for moderate-penetrance genes like BRIP1 and PALB2, as discussions about the timing of risk-reducing surgery are more nuanced in this population. Finally, which providers are responsible for facilitating cascade testing may be unclear; oncologists and genetic counselors not primarily treating probands’ relatives may assume the proper information has been passed along to family members without a practical means to follow up, and primary care providers may assume it is being taken care of by the oncology provider.
Continue to: Environmental or system factors...
Environmental or system factors
Accessibility of genetic counseling and testing is a common barrier to cascade testing. Family members may be geographically remote and connecting them to counseling and testing can be challenging. Working with local genetic counselors can facilitate this process. Insurance coverage of testing is a common perceived barrier; however, many testing companies now provide cascade testing free of charge if within a certain window from the initial test. Despite this, patients often site cost as a barrier to undergoing testing. Concerns about insurance coverage are common after a positive result. The Genetic Information Nondiscrimination Act of 2008 prohibits discrimination against employees or insurance applicants because of genetic information. Life insurance or long-term care policies, however, can incorporate genetic testing information into policy rates, so patients should be recommended to consider purchasing life insurance prior to undergoing genetic testing. This is especially important if the person considering testing has not yet been diagnosed with cancer.
Implications of a positive result
Family members who receive a positive test result should be referred for genetic counseling and to the appropriate specialists for evidence-based screening and discussion for risk-reducing surgery (FIGURE).7 For mutations associated with hereditary breast and ovarian cancer, referral to breast and gynecologic surgeons with expertise in risk reducing surgery is critical as the risk of diagnosing an occult malignancy is approximately 1%.22 Surgical technique with a 2-cm margin on the
Patient resources: decision aids, websites
As genetic testing becomes more accessible and people are tested at younger ages, studies examining the balance of risk reduction and quality of life (QOL) are increasingly important. Fertility concerns, effects of early menopause, and the interrelatedness between decisions for breast and gynecologic risk reduction should all be considered in the counseling for surgical risk reduction. Patient decision aids can help mutation carriers navigate the complex information and decisions.25 Websites specifically designed by advocacy groups can be useful adjuncts to in-office counseling (Facing Our Risk Empowered, FORCE; Facingourrisk.org).
Family letters
The American College of Obstetricians and Gynecologists recommends an ObGyn have a letter or documentation stating that the patient’s relative has a specific mutation before initiating cascade testing for an at-risk family member. The indicated test (such as BRCA1) should be ordered only after the patient has been counseled about potential outcomes and has expressly decided to be tested.26 Letters, such as the example given in the American College of Obstetricians and Gynecologists practice bulletin,26 are a key component of communication between oncology providers, probands, family members, and their primary care providers. ObGyn providers should work together with genetic counselors and gynecologic oncologists to determine the most efficient strategies in their communities.
Technology
Access to genetic testing and genetic counseling has been improved with the rise in telemedicine. Geographically remote patients can now access genetic counseling through medical center–based counselors as well as company-provided genetic counseling over the phone. Patients also can submit samples remotely without needing to be tested in a doctor’s office.
Databases from cancer centers that detail cascade genetic testing rates. As the preventive impact of cascade genetic testing becomes clearer, strategies to have recurrent discussions with cancer patients regarding their family members’ risk should be implemented. It is still unclear which providers—genetic counselors, gynecologic oncologists, medical oncologists, breast surgeons, ObGyns, to name a few—are primarily responsible for remembering to have these follow-up discussions, and despite advances, the burden still rests on the cancer patient themselves. Databases with automated follow-up surveys done every 6 to 12 months could provide some aid to busy providers in this regard.
Emerging research
If gynecologic risk-reducing surgery is chosen, clinical trial involvement should be encouraged. The Women Choosing Surgical Prevention (NCT02760849) in the United States and the TUBA study (NCT02321228) in the Netherlands were designed to compare menopause-related QOL between standard risk-reducing salpingo-oophorectomy (RRSO) and the innovative risk-reducing salpingectomy with delayed oophorectomy for mutation carriers. Results from the nonrandomized controlled TUBA trial suggest that patients have better menopause-related QOL after risk-reducing salpingectomy than after RRSO, regardless of hormone replacement therapy.27 International collaboration is continuing to better understand oncologic safety. In the United States, the SOROCk trial (NCT04251052) is a noninferiority surgical choice study underway for BRCA1 mutation carriers aged 35 to 50, powered to determine oncologic outcome differences in addition to QOL outcomes between RRSO and delayed oophorectomy arms.
Returning to the case
The patient and her family underwent genetic counseling. The patient’s 2 daughters, each in their 50s, underwent cascade genetic testing and were found to carry the same pathogenic mutation in BRCA2. After counseling from both breast and gynecologic surgeons, they both elected to undergo risk reducing bilateral salpingo-oophorectomy with hysterectomy. Both now complete regular screening for breast cancer and melanoma with plans to start screening for pancreatic cancer. Both are currently cancer free.
Summary
Cascade genetic testing is an efficient strategy to identify mutation carriers for hereditary breast and ovarian cancer syndrome. Implementation of the best patient-centric care will require continued collaboration and communication across and within disciplines. ●
Cascade, or targeted, genetic testing within families known to carry a hereditary mutation in a cancer susceptibility gene should be performed on all living first-degree family members over the age of 18. All mutation carriers should be connected to a multidisciplinary care team (FIGURE) to ensure implementation of evidence-based screening and risk-reducing surgery for cancer prevention. If gynecologic risk-reducing surgery is chosen, clinical trial involvement should be encouraged.
- Gabai-Kapara E, Lahad A, Kaufman B, et al. Population-based screening for breast and ovarian cancer risk due to BRCA1 and BRCA2. Proc Natl Acad Sci U S A. 2014;111:14205-14210.
- Norquist BM, Harrell MI, Brady MF, et al. Inherited mutations in women with ovarian carcinoma. JAMA Oncol. 2016;2:482-490.
- Yamauchi H, Takei J. Management of hereditary breast and ovarian cancer. Int J Clin Oncol. 2018;23:45-51.
- Kahn RM, Gordhandas S, Maddy BP, et al. Universal endometrial cancer tumor typing: how much has immunohistochemistry, microsatellite instability, and MLH1 methylation improved the diagnosis of Lynch syndrome across the population? Cancer. 2019;125:3172-3183.
- Jasperson KW, Tuohy TM, Neklason DW, et al. Hereditary and familial colon cancer. Gastroenterology. 2010;138:2044-2058.
- Gupta S, Provenzale D, Llor X, et al. NCCN guidelines insights: genetic/familial high-risk assessment: colorectal, version 2.2019. J Natl Compr Canc Netw. 2019;17:1032-1041.
- Daly MB, Pal T, Berry MP, et al. Genetic/familial high-risk assessment: breast, ovarian, and pancreatic, version 2.2021, NCCN clinical practice guidelines in oncology. J Natl Compr Canc Netw. 2021;19:77-102.
- King MC, Levy-Lahad E, Lahad A. Population-based screening for BRCA1 and BRCA2: 2014 Lasker Award. JAMA. 2014;312:1091-1092.
- Samimi G, et al. Traceback: a proposed framework to increase identification and genetic counseling of BRCA1 and BRCA2 mutation carriers through family-based outreach. J Clin Oncol. 2017;35:2329-2337.
- Offit K, Tkachuk KA, Stadler ZK, et al. Cascading after peridiagnostic cancer genetic testing: an alternative to population-based screening. J Clin Oncol. 2020;38:1398-1408.
- Bellcross CA, Kolor K, Goddard KAB, et al. Awareness and utilization of BRCA1/2 testing among U.S. primary care physicians. Am J Prev Med. 2011;40:61-66.
- Cross DS, Rahm AK, Kauffman TL, et al. Underutilization of Lynch syndrome screening in a multisite study of patients with colorectal cancer. Genet Med. 2013;15:933-940.
- Beitsch PD, Whitworth PW, Hughes K, et al. Underdiagnosis of hereditary breast cancer: are genetic testing guidelines a tool or an obstacle? J Clin Oncol. 2019;37:453-460.
- Childers CP, Childers KK, Maggard-Gibbons M, et al. National estimates of genetic testing in women with a history of breast or ovarian cancer. J Clin Oncol. 2017;35:3800-3806.
- Samadder NJ, Riegert-Johnson D, Boardman L, et al. Comparison of universal genetic testing vs guideline-directed targeted testing for patients with hereditary cancer syndrome. JAMA Oncol. 2021;7:230-237.
- Sharaf RN, Myer P, Stave CD, et al. Uptake of genetic testing by relatives of Lynch syndrome probands: a systematic review. Clin Gastroenterol Hepatol. 2013;11:1093-1100.
- Menko FH, Ter Stege JA, van der Kolk LE, et al. The uptake of presymptomatic genetic testing in hereditary breast-ovarian cancer and Lynch syndrome: a systematic review of the literature and implications for clinical practice. Fam Cancer. 2019;18:127-135.
- Griffin NE, Buchanan TR, Smith SH, et al. Low rates of cascade genetic testing among families with hereditary gynecologic cancer: an opportunity to improve cancer prevention. Gynecol Oncol. 2020;156:140-146.
- Roberts MC, Dotson WD, DeVore CS, et al. Delivery of cascade screening for hereditary conditions: a scoping review of the literature. Health Aff (Millwood). 2018;37:801-808.
- Finch AP, Lubinski J, Møller P, et al. Impact of oophorectomy on cancer incidence and mortality in women with a BRCA1 or BRCA2 mutation. J Clin Oncol. 2014;32:1547-1553.
- Srinivasan S, Won NY, Dotson WD, et al. Barriers and facilitators for cascade testing in genetic conditions: a systematic review. Eur J Hum Genet. 2020;28:1631-1644.
- Piedimonte S, Frank C, Laprise C, et al. Occult tubal carcinoma after risk-reducing salpingo-oophorectomy: a systematic review. Obstet Gynecol. 2020;135:498-508.
- Shu CA, Pike MC, Jotwani AR, et al. Uterine cancer after risk-reducing salpingo-oophorectomy without hysterectomy in women with BRCA mutations. JAMA Oncol. 2016;2:1434-1440.
- Gordhandas S, Norquist BM, Pennington KP, et al. Hormone replacement therapy after risk reducing salpingo-oophorectomy in patients with BRCA1 or BRCA2 mutations; a systematic review of risks and benefits. Gynecol Oncol. 2019;153:192-200.
- Steenbeek MP, van Bommel MHD, Harmsen MG, et al. Evaluation of a patient decision aid for BRCA1/2 pathogenic variant carriers choosing an ovarian cancer prevention strategy. Gynecol Oncol. 2021;163:371-377.
- Committee on Gynecologic Practice. ACOG committee opinion No. 727: Cascade testing: testing women for known hereditary genetic mutations associated with cancer. Obstet Gynecol. 2018;131:E31-E34.
- Steenbeek MP, Harmsen MG, Hoogerbrugge N, et al. Association of salpingectomy with delayed oophorectomy versus salpingo-oophorectomy with quality of life in BRCA1/2 pathogenic variant carriers: a nonrandomized controlled trial. JAMA Oncol. 2021;7:1203-1212.
Dr. Stock is a Fellow in the Division of Gynecologic Oncology, Washington University School of Medicine, St. Louis, Missouri.
Dr. Mutch is Ira C. and Judith Gall Professor and Vice Chair of Obstetrics and Gynecology in the Department of ObGyn, Division of Gynecologic Oncology, Washington University School of Medicine.
Dr. Hagemann is Associate Professor of Obstetrics and Gynecology, and Director of Hereditary Genetics Clinic in the Division of Gynecologic Oncology, Washington University School of Medicine.
The authors report no financial relationships relevant to this article.
Dr. Stock is a Fellow in the Division of Gynecologic Oncology, Washington University School of Medicine, St. Louis, Missouri.
Dr. Mutch is Ira C. and Judith Gall Professor and Vice Chair of Obstetrics and Gynecology in the Department of ObGyn, Division of Gynecologic Oncology, Washington University School of Medicine.
Dr. Hagemann is Associate Professor of Obstetrics and Gynecology, and Director of Hereditary Genetics Clinic in the Division of Gynecologic Oncology, Washington University School of Medicine.
The authors report no financial relationships relevant to this article.
Dr. Stock is a Fellow in the Division of Gynecologic Oncology, Washington University School of Medicine, St. Louis, Missouri.
Dr. Mutch is Ira C. and Judith Gall Professor and Vice Chair of Obstetrics and Gynecology in the Department of ObGyn, Division of Gynecologic Oncology, Washington University School of Medicine.
Dr. Hagemann is Associate Professor of Obstetrics and Gynecology, and Director of Hereditary Genetics Clinic in the Division of Gynecologic Oncology, Washington University School of Medicine.
The authors report no financial relationships relevant to this article.
CASE Woman with BRCA2 mutation
An 80-year-old woman presents for evaluation of newly diagnosed metastatic pancreatic adenocarcinoma. Her medical history is notable for breast cancer. Genetic testing of pancreatic tumor tissue detected a pathogenic variant in BRCA2. Family history revealed a history of melanoma as well as bladder, prostate, breast, and colon cancer. The patient subsequently underwent germline genetic testing with an 86-gene panel and a pathogenic mutation in BRCA2 was identified.
Watch a video of this patient and her clinician, Dr. Andrea Hagemann: https://www.youtube.com/watch?
Methods of genetic testing
It is estimated that 1 in 300 to 1 in 500 women in the United States carry a deleterious mutation in BRCA1 or BRCA2. This equates to between 250,000 and 415,000 women who are at high risk for breast and ovarian cancer.1 Looking at all women with cancer, 20% with ovarian,2 10% with breast,3 2% to 3% with endometrial,4 and 5% with colon cancer5 will have a germline mutation predisposing them to cancer. Identification of germline or somatic (tumor) mutations now inform treatment for patients with cancer. An equally important goal of germline genetic testing is cancer prevention. Cancer prevention strategies include risk-based screening for breast, colon, melanoma, and pancreatic cancer and prophylactic surgeries to reduce the risk of breast and ovarian cancer based on mutation type. Evidence-based screening guidelines by mutation type and absolute risk of associated cancers can be found on the National Comprehensive Cancer Network (NCCN).6,7
Multiple strategies have been proposed to identify patients for germline genetic testing. Patients can be identified based on a detailed multigenerational family history. This strategy requires clinicians or genetic counselors to take and update family histories, to recognize when a patient requires referral for testing, and for such testing to be completed. Even then the generation of a detailed pedigree is not very sensitive or specific. Population-based screening for high-penetrance breast and ovarian cancer susceptibility genes, regardless of family history, also has been proposed.8 Such a strategy has become increasingly realistic with decreasing cost and increasing availability of genetic testing. However, it would require increased genetic counseling resources to feasibly and equitably reach the target population and to explain the results to those patients and their relatives.
An alternative is to test the enriched population of family members of a patient with cancer who has been found to carry a pathogenic variant in a clinically relevant cancer susceptibility gene. This type of testing is termed cascade genetic testing. Cascade testing in first-degree family members carries a 50% probability of detecting the same pathogenic mutation. A related testing model is traceback testing where genetic testing is performed on pathology or tumor registry specimens from deceased patients with cancer.9 This genetic testing information is then provided to the family. Traceback models of genetic testing are an active area of research but can introduce ethical dilemmas. The more widely accepted cascade testing starts with the testing of a living patient affected with cancer. A recent article demonstrated the feasibility of a cascade testing model. Using a multiple linear regression model, the authors determined that all carriers of pathogenic mutations in 18 clinically relevant cancer susceptibility genes in the United States could be identified in 9.9 years if there was a 70% cascade testing rate of first-, second- and third-degree relatives, compared to 59.5 years with no cascade testing.10
Gaps in practice
Identification of mutation carriers, either through screening triggered by family history or through testing of patients affected with cancer, represents a gap between guidelines and clinical practice. Current NCCN guidelines outline genetic testing criteria for hereditary breast and ovarian cancer syndrome and for hereditary colorectal cancer. Despite well-established criteria, a survey in the United States revealed that only 19% of primary care providers were able to accurately assess family history for BRCA1 and 2 testing.11 Looking at patients who meet criteria for testing for Lynch syndrome, only 1 in 4 individuals have undergone genetic testing.12 Among patients diagnosed with breast and ovarian cancer, current NCCN guidelines recommend germline genetic testing for all patients with epithelial ovarian cancer; emerging evidence suggests all patients with breast cancer should be offered germline genetic testing.7,13 Large population-based studies have repeatedly demonstrated that testing rates fall short of this goal, with only 10% to 30% of patients undergoing genetic testing.9,14
Among families with a known hereditary mutation, rates of cascade genetic testing are also low, ranging from 17% to 50%.15-18 Evidence-based management guidelines, for both hereditary breast and ovarian cancer as well as Lynch syndrome, have been shown to reduce mortality.19,20 Failure to identify patients who carry these genetic mutations equates to increased mortality for our patients.
Barriers to cascade genetic testing
Cascade genetic testing ideally would be performed on entire families. Actual practice is far from ideal, and barriers to cascade testing exist. Barriers encompass resistance on the part of the family and provider as well as environmental or system factors.
Family factors
Because of privacy laws, the responsibility of disclosure of genetic testing results to family members falls primarily to the patient. Proband education is critical to ensure disclosure amongst family members. Family dynamics and geographic distribution of family members can further complicate disclosure. Following disclosure, family member gender, education, and demographics as well as personal views, attitudes, and emotions affect whether a family member decides to undergo testing.21 Furthermore, insurance status and awareness of and access to specialty-specific care for the proband’s family members may influence cascade genetic testing rates.
Provider factors
Provider factors that affect cascade genetic testing include awareness of testing guidelines, interpretation of genetic testing results, and education and knowledge of specific mutations. For instance, providers must recognize that cascade testing is not appropriate for variants of uncertain significance. This can lead to unnecessary surveillance testing and prophylactic surgeries. Providers, however, must continue to follow patients and periodically update testing results as variants may be reclassified over time. Additionally, providers must be knowledgeable about the complex and nuanced nature of the screening guidelines for each mutation. The NCCN provides detailed recommendations by mutation.7 Patients may benefit from care with cancer specialists who are aware of the guidelines, particularly for moderate-penetrance genes like BRIP1 and PALB2, as discussions about the timing of risk-reducing surgery are more nuanced in this population. Finally, which providers are responsible for facilitating cascade testing may be unclear; oncologists and genetic counselors not primarily treating probands’ relatives may assume the proper information has been passed along to family members without a practical means to follow up, and primary care providers may assume it is being taken care of by the oncology provider.
Continue to: Environmental or system factors...
Environmental or system factors
Accessibility of genetic counseling and testing is a common barrier to cascade testing. Family members may be geographically remote and connecting them to counseling and testing can be challenging. Working with local genetic counselors can facilitate this process. Insurance coverage of testing is a common perceived barrier; however, many testing companies now provide cascade testing free of charge if within a certain window from the initial test. Despite this, patients often site cost as a barrier to undergoing testing. Concerns about insurance coverage are common after a positive result. The Genetic Information Nondiscrimination Act of 2008 prohibits discrimination against employees or insurance applicants because of genetic information. Life insurance or long-term care policies, however, can incorporate genetic testing information into policy rates, so patients should be recommended to consider purchasing life insurance prior to undergoing genetic testing. This is especially important if the person considering testing has not yet been diagnosed with cancer.
Implications of a positive result
Family members who receive a positive test result should be referred for genetic counseling and to the appropriate specialists for evidence-based screening and discussion for risk-reducing surgery (FIGURE).7 For mutations associated with hereditary breast and ovarian cancer, referral to breast and gynecologic surgeons with expertise in risk reducing surgery is critical as the risk of diagnosing an occult malignancy is approximately 1%.22 Surgical technique with a 2-cm margin on the
Patient resources: decision aids, websites
As genetic testing becomes more accessible and people are tested at younger ages, studies examining the balance of risk reduction and quality of life (QOL) are increasingly important. Fertility concerns, effects of early menopause, and the interrelatedness between decisions for breast and gynecologic risk reduction should all be considered in the counseling for surgical risk reduction. Patient decision aids can help mutation carriers navigate the complex information and decisions.25 Websites specifically designed by advocacy groups can be useful adjuncts to in-office counseling (Facing Our Risk Empowered, FORCE; Facingourrisk.org).
Family letters
The American College of Obstetricians and Gynecologists recommends an ObGyn have a letter or documentation stating that the patient’s relative has a specific mutation before initiating cascade testing for an at-risk family member. The indicated test (such as BRCA1) should be ordered only after the patient has been counseled about potential outcomes and has expressly decided to be tested.26 Letters, such as the example given in the American College of Obstetricians and Gynecologists practice bulletin,26 are a key component of communication between oncology providers, probands, family members, and their primary care providers. ObGyn providers should work together with genetic counselors and gynecologic oncologists to determine the most efficient strategies in their communities.
Technology
Access to genetic testing and genetic counseling has been improved with the rise in telemedicine. Geographically remote patients can now access genetic counseling through medical center–based counselors as well as company-provided genetic counseling over the phone. Patients also can submit samples remotely without needing to be tested in a doctor’s office.
Databases from cancer centers that detail cascade genetic testing rates. As the preventive impact of cascade genetic testing becomes clearer, strategies to have recurrent discussions with cancer patients regarding their family members’ risk should be implemented. It is still unclear which providers—genetic counselors, gynecologic oncologists, medical oncologists, breast surgeons, ObGyns, to name a few—are primarily responsible for remembering to have these follow-up discussions, and despite advances, the burden still rests on the cancer patient themselves. Databases with automated follow-up surveys done every 6 to 12 months could provide some aid to busy providers in this regard.
Emerging research
If gynecologic risk-reducing surgery is chosen, clinical trial involvement should be encouraged. The Women Choosing Surgical Prevention (NCT02760849) in the United States and the TUBA study (NCT02321228) in the Netherlands were designed to compare menopause-related QOL between standard risk-reducing salpingo-oophorectomy (RRSO) and the innovative risk-reducing salpingectomy with delayed oophorectomy for mutation carriers. Results from the nonrandomized controlled TUBA trial suggest that patients have better menopause-related QOL after risk-reducing salpingectomy than after RRSO, regardless of hormone replacement therapy.27 International collaboration is continuing to better understand oncologic safety. In the United States, the SOROCk trial (NCT04251052) is a noninferiority surgical choice study underway for BRCA1 mutation carriers aged 35 to 50, powered to determine oncologic outcome differences in addition to QOL outcomes between RRSO and delayed oophorectomy arms.
Returning to the case
The patient and her family underwent genetic counseling. The patient’s 2 daughters, each in their 50s, underwent cascade genetic testing and were found to carry the same pathogenic mutation in BRCA2. After counseling from both breast and gynecologic surgeons, they both elected to undergo risk reducing bilateral salpingo-oophorectomy with hysterectomy. Both now complete regular screening for breast cancer and melanoma with plans to start screening for pancreatic cancer. Both are currently cancer free.
Summary
Cascade genetic testing is an efficient strategy to identify mutation carriers for hereditary breast and ovarian cancer syndrome. Implementation of the best patient-centric care will require continued collaboration and communication across and within disciplines. ●
Cascade, or targeted, genetic testing within families known to carry a hereditary mutation in a cancer susceptibility gene should be performed on all living first-degree family members over the age of 18. All mutation carriers should be connected to a multidisciplinary care team (FIGURE) to ensure implementation of evidence-based screening and risk-reducing surgery for cancer prevention. If gynecologic risk-reducing surgery is chosen, clinical trial involvement should be encouraged.
CASE Woman with BRCA2 mutation
An 80-year-old woman presents for evaluation of newly diagnosed metastatic pancreatic adenocarcinoma. Her medical history is notable for breast cancer. Genetic testing of pancreatic tumor tissue detected a pathogenic variant in BRCA2. Family history revealed a history of melanoma as well as bladder, prostate, breast, and colon cancer. The patient subsequently underwent germline genetic testing with an 86-gene panel and a pathogenic mutation in BRCA2 was identified.
Watch a video of this patient and her clinician, Dr. Andrea Hagemann: https://www.youtube.com/watch?
Methods of genetic testing
It is estimated that 1 in 300 to 1 in 500 women in the United States carry a deleterious mutation in BRCA1 or BRCA2. This equates to between 250,000 and 415,000 women who are at high risk for breast and ovarian cancer.1 Looking at all women with cancer, 20% with ovarian,2 10% with breast,3 2% to 3% with endometrial,4 and 5% with colon cancer5 will have a germline mutation predisposing them to cancer. Identification of germline or somatic (tumor) mutations now inform treatment for patients with cancer. An equally important goal of germline genetic testing is cancer prevention. Cancer prevention strategies include risk-based screening for breast, colon, melanoma, and pancreatic cancer and prophylactic surgeries to reduce the risk of breast and ovarian cancer based on mutation type. Evidence-based screening guidelines by mutation type and absolute risk of associated cancers can be found on the National Comprehensive Cancer Network (NCCN).6,7
Multiple strategies have been proposed to identify patients for germline genetic testing. Patients can be identified based on a detailed multigenerational family history. This strategy requires clinicians or genetic counselors to take and update family histories, to recognize when a patient requires referral for testing, and for such testing to be completed. Even then the generation of a detailed pedigree is not very sensitive or specific. Population-based screening for high-penetrance breast and ovarian cancer susceptibility genes, regardless of family history, also has been proposed.8 Such a strategy has become increasingly realistic with decreasing cost and increasing availability of genetic testing. However, it would require increased genetic counseling resources to feasibly and equitably reach the target population and to explain the results to those patients and their relatives.
An alternative is to test the enriched population of family members of a patient with cancer who has been found to carry a pathogenic variant in a clinically relevant cancer susceptibility gene. This type of testing is termed cascade genetic testing. Cascade testing in first-degree family members carries a 50% probability of detecting the same pathogenic mutation. A related testing model is traceback testing where genetic testing is performed on pathology or tumor registry specimens from deceased patients with cancer.9 This genetic testing information is then provided to the family. Traceback models of genetic testing are an active area of research but can introduce ethical dilemmas. The more widely accepted cascade testing starts with the testing of a living patient affected with cancer. A recent article demonstrated the feasibility of a cascade testing model. Using a multiple linear regression model, the authors determined that all carriers of pathogenic mutations in 18 clinically relevant cancer susceptibility genes in the United States could be identified in 9.9 years if there was a 70% cascade testing rate of first-, second- and third-degree relatives, compared to 59.5 years with no cascade testing.10
Gaps in practice
Identification of mutation carriers, either through screening triggered by family history or through testing of patients affected with cancer, represents a gap between guidelines and clinical practice. Current NCCN guidelines outline genetic testing criteria for hereditary breast and ovarian cancer syndrome and for hereditary colorectal cancer. Despite well-established criteria, a survey in the United States revealed that only 19% of primary care providers were able to accurately assess family history for BRCA1 and 2 testing.11 Looking at patients who meet criteria for testing for Lynch syndrome, only 1 in 4 individuals have undergone genetic testing.12 Among patients diagnosed with breast and ovarian cancer, current NCCN guidelines recommend germline genetic testing for all patients with epithelial ovarian cancer; emerging evidence suggests all patients with breast cancer should be offered germline genetic testing.7,13 Large population-based studies have repeatedly demonstrated that testing rates fall short of this goal, with only 10% to 30% of patients undergoing genetic testing.9,14
Among families with a known hereditary mutation, rates of cascade genetic testing are also low, ranging from 17% to 50%.15-18 Evidence-based management guidelines, for both hereditary breast and ovarian cancer as well as Lynch syndrome, have been shown to reduce mortality.19,20 Failure to identify patients who carry these genetic mutations equates to increased mortality for our patients.
Barriers to cascade genetic testing
Cascade genetic testing ideally would be performed on entire families. Actual practice is far from ideal, and barriers to cascade testing exist. Barriers encompass resistance on the part of the family and provider as well as environmental or system factors.
Family factors
Because of privacy laws, the responsibility of disclosure of genetic testing results to family members falls primarily to the patient. Proband education is critical to ensure disclosure amongst family members. Family dynamics and geographic distribution of family members can further complicate disclosure. Following disclosure, family member gender, education, and demographics as well as personal views, attitudes, and emotions affect whether a family member decides to undergo testing.21 Furthermore, insurance status and awareness of and access to specialty-specific care for the proband’s family members may influence cascade genetic testing rates.
Provider factors
Provider factors that affect cascade genetic testing include awareness of testing guidelines, interpretation of genetic testing results, and education and knowledge of specific mutations. For instance, providers must recognize that cascade testing is not appropriate for variants of uncertain significance. This can lead to unnecessary surveillance testing and prophylactic surgeries. Providers, however, must continue to follow patients and periodically update testing results as variants may be reclassified over time. Additionally, providers must be knowledgeable about the complex and nuanced nature of the screening guidelines for each mutation. The NCCN provides detailed recommendations by mutation.7 Patients may benefit from care with cancer specialists who are aware of the guidelines, particularly for moderate-penetrance genes like BRIP1 and PALB2, as discussions about the timing of risk-reducing surgery are more nuanced in this population. Finally, which providers are responsible for facilitating cascade testing may be unclear; oncologists and genetic counselors not primarily treating probands’ relatives may assume the proper information has been passed along to family members without a practical means to follow up, and primary care providers may assume it is being taken care of by the oncology provider.
Continue to: Environmental or system factors...
Environmental or system factors
Accessibility of genetic counseling and testing is a common barrier to cascade testing. Family members may be geographically remote and connecting them to counseling and testing can be challenging. Working with local genetic counselors can facilitate this process. Insurance coverage of testing is a common perceived barrier; however, many testing companies now provide cascade testing free of charge if within a certain window from the initial test. Despite this, patients often site cost as a barrier to undergoing testing. Concerns about insurance coverage are common after a positive result. The Genetic Information Nondiscrimination Act of 2008 prohibits discrimination against employees or insurance applicants because of genetic information. Life insurance or long-term care policies, however, can incorporate genetic testing information into policy rates, so patients should be recommended to consider purchasing life insurance prior to undergoing genetic testing. This is especially important if the person considering testing has not yet been diagnosed with cancer.
Implications of a positive result
Family members who receive a positive test result should be referred for genetic counseling and to the appropriate specialists for evidence-based screening and discussion for risk-reducing surgery (FIGURE).7 For mutations associated with hereditary breast and ovarian cancer, referral to breast and gynecologic surgeons with expertise in risk reducing surgery is critical as the risk of diagnosing an occult malignancy is approximately 1%.22 Surgical technique with a 2-cm margin on the
Patient resources: decision aids, websites
As genetic testing becomes more accessible and people are tested at younger ages, studies examining the balance of risk reduction and quality of life (QOL) are increasingly important. Fertility concerns, effects of early menopause, and the interrelatedness between decisions for breast and gynecologic risk reduction should all be considered in the counseling for surgical risk reduction. Patient decision aids can help mutation carriers navigate the complex information and decisions.25 Websites specifically designed by advocacy groups can be useful adjuncts to in-office counseling (Facing Our Risk Empowered, FORCE; Facingourrisk.org).
Family letters
The American College of Obstetricians and Gynecologists recommends an ObGyn have a letter or documentation stating that the patient’s relative has a specific mutation before initiating cascade testing for an at-risk family member. The indicated test (such as BRCA1) should be ordered only after the patient has been counseled about potential outcomes and has expressly decided to be tested.26 Letters, such as the example given in the American College of Obstetricians and Gynecologists practice bulletin,26 are a key component of communication between oncology providers, probands, family members, and their primary care providers. ObGyn providers should work together with genetic counselors and gynecologic oncologists to determine the most efficient strategies in their communities.
Technology
Access to genetic testing and genetic counseling has been improved with the rise in telemedicine. Geographically remote patients can now access genetic counseling through medical center–based counselors as well as company-provided genetic counseling over the phone. Patients also can submit samples remotely without needing to be tested in a doctor’s office.
Databases from cancer centers that detail cascade genetic testing rates. As the preventive impact of cascade genetic testing becomes clearer, strategies to have recurrent discussions with cancer patients regarding their family members’ risk should be implemented. It is still unclear which providers—genetic counselors, gynecologic oncologists, medical oncologists, breast surgeons, ObGyns, to name a few—are primarily responsible for remembering to have these follow-up discussions, and despite advances, the burden still rests on the cancer patient themselves. Databases with automated follow-up surveys done every 6 to 12 months could provide some aid to busy providers in this regard.
Emerging research
If gynecologic risk-reducing surgery is chosen, clinical trial involvement should be encouraged. The Women Choosing Surgical Prevention (NCT02760849) in the United States and the TUBA study (NCT02321228) in the Netherlands were designed to compare menopause-related QOL between standard risk-reducing salpingo-oophorectomy (RRSO) and the innovative risk-reducing salpingectomy with delayed oophorectomy for mutation carriers. Results from the nonrandomized controlled TUBA trial suggest that patients have better menopause-related QOL after risk-reducing salpingectomy than after RRSO, regardless of hormone replacement therapy.27 International collaboration is continuing to better understand oncologic safety. In the United States, the SOROCk trial (NCT04251052) is a noninferiority surgical choice study underway for BRCA1 mutation carriers aged 35 to 50, powered to determine oncologic outcome differences in addition to QOL outcomes between RRSO and delayed oophorectomy arms.
Returning to the case
The patient and her family underwent genetic counseling. The patient’s 2 daughters, each in their 50s, underwent cascade genetic testing and were found to carry the same pathogenic mutation in BRCA2. After counseling from both breast and gynecologic surgeons, they both elected to undergo risk reducing bilateral salpingo-oophorectomy with hysterectomy. Both now complete regular screening for breast cancer and melanoma with plans to start screening for pancreatic cancer. Both are currently cancer free.
Summary
Cascade genetic testing is an efficient strategy to identify mutation carriers for hereditary breast and ovarian cancer syndrome. Implementation of the best patient-centric care will require continued collaboration and communication across and within disciplines. ●
Cascade, or targeted, genetic testing within families known to carry a hereditary mutation in a cancer susceptibility gene should be performed on all living first-degree family members over the age of 18. All mutation carriers should be connected to a multidisciplinary care team (FIGURE) to ensure implementation of evidence-based screening and risk-reducing surgery for cancer prevention. If gynecologic risk-reducing surgery is chosen, clinical trial involvement should be encouraged.
- Gabai-Kapara E, Lahad A, Kaufman B, et al. Population-based screening for breast and ovarian cancer risk due to BRCA1 and BRCA2. Proc Natl Acad Sci U S A. 2014;111:14205-14210.
- Norquist BM, Harrell MI, Brady MF, et al. Inherited mutations in women with ovarian carcinoma. JAMA Oncol. 2016;2:482-490.
- Yamauchi H, Takei J. Management of hereditary breast and ovarian cancer. Int J Clin Oncol. 2018;23:45-51.
- Kahn RM, Gordhandas S, Maddy BP, et al. Universal endometrial cancer tumor typing: how much has immunohistochemistry, microsatellite instability, and MLH1 methylation improved the diagnosis of Lynch syndrome across the population? Cancer. 2019;125:3172-3183.
- Jasperson KW, Tuohy TM, Neklason DW, et al. Hereditary and familial colon cancer. Gastroenterology. 2010;138:2044-2058.
- Gupta S, Provenzale D, Llor X, et al. NCCN guidelines insights: genetic/familial high-risk assessment: colorectal, version 2.2019. J Natl Compr Canc Netw. 2019;17:1032-1041.
- Daly MB, Pal T, Berry MP, et al. Genetic/familial high-risk assessment: breast, ovarian, and pancreatic, version 2.2021, NCCN clinical practice guidelines in oncology. J Natl Compr Canc Netw. 2021;19:77-102.
- King MC, Levy-Lahad E, Lahad A. Population-based screening for BRCA1 and BRCA2: 2014 Lasker Award. JAMA. 2014;312:1091-1092.
- Samimi G, et al. Traceback: a proposed framework to increase identification and genetic counseling of BRCA1 and BRCA2 mutation carriers through family-based outreach. J Clin Oncol. 2017;35:2329-2337.
- Offit K, Tkachuk KA, Stadler ZK, et al. Cascading after peridiagnostic cancer genetic testing: an alternative to population-based screening. J Clin Oncol. 2020;38:1398-1408.
- Bellcross CA, Kolor K, Goddard KAB, et al. Awareness and utilization of BRCA1/2 testing among U.S. primary care physicians. Am J Prev Med. 2011;40:61-66.
- Cross DS, Rahm AK, Kauffman TL, et al. Underutilization of Lynch syndrome screening in a multisite study of patients with colorectal cancer. Genet Med. 2013;15:933-940.
- Beitsch PD, Whitworth PW, Hughes K, et al. Underdiagnosis of hereditary breast cancer: are genetic testing guidelines a tool or an obstacle? J Clin Oncol. 2019;37:453-460.
- Childers CP, Childers KK, Maggard-Gibbons M, et al. National estimates of genetic testing in women with a history of breast or ovarian cancer. J Clin Oncol. 2017;35:3800-3806.
- Samadder NJ, Riegert-Johnson D, Boardman L, et al. Comparison of universal genetic testing vs guideline-directed targeted testing for patients with hereditary cancer syndrome. JAMA Oncol. 2021;7:230-237.
- Sharaf RN, Myer P, Stave CD, et al. Uptake of genetic testing by relatives of Lynch syndrome probands: a systematic review. Clin Gastroenterol Hepatol. 2013;11:1093-1100.
- Menko FH, Ter Stege JA, van der Kolk LE, et al. The uptake of presymptomatic genetic testing in hereditary breast-ovarian cancer and Lynch syndrome: a systematic review of the literature and implications for clinical practice. Fam Cancer. 2019;18:127-135.
- Griffin NE, Buchanan TR, Smith SH, et al. Low rates of cascade genetic testing among families with hereditary gynecologic cancer: an opportunity to improve cancer prevention. Gynecol Oncol. 2020;156:140-146.
- Roberts MC, Dotson WD, DeVore CS, et al. Delivery of cascade screening for hereditary conditions: a scoping review of the literature. Health Aff (Millwood). 2018;37:801-808.
- Finch AP, Lubinski J, Møller P, et al. Impact of oophorectomy on cancer incidence and mortality in women with a BRCA1 or BRCA2 mutation. J Clin Oncol. 2014;32:1547-1553.
- Srinivasan S, Won NY, Dotson WD, et al. Barriers and facilitators for cascade testing in genetic conditions: a systematic review. Eur J Hum Genet. 2020;28:1631-1644.
- Piedimonte S, Frank C, Laprise C, et al. Occult tubal carcinoma after risk-reducing salpingo-oophorectomy: a systematic review. Obstet Gynecol. 2020;135:498-508.
- Shu CA, Pike MC, Jotwani AR, et al. Uterine cancer after risk-reducing salpingo-oophorectomy without hysterectomy in women with BRCA mutations. JAMA Oncol. 2016;2:1434-1440.
- Gordhandas S, Norquist BM, Pennington KP, et al. Hormone replacement therapy after risk reducing salpingo-oophorectomy in patients with BRCA1 or BRCA2 mutations; a systematic review of risks and benefits. Gynecol Oncol. 2019;153:192-200.
- Steenbeek MP, van Bommel MHD, Harmsen MG, et al. Evaluation of a patient decision aid for BRCA1/2 pathogenic variant carriers choosing an ovarian cancer prevention strategy. Gynecol Oncol. 2021;163:371-377.
- Committee on Gynecologic Practice. ACOG committee opinion No. 727: Cascade testing: testing women for known hereditary genetic mutations associated with cancer. Obstet Gynecol. 2018;131:E31-E34.
- Steenbeek MP, Harmsen MG, Hoogerbrugge N, et al. Association of salpingectomy with delayed oophorectomy versus salpingo-oophorectomy with quality of life in BRCA1/2 pathogenic variant carriers: a nonrandomized controlled trial. JAMA Oncol. 2021;7:1203-1212.
- Gabai-Kapara E, Lahad A, Kaufman B, et al. Population-based screening for breast and ovarian cancer risk due to BRCA1 and BRCA2. Proc Natl Acad Sci U S A. 2014;111:14205-14210.
- Norquist BM, Harrell MI, Brady MF, et al. Inherited mutations in women with ovarian carcinoma. JAMA Oncol. 2016;2:482-490.
- Yamauchi H, Takei J. Management of hereditary breast and ovarian cancer. Int J Clin Oncol. 2018;23:45-51.
- Kahn RM, Gordhandas S, Maddy BP, et al. Universal endometrial cancer tumor typing: how much has immunohistochemistry, microsatellite instability, and MLH1 methylation improved the diagnosis of Lynch syndrome across the population? Cancer. 2019;125:3172-3183.
- Jasperson KW, Tuohy TM, Neklason DW, et al. Hereditary and familial colon cancer. Gastroenterology. 2010;138:2044-2058.
- Gupta S, Provenzale D, Llor X, et al. NCCN guidelines insights: genetic/familial high-risk assessment: colorectal, version 2.2019. J Natl Compr Canc Netw. 2019;17:1032-1041.
- Daly MB, Pal T, Berry MP, et al. Genetic/familial high-risk assessment: breast, ovarian, and pancreatic, version 2.2021, NCCN clinical practice guidelines in oncology. J Natl Compr Canc Netw. 2021;19:77-102.
- King MC, Levy-Lahad E, Lahad A. Population-based screening for BRCA1 and BRCA2: 2014 Lasker Award. JAMA. 2014;312:1091-1092.
- Samimi G, et al. Traceback: a proposed framework to increase identification and genetic counseling of BRCA1 and BRCA2 mutation carriers through family-based outreach. J Clin Oncol. 2017;35:2329-2337.
- Offit K, Tkachuk KA, Stadler ZK, et al. Cascading after peridiagnostic cancer genetic testing: an alternative to population-based screening. J Clin Oncol. 2020;38:1398-1408.
- Bellcross CA, Kolor K, Goddard KAB, et al. Awareness and utilization of BRCA1/2 testing among U.S. primary care physicians. Am J Prev Med. 2011;40:61-66.
- Cross DS, Rahm AK, Kauffman TL, et al. Underutilization of Lynch syndrome screening in a multisite study of patients with colorectal cancer. Genet Med. 2013;15:933-940.
- Beitsch PD, Whitworth PW, Hughes K, et al. Underdiagnosis of hereditary breast cancer: are genetic testing guidelines a tool or an obstacle? J Clin Oncol. 2019;37:453-460.
- Childers CP, Childers KK, Maggard-Gibbons M, et al. National estimates of genetic testing in women with a history of breast or ovarian cancer. J Clin Oncol. 2017;35:3800-3806.
- Samadder NJ, Riegert-Johnson D, Boardman L, et al. Comparison of universal genetic testing vs guideline-directed targeted testing for patients with hereditary cancer syndrome. JAMA Oncol. 2021;7:230-237.
- Sharaf RN, Myer P, Stave CD, et al. Uptake of genetic testing by relatives of Lynch syndrome probands: a systematic review. Clin Gastroenterol Hepatol. 2013;11:1093-1100.
- Menko FH, Ter Stege JA, van der Kolk LE, et al. The uptake of presymptomatic genetic testing in hereditary breast-ovarian cancer and Lynch syndrome: a systematic review of the literature and implications for clinical practice. Fam Cancer. 2019;18:127-135.
- Griffin NE, Buchanan TR, Smith SH, et al. Low rates of cascade genetic testing among families with hereditary gynecologic cancer: an opportunity to improve cancer prevention. Gynecol Oncol. 2020;156:140-146.
- Roberts MC, Dotson WD, DeVore CS, et al. Delivery of cascade screening for hereditary conditions: a scoping review of the literature. Health Aff (Millwood). 2018;37:801-808.
- Finch AP, Lubinski J, Møller P, et al. Impact of oophorectomy on cancer incidence and mortality in women with a BRCA1 or BRCA2 mutation. J Clin Oncol. 2014;32:1547-1553.
- Srinivasan S, Won NY, Dotson WD, et al. Barriers and facilitators for cascade testing in genetic conditions: a systematic review. Eur J Hum Genet. 2020;28:1631-1644.
- Piedimonte S, Frank C, Laprise C, et al. Occult tubal carcinoma after risk-reducing salpingo-oophorectomy: a systematic review. Obstet Gynecol. 2020;135:498-508.
- Shu CA, Pike MC, Jotwani AR, et al. Uterine cancer after risk-reducing salpingo-oophorectomy without hysterectomy in women with BRCA mutations. JAMA Oncol. 2016;2:1434-1440.
- Gordhandas S, Norquist BM, Pennington KP, et al. Hormone replacement therapy after risk reducing salpingo-oophorectomy in patients with BRCA1 or BRCA2 mutations; a systematic review of risks and benefits. Gynecol Oncol. 2019;153:192-200.
- Steenbeek MP, van Bommel MHD, Harmsen MG, et al. Evaluation of a patient decision aid for BRCA1/2 pathogenic variant carriers choosing an ovarian cancer prevention strategy. Gynecol Oncol. 2021;163:371-377.
- Committee on Gynecologic Practice. ACOG committee opinion No. 727: Cascade testing: testing women for known hereditary genetic mutations associated with cancer. Obstet Gynecol. 2018;131:E31-E34.
- Steenbeek MP, Harmsen MG, Hoogerbrugge N, et al. Association of salpingectomy with delayed oophorectomy versus salpingo-oophorectomy with quality of life in BRCA1/2 pathogenic variant carriers: a nonrandomized controlled trial. JAMA Oncol. 2021;7:1203-1212.
Large analysis confirms safety of nipple-sparing mastectomy
A new analysis of over 22,000 mastectomy patients confirms what smaller studies have indicated: Patients who undergo nipple-sparing mastectomy have overall and disease-free survival similar to that of those who receive a total mastectomy.
When nipple-sparing mastectomy was introduced, many experts felt uneasy about opting for the less invasive procedure, recalled Rosa Hwang, MD, associate medical director for breast surgery at MD Anderson Cancer Center in Houston. “The concern was leaving all this skin,” said Dr. Hwang. “Are you going to leave cancer behind” and increase the risk of local recurrence?
Over the past 2 decades, the number of patients undergoing nipple-sparing mastectomy increased and, in turn, studies began to demonstrate the safety of the procedure.
However, large analyses evaluating long-term outcomes – namely, overall survival and breast cancer-specific survival – of nipple-sparing mastectomy were still lacking.
The latest study, published online Nov. 20 in Annals of Surgical Oncology, compared the long-term prognosis and survival benefits of nipple-sparing to total mastectomy in thousands of women. The analysis, which pulled data from the SEER cancer database, included 5,765 patients who underwent the nipple-sparing procedure and 17,289 patients who had a total mastectomy.
The authors found that overall survival and breast cancer–specific survival were similar for women undergoing nipple-sparing mastectomy and those receiving a total mastectomy. In fact, over the long-term, the nipple-sparing group slightly edged out the total mastectomy group in overall survival (94.61% vs. 93% at 5 years and 86.34% vs. 83.48% at 10 years, respectively) and in breast cancer-specific survival rates (96.16% vs. 95.74% at 5 years, and 92.2% vs. 91.37% at 10 years). The differences, however, were not significant.
The study also found that certain subgroups – including White women, women over age 46, those with a median household income of $70,000 or more, hormone receptor-positive, and HER2 negative – had significantly better overall survival rate with the nipple-sparing procedure (P < .05). However, the authors noted, the survival advantage in the nipple-sparing group did not extend to breast cancer–specific survival.
Dr. Hwang, who was not involved in the current analysis, said the significant overall survival result in the subgroup analysis was surprising because “there’s no biological reason why one would expect that to be true.”
Given that the subgroups did not demonstrate better breast cancer–specific survival, Dr. Hwang believes the overall survival finding may have more to do with comorbidities, which the study did not account for, than type of mastectomy.
When choosing who is eligible for a nipple-sparing mastectomy, “We’re more selective,” Dr. Hwang said. For instance, patients with uncontrolled diabetes or who smoke are unlikely to be candidates. “So, I think it’s possible that medical comorbidities and medical conditions between these groups [were] different.”
According to the authors, coding inconsistencies represent another possible weakness of the study. From 1998 to 2010, “the term ‘nipple-sparing mastectomy’ was coded as a [total mastectomy] with the ‘subcutaneous mastectomy’ code.” It’s possible that some patients receiving the nipple-sparing procedure before 2011 were not appropriately coded in the current study.
Moving forward, a large prospective study that includes comorbidities would be helpful, but overall the study helps validate that “nipple-sparing mastectomy is a safe operation for selected patients,” Dr. Hwang said.
A version of this article first appeared on Medscape.com.
A new analysis of over 22,000 mastectomy patients confirms what smaller studies have indicated: Patients who undergo nipple-sparing mastectomy have overall and disease-free survival similar to that of those who receive a total mastectomy.
When nipple-sparing mastectomy was introduced, many experts felt uneasy about opting for the less invasive procedure, recalled Rosa Hwang, MD, associate medical director for breast surgery at MD Anderson Cancer Center in Houston. “The concern was leaving all this skin,” said Dr. Hwang. “Are you going to leave cancer behind” and increase the risk of local recurrence?
Over the past 2 decades, the number of patients undergoing nipple-sparing mastectomy increased and, in turn, studies began to demonstrate the safety of the procedure.
However, large analyses evaluating long-term outcomes – namely, overall survival and breast cancer-specific survival – of nipple-sparing mastectomy were still lacking.
The latest study, published online Nov. 20 in Annals of Surgical Oncology, compared the long-term prognosis and survival benefits of nipple-sparing to total mastectomy in thousands of women. The analysis, which pulled data from the SEER cancer database, included 5,765 patients who underwent the nipple-sparing procedure and 17,289 patients who had a total mastectomy.
The authors found that overall survival and breast cancer–specific survival were similar for women undergoing nipple-sparing mastectomy and those receiving a total mastectomy. In fact, over the long-term, the nipple-sparing group slightly edged out the total mastectomy group in overall survival (94.61% vs. 93% at 5 years and 86.34% vs. 83.48% at 10 years, respectively) and in breast cancer-specific survival rates (96.16% vs. 95.74% at 5 years, and 92.2% vs. 91.37% at 10 years). The differences, however, were not significant.
The study also found that certain subgroups – including White women, women over age 46, those with a median household income of $70,000 or more, hormone receptor-positive, and HER2 negative – had significantly better overall survival rate with the nipple-sparing procedure (P < .05). However, the authors noted, the survival advantage in the nipple-sparing group did not extend to breast cancer–specific survival.
Dr. Hwang, who was not involved in the current analysis, said the significant overall survival result in the subgroup analysis was surprising because “there’s no biological reason why one would expect that to be true.”
Given that the subgroups did not demonstrate better breast cancer–specific survival, Dr. Hwang believes the overall survival finding may have more to do with comorbidities, which the study did not account for, than type of mastectomy.
When choosing who is eligible for a nipple-sparing mastectomy, “We’re more selective,” Dr. Hwang said. For instance, patients with uncontrolled diabetes or who smoke are unlikely to be candidates. “So, I think it’s possible that medical comorbidities and medical conditions between these groups [were] different.”
According to the authors, coding inconsistencies represent another possible weakness of the study. From 1998 to 2010, “the term ‘nipple-sparing mastectomy’ was coded as a [total mastectomy] with the ‘subcutaneous mastectomy’ code.” It’s possible that some patients receiving the nipple-sparing procedure before 2011 were not appropriately coded in the current study.
Moving forward, a large prospective study that includes comorbidities would be helpful, but overall the study helps validate that “nipple-sparing mastectomy is a safe operation for selected patients,” Dr. Hwang said.
A version of this article first appeared on Medscape.com.
A new analysis of over 22,000 mastectomy patients confirms what smaller studies have indicated: Patients who undergo nipple-sparing mastectomy have overall and disease-free survival similar to that of those who receive a total mastectomy.
When nipple-sparing mastectomy was introduced, many experts felt uneasy about opting for the less invasive procedure, recalled Rosa Hwang, MD, associate medical director for breast surgery at MD Anderson Cancer Center in Houston. “The concern was leaving all this skin,” said Dr. Hwang. “Are you going to leave cancer behind” and increase the risk of local recurrence?
Over the past 2 decades, the number of patients undergoing nipple-sparing mastectomy increased and, in turn, studies began to demonstrate the safety of the procedure.
However, large analyses evaluating long-term outcomes – namely, overall survival and breast cancer-specific survival – of nipple-sparing mastectomy were still lacking.
The latest study, published online Nov. 20 in Annals of Surgical Oncology, compared the long-term prognosis and survival benefits of nipple-sparing to total mastectomy in thousands of women. The analysis, which pulled data from the SEER cancer database, included 5,765 patients who underwent the nipple-sparing procedure and 17,289 patients who had a total mastectomy.
The authors found that overall survival and breast cancer–specific survival were similar for women undergoing nipple-sparing mastectomy and those receiving a total mastectomy. In fact, over the long-term, the nipple-sparing group slightly edged out the total mastectomy group in overall survival (94.61% vs. 93% at 5 years and 86.34% vs. 83.48% at 10 years, respectively) and in breast cancer-specific survival rates (96.16% vs. 95.74% at 5 years, and 92.2% vs. 91.37% at 10 years). The differences, however, were not significant.
The study also found that certain subgroups – including White women, women over age 46, those with a median household income of $70,000 or more, hormone receptor-positive, and HER2 negative – had significantly better overall survival rate with the nipple-sparing procedure (P < .05). However, the authors noted, the survival advantage in the nipple-sparing group did not extend to breast cancer–specific survival.
Dr. Hwang, who was not involved in the current analysis, said the significant overall survival result in the subgroup analysis was surprising because “there’s no biological reason why one would expect that to be true.”
Given that the subgroups did not demonstrate better breast cancer–specific survival, Dr. Hwang believes the overall survival finding may have more to do with comorbidities, which the study did not account for, than type of mastectomy.
When choosing who is eligible for a nipple-sparing mastectomy, “We’re more selective,” Dr. Hwang said. For instance, patients with uncontrolled diabetes or who smoke are unlikely to be candidates. “So, I think it’s possible that medical comorbidities and medical conditions between these groups [were] different.”
According to the authors, coding inconsistencies represent another possible weakness of the study. From 1998 to 2010, “the term ‘nipple-sparing mastectomy’ was coded as a [total mastectomy] with the ‘subcutaneous mastectomy’ code.” It’s possible that some patients receiving the nipple-sparing procedure before 2011 were not appropriately coded in the current study.
Moving forward, a large prospective study that includes comorbidities would be helpful, but overall the study helps validate that “nipple-sparing mastectomy is a safe operation for selected patients,” Dr. Hwang said.
A version of this article first appeared on Medscape.com.
IUDs may increase background enhancement on breast MRI
Intrauterine contraceptive devices (IUDs) have been linked to increased background enhancement on breast MRI, according to research presented at the Radiological Society of North America 2021 annual meeting.
About 10.4% of women 15-49 years of age who use contraception have an IUD or contraceptive implant, according to the Centers for Disease Control and Prevention. Unlike oral or transdermal hormonal contraceptives and hormone replacement therapy, levonorgestrel-releasing IUDs release a small amount of the hormone directly into the uterus and are thought to have a much more localized effect, Luisa Huck, MD, the lead author of the study, said in an interview.
But women with IUDs have long reported adverse effects associated with other hormonal medication. “In the past, some women reported depression, headaches, sleep disorders, and panic attacks,” noted Dr. Huck, a radiology resident at RWTH Aachen University in Germany.
Christiane Kuhl, MD, chief of the department of radiology at RWTH Aachen University and senior author of the research, had also observed that women with hormonal IUDs often have increased background parenchymal enhancement (BPE) on contrast-enhanced MRI. BPE “has been established as a sensitive marker of hormonal stimulation of breast,” the study authors wrote, and previous studies have shown that women using hormonal medications have higher BPE on breast MRIs.
To better understand whether IUDs can increase BPE, Dr. Huck and colleagues used the hospital database to search for premenopausal women who had undergone breast MRIs for screening between January 2014 and July 2020. To be included, women had to have had at least two scans: one with and one without an IUD in place, with the scan conducted at least 4 weeks after IUD placement or removal. All women in the study had no history of breast cancer or hormone or antihormone intake.
The study involved 48 women with an average age of 45 years and a median of 27 months between the two scans. Forty-six of the women had the Mirena levonorgestrel-releasing IUD and two had the Jaydess IUD. To account for hormone variations between patients, the researchers used each patient as their own reference point. To control for age-related effects, 25 women had their first MRI without an IUD and their second scan with an IUD in place. The second group of 23 women underwent their first MRI with an IUD and had it removed before the second scan.
Hormonal effects on breast enhancement are very complex, and hormonal stimulation is not always predictably correlated with changes on MRI imaging.
For 23 women in the study, background enhancement was higher on scans with the IUD than without (P < .001). For 24 women, there was no change in BPE with or without an IUD, and one woman had lower BPE with an IUD than without.
“It is very interesting and relevant to practice to consider that the presence of an intrauterine device would have potential impact on the enhancement we see in the breast on MRI imaging,” Samantha Heller, MD, PhD, associate professor of radiology at New York University, said in an interview.
However, the study used BPE as a measure for hormonal shifts, and “hormonal effects on breast enhancement are very complex, and hormonal stimulation is not always predictably correlated with changes on MRI imaging,” she noted. BPE on MRI can fluctuate, so testing actual hormone levels in patients with elevated BPE could be helpful to identify hormonal shifts, she added. It is also important to understand why half of the women in the study showed no variation in BPE, she said.
The study findings are not very surprising, considering that it is known that low levels of progesterone from IUDs circulate in the blood stream, Frances Casey, MD, MPH, associate professor in the department of obstetrics and gynecology at Virginia Commonwealth University in Richmond, said in an interview. They do not suggest that there should be any changes to IUD guidelines, she added.
However, “the study findings raise the question as to whether IUD status should be documented as a matter of course prior to performing breast MRI,” said Dr. Heller. “It is standard to document the timing of a woman’s menstrual cycle, as well as to note any hormone suppression or replacement therapy. This is in part so that the radiologist may understand the etiology of any observed variation in background enhancement,” she explained.
Although increased enhancement on MRI has sometimes been linked to higher chances of recommendations for additional imaging or biopsies, she noted, “more work would be needed to understand the impact – if any – of an IUD on breast MRI recommendations due to enhancement changes.”
Dr. Huck, Dr. Heller, and Dr. Casey disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Intrauterine contraceptive devices (IUDs) have been linked to increased background enhancement on breast MRI, according to research presented at the Radiological Society of North America 2021 annual meeting.
About 10.4% of women 15-49 years of age who use contraception have an IUD or contraceptive implant, according to the Centers for Disease Control and Prevention. Unlike oral or transdermal hormonal contraceptives and hormone replacement therapy, levonorgestrel-releasing IUDs release a small amount of the hormone directly into the uterus and are thought to have a much more localized effect, Luisa Huck, MD, the lead author of the study, said in an interview.
But women with IUDs have long reported adverse effects associated with other hormonal medication. “In the past, some women reported depression, headaches, sleep disorders, and panic attacks,” noted Dr. Huck, a radiology resident at RWTH Aachen University in Germany.
Christiane Kuhl, MD, chief of the department of radiology at RWTH Aachen University and senior author of the research, had also observed that women with hormonal IUDs often have increased background parenchymal enhancement (BPE) on contrast-enhanced MRI. BPE “has been established as a sensitive marker of hormonal stimulation of breast,” the study authors wrote, and previous studies have shown that women using hormonal medications have higher BPE on breast MRIs.
To better understand whether IUDs can increase BPE, Dr. Huck and colleagues used the hospital database to search for premenopausal women who had undergone breast MRIs for screening between January 2014 and July 2020. To be included, women had to have had at least two scans: one with and one without an IUD in place, with the scan conducted at least 4 weeks after IUD placement or removal. All women in the study had no history of breast cancer or hormone or antihormone intake.
The study involved 48 women with an average age of 45 years and a median of 27 months between the two scans. Forty-six of the women had the Mirena levonorgestrel-releasing IUD and two had the Jaydess IUD. To account for hormone variations between patients, the researchers used each patient as their own reference point. To control for age-related effects, 25 women had their first MRI without an IUD and their second scan with an IUD in place. The second group of 23 women underwent their first MRI with an IUD and had it removed before the second scan.
Hormonal effects on breast enhancement are very complex, and hormonal stimulation is not always predictably correlated with changes on MRI imaging.
For 23 women in the study, background enhancement was higher on scans with the IUD than without (P < .001). For 24 women, there was no change in BPE with or without an IUD, and one woman had lower BPE with an IUD than without.
“It is very interesting and relevant to practice to consider that the presence of an intrauterine device would have potential impact on the enhancement we see in the breast on MRI imaging,” Samantha Heller, MD, PhD, associate professor of radiology at New York University, said in an interview.
However, the study used BPE as a measure for hormonal shifts, and “hormonal effects on breast enhancement are very complex, and hormonal stimulation is not always predictably correlated with changes on MRI imaging,” she noted. BPE on MRI can fluctuate, so testing actual hormone levels in patients with elevated BPE could be helpful to identify hormonal shifts, she added. It is also important to understand why half of the women in the study showed no variation in BPE, she said.
The study findings are not very surprising, considering that it is known that low levels of progesterone from IUDs circulate in the blood stream, Frances Casey, MD, MPH, associate professor in the department of obstetrics and gynecology at Virginia Commonwealth University in Richmond, said in an interview. They do not suggest that there should be any changes to IUD guidelines, she added.
However, “the study findings raise the question as to whether IUD status should be documented as a matter of course prior to performing breast MRI,” said Dr. Heller. “It is standard to document the timing of a woman’s menstrual cycle, as well as to note any hormone suppression or replacement therapy. This is in part so that the radiologist may understand the etiology of any observed variation in background enhancement,” she explained.
Although increased enhancement on MRI has sometimes been linked to higher chances of recommendations for additional imaging or biopsies, she noted, “more work would be needed to understand the impact – if any – of an IUD on breast MRI recommendations due to enhancement changes.”
Dr. Huck, Dr. Heller, and Dr. Casey disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Intrauterine contraceptive devices (IUDs) have been linked to increased background enhancement on breast MRI, according to research presented at the Radiological Society of North America 2021 annual meeting.
About 10.4% of women 15-49 years of age who use contraception have an IUD or contraceptive implant, according to the Centers for Disease Control and Prevention. Unlike oral or transdermal hormonal contraceptives and hormone replacement therapy, levonorgestrel-releasing IUDs release a small amount of the hormone directly into the uterus and are thought to have a much more localized effect, Luisa Huck, MD, the lead author of the study, said in an interview.
But women with IUDs have long reported adverse effects associated with other hormonal medication. “In the past, some women reported depression, headaches, sleep disorders, and panic attacks,” noted Dr. Huck, a radiology resident at RWTH Aachen University in Germany.
Christiane Kuhl, MD, chief of the department of radiology at RWTH Aachen University and senior author of the research, had also observed that women with hormonal IUDs often have increased background parenchymal enhancement (BPE) on contrast-enhanced MRI. BPE “has been established as a sensitive marker of hormonal stimulation of breast,” the study authors wrote, and previous studies have shown that women using hormonal medications have higher BPE on breast MRIs.
To better understand whether IUDs can increase BPE, Dr. Huck and colleagues used the hospital database to search for premenopausal women who had undergone breast MRIs for screening between January 2014 and July 2020. To be included, women had to have had at least two scans: one with and one without an IUD in place, with the scan conducted at least 4 weeks after IUD placement or removal. All women in the study had no history of breast cancer or hormone or antihormone intake.
The study involved 48 women with an average age of 45 years and a median of 27 months between the two scans. Forty-six of the women had the Mirena levonorgestrel-releasing IUD and two had the Jaydess IUD. To account for hormone variations between patients, the researchers used each patient as their own reference point. To control for age-related effects, 25 women had their first MRI without an IUD and their second scan with an IUD in place. The second group of 23 women underwent their first MRI with an IUD and had it removed before the second scan.
Hormonal effects on breast enhancement are very complex, and hormonal stimulation is not always predictably correlated with changes on MRI imaging.
For 23 women in the study, background enhancement was higher on scans with the IUD than without (P < .001). For 24 women, there was no change in BPE with or without an IUD, and one woman had lower BPE with an IUD than without.
“It is very interesting and relevant to practice to consider that the presence of an intrauterine device would have potential impact on the enhancement we see in the breast on MRI imaging,” Samantha Heller, MD, PhD, associate professor of radiology at New York University, said in an interview.
However, the study used BPE as a measure for hormonal shifts, and “hormonal effects on breast enhancement are very complex, and hormonal stimulation is not always predictably correlated with changes on MRI imaging,” she noted. BPE on MRI can fluctuate, so testing actual hormone levels in patients with elevated BPE could be helpful to identify hormonal shifts, she added. It is also important to understand why half of the women in the study showed no variation in BPE, she said.
The study findings are not very surprising, considering that it is known that low levels of progesterone from IUDs circulate in the blood stream, Frances Casey, MD, MPH, associate professor in the department of obstetrics and gynecology at Virginia Commonwealth University in Richmond, said in an interview. They do not suggest that there should be any changes to IUD guidelines, she added.
However, “the study findings raise the question as to whether IUD status should be documented as a matter of course prior to performing breast MRI,” said Dr. Heller. “It is standard to document the timing of a woman’s menstrual cycle, as well as to note any hormone suppression or replacement therapy. This is in part so that the radiologist may understand the etiology of any observed variation in background enhancement,” she explained.
Although increased enhancement on MRI has sometimes been linked to higher chances of recommendations for additional imaging or biopsies, she noted, “more work would be needed to understand the impact – if any – of an IUD on breast MRI recommendations due to enhancement changes.”
Dr. Huck, Dr. Heller, and Dr. Casey disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Risk for breast cancer recurrence persists past 30 years
The data come from a Danish study involving 20,315 women who were treated for early operable breast cancer between 1987 and 2004, all of whom were disease-free at 10 years.
Further follow-up showed that 2,595 women had a breast cancer recurrence more than 10 years after their primary diagnosis.
The cumulative incidence of recurrence was 8.5% at 15 years; 12.5% at 20 years; 15.2% at 25 years, and 16.6% at 32 years.
Recurrence risk was greatest early in the study period.
Women who had primary tumors larger than 20 mm, lymph node-positive disease, and estrogen receptor-positive tumors were at higher risk for late recurrence.
“Such patients may warrant extended surveillance, more aggressive treatment, or new therapy approaches,” said the investigators, led by Rikke Pedersen, MD, a PhD candidate in epidemiology at Aarhus University Hospital, Denmark.
“Our observed high cumulative incidence of late breast cancer recurrence is a concern given the increasing prevalence of long-term survivors.” Among other things, a new model to better select women for prolonged surveillance is needed, they said.
The new findings were published online Nov. 8 in the Journal of the National Cancer Institute (NCI).
This study confirms previous investigations, but it is the first to report that breast cancer can recur more than 30 years after diagnosis, note the authors of an accompanying editorial, Serban Negoita, MD, DrPH, and Esmeralda Ramirez-Peña, PhD, MPH, both from the National Cancer Institute.
The caveat is that treatment has evolved considerably since the women in the study were diagnosed, so the prognostic value of the findings with current treatment regimens is uncertain, they note. Some studies haven’t found a recurrence benefit for aggressive upfront treatment, but those studies had shorter follow-ups.
Research into the issue is “increasingly important” to guide clinical management and counsel women who are living longer after their primary diagnosis, they comment.
Further details from the study
Data for the study came from the Danish Breast Cancer Group clinical database and other national databases. The researchers focused on women who were disease-free at 10 years after their primary diagnosis, which was stage I or II disease. Median age was 55 years.
Cumulative incidence for breast cancer recurrence was highest for grade 1 tumors with four or more positive lymph nodes (37.9% 10-25 years after the primary diagnosis) and was lowest for patients with grade 3 disease and no involved lymph nodes (7.5%).
The finding of higher recurrence incidence with lower grade tumors goes against some previous reports, the researchers commented. It may be that some tumors considered lower risk decades ago, and treated accordingly, would be considered higher risk in more recent times.
The cumulative incidence of late recurrence was also higher in younger patients and those treated with breast-conserving surgery instead of mastectomy, the team reported.
Adjusted hazard ratios followed the incidence trends, with higher hazards of recurrence for women diagnosed before age 40 as well as those who had breast-conserving surgery, four or more positive lymph nodes, and primary tumors 20 mm or more across.
The work was funded by the Danish Cancer Society and Aarhus University. Lead author Dr. Pedersen reports no disclosures, but coauthors report ties to Amgen, Novo Nordisk, Roche, and other companies. The editorialists have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
The data come from a Danish study involving 20,315 women who were treated for early operable breast cancer between 1987 and 2004, all of whom were disease-free at 10 years.
Further follow-up showed that 2,595 women had a breast cancer recurrence more than 10 years after their primary diagnosis.
The cumulative incidence of recurrence was 8.5% at 15 years; 12.5% at 20 years; 15.2% at 25 years, and 16.6% at 32 years.
Recurrence risk was greatest early in the study period.
Women who had primary tumors larger than 20 mm, lymph node-positive disease, and estrogen receptor-positive tumors were at higher risk for late recurrence.
“Such patients may warrant extended surveillance, more aggressive treatment, or new therapy approaches,” said the investigators, led by Rikke Pedersen, MD, a PhD candidate in epidemiology at Aarhus University Hospital, Denmark.
“Our observed high cumulative incidence of late breast cancer recurrence is a concern given the increasing prevalence of long-term survivors.” Among other things, a new model to better select women for prolonged surveillance is needed, they said.
The new findings were published online Nov. 8 in the Journal of the National Cancer Institute (NCI).
This study confirms previous investigations, but it is the first to report that breast cancer can recur more than 30 years after diagnosis, note the authors of an accompanying editorial, Serban Negoita, MD, DrPH, and Esmeralda Ramirez-Peña, PhD, MPH, both from the National Cancer Institute.
The caveat is that treatment has evolved considerably since the women in the study were diagnosed, so the prognostic value of the findings with current treatment regimens is uncertain, they note. Some studies haven’t found a recurrence benefit for aggressive upfront treatment, but those studies had shorter follow-ups.
Research into the issue is “increasingly important” to guide clinical management and counsel women who are living longer after their primary diagnosis, they comment.
Further details from the study
Data for the study came from the Danish Breast Cancer Group clinical database and other national databases. The researchers focused on women who were disease-free at 10 years after their primary diagnosis, which was stage I or II disease. Median age was 55 years.
Cumulative incidence for breast cancer recurrence was highest for grade 1 tumors with four or more positive lymph nodes (37.9% 10-25 years after the primary diagnosis) and was lowest for patients with grade 3 disease and no involved lymph nodes (7.5%).
The finding of higher recurrence incidence with lower grade tumors goes against some previous reports, the researchers commented. It may be that some tumors considered lower risk decades ago, and treated accordingly, would be considered higher risk in more recent times.
The cumulative incidence of late recurrence was also higher in younger patients and those treated with breast-conserving surgery instead of mastectomy, the team reported.
Adjusted hazard ratios followed the incidence trends, with higher hazards of recurrence for women diagnosed before age 40 as well as those who had breast-conserving surgery, four or more positive lymph nodes, and primary tumors 20 mm or more across.
The work was funded by the Danish Cancer Society and Aarhus University. Lead author Dr. Pedersen reports no disclosures, but coauthors report ties to Amgen, Novo Nordisk, Roche, and other companies. The editorialists have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
The data come from a Danish study involving 20,315 women who were treated for early operable breast cancer between 1987 and 2004, all of whom were disease-free at 10 years.
Further follow-up showed that 2,595 women had a breast cancer recurrence more than 10 years after their primary diagnosis.
The cumulative incidence of recurrence was 8.5% at 15 years; 12.5% at 20 years; 15.2% at 25 years, and 16.6% at 32 years.
Recurrence risk was greatest early in the study period.
Women who had primary tumors larger than 20 mm, lymph node-positive disease, and estrogen receptor-positive tumors were at higher risk for late recurrence.
“Such patients may warrant extended surveillance, more aggressive treatment, or new therapy approaches,” said the investigators, led by Rikke Pedersen, MD, a PhD candidate in epidemiology at Aarhus University Hospital, Denmark.
“Our observed high cumulative incidence of late breast cancer recurrence is a concern given the increasing prevalence of long-term survivors.” Among other things, a new model to better select women for prolonged surveillance is needed, they said.
The new findings were published online Nov. 8 in the Journal of the National Cancer Institute (NCI).
This study confirms previous investigations, but it is the first to report that breast cancer can recur more than 30 years after diagnosis, note the authors of an accompanying editorial, Serban Negoita, MD, DrPH, and Esmeralda Ramirez-Peña, PhD, MPH, both from the National Cancer Institute.
The caveat is that treatment has evolved considerably since the women in the study were diagnosed, so the prognostic value of the findings with current treatment regimens is uncertain, they note. Some studies haven’t found a recurrence benefit for aggressive upfront treatment, but those studies had shorter follow-ups.
Research into the issue is “increasingly important” to guide clinical management and counsel women who are living longer after their primary diagnosis, they comment.
Further details from the study
Data for the study came from the Danish Breast Cancer Group clinical database and other national databases. The researchers focused on women who were disease-free at 10 years after their primary diagnosis, which was stage I or II disease. Median age was 55 years.
Cumulative incidence for breast cancer recurrence was highest for grade 1 tumors with four or more positive lymph nodes (37.9% 10-25 years after the primary diagnosis) and was lowest for patients with grade 3 disease and no involved lymph nodes (7.5%).
The finding of higher recurrence incidence with lower grade tumors goes against some previous reports, the researchers commented. It may be that some tumors considered lower risk decades ago, and treated accordingly, would be considered higher risk in more recent times.
The cumulative incidence of late recurrence was also higher in younger patients and those treated with breast-conserving surgery instead of mastectomy, the team reported.
Adjusted hazard ratios followed the incidence trends, with higher hazards of recurrence for women diagnosed before age 40 as well as those who had breast-conserving surgery, four or more positive lymph nodes, and primary tumors 20 mm or more across.
The work was funded by the Danish Cancer Society and Aarhus University. Lead author Dr. Pedersen reports no disclosures, but coauthors report ties to Amgen, Novo Nordisk, Roche, and other companies. The editorialists have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.