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ExteNET: Benefit of extended neratinib in HER2+ breast cancer sustained
MADRID – who received postoperative trastuzumab (Herceptin) and chemotherapy, long-term follow-up results from the ExteNET trial show.
In a planned intention-to-treat analysis at 5 years of follow-up, extended adjuvant therapy with the tyrosine kinase inhibitor neratinib was associated with a small but significant improvement in invasive disease-free survival (iDFS), compared with placebo, with most of the benefit occurring in women with hormone receptor–positive disease, reported Miguel Martin, MD, of the Gregorio Marañón Health Research Institute in Madrid.
Data from an earlier analysis of the trial supported the Food and Drug Administration’s decision to approve neratinib in the extended adjuvant setting in July 2017.
In the ExteNET trial, 2,840 women with early HER2-positive breast cancer who had undergone surgery and adjuvant treatment with trastuzumab and chemotherapy were stratified by nodal and hormone receptor status and by concurrent vs. sequential chemotherapy and trastuzumab, and were then randomly assigned to receive oral neratinib 240 mg/day for 1 year, or placebo. Analyses of iDFS were planned for 2 and 5 years, and an overall survival analysis was planned after 248 patient deaths had occurred. Overall survival data have not matured as yet, Dr. Martin noted.
Results of an unspecified 3-year analysis of the trial, presented at the San Antonio Breast Cancer Symposium in 2015, showed a continued benefit for the addition of neratinib, a finding that has now been extended out to 5 years.
At ESMO 2017, Dr. Martin presented data on all efficacy endpoints except overall survival in the intention-to-treat population.
By the cutoff date in March 2017, 2,117 of the original 2,840 patients (76%) gave consent for collection of additional data, including 1,028 who had been assigned to neratinib, and 1,089 assigned to placebo.
The 5-year iDFS rate was 90.2% for patients assigned to neratinib, compared with 87.7% for those assigned to placebo, an absolute difference of 2.5%. This translated into a hazard ratio favoring neratinib of 0.73 (P = .008). Neratinib was also significantly better than placebo for DFS in patients with ductal carcinoma in situ (89.7% vs. 86.8, HR, 0.71, P = .004).
However, there were no significant differences at 5 years between trial arms in either distant DFS, time to distant recurrence, or central nervous system recurrences. Dr. Martin noted that the although there were fewer CNS recurrences with neratinib (1.30% vs. 1.82%), the total number of cases was too small to detect a possible difference.
In a subgroup analysis, neratinib trended toward better performance in all categories, but was significantly better than placebo only among patients from Asia, Eastern Europe, and South America, and among patients with four or more positive lymph nodes.
An analysis of iDFS by hormone receptor status showed that for HR-positive patients, the 5-year iDFS rate was 91.2% with neratinib vs. 86.8% with placebo, translating into a hazard ratio of 0.60, P = .002). In contrast, iDFS rates were nearly identical among HR-negative patients, at 88.9% vs. 88.8%, respectively.
Following treatment discontinuation, there was no evidence of increased symptomatic cardiotoxicity or second primary malignancies vs. placebo, and no late-term consequences of neratinib-associated diarrhea, Dr. Martin said.
A separate poster on health-related quality of life, also presented at ESMO 2017, showed that patients assigned to neratinib had a drop in quality-of-life measures during the first month of treatment, possibly because of diarrhea, but then had a steady improvement toward baseline. There is an ongoing study to evaluate whether loperamide-based regimens can reduce or prevent neratinib-associated diarrhea, the investigators noted.
“In ExteNET, we’ve seen continued demonstration of clinically significant benefit, particularly in higher-risk, hormone receptor–positive disease, despite many limitations, with change in sponsor and initial plan for only 2 years of follow-up,” said Hope S. Rugo, MD, from the University of California, San Francisco, the invited discussant.
“Survival data is pending, and we’re looking forward to seeing that in 2019, but the reduction in distant events, although small, is still encouraging,” she said.
The trial is sponsored by Puma Biotechnology. Dr. Martin disclosed honoraria from Roche/Genentech, Novartis, Amgen, AstraZeneca, Pfizer, PharmaMar, and Lilly, and research grants from Roche and Novartis. Dr Rugo disclosed travel support from PUMA and Mylan, research support from Genentech/Roche, and honoraria from Biotheranostics. She also serves on the Oncology Practice Advisory Board.
MADRID – who received postoperative trastuzumab (Herceptin) and chemotherapy, long-term follow-up results from the ExteNET trial show.
In a planned intention-to-treat analysis at 5 years of follow-up, extended adjuvant therapy with the tyrosine kinase inhibitor neratinib was associated with a small but significant improvement in invasive disease-free survival (iDFS), compared with placebo, with most of the benefit occurring in women with hormone receptor–positive disease, reported Miguel Martin, MD, of the Gregorio Marañón Health Research Institute in Madrid.
Data from an earlier analysis of the trial supported the Food and Drug Administration’s decision to approve neratinib in the extended adjuvant setting in July 2017.
In the ExteNET trial, 2,840 women with early HER2-positive breast cancer who had undergone surgery and adjuvant treatment with trastuzumab and chemotherapy were stratified by nodal and hormone receptor status and by concurrent vs. sequential chemotherapy and trastuzumab, and were then randomly assigned to receive oral neratinib 240 mg/day for 1 year, or placebo. Analyses of iDFS were planned for 2 and 5 years, and an overall survival analysis was planned after 248 patient deaths had occurred. Overall survival data have not matured as yet, Dr. Martin noted.
Results of an unspecified 3-year analysis of the trial, presented at the San Antonio Breast Cancer Symposium in 2015, showed a continued benefit for the addition of neratinib, a finding that has now been extended out to 5 years.
At ESMO 2017, Dr. Martin presented data on all efficacy endpoints except overall survival in the intention-to-treat population.
By the cutoff date in March 2017, 2,117 of the original 2,840 patients (76%) gave consent for collection of additional data, including 1,028 who had been assigned to neratinib, and 1,089 assigned to placebo.
The 5-year iDFS rate was 90.2% for patients assigned to neratinib, compared with 87.7% for those assigned to placebo, an absolute difference of 2.5%. This translated into a hazard ratio favoring neratinib of 0.73 (P = .008). Neratinib was also significantly better than placebo for DFS in patients with ductal carcinoma in situ (89.7% vs. 86.8, HR, 0.71, P = .004).
However, there were no significant differences at 5 years between trial arms in either distant DFS, time to distant recurrence, or central nervous system recurrences. Dr. Martin noted that the although there were fewer CNS recurrences with neratinib (1.30% vs. 1.82%), the total number of cases was too small to detect a possible difference.
In a subgroup analysis, neratinib trended toward better performance in all categories, but was significantly better than placebo only among patients from Asia, Eastern Europe, and South America, and among patients with four or more positive lymph nodes.
An analysis of iDFS by hormone receptor status showed that for HR-positive patients, the 5-year iDFS rate was 91.2% with neratinib vs. 86.8% with placebo, translating into a hazard ratio of 0.60, P = .002). In contrast, iDFS rates were nearly identical among HR-negative patients, at 88.9% vs. 88.8%, respectively.
Following treatment discontinuation, there was no evidence of increased symptomatic cardiotoxicity or second primary malignancies vs. placebo, and no late-term consequences of neratinib-associated diarrhea, Dr. Martin said.
A separate poster on health-related quality of life, also presented at ESMO 2017, showed that patients assigned to neratinib had a drop in quality-of-life measures during the first month of treatment, possibly because of diarrhea, but then had a steady improvement toward baseline. There is an ongoing study to evaluate whether loperamide-based regimens can reduce or prevent neratinib-associated diarrhea, the investigators noted.
“In ExteNET, we’ve seen continued demonstration of clinically significant benefit, particularly in higher-risk, hormone receptor–positive disease, despite many limitations, with change in sponsor and initial plan for only 2 years of follow-up,” said Hope S. Rugo, MD, from the University of California, San Francisco, the invited discussant.
“Survival data is pending, and we’re looking forward to seeing that in 2019, but the reduction in distant events, although small, is still encouraging,” she said.
The trial is sponsored by Puma Biotechnology. Dr. Martin disclosed honoraria from Roche/Genentech, Novartis, Amgen, AstraZeneca, Pfizer, PharmaMar, and Lilly, and research grants from Roche and Novartis. Dr Rugo disclosed travel support from PUMA and Mylan, research support from Genentech/Roche, and honoraria from Biotheranostics. She also serves on the Oncology Practice Advisory Board.
MADRID – who received postoperative trastuzumab (Herceptin) and chemotherapy, long-term follow-up results from the ExteNET trial show.
In a planned intention-to-treat analysis at 5 years of follow-up, extended adjuvant therapy with the tyrosine kinase inhibitor neratinib was associated with a small but significant improvement in invasive disease-free survival (iDFS), compared with placebo, with most of the benefit occurring in women with hormone receptor–positive disease, reported Miguel Martin, MD, of the Gregorio Marañón Health Research Institute in Madrid.
Data from an earlier analysis of the trial supported the Food and Drug Administration’s decision to approve neratinib in the extended adjuvant setting in July 2017.
In the ExteNET trial, 2,840 women with early HER2-positive breast cancer who had undergone surgery and adjuvant treatment with trastuzumab and chemotherapy were stratified by nodal and hormone receptor status and by concurrent vs. sequential chemotherapy and trastuzumab, and were then randomly assigned to receive oral neratinib 240 mg/day for 1 year, or placebo. Analyses of iDFS were planned for 2 and 5 years, and an overall survival analysis was planned after 248 patient deaths had occurred. Overall survival data have not matured as yet, Dr. Martin noted.
Results of an unspecified 3-year analysis of the trial, presented at the San Antonio Breast Cancer Symposium in 2015, showed a continued benefit for the addition of neratinib, a finding that has now been extended out to 5 years.
At ESMO 2017, Dr. Martin presented data on all efficacy endpoints except overall survival in the intention-to-treat population.
By the cutoff date in March 2017, 2,117 of the original 2,840 patients (76%) gave consent for collection of additional data, including 1,028 who had been assigned to neratinib, and 1,089 assigned to placebo.
The 5-year iDFS rate was 90.2% for patients assigned to neratinib, compared with 87.7% for those assigned to placebo, an absolute difference of 2.5%. This translated into a hazard ratio favoring neratinib of 0.73 (P = .008). Neratinib was also significantly better than placebo for DFS in patients with ductal carcinoma in situ (89.7% vs. 86.8, HR, 0.71, P = .004).
However, there were no significant differences at 5 years between trial arms in either distant DFS, time to distant recurrence, or central nervous system recurrences. Dr. Martin noted that the although there were fewer CNS recurrences with neratinib (1.30% vs. 1.82%), the total number of cases was too small to detect a possible difference.
In a subgroup analysis, neratinib trended toward better performance in all categories, but was significantly better than placebo only among patients from Asia, Eastern Europe, and South America, and among patients with four or more positive lymph nodes.
An analysis of iDFS by hormone receptor status showed that for HR-positive patients, the 5-year iDFS rate was 91.2% with neratinib vs. 86.8% with placebo, translating into a hazard ratio of 0.60, P = .002). In contrast, iDFS rates were nearly identical among HR-negative patients, at 88.9% vs. 88.8%, respectively.
Following treatment discontinuation, there was no evidence of increased symptomatic cardiotoxicity or second primary malignancies vs. placebo, and no late-term consequences of neratinib-associated diarrhea, Dr. Martin said.
A separate poster on health-related quality of life, also presented at ESMO 2017, showed that patients assigned to neratinib had a drop in quality-of-life measures during the first month of treatment, possibly because of diarrhea, but then had a steady improvement toward baseline. There is an ongoing study to evaluate whether loperamide-based regimens can reduce or prevent neratinib-associated diarrhea, the investigators noted.
“In ExteNET, we’ve seen continued demonstration of clinically significant benefit, particularly in higher-risk, hormone receptor–positive disease, despite many limitations, with change in sponsor and initial plan for only 2 years of follow-up,” said Hope S. Rugo, MD, from the University of California, San Francisco, the invited discussant.
“Survival data is pending, and we’re looking forward to seeing that in 2019, but the reduction in distant events, although small, is still encouraging,” she said.
The trial is sponsored by Puma Biotechnology. Dr. Martin disclosed honoraria from Roche/Genentech, Novartis, Amgen, AstraZeneca, Pfizer, PharmaMar, and Lilly, and research grants from Roche and Novartis. Dr Rugo disclosed travel support from PUMA and Mylan, research support from Genentech/Roche, and honoraria from Biotheranostics. She also serves on the Oncology Practice Advisory Board.
AT ESMO 2017
Key clinical point: Neratinib after adjuvant trastuzumab and chemotherapy continued to show improved invasive disease-free survival at 5 years in women with early HER2+ breast cancer.
Major finding: The 5-year iDFS rate was 90.2% for patients assigned to neratinib, compared with 87.7% for those assigned to placebo.
Data source: 5-year follow-up of randomized phase 3 trial in 2,840 women with HER2+ breast cancer treated with surgery and adjuvant chemotherapy/trastuzumab.
Disclosures: The trial is sponsored by Puma Biotechnology. Dr. Martin disclosed honoraria from Roche/Genentech, Novartis, Amgen, AstraZeneca, Pfizer, PharmaMar, and Lilly, and research grants from Roche and Novartis. Dr Rugo disclosed travel support from PUMA and Mylan, research support from Genentech/Roche, and honoraria from Biotheranostics. She also serves on the Oncology Practice Advisory Board.
Hyperlipidemia diagnosis protects against breast cancer
BARCELONA – Women diagnosed with hyperlipidemia had a strikingly reduced risk of subsequently developing breast cancer in a big-data, case-control study, Paul R. Carter, MD, reported at the annual congress of the European Society of Cardiology.
Moreover, those baseline hyperlipidemic women who later got breast cancer had a 40% lower risk of all-cause mortality than did matched nonhyperlipidemic controls diagnosed with the malignancy during follow-up, according to Dr. Carter, a cardiology fellow at Cambridge (England) University.
The inference isn’t that hyperlipidemia somehow protects against the most common type of cancer in women. Indeed, preclinical evidence indicates high cholesterol drives several key steps in carcinogenesis. Rather, the strong implication is that the explanation for the observed preventive effect lies in the pleotropic effects of the statin therapy routinely prescribed in accordance with guidelines once women received the diagnosis of hyperlipidemia, he continued.
“The results of this study provide the strongest justification to date for a clinical trial evaluating the protective effect of statins in patients with breast cancer, and this is what we intend to do,” according to Dr. Carter.
He presented a retrospective longitudinal study of the Algorithm for Comorbidities, Associations, Length of Stay and Mortality database, comprising more than 1.2 million patients admitted for various reasons to selected hospitals in northern England during 2000-2014. This big-data study entailed recruitment of 16,043 women aged 40 years and older who were diagnosed with hyperlipidemia during their hospital stay along with an equal number of age-matched women with normal lipid levels. None of the participants had a breast cancer diagnosis at baseline.
The all-cause mortality rate in baseline hyperlipidemic women who later developed breast cancer was 27.4%, significantly lower than the 37.4% rate in normolipidemic women with breast cancer. This translated into an adjusted 40% relative risk reduction.
All-cause mortality occurred during follow-up in 13.7% of breast cancer–free women with baseline hyperlipidemia, compared with 23.6% of nonhyperlipidemic controls without breast cancer.
In an analysis adjusted for age, ethnicity, and the top-10 causes of death in the U.K., women with baseline hyperlipidemia were 40% less likely to die during follow-up than were women without high cholesterol.
Dr. Carter reported having no financial conflicts of interest regarding his study, which was conducted free of commercial support.
BARCELONA – Women diagnosed with hyperlipidemia had a strikingly reduced risk of subsequently developing breast cancer in a big-data, case-control study, Paul R. Carter, MD, reported at the annual congress of the European Society of Cardiology.
Moreover, those baseline hyperlipidemic women who later got breast cancer had a 40% lower risk of all-cause mortality than did matched nonhyperlipidemic controls diagnosed with the malignancy during follow-up, according to Dr. Carter, a cardiology fellow at Cambridge (England) University.
The inference isn’t that hyperlipidemia somehow protects against the most common type of cancer in women. Indeed, preclinical evidence indicates high cholesterol drives several key steps in carcinogenesis. Rather, the strong implication is that the explanation for the observed preventive effect lies in the pleotropic effects of the statin therapy routinely prescribed in accordance with guidelines once women received the diagnosis of hyperlipidemia, he continued.
“The results of this study provide the strongest justification to date for a clinical trial evaluating the protective effect of statins in patients with breast cancer, and this is what we intend to do,” according to Dr. Carter.
He presented a retrospective longitudinal study of the Algorithm for Comorbidities, Associations, Length of Stay and Mortality database, comprising more than 1.2 million patients admitted for various reasons to selected hospitals in northern England during 2000-2014. This big-data study entailed recruitment of 16,043 women aged 40 years and older who were diagnosed with hyperlipidemia during their hospital stay along with an equal number of age-matched women with normal lipid levels. None of the participants had a breast cancer diagnosis at baseline.
The all-cause mortality rate in baseline hyperlipidemic women who later developed breast cancer was 27.4%, significantly lower than the 37.4% rate in normolipidemic women with breast cancer. This translated into an adjusted 40% relative risk reduction.
All-cause mortality occurred during follow-up in 13.7% of breast cancer–free women with baseline hyperlipidemia, compared with 23.6% of nonhyperlipidemic controls without breast cancer.
In an analysis adjusted for age, ethnicity, and the top-10 causes of death in the U.K., women with baseline hyperlipidemia were 40% less likely to die during follow-up than were women without high cholesterol.
Dr. Carter reported having no financial conflicts of interest regarding his study, which was conducted free of commercial support.
BARCELONA – Women diagnosed with hyperlipidemia had a strikingly reduced risk of subsequently developing breast cancer in a big-data, case-control study, Paul R. Carter, MD, reported at the annual congress of the European Society of Cardiology.
Moreover, those baseline hyperlipidemic women who later got breast cancer had a 40% lower risk of all-cause mortality than did matched nonhyperlipidemic controls diagnosed with the malignancy during follow-up, according to Dr. Carter, a cardiology fellow at Cambridge (England) University.
The inference isn’t that hyperlipidemia somehow protects against the most common type of cancer in women. Indeed, preclinical evidence indicates high cholesterol drives several key steps in carcinogenesis. Rather, the strong implication is that the explanation for the observed preventive effect lies in the pleotropic effects of the statin therapy routinely prescribed in accordance with guidelines once women received the diagnosis of hyperlipidemia, he continued.
“The results of this study provide the strongest justification to date for a clinical trial evaluating the protective effect of statins in patients with breast cancer, and this is what we intend to do,” according to Dr. Carter.
He presented a retrospective longitudinal study of the Algorithm for Comorbidities, Associations, Length of Stay and Mortality database, comprising more than 1.2 million patients admitted for various reasons to selected hospitals in northern England during 2000-2014. This big-data study entailed recruitment of 16,043 women aged 40 years and older who were diagnosed with hyperlipidemia during their hospital stay along with an equal number of age-matched women with normal lipid levels. None of the participants had a breast cancer diagnosis at baseline.
The all-cause mortality rate in baseline hyperlipidemic women who later developed breast cancer was 27.4%, significantly lower than the 37.4% rate in normolipidemic women with breast cancer. This translated into an adjusted 40% relative risk reduction.
All-cause mortality occurred during follow-up in 13.7% of breast cancer–free women with baseline hyperlipidemia, compared with 23.6% of nonhyperlipidemic controls without breast cancer.
In an analysis adjusted for age, ethnicity, and the top-10 causes of death in the U.K., women with baseline hyperlipidemia were 40% less likely to die during follow-up than were women without high cholesterol.
Dr. Carter reported having no financial conflicts of interest regarding his study, which was conducted free of commercial support.
AT THE ESC CONGRESS 2017
Key clinical point:
Major finding: The risk of subsequent development of breast cancer was one-third lower in women diagnosed with hyperlipidemia than in controls with normal lipid levels.
Data source: A retrospective longitudinal case-control study of 16,043 U.K. women aged 40 years or older when diagnosed with hyperlipidemia and an equal number of age-matched women with normal lipids.
Disclosures: The presenter reported having no financial conflicts of interest regarding his study, which was conducted free of commercial support.
David Henry's JCSO podcast, September-October 2017
In this podcast, coinciding with breast cancer awareness month, Dr David Henry highlights an article by contributor Jane de Lartigue on recent advances in the use of targeted therapies in multiple breast cancer subtypes and another by a practicing oncologist on the positive impact of centralizing breast cancer care in an urban public hospital. Patient-reported outcomes are the focus a review on PROs in palliative and supportive interventions rural cancer patients and an original research report on findings on adverse events from systemic treatment of cancer and patient-reported quality of life. Also featured are two Community Translations columns on the approvals for atezolizumab for non–small-cell lung cancer and lenalidomide as standard of care for multiple myeloma in the maintenance setting, and two case reports on familial essential thrombocythemia associated with JAK2 V617F mutation in siblings and on managing tonsillar carcinoma with advanced radiation and chemotherapy techniques.
Listen to the podcast below.
In this podcast, coinciding with breast cancer awareness month, Dr David Henry highlights an article by contributor Jane de Lartigue on recent advances in the use of targeted therapies in multiple breast cancer subtypes and another by a practicing oncologist on the positive impact of centralizing breast cancer care in an urban public hospital. Patient-reported outcomes are the focus a review on PROs in palliative and supportive interventions rural cancer patients and an original research report on findings on adverse events from systemic treatment of cancer and patient-reported quality of life. Also featured are two Community Translations columns on the approvals for atezolizumab for non–small-cell lung cancer and lenalidomide as standard of care for multiple myeloma in the maintenance setting, and two case reports on familial essential thrombocythemia associated with JAK2 V617F mutation in siblings and on managing tonsillar carcinoma with advanced radiation and chemotherapy techniques.
Listen to the podcast below.
In this podcast, coinciding with breast cancer awareness month, Dr David Henry highlights an article by contributor Jane de Lartigue on recent advances in the use of targeted therapies in multiple breast cancer subtypes and another by a practicing oncologist on the positive impact of centralizing breast cancer care in an urban public hospital. Patient-reported outcomes are the focus a review on PROs in palliative and supportive interventions rural cancer patients and an original research report on findings on adverse events from systemic treatment of cancer and patient-reported quality of life. Also featured are two Community Translations columns on the approvals for atezolizumab for non–small-cell lung cancer and lenalidomide as standard of care for multiple myeloma in the maintenance setting, and two case reports on familial essential thrombocythemia associated with JAK2 V617F mutation in siblings and on managing tonsillar carcinoma with advanced radiation and chemotherapy techniques.
Listen to the podcast below.
FDA approves abemaciclib for advanced breast cancer
The Food and Drug Administration has approved abemaciclib (Verzenio) to be given in combination with fulvestrant, to treat patients who have hormone receptor (HR)–positive, human epidermal growth factor receptor 2 (HER2)–negative advanced or metastatic breast cancer that has progressed after taking endocrine therapy.
This is the third cyclin-dependent kinase 4/6 (CDK4/6) inhibitor approved for the treatment of advanced breast cancer. Palbociclib (Ibrance) was granted accelerated approval in February 2015, in combination with letrozole, for the treatment of HR-positive, HER2-negative advanced breast cancer as initial endocrine-based therapy in postmenopausal women. Ribociclib (Kisqali) was approved in March 2017, in combination with any aromatase inhibitor, also for the treatment of HR-positive, HER2-negative advanced breast cancer as initial endocrine-based therapy in postmenopausal women.
Approval of abemaciclib in combination with fulvestrant was based on a median progression-free survival of 16.4 months for patients taking abemaciclib with fulvestrant, compared with 9.3 months for patients taking a placebo with fulvestrant, in a randomized trial. All 669 patients in the trial had HR-positive, HER2-negative breast cancer that had progressed after treatment with endocrine therapy and had not received chemotherapy once the cancer had metastasized.
Approval of abemaciclib as a single agent was based on an overall response rate of 19.7% in a single-arm trial of 132 patients with HR-positive, HER2-negative breast cancer that had progressed after treatment with endocrine therapy and chemotherapy after the cancer metastasized.
Common side effects of abemaciclib include diarrhea, neutropenia, leukopenia, nausea, abdominal pain, infections, fatigue, anemia, decreased appetite, vomiting, and headache.
Serious side effects include diarrhea, neutropenia, elevated liver blood tests, and deep venous thrombosis/pulmonary embolism, the FDA said.
Approval was granted to Eli Lilly.
The Food and Drug Administration has approved abemaciclib (Verzenio) to be given in combination with fulvestrant, to treat patients who have hormone receptor (HR)–positive, human epidermal growth factor receptor 2 (HER2)–negative advanced or metastatic breast cancer that has progressed after taking endocrine therapy.
This is the third cyclin-dependent kinase 4/6 (CDK4/6) inhibitor approved for the treatment of advanced breast cancer. Palbociclib (Ibrance) was granted accelerated approval in February 2015, in combination with letrozole, for the treatment of HR-positive, HER2-negative advanced breast cancer as initial endocrine-based therapy in postmenopausal women. Ribociclib (Kisqali) was approved in March 2017, in combination with any aromatase inhibitor, also for the treatment of HR-positive, HER2-negative advanced breast cancer as initial endocrine-based therapy in postmenopausal women.
Approval of abemaciclib in combination with fulvestrant was based on a median progression-free survival of 16.4 months for patients taking abemaciclib with fulvestrant, compared with 9.3 months for patients taking a placebo with fulvestrant, in a randomized trial. All 669 patients in the trial had HR-positive, HER2-negative breast cancer that had progressed after treatment with endocrine therapy and had not received chemotherapy once the cancer had metastasized.
Approval of abemaciclib as a single agent was based on an overall response rate of 19.7% in a single-arm trial of 132 patients with HR-positive, HER2-negative breast cancer that had progressed after treatment with endocrine therapy and chemotherapy after the cancer metastasized.
Common side effects of abemaciclib include diarrhea, neutropenia, leukopenia, nausea, abdominal pain, infections, fatigue, anemia, decreased appetite, vomiting, and headache.
Serious side effects include diarrhea, neutropenia, elevated liver blood tests, and deep venous thrombosis/pulmonary embolism, the FDA said.
Approval was granted to Eli Lilly.
The Food and Drug Administration has approved abemaciclib (Verzenio) to be given in combination with fulvestrant, to treat patients who have hormone receptor (HR)–positive, human epidermal growth factor receptor 2 (HER2)–negative advanced or metastatic breast cancer that has progressed after taking endocrine therapy.
This is the third cyclin-dependent kinase 4/6 (CDK4/6) inhibitor approved for the treatment of advanced breast cancer. Palbociclib (Ibrance) was granted accelerated approval in February 2015, in combination with letrozole, for the treatment of HR-positive, HER2-negative advanced breast cancer as initial endocrine-based therapy in postmenopausal women. Ribociclib (Kisqali) was approved in March 2017, in combination with any aromatase inhibitor, also for the treatment of HR-positive, HER2-negative advanced breast cancer as initial endocrine-based therapy in postmenopausal women.
Approval of abemaciclib in combination with fulvestrant was based on a median progression-free survival of 16.4 months for patients taking abemaciclib with fulvestrant, compared with 9.3 months for patients taking a placebo with fulvestrant, in a randomized trial. All 669 patients in the trial had HR-positive, HER2-negative breast cancer that had progressed after treatment with endocrine therapy and had not received chemotherapy once the cancer had metastasized.
Approval of abemaciclib as a single agent was based on an overall response rate of 19.7% in a single-arm trial of 132 patients with HR-positive, HER2-negative breast cancer that had progressed after treatment with endocrine therapy and chemotherapy after the cancer metastasized.
Common side effects of abemaciclib include diarrhea, neutropenia, leukopenia, nausea, abdominal pain, infections, fatigue, anemia, decreased appetite, vomiting, and headache.
Serious side effects include diarrhea, neutropenia, elevated liver blood tests, and deep venous thrombosis/pulmonary embolism, the FDA said.
Approval was granted to Eli Lilly.
HER2 status differed between primary tumor and CTCs in 18.8% of women with MBC
Discordance in HER2 status between the primary breast tumor and circulating tumor cells (CTCs) in women with HER2-negative metastatic disease was 18.8% in a prospective cohort of patients.
The probability of discordance decreased with increasing age but increased with primary tumors that were hormone-receptor positive, higher grade, and of lobular histology, Amelie De Gregorio, MD, and associates reported in JCO Precision Oncology.
The investigators evaluated the HER2 status of CTCs obtained from women with HER2-negative breast cancer screened in the ongoing German DETECT III trial, which is aimed at determining the efficacy of lapatinib in patients with initially HER2-negative metastatic breast cancer but HER2-positive CTCs. HER2 discordance was defined as the presence of a single CTC or more within 7.5 mL of peripheral blood that showed a strong immunohistochemical (IHC) staining intensity (IHC score 3+).
Out of 1,123 women screened, at least one CTC was detected in blood samples from 711 women (63.3%; 95% confidence interval, 60.4%-66.1%). The median number of CTCs detected was seven (interquartile range, 2-30; range, 1-35,078 CTCs), and discordance in HER2 phenotype between primary tumor and CTCs was found in 134 patients (18.8%), Dr. De Gregorio of University Hospital Ulm (Germany) and associates reported (JCO Precis Oncol. 2017 Sep 28. doi: 10.1200/PO.17.00023).
In a multivariable analysis, histologic type (lobular vs. ductal; odds ratio, 2.67; P less than .001), hormone receptor status (positive vs. negative; OR, 2.84; P = .024), and CTC number (greater than 5 vs. 1-4 CTCs; OR, 7.64; P less than .001) significantly and independently predicted discordance in HER2 phenotype between primary tumor and CTCs. There was also a significant effect of age, with the probability of discordance decreasing with increasing age, the investigators noted.
“The knowledge of factors associated with discordance in HER2 status may be incorporated into today’s clinical practice by guiding the decision process for performing biopsy to characterize metastatic relapse,” the investigators wrote.
“Moreover, the concept of liquid biopsy using CTCs as a real-time noninvasive monitoring tool to evaluate tumor biology, progression, and heterogeneity as a basis for more personalized treatment decisions should be tested in prospective randomized clinical trials,” they added.
The DETECT study program is supported by the Investigator-Initiated Study Program of Janssen Diagnostics, with clinical trials also supported by Pierre Fabre Pharma, TEVA Pharmaceuticals Industries, Amgen, Novartis Pharma, and Eisai. Dr. De Gregorio disclosed an advisory role with Roche Pharma AG; several coauthors disclosed consultancy and funding from various pharmaceutical companies.
[email protected]
On Twitter @nikolaideslaura
Discordance in HER2 status between the primary breast tumor and circulating tumor cells (CTCs) in women with HER2-negative metastatic disease was 18.8% in a prospective cohort of patients.
The probability of discordance decreased with increasing age but increased with primary tumors that were hormone-receptor positive, higher grade, and of lobular histology, Amelie De Gregorio, MD, and associates reported in JCO Precision Oncology.
The investigators evaluated the HER2 status of CTCs obtained from women with HER2-negative breast cancer screened in the ongoing German DETECT III trial, which is aimed at determining the efficacy of lapatinib in patients with initially HER2-negative metastatic breast cancer but HER2-positive CTCs. HER2 discordance was defined as the presence of a single CTC or more within 7.5 mL of peripheral blood that showed a strong immunohistochemical (IHC) staining intensity (IHC score 3+).
Out of 1,123 women screened, at least one CTC was detected in blood samples from 711 women (63.3%; 95% confidence interval, 60.4%-66.1%). The median number of CTCs detected was seven (interquartile range, 2-30; range, 1-35,078 CTCs), and discordance in HER2 phenotype between primary tumor and CTCs was found in 134 patients (18.8%), Dr. De Gregorio of University Hospital Ulm (Germany) and associates reported (JCO Precis Oncol. 2017 Sep 28. doi: 10.1200/PO.17.00023).
In a multivariable analysis, histologic type (lobular vs. ductal; odds ratio, 2.67; P less than .001), hormone receptor status (positive vs. negative; OR, 2.84; P = .024), and CTC number (greater than 5 vs. 1-4 CTCs; OR, 7.64; P less than .001) significantly and independently predicted discordance in HER2 phenotype between primary tumor and CTCs. There was also a significant effect of age, with the probability of discordance decreasing with increasing age, the investigators noted.
“The knowledge of factors associated with discordance in HER2 status may be incorporated into today’s clinical practice by guiding the decision process for performing biopsy to characterize metastatic relapse,” the investigators wrote.
“Moreover, the concept of liquid biopsy using CTCs as a real-time noninvasive monitoring tool to evaluate tumor biology, progression, and heterogeneity as a basis for more personalized treatment decisions should be tested in prospective randomized clinical trials,” they added.
The DETECT study program is supported by the Investigator-Initiated Study Program of Janssen Diagnostics, with clinical trials also supported by Pierre Fabre Pharma, TEVA Pharmaceuticals Industries, Amgen, Novartis Pharma, and Eisai. Dr. De Gregorio disclosed an advisory role with Roche Pharma AG; several coauthors disclosed consultancy and funding from various pharmaceutical companies.
[email protected]
On Twitter @nikolaideslaura
Discordance in HER2 status between the primary breast tumor and circulating tumor cells (CTCs) in women with HER2-negative metastatic disease was 18.8% in a prospective cohort of patients.
The probability of discordance decreased with increasing age but increased with primary tumors that were hormone-receptor positive, higher grade, and of lobular histology, Amelie De Gregorio, MD, and associates reported in JCO Precision Oncology.
The investigators evaluated the HER2 status of CTCs obtained from women with HER2-negative breast cancer screened in the ongoing German DETECT III trial, which is aimed at determining the efficacy of lapatinib in patients with initially HER2-negative metastatic breast cancer but HER2-positive CTCs. HER2 discordance was defined as the presence of a single CTC or more within 7.5 mL of peripheral blood that showed a strong immunohistochemical (IHC) staining intensity (IHC score 3+).
Out of 1,123 women screened, at least one CTC was detected in blood samples from 711 women (63.3%; 95% confidence interval, 60.4%-66.1%). The median number of CTCs detected was seven (interquartile range, 2-30; range, 1-35,078 CTCs), and discordance in HER2 phenotype between primary tumor and CTCs was found in 134 patients (18.8%), Dr. De Gregorio of University Hospital Ulm (Germany) and associates reported (JCO Precis Oncol. 2017 Sep 28. doi: 10.1200/PO.17.00023).
In a multivariable analysis, histologic type (lobular vs. ductal; odds ratio, 2.67; P less than .001), hormone receptor status (positive vs. negative; OR, 2.84; P = .024), and CTC number (greater than 5 vs. 1-4 CTCs; OR, 7.64; P less than .001) significantly and independently predicted discordance in HER2 phenotype between primary tumor and CTCs. There was also a significant effect of age, with the probability of discordance decreasing with increasing age, the investigators noted.
“The knowledge of factors associated with discordance in HER2 status may be incorporated into today’s clinical practice by guiding the decision process for performing biopsy to characterize metastatic relapse,” the investigators wrote.
“Moreover, the concept of liquid biopsy using CTCs as a real-time noninvasive monitoring tool to evaluate tumor biology, progression, and heterogeneity as a basis for more personalized treatment decisions should be tested in prospective randomized clinical trials,” they added.
The DETECT study program is supported by the Investigator-Initiated Study Program of Janssen Diagnostics, with clinical trials also supported by Pierre Fabre Pharma, TEVA Pharmaceuticals Industries, Amgen, Novartis Pharma, and Eisai. Dr. De Gregorio disclosed an advisory role with Roche Pharma AG; several coauthors disclosed consultancy and funding from various pharmaceutical companies.
[email protected]
On Twitter @nikolaideslaura
FROM JCO PRECISION ONCOLOGY
Key clinical point:
Major finding: Histologic type (lobular vs. ductal; odds ratio, 2.67; P less than .001), hormone receptor status (positive vs. negative; OR, 2.84; P = .024), and CTC number (more than 5 vs. 1-4 CTCs; OR, 7.64; P less than .001) significantly predicted HER2 discordance between primary tumor and CTCs.
Data source: A prospective cohort of 1,123 women with metastatic breast cancer screened for the ongoing DETECT III trial in Germany.
Disclosures: The DETECT study program is supported by the Investigator-Initiated Study Program of Janssen Diagnostics, with clinical trials also supported by Pierre Fabre Pharma, TEVA Pharmaceuticals Industries, Amgen, Novartis Pharma, and Eisai. Dr. De Gregorio disclosed an advisory role with Roche Pharma AG; several coauthors disclosed consultancy and funding from various pharaceutical companies.
Two cases of possible remission in metastatic triple-negative breast cancer
Triple-negative breast cancer (TNBC) has been shown to generally have a poor prognosis. Within the first 3-5 years of diagnosis, the mortality rate is the highest of all the subtypes of breast cancer, although late relapses are less common.1,2 TNBC is markedly heterogeneous tumor, and the individual prognosis can vary widely.1,3 Metastatic TNBC is generally considered a noncurable disease. The median time from recurrence to death for metastatic disease is about 9 months, compared with 20 months for patients with other subtypes of breast cancers.4,5 The median survival time for patients with metastatic TNBC is about 13 months.3
New targeted therapies are emerging for breast cancer, but there are currently no effective targeted therapies for patients with TNBC. In addition, few reports in the literature that discuss long-term complete remissions in patients who have metastatic TNBC. Here, we describe two cases in which patients with metastatic TNBC achieved sustained complete response on conventional chemotherapy regimens.
Case presentations and summaries
Case 1
A 59-year-old woman (age in 2015) had been diagnosed on biopsy in February 2005 with locally advanced right breast cancer (stage T2N2bM0). She underwent lumpectomy, and the results of her pathology tests revealed a triple-negative invasive ductal carcinoma. She was started on 4 cycles of neoadjuvant doxorubicin (60 mg/m2 IV) and cyclophosphamide (600 mg/m2 IV)
In November 2007, the patient was found to have right chest wall metastasis confirmed by ultrasound-guided needle biopsy, and underwent right-side chest wall and partial sternum resection. In May 2008, she had recurrence in the left axilla, and biopsy results showed that she had TNBC disease. She was started on weekly paclitaxel (90 mg/m2) and bevacizumab (10 mg/kg every 2 weeks) continued until July 2008. Chemotherapy was stopped in July 2008 because of a methicillin-resistant Staphylococcus aureus (MRSA) infection of the chest wall and was not resumed after the infection had resolved.
A follow-up positron-emission tomography– computed tomography (PET-CT) scan in June 2009, showed no evidence of disease and the scan was negative for disease in her left axilla. Another PET scan about a year later, in September 2010, was also negative for any disease recurrence.
The patient has continued her follow-up with physical examinations and imaging scans. A CT scan of the abdomen and pelvis (December 2010), an MRI of the breasts (February 2011, August 2015), and a PET-CT scan (April 2015, Figure 1) were all negative for any evidence of disease. In September 2011, she had a CT-guided biopsy of a medial right clavicle and costal junction lesion; and in November 2011 and January 2013, surgical biopsies of the right chest wall and first rib lesions, all negative for any evidence for malignancy. At her last follow-up in January 2017, the patient remained in remission.
Case 2
A 68-year old woman (age in 2015) had been diagnosed in Russia in 2004 with infiltrating ductal carcinoma of the right breast (T4N1M0; receptor status unknown at that time). She underwent a right modified radical mastectomy and received adjuvant chemotherapy with 4 cycles of cyclophosphamide (100 mg/m2 day 1 to day 14), methotrexate (40 mg/m2 IV day 1 and day 8), and fluorouracil (600 mg/m2 IV, day 1 and day 8) followed by 2 cycles of docetaxel (75 mg/m2 IV) and anthracycline adriyamycin (50 mg/m2 IV). The patient later received radiation therapy (radiation dose not known, treatment was received in Russia), and completed her treatment in November 2004.
The patient moved to the United States and was started on 25 mg daily exemestane in February 2005. In March 2009, she was diagnosed by biopsy to have recurrence in her internal mammary and hilar lymph nodes and sternum. The cancer was found to be ER- and PR-negative and HER2-neu–negative. The patient was treated with radiation therapy (37.5 Gy in 15 fractions) to sternum and hilar and internal mammary lymph nodes with improvement in pain and shrinkage of lymph nodes size. In May 2009, she was started on 1,500 mg oral twice a day capecitabine (3 cycles). The therapy was started after completion of radiation treatment due to progression of disease. She developed hand-and-foot syndrome as side effect of the capecitabine, so the dose was reduced. She was switched to gemcitabine (1,000 mg/m2 on days 1, 8, and 15, every 28-day cycle) as a single-agent therapy and completed 3 cycles. A follow-up PET-CT scan in February 2010 showed no evidence of disease.
In May 2010, the patient had a recurrence in the same metastatic foci as before, and she was again started on gemcitabine (1,000 mg/m2 on days 1, 8, and 15, every 28-day cycle). She continued gemcitabine until there was evidence of disease progression on a PET-CT scan in October 2010, which showed new areas of disease in the left parasternal region, left sternum, prevascular mediastinal nodes, and left supraclavicular, hilar and axillary adenopathy, and fourth thoracic vertebra. Gemcitabine was discontinued and patient was started on weekly paclitaxel (90 mg/m2) for 6 cycles. Paclitaxel was discontinued after 6 weeks because she developed a drug-related rash. A follow-up PET-CT scan in December 2010 again showed complete resolution of disease in terms of response.
In March 2011, PET imaging showed progression of disease in the left chest wall and axillary lymph nodes, so the patient was started on eribulin therapy (1.4 mg/m2 on days 1 and 8 every 21-day cycle) and completed 3 cycles. In May 2011, PET imaging showed complete response to treatment with no evidence of recurrent or metastatic disease. The patient has not had chemotherapy since November 2011, and surveillance PET imaging has not demonstrated any recurrence of disease (Figure 2). Following her last follow-up in November 2016, the patient remains in remission.
Discussion
Triple-negative breast cancers (TNBCs) are defined as tumors that lack expression of estrogen receptor (ER), progesterone receptor (PR), and HER2, and represent about 12%-17% of breast cancer cases.1,6 TNBCs tend to be larger in size at diagnosis than are other subtypes, are usually high-grade (poorly differentiated), and are more likely to be invasive ductal carcinomas.1,7 TNBC and the basal-like breast cancers as a group are associated with an adverse prognosis.1,7 There is no standard preferred chemotherapy and no biologic therapy available for TNBC.1,6-7 A sharp decline in survival outcome during the first 3-5 years after diagnosis initial is observed in TNBC, although the distant relapses after this time are less common.1 Beyond 10 years from diagnosis, the relapses are seen more common among patients with ER-positive cancers than among those with ER-negative subtype cancers. Therefore, although TNBCs are biologically aggressive, many are possibly curable, and this reflects their interesting characteristic heterogeneity.1,6
Chemotherapy is currently the mainstay of systemic medical treatment. Although patients with TNBC have a worse outcome after chemotherapy than patients with breast cancers of other subtypes, it still improves their outcome to a greater extent than in patients with ER-positive subtypes.1,6,7 Considering the heterogeneity of TNBC, it is difficult to predict which patients will benefit more from chemotherapy. The same has been observed in previous studies when subgroups of women with TNBC were extremely sensitive to chemotherapy, whereas in others it was of uncertain benefit.1
Currently, there is no preferred standard form of chemotherapy for TNBC. There are few case reports that demonstrate long-term survival and complete remission in metastatic TNBC. Shakir has reported on a significant clinical response to nab-paclitaxel monotherapy in a patient with triple-negative BRCA1-positive breast cancer, although patient survived a little more than 5 years and died with central nervous system recurrence.8 Montero and Gluck have described a patient with metastatic TNBC who was treated with nab-paclitaxel, gemcitabine, and bevacizumab and who also survived for 5 years after diagnosis.9 Different retrospective analyses have suggested that the addition of docetaxel or paclitaxel to anthracycline-containing adjuvant regimens may be of greater benefit for the treatment of TNBC than for ER-positive tumors.10 A meta-analysis of trials comparing the effects of cyclophosphamide, methotrexate, and fluorouracil (CMF, which was used in Case 2) with anthracycline-containing regimens has suggested that the latter therapy regimen is more effective against TNBC,11 although another retrospective analysis of a separate trial suggested the opposite for basal-like breast cancers. 12 The authors of the latter analysis concluded that anthracycline-containing adjuvant chemotherapy regimens are inferior to adjuvant CMF in women with basal breast cancer.12
Miller and colleagues have shown that the addition of bevacizumab (angiogenesis inhibitor) to paclitaxel (used in Case 1) improved progression-free survival (median PFS, 11.8 vs 5.9 months; hazard ratio [HR] for progression, 0.60; P < .001) in women with TNBC as it did in the overall study group (HR, 0.53 and 0.60, respectively), although the overall survival rate was similar in the two groups (median OS, 26.7 vs 25.2 months; HR, 0.88; P = .16).13
An interesting clinical target in TNBC is the enzyme poly (adenosine diphosphate– ribose) polymerase (PARP), which is involved in base-excision repair after DNA damage. PARP inhibitors have shown encouraging clinical activity in trials of tumors arising in BRCA mutation carriers and in sporadic TNBC cancers.14 Similarly, the use of an oral PARP inhibitor, olaparib, resulted in tumor regression in up to 41% of patients carrying BRCA mutations, most of whom had TNBC.15
Conclusion
TNBC and basal-like breast cancers show aggressive clinical behavior, but a subgroup of these cancers may be markedly sensitive to chemotherapy and associated with a good prognosis when treated with conventional chemotherapy regimens. The two cases presented here show that some patients can get a prolonged disease control from chemotherapy, even after progressing on multiple previous chemotherapy regimens and that after, 5 years or so, these rare patients could be in true long-term remission. Novel approaches, for example PARP inhibitors, have shown encouraging clinical activity in trials of tumors arising in BRCA mutation carriers and as well as sporadic TNBC.
1. Foulkes WD, Smith IE, Reis-Filho JS, Triple-negative breast cancer. N Engl J Med. 2010;363:1938-1948.
2. Pogoda K, Niwińska A, Murawska M, Pieńkowski T. Analysis of pattern, time and risk factors influencing recurrence in triple-negative breast cancer patients. Med Oncol. 2013;30(1):388.
3. Kassam F, Enright K, Dent R, et al. Survival outcomes for patients with metastatic triple-negative breast cancer: implications for clinical practice and trial design. Clin Breast Cancer. 2009;9(1):29-33.
4. Perou CM. Molecular stratification of triple-negative breast cancers. Oncologist. 2010;15(suppl 5):39-48.
5. Rakha EA, Chan S. Metastatic triple-negative breast cancer. Clin Oncol (R Coll Radiol). 2011;23(9):587-600.
6. Williams N, Harris L. Triple-negative breast cancer in the post-genomic era. Oncology (Williston Park). 2013;27(9):859-860, 864.
7. Randhawa SK, Venur VA, Kawsar H, et al. A retrospective comparison of the characteristics and recurrence outcome of triple-negative and triple-positive breast cancer. J Clin Oncol. 2013;31(suppl; abstr 1038).
8. Shakir AR. Strong and sustained response to treatment with carboplatin plus nab-paclitaxel in a patient with metastatic, triple-negative, BRCA1-positive breast cancer. Case Rep Oncol. 2014;7(1)252-259.
9. Montero A, Glück S. Long-term complete remission with nab-paclitaxel, bevacizumab, and gemcitabine combination therapy in a patient with triple-negative metastatic breast cancer. Case Rep Oncol. 2012;5(3):687-692.
10. Hayes DF, Thor AD, Dressler LG, et al. HER2 and response to paclitaxel in node-positive breast cancer. N Engl J Med. 2007;357:1496-1506.
11. Di Leo A, Isola J, Piette F, et al. A meta- analysis of phase III trials evaluating the predictive value of HER2 and topoisomerase alpha in early breast cancer patients treated with CMF or anthracycline-based adjuvant therapy [SABCS, abstract 705]. http://cancerres.aacrjournals.org/content/69/2_Supplement/705. Published 2008. Accessed May 4, 2017.
12. Cheang M, Chia SK, Tu D, et al. Anthracycline in basal breast cancer: the NCIC-CTG trial MA5 comparing adjuvant CMF to CEF [ASCO; abstract 519]. http://meetinglibrary.asco.org/content/35150-65. Published 2009. Accessed May 4, 2017.
13. Miller K, Wang M, Gralow J, et al. Paclitaxel plus bevacizumab versus paclitaxel alone for metastatic breast cancer. N Engl J Med. 2007;357:2666-2676.
14. Fong PC, Boss DS, Yap TA, et al. Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers. N Engl J Med. 2009;361:123-134.
15. Tutt A, Robson M, Garber JE, et al. Oral poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and advanced breast cancer: a proof-of-concept trial. Lancet. 2010;376:235-244.
Triple-negative breast cancer (TNBC) has been shown to generally have a poor prognosis. Within the first 3-5 years of diagnosis, the mortality rate is the highest of all the subtypes of breast cancer, although late relapses are less common.1,2 TNBC is markedly heterogeneous tumor, and the individual prognosis can vary widely.1,3 Metastatic TNBC is generally considered a noncurable disease. The median time from recurrence to death for metastatic disease is about 9 months, compared with 20 months for patients with other subtypes of breast cancers.4,5 The median survival time for patients with metastatic TNBC is about 13 months.3
New targeted therapies are emerging for breast cancer, but there are currently no effective targeted therapies for patients with TNBC. In addition, few reports in the literature that discuss long-term complete remissions in patients who have metastatic TNBC. Here, we describe two cases in which patients with metastatic TNBC achieved sustained complete response on conventional chemotherapy regimens.
Case presentations and summaries
Case 1
A 59-year-old woman (age in 2015) had been diagnosed on biopsy in February 2005 with locally advanced right breast cancer (stage T2N2bM0). She underwent lumpectomy, and the results of her pathology tests revealed a triple-negative invasive ductal carcinoma. She was started on 4 cycles of neoadjuvant doxorubicin (60 mg/m2 IV) and cyclophosphamide (600 mg/m2 IV)
In November 2007, the patient was found to have right chest wall metastasis confirmed by ultrasound-guided needle biopsy, and underwent right-side chest wall and partial sternum resection. In May 2008, she had recurrence in the left axilla, and biopsy results showed that she had TNBC disease. She was started on weekly paclitaxel (90 mg/m2) and bevacizumab (10 mg/kg every 2 weeks) continued until July 2008. Chemotherapy was stopped in July 2008 because of a methicillin-resistant Staphylococcus aureus (MRSA) infection of the chest wall and was not resumed after the infection had resolved.
A follow-up positron-emission tomography– computed tomography (PET-CT) scan in June 2009, showed no evidence of disease and the scan was negative for disease in her left axilla. Another PET scan about a year later, in September 2010, was also negative for any disease recurrence.
The patient has continued her follow-up with physical examinations and imaging scans. A CT scan of the abdomen and pelvis (December 2010), an MRI of the breasts (February 2011, August 2015), and a PET-CT scan (April 2015, Figure 1) were all negative for any evidence of disease. In September 2011, she had a CT-guided biopsy of a medial right clavicle and costal junction lesion; and in November 2011 and January 2013, surgical biopsies of the right chest wall and first rib lesions, all negative for any evidence for malignancy. At her last follow-up in January 2017, the patient remained in remission.
Case 2
A 68-year old woman (age in 2015) had been diagnosed in Russia in 2004 with infiltrating ductal carcinoma of the right breast (T4N1M0; receptor status unknown at that time). She underwent a right modified radical mastectomy and received adjuvant chemotherapy with 4 cycles of cyclophosphamide (100 mg/m2 day 1 to day 14), methotrexate (40 mg/m2 IV day 1 and day 8), and fluorouracil (600 mg/m2 IV, day 1 and day 8) followed by 2 cycles of docetaxel (75 mg/m2 IV) and anthracycline adriyamycin (50 mg/m2 IV). The patient later received radiation therapy (radiation dose not known, treatment was received in Russia), and completed her treatment in November 2004.
The patient moved to the United States and was started on 25 mg daily exemestane in February 2005. In March 2009, she was diagnosed by biopsy to have recurrence in her internal mammary and hilar lymph nodes and sternum. The cancer was found to be ER- and PR-negative and HER2-neu–negative. The patient was treated with radiation therapy (37.5 Gy in 15 fractions) to sternum and hilar and internal mammary lymph nodes with improvement in pain and shrinkage of lymph nodes size. In May 2009, she was started on 1,500 mg oral twice a day capecitabine (3 cycles). The therapy was started after completion of radiation treatment due to progression of disease. She developed hand-and-foot syndrome as side effect of the capecitabine, so the dose was reduced. She was switched to gemcitabine (1,000 mg/m2 on days 1, 8, and 15, every 28-day cycle) as a single-agent therapy and completed 3 cycles. A follow-up PET-CT scan in February 2010 showed no evidence of disease.
In May 2010, the patient had a recurrence in the same metastatic foci as before, and she was again started on gemcitabine (1,000 mg/m2 on days 1, 8, and 15, every 28-day cycle). She continued gemcitabine until there was evidence of disease progression on a PET-CT scan in October 2010, which showed new areas of disease in the left parasternal region, left sternum, prevascular mediastinal nodes, and left supraclavicular, hilar and axillary adenopathy, and fourth thoracic vertebra. Gemcitabine was discontinued and patient was started on weekly paclitaxel (90 mg/m2) for 6 cycles. Paclitaxel was discontinued after 6 weeks because she developed a drug-related rash. A follow-up PET-CT scan in December 2010 again showed complete resolution of disease in terms of response.
In March 2011, PET imaging showed progression of disease in the left chest wall and axillary lymph nodes, so the patient was started on eribulin therapy (1.4 mg/m2 on days 1 and 8 every 21-day cycle) and completed 3 cycles. In May 2011, PET imaging showed complete response to treatment with no evidence of recurrent or metastatic disease. The patient has not had chemotherapy since November 2011, and surveillance PET imaging has not demonstrated any recurrence of disease (Figure 2). Following her last follow-up in November 2016, the patient remains in remission.
Discussion
Triple-negative breast cancers (TNBCs) are defined as tumors that lack expression of estrogen receptor (ER), progesterone receptor (PR), and HER2, and represent about 12%-17% of breast cancer cases.1,6 TNBCs tend to be larger in size at diagnosis than are other subtypes, are usually high-grade (poorly differentiated), and are more likely to be invasive ductal carcinomas.1,7 TNBC and the basal-like breast cancers as a group are associated with an adverse prognosis.1,7 There is no standard preferred chemotherapy and no biologic therapy available for TNBC.1,6-7 A sharp decline in survival outcome during the first 3-5 years after diagnosis initial is observed in TNBC, although the distant relapses after this time are less common.1 Beyond 10 years from diagnosis, the relapses are seen more common among patients with ER-positive cancers than among those with ER-negative subtype cancers. Therefore, although TNBCs are biologically aggressive, many are possibly curable, and this reflects their interesting characteristic heterogeneity.1,6
Chemotherapy is currently the mainstay of systemic medical treatment. Although patients with TNBC have a worse outcome after chemotherapy than patients with breast cancers of other subtypes, it still improves their outcome to a greater extent than in patients with ER-positive subtypes.1,6,7 Considering the heterogeneity of TNBC, it is difficult to predict which patients will benefit more from chemotherapy. The same has been observed in previous studies when subgroups of women with TNBC were extremely sensitive to chemotherapy, whereas in others it was of uncertain benefit.1
Currently, there is no preferred standard form of chemotherapy for TNBC. There are few case reports that demonstrate long-term survival and complete remission in metastatic TNBC. Shakir has reported on a significant clinical response to nab-paclitaxel monotherapy in a patient with triple-negative BRCA1-positive breast cancer, although patient survived a little more than 5 years and died with central nervous system recurrence.8 Montero and Gluck have described a patient with metastatic TNBC who was treated with nab-paclitaxel, gemcitabine, and bevacizumab and who also survived for 5 years after diagnosis.9 Different retrospective analyses have suggested that the addition of docetaxel or paclitaxel to anthracycline-containing adjuvant regimens may be of greater benefit for the treatment of TNBC than for ER-positive tumors.10 A meta-analysis of trials comparing the effects of cyclophosphamide, methotrexate, and fluorouracil (CMF, which was used in Case 2) with anthracycline-containing regimens has suggested that the latter therapy regimen is more effective against TNBC,11 although another retrospective analysis of a separate trial suggested the opposite for basal-like breast cancers. 12 The authors of the latter analysis concluded that anthracycline-containing adjuvant chemotherapy regimens are inferior to adjuvant CMF in women with basal breast cancer.12
Miller and colleagues have shown that the addition of bevacizumab (angiogenesis inhibitor) to paclitaxel (used in Case 1) improved progression-free survival (median PFS, 11.8 vs 5.9 months; hazard ratio [HR] for progression, 0.60; P < .001) in women with TNBC as it did in the overall study group (HR, 0.53 and 0.60, respectively), although the overall survival rate was similar in the two groups (median OS, 26.7 vs 25.2 months; HR, 0.88; P = .16).13
An interesting clinical target in TNBC is the enzyme poly (adenosine diphosphate– ribose) polymerase (PARP), which is involved in base-excision repair after DNA damage. PARP inhibitors have shown encouraging clinical activity in trials of tumors arising in BRCA mutation carriers and in sporadic TNBC cancers.14 Similarly, the use of an oral PARP inhibitor, olaparib, resulted in tumor regression in up to 41% of patients carrying BRCA mutations, most of whom had TNBC.15
Conclusion
TNBC and basal-like breast cancers show aggressive clinical behavior, but a subgroup of these cancers may be markedly sensitive to chemotherapy and associated with a good prognosis when treated with conventional chemotherapy regimens. The two cases presented here show that some patients can get a prolonged disease control from chemotherapy, even after progressing on multiple previous chemotherapy regimens and that after, 5 years or so, these rare patients could be in true long-term remission. Novel approaches, for example PARP inhibitors, have shown encouraging clinical activity in trials of tumors arising in BRCA mutation carriers and as well as sporadic TNBC.
Triple-negative breast cancer (TNBC) has been shown to generally have a poor prognosis. Within the first 3-5 years of diagnosis, the mortality rate is the highest of all the subtypes of breast cancer, although late relapses are less common.1,2 TNBC is markedly heterogeneous tumor, and the individual prognosis can vary widely.1,3 Metastatic TNBC is generally considered a noncurable disease. The median time from recurrence to death for metastatic disease is about 9 months, compared with 20 months for patients with other subtypes of breast cancers.4,5 The median survival time for patients with metastatic TNBC is about 13 months.3
New targeted therapies are emerging for breast cancer, but there are currently no effective targeted therapies for patients with TNBC. In addition, few reports in the literature that discuss long-term complete remissions in patients who have metastatic TNBC. Here, we describe two cases in which patients with metastatic TNBC achieved sustained complete response on conventional chemotherapy regimens.
Case presentations and summaries
Case 1
A 59-year-old woman (age in 2015) had been diagnosed on biopsy in February 2005 with locally advanced right breast cancer (stage T2N2bM0). She underwent lumpectomy, and the results of her pathology tests revealed a triple-negative invasive ductal carcinoma. She was started on 4 cycles of neoadjuvant doxorubicin (60 mg/m2 IV) and cyclophosphamide (600 mg/m2 IV)
In November 2007, the patient was found to have right chest wall metastasis confirmed by ultrasound-guided needle biopsy, and underwent right-side chest wall and partial sternum resection. In May 2008, she had recurrence in the left axilla, and biopsy results showed that she had TNBC disease. She was started on weekly paclitaxel (90 mg/m2) and bevacizumab (10 mg/kg every 2 weeks) continued until July 2008. Chemotherapy was stopped in July 2008 because of a methicillin-resistant Staphylococcus aureus (MRSA) infection of the chest wall and was not resumed after the infection had resolved.
A follow-up positron-emission tomography– computed tomography (PET-CT) scan in June 2009, showed no evidence of disease and the scan was negative for disease in her left axilla. Another PET scan about a year later, in September 2010, was also negative for any disease recurrence.
The patient has continued her follow-up with physical examinations and imaging scans. A CT scan of the abdomen and pelvis (December 2010), an MRI of the breasts (February 2011, August 2015), and a PET-CT scan (April 2015, Figure 1) were all negative for any evidence of disease. In September 2011, she had a CT-guided biopsy of a medial right clavicle and costal junction lesion; and in November 2011 and January 2013, surgical biopsies of the right chest wall and first rib lesions, all negative for any evidence for malignancy. At her last follow-up in January 2017, the patient remained in remission.
Case 2
A 68-year old woman (age in 2015) had been diagnosed in Russia in 2004 with infiltrating ductal carcinoma of the right breast (T4N1M0; receptor status unknown at that time). She underwent a right modified radical mastectomy and received adjuvant chemotherapy with 4 cycles of cyclophosphamide (100 mg/m2 day 1 to day 14), methotrexate (40 mg/m2 IV day 1 and day 8), and fluorouracil (600 mg/m2 IV, day 1 and day 8) followed by 2 cycles of docetaxel (75 mg/m2 IV) and anthracycline adriyamycin (50 mg/m2 IV). The patient later received radiation therapy (radiation dose not known, treatment was received in Russia), and completed her treatment in November 2004.
The patient moved to the United States and was started on 25 mg daily exemestane in February 2005. In March 2009, she was diagnosed by biopsy to have recurrence in her internal mammary and hilar lymph nodes and sternum. The cancer was found to be ER- and PR-negative and HER2-neu–negative. The patient was treated with radiation therapy (37.5 Gy in 15 fractions) to sternum and hilar and internal mammary lymph nodes with improvement in pain and shrinkage of lymph nodes size. In May 2009, she was started on 1,500 mg oral twice a day capecitabine (3 cycles). The therapy was started after completion of radiation treatment due to progression of disease. She developed hand-and-foot syndrome as side effect of the capecitabine, so the dose was reduced. She was switched to gemcitabine (1,000 mg/m2 on days 1, 8, and 15, every 28-day cycle) as a single-agent therapy and completed 3 cycles. A follow-up PET-CT scan in February 2010 showed no evidence of disease.
In May 2010, the patient had a recurrence in the same metastatic foci as before, and she was again started on gemcitabine (1,000 mg/m2 on days 1, 8, and 15, every 28-day cycle). She continued gemcitabine until there was evidence of disease progression on a PET-CT scan in October 2010, which showed new areas of disease in the left parasternal region, left sternum, prevascular mediastinal nodes, and left supraclavicular, hilar and axillary adenopathy, and fourth thoracic vertebra. Gemcitabine was discontinued and patient was started on weekly paclitaxel (90 mg/m2) for 6 cycles. Paclitaxel was discontinued after 6 weeks because she developed a drug-related rash. A follow-up PET-CT scan in December 2010 again showed complete resolution of disease in terms of response.
In March 2011, PET imaging showed progression of disease in the left chest wall and axillary lymph nodes, so the patient was started on eribulin therapy (1.4 mg/m2 on days 1 and 8 every 21-day cycle) and completed 3 cycles. In May 2011, PET imaging showed complete response to treatment with no evidence of recurrent or metastatic disease. The patient has not had chemotherapy since November 2011, and surveillance PET imaging has not demonstrated any recurrence of disease (Figure 2). Following her last follow-up in November 2016, the patient remains in remission.
Discussion
Triple-negative breast cancers (TNBCs) are defined as tumors that lack expression of estrogen receptor (ER), progesterone receptor (PR), and HER2, and represent about 12%-17% of breast cancer cases.1,6 TNBCs tend to be larger in size at diagnosis than are other subtypes, are usually high-grade (poorly differentiated), and are more likely to be invasive ductal carcinomas.1,7 TNBC and the basal-like breast cancers as a group are associated with an adverse prognosis.1,7 There is no standard preferred chemotherapy and no biologic therapy available for TNBC.1,6-7 A sharp decline in survival outcome during the first 3-5 years after diagnosis initial is observed in TNBC, although the distant relapses after this time are less common.1 Beyond 10 years from diagnosis, the relapses are seen more common among patients with ER-positive cancers than among those with ER-negative subtype cancers. Therefore, although TNBCs are biologically aggressive, many are possibly curable, and this reflects their interesting characteristic heterogeneity.1,6
Chemotherapy is currently the mainstay of systemic medical treatment. Although patients with TNBC have a worse outcome after chemotherapy than patients with breast cancers of other subtypes, it still improves their outcome to a greater extent than in patients with ER-positive subtypes.1,6,7 Considering the heterogeneity of TNBC, it is difficult to predict which patients will benefit more from chemotherapy. The same has been observed in previous studies when subgroups of women with TNBC were extremely sensitive to chemotherapy, whereas in others it was of uncertain benefit.1
Currently, there is no preferred standard form of chemotherapy for TNBC. There are few case reports that demonstrate long-term survival and complete remission in metastatic TNBC. Shakir has reported on a significant clinical response to nab-paclitaxel monotherapy in a patient with triple-negative BRCA1-positive breast cancer, although patient survived a little more than 5 years and died with central nervous system recurrence.8 Montero and Gluck have described a patient with metastatic TNBC who was treated with nab-paclitaxel, gemcitabine, and bevacizumab and who also survived for 5 years after diagnosis.9 Different retrospective analyses have suggested that the addition of docetaxel or paclitaxel to anthracycline-containing adjuvant regimens may be of greater benefit for the treatment of TNBC than for ER-positive tumors.10 A meta-analysis of trials comparing the effects of cyclophosphamide, methotrexate, and fluorouracil (CMF, which was used in Case 2) with anthracycline-containing regimens has suggested that the latter therapy regimen is more effective against TNBC,11 although another retrospective analysis of a separate trial suggested the opposite for basal-like breast cancers. 12 The authors of the latter analysis concluded that anthracycline-containing adjuvant chemotherapy regimens are inferior to adjuvant CMF in women with basal breast cancer.12
Miller and colleagues have shown that the addition of bevacizumab (angiogenesis inhibitor) to paclitaxel (used in Case 1) improved progression-free survival (median PFS, 11.8 vs 5.9 months; hazard ratio [HR] for progression, 0.60; P < .001) in women with TNBC as it did in the overall study group (HR, 0.53 and 0.60, respectively), although the overall survival rate was similar in the two groups (median OS, 26.7 vs 25.2 months; HR, 0.88; P = .16).13
An interesting clinical target in TNBC is the enzyme poly (adenosine diphosphate– ribose) polymerase (PARP), which is involved in base-excision repair after DNA damage. PARP inhibitors have shown encouraging clinical activity in trials of tumors arising in BRCA mutation carriers and in sporadic TNBC cancers.14 Similarly, the use of an oral PARP inhibitor, olaparib, resulted in tumor regression in up to 41% of patients carrying BRCA mutations, most of whom had TNBC.15
Conclusion
TNBC and basal-like breast cancers show aggressive clinical behavior, but a subgroup of these cancers may be markedly sensitive to chemotherapy and associated with a good prognosis when treated with conventional chemotherapy regimens. The two cases presented here show that some patients can get a prolonged disease control from chemotherapy, even after progressing on multiple previous chemotherapy regimens and that after, 5 years or so, these rare patients could be in true long-term remission. Novel approaches, for example PARP inhibitors, have shown encouraging clinical activity in trials of tumors arising in BRCA mutation carriers and as well as sporadic TNBC.
1. Foulkes WD, Smith IE, Reis-Filho JS, Triple-negative breast cancer. N Engl J Med. 2010;363:1938-1948.
2. Pogoda K, Niwińska A, Murawska M, Pieńkowski T. Analysis of pattern, time and risk factors influencing recurrence in triple-negative breast cancer patients. Med Oncol. 2013;30(1):388.
3. Kassam F, Enright K, Dent R, et al. Survival outcomes for patients with metastatic triple-negative breast cancer: implications for clinical practice and trial design. Clin Breast Cancer. 2009;9(1):29-33.
4. Perou CM. Molecular stratification of triple-negative breast cancers. Oncologist. 2010;15(suppl 5):39-48.
5. Rakha EA, Chan S. Metastatic triple-negative breast cancer. Clin Oncol (R Coll Radiol). 2011;23(9):587-600.
6. Williams N, Harris L. Triple-negative breast cancer in the post-genomic era. Oncology (Williston Park). 2013;27(9):859-860, 864.
7. Randhawa SK, Venur VA, Kawsar H, et al. A retrospective comparison of the characteristics and recurrence outcome of triple-negative and triple-positive breast cancer. J Clin Oncol. 2013;31(suppl; abstr 1038).
8. Shakir AR. Strong and sustained response to treatment with carboplatin plus nab-paclitaxel in a patient with metastatic, triple-negative, BRCA1-positive breast cancer. Case Rep Oncol. 2014;7(1)252-259.
9. Montero A, Glück S. Long-term complete remission with nab-paclitaxel, bevacizumab, and gemcitabine combination therapy in a patient with triple-negative metastatic breast cancer. Case Rep Oncol. 2012;5(3):687-692.
10. Hayes DF, Thor AD, Dressler LG, et al. HER2 and response to paclitaxel in node-positive breast cancer. N Engl J Med. 2007;357:1496-1506.
11. Di Leo A, Isola J, Piette F, et al. A meta- analysis of phase III trials evaluating the predictive value of HER2 and topoisomerase alpha in early breast cancer patients treated with CMF or anthracycline-based adjuvant therapy [SABCS, abstract 705]. http://cancerres.aacrjournals.org/content/69/2_Supplement/705. Published 2008. Accessed May 4, 2017.
12. Cheang M, Chia SK, Tu D, et al. Anthracycline in basal breast cancer: the NCIC-CTG trial MA5 comparing adjuvant CMF to CEF [ASCO; abstract 519]. http://meetinglibrary.asco.org/content/35150-65. Published 2009. Accessed May 4, 2017.
13. Miller K, Wang M, Gralow J, et al. Paclitaxel plus bevacizumab versus paclitaxel alone for metastatic breast cancer. N Engl J Med. 2007;357:2666-2676.
14. Fong PC, Boss DS, Yap TA, et al. Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers. N Engl J Med. 2009;361:123-134.
15. Tutt A, Robson M, Garber JE, et al. Oral poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and advanced breast cancer: a proof-of-concept trial. Lancet. 2010;376:235-244.
1. Foulkes WD, Smith IE, Reis-Filho JS, Triple-negative breast cancer. N Engl J Med. 2010;363:1938-1948.
2. Pogoda K, Niwińska A, Murawska M, Pieńkowski T. Analysis of pattern, time and risk factors influencing recurrence in triple-negative breast cancer patients. Med Oncol. 2013;30(1):388.
3. Kassam F, Enright K, Dent R, et al. Survival outcomes for patients with metastatic triple-negative breast cancer: implications for clinical practice and trial design. Clin Breast Cancer. 2009;9(1):29-33.
4. Perou CM. Molecular stratification of triple-negative breast cancers. Oncologist. 2010;15(suppl 5):39-48.
5. Rakha EA, Chan S. Metastatic triple-negative breast cancer. Clin Oncol (R Coll Radiol). 2011;23(9):587-600.
6. Williams N, Harris L. Triple-negative breast cancer in the post-genomic era. Oncology (Williston Park). 2013;27(9):859-860, 864.
7. Randhawa SK, Venur VA, Kawsar H, et al. A retrospective comparison of the characteristics and recurrence outcome of triple-negative and triple-positive breast cancer. J Clin Oncol. 2013;31(suppl; abstr 1038).
8. Shakir AR. Strong and sustained response to treatment with carboplatin plus nab-paclitaxel in a patient with metastatic, triple-negative, BRCA1-positive breast cancer. Case Rep Oncol. 2014;7(1)252-259.
9. Montero A, Glück S. Long-term complete remission with nab-paclitaxel, bevacizumab, and gemcitabine combination therapy in a patient with triple-negative metastatic breast cancer. Case Rep Oncol. 2012;5(3):687-692.
10. Hayes DF, Thor AD, Dressler LG, et al. HER2 and response to paclitaxel in node-positive breast cancer. N Engl J Med. 2007;357:1496-1506.
11. Di Leo A, Isola J, Piette F, et al. A meta- analysis of phase III trials evaluating the predictive value of HER2 and topoisomerase alpha in early breast cancer patients treated with CMF or anthracycline-based adjuvant therapy [SABCS, abstract 705]. http://cancerres.aacrjournals.org/content/69/2_Supplement/705. Published 2008. Accessed May 4, 2017.
12. Cheang M, Chia SK, Tu D, et al. Anthracycline in basal breast cancer: the NCIC-CTG trial MA5 comparing adjuvant CMF to CEF [ASCO; abstract 519]. http://meetinglibrary.asco.org/content/35150-65. Published 2009. Accessed May 4, 2017.
13. Miller K, Wang M, Gralow J, et al. Paclitaxel plus bevacizumab versus paclitaxel alone for metastatic breast cancer. N Engl J Med. 2007;357:2666-2676.
14. Fong PC, Boss DS, Yap TA, et al. Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers. N Engl J Med. 2009;361:123-134.
15. Tutt A, Robson M, Garber JE, et al. Oral poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and advanced breast cancer: a proof-of-concept trial. Lancet. 2010;376:235-244.
Breast density and optimal screening for breast cancer
MY STORY: Prologue
My aunt received a breast cancer diagnosis at age 40, and she died at age 60, in 1970. Then, in 1975, my mother’s breast cancer was found at age 55, but only after she was examined for nipple retraction; on mammography, the cancer had been obscured by dense breast tissue. Mom had 2 metastatic nodes but participated in the earliest clinical trials of chemotherapy and lived free of breast cancer for another 41 years. Naturally I thought that, were I to develop this disease, I would want it found earlier. Ironically, it was, but only because I had spent my career trying to understand the optimal screening approaches for women with dense breasts—women like me.
Cancers are masked on mammography in dense breasts
For women, screening mammography is an important step in reducing the risk of dying from breast cancer. The greatest benefits are realized by those who start annual screening at age 40, or 45 at the latest.1 As it takes 9 to 10 years to see a benefit from breast cancer screening at the population level, it is not logical to continue this testing when life expectancy is less than 10 years, as is the case with women age 85 or older, even those in the healthiest quartile.2–4 However, despite recent advances, the development of 3D mammography (tomosynthesis) (FIGURE 1) in particular, cancers can still be masked by dense breast tissue. Both 2D and 3D mammograms are x-rays; both dense tissue and cancers absorb x-rays and appear white.
Breast density is determined on mammography and is categorized as fatty, scattered fibroglandular, heterogeneously dense, or extremely dense (FIGURE 2).5 Tissue in the heterogeneous and extreme categories is considered dense. More than half of women in their 40s have dense breasts; with some fatty involution occurring around menopause, the proportion drops to 25% for women in their 60s.6 About half of breast cancers have calcifications, which on mammography are usually easily visible even in dense breasts. The problem is with noncalcified invasive cancers that can be hidden by dense tissue (FIGURE 3).
3D mammography improves cancer detection but is of minimal benefit in extremely dense breasts
Although 3D mammography improves cancer detection in most women, any benefit is minimal in women with extremely dense breasts, as there is no inherent soft-tissue contrast.7 Masked cancers are often only discovered because of a lump after a normal screening mammogram, as so-called “interval cancers.” Compared with screen-detected cancers, interval cancers tend to be more biologically aggressive, to have spread to lymph nodes, and to have worse prognoses. However, even some small screen-detected cancers are biologically aggressive and can spread to lymph nodes quickly, and no screening test or combination of screening tests can prevent this occurrence completely, regardless of breast density.
Related article:
Get smart about dense breasts
MRI provides early detection across all breast densities
In all tissue densities, contrast-enhanced magnetic resonance imaging (MRI) is far better than mammography in detecting breast cancer.8 Women at high risk for breast cancer caused by mutations in BRCA1, BRCA2, p53, and other genes have poor outcomes with screening mammography alone—up to 50% of cancers are interval cancers. Annual screening MRI reduces this percentage significantly, to 11% in women with pathogenic BRCA1 mutations and to 4% in women with BRCA2 mutations.9 Warner and colleagues found a decrease in late-stage cancers in high-risk women who underwent annual MRI screenings compared to high-risk women unable to have MRI.10
The use of MRI for screening is limited by availability, patient tolerance,11 and high cost. Research is being conducted to further validate approaches using shortened screening MRI times (so-called “abbreviated” or “fast” MRI) and, thereby, improve access, tolerance, and reduce associated costs; several investigators already have reported promising results, and a few centers offer this modality directly to patients willing to pay $300 to $350 out of pocket.12,13 Even in normal-risk women, MRI significantly increases detection of early breast cancer after a normal mammogram and ultrasound, and the cancer detection benefit of MRI is seen across all breast densities.14
Most health insurance plans cover screening MRI only for women who meet defined risk criteria, including women who have a known disease-causing mutation—or are suspected of having one, given a family history of breast cancer with higher than 20% to 25% lifetime risk by a model that predicts mutation carrier status—as well as women who had chest radiation therapy before age 30, typically for Hodgkin lymphoma, and at least 8 years earlier.15 In addition, MRI can be considered in women with atypical breast biopsy results or a personal history of lobular carcinoma in situ (LCIS).16
Screening MRI should start by age 25 in women with disease-causing mutations, or at the time of atypical or LCIS biopsy results, and should be performed annually unless the woman is pregnant or has a metallic implant, renal insufficiency, or another contraindication to MRI. MRI can be beneficial in women with a personal history of cancer, although annual mammography remains the standard of care.17–19
MRI and mammography can be performed at the same time or on an alternating 6-month basis, with mammography usually starting only after age 30 because of the small risk that radiation poses for younger women. There are a few other impediments to having breast MRI: The woman must lie on her stomach within a confined space (tunnel), the contrast that is injected may not be well tolerated, and insurance does not cover the test for women who do not meet the defined risk criteria.11
Read why mammography supplemented by US is best for women with dense breasts.
Ultrasonography supplements mammography
Mammography supplemented with ultrasonography (US) has been studied as a “Goldilocks” or best-fit solution for the screening of women with dense breasts, as detection of invasive cancers is improved with the 2 modalities over mammography alone, and US is less invasive, better tolerated, and lower in cost than the more sensitive MRI.
In women with dense breasts, US has been found to improve cancer detection over mammography alone, and early results suggest a larger cancer detection benefit from US than from 3D mammography, although research is ongoing.20 Adding US reduces the interval cancer rate in women with dense breasts to less than 10% of all cancers found—similar to results for women with fatty breasts.17,21,22
US can be performed by a trained technologist or a physician using a small transducer, which usually provides diagnostic images (so that most callbacks would be for a true finding), or a larger transducer and an automated system can be used to create more than a thousand images for radiologist review.23,24 Use of a hybrid system, a small transducer with an automated arm, has been validated as well.25 Screening US is not available universally, and with all these approaches optimal performance requires trained personnel. Supplemental screening US usually is covered by insurance but is nearly always subject to a deductible/copay.
Related article:
Educate patients about dense breasts and cancer risk
Reducing false-positives, callbacks, and additional testing
Mammography carries a risk of false-positives. On average, 11% to 12% of women are called back for additional testing after a screening mammogram, and in more than 95% of women brought back for extra testing, no cancer is found.26 Women with dense breasts are more likely than those with less dense breasts to be called back.27 US and MRI improve cancer detection and therefore yield additional positive, but also false-positive, findings. Notably, callbacks decrease after the first round of screening with any modality or combination of tests, as long as prior examinations are available for comparison.
One advantage of 3D over 2D mammography is a decrease in extra testing for areas of asymmetry, which are often recognizable on 3D mammography as representing normal superimposed tissue.28–30 Architectural distortion, which is better seen on 3D mammography and usually represents either cancer or a benign radial scar, can lead to false-positive biopsies, although the average biopsy rate is no higher for 3D than for 2D alone.31 Typically, the 3D and 2D examinations are performed together (slightly more than doubling the radiation dose), or synthetic 2D images can be created from the 3D slices (resulting in a total radiation dose almost the same as standard 2D alone).
Most additional cancers seen on 3D mammography or US are lower-grade invasive cancers with good prognoses. Some aggressive high-grade breast cancers go undetected even when mammography is supplemented with US, either because they are too small to be seen or because they resemble common benign masses and may not be recognized. MRI is particularly effective in depicting high-grade cancers, even small ones.
The TABLE summarizes the relative rates of cancer detection and additional testing by various breast screening tests or combinations of tests. Neither clinical breast examination by a physician or other health care professional nor routine breast self-examination reduces the number of deaths caused by breast cancer. Nevertheless, women should monitor any changes in their breasts and report these changes to their clinician. A new lump, skin or nipple retraction, or a spontaneous clear or bloody nipple discharge merits diagnostic breast imaging even if a recent screening mammogram was normal.
FIGURE 4 is an updated decision support tool that suggests strategies for optimizingcancer detection with widely available screening methods.
Read how to take advantage of today’s technology for breast density screening
MY STORY: Epilogue
My annual 3D mammograms were normal, even the year my cancer was present. In 2014, I entered my family history into the IBIS Breast Cancer Risk Evaluation Tool (Tyrer-Cuzick model of breast cancer risk) (http://www.ems-trials.org/riskevaluator/) and calculated my lifetime risk at 19.7%. That is when I decided to have a screening MRI. My invasive breast cancer was easily seen on MRI and then on US. The cancer was node-negative, easily confirmed with needle biopsy, and treated with lumpectomy and radiation. There was no need for chemotherapy.
My personal experience prompted me to join JoAnn Pushkin and Cindy Henke-Sarmento, RT(R)(M), BA, in developing a website, www.DenseBreast-info.org, to give women and their physicians easy access to information on making decisions about screening in dense breasts.
My colleagues and I are often asked what is the best way to order supplemental imaging for a patient who may have dense breasts. Even in cases in which a mammogram does not exist or is unavailable, the following prescription can be implemented easily at centers that offer US: “2D plus 3D mammogram if available; if dense, perform ultrasound as needed.”
Related article:
DenseBreast-info.org: What this resource can offer you, and your patients
Breast density screening: Take advantage of today’s technology
Breast screening and diagnostic imaging have improved significantly since the 1970s, when many of the randomized trials of mammography were conducted. Breast density is one of the most common and important risk factors for development of breast cancer and is now incorporated into the Breast Cancer Surveillance Consortium model (https://tools.bcsc-scc.org/BC5yearRisk/calculator.htm) and the Tyrer-Cuzick model (see also http://densebreast-info.org/explanation-of-dense-breast-risk-models.aspx).32 Although we continue to validate newer approaches, women should take advantage of the improved methods of early cancer detection, particularly if they have dense breasts or are at high risk for breast cancer.
Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.
- Oeffinger KC, Fontham ET, Etzioni R, et al; American Cancer Society. Breast cancer screening for women at average risk: 2015 guideline update from the American Cancer Society. JAMA. 2015;314(15):1599–1614.
- Tabar L, Yen MF, Vitak B, Chen HH, Smith RA, Duffy SW. Mammography service screening and mortality in breast cancer patients: 20-year follow-up before and after introduction of screening. Lancet. 2003;361(9367):1405–1410.
- Lee SJ, Boscardin WJ, Stijacic-Cenzer I, Conell-Price J, O’Brien S, Walter LC. Time lag to benefit after screening for breast and colorectal cancer: meta-analysis of survival data from the United States, Sweden, United Kingdom, and Denmark. BMJ. 2013;346:e8441.
- Walter LC, Covinsky KE. Cancer screening in elderly patients: a framework for individualized decision making. JAMA. 2001;285(21):2750–2756.
- Sickles EA, D’Orsi CJ, Bassett LW, et al. ACR BI-RADS mammography. In: D’Orsi CJ, Sickles EA, Mendelson EB, et al, eds. ACR BI-RADS Atlas, Breast Imaging Reporting and Data System. 5th ed. Reston, VA: American College of Radiology; 2013.
- Sprague BL, Gangnon RE, Burt V, et al. Prevalence of mammographically dense breasts in the United States. J Natl Cancer Inst. 2014;106(10).
- Rafferty EA, Durand MA, Conant EF, et al. Breast cancer screening using tomosynthesis and digital mammography in dense and nondense breasts. JAMA. 2016;315(16):1784–1786.
- Berg WA. Tailored supplemental screening for breast cancer: what now and what next? AJR Am J Roentgenol. 2009;192(2):390–399.
- Heijnsdijk EA, Warner E, Gilbert FJ, et al. Differences in natural history between breast cancers in BRCA1 and BRCA2 mutation carriers and effects of MRI screening—MRISC, MARIBS, and Canadian studies combined. Cancer Epidemiol Biomarkers Prev. 2012;21(9):1458–1468.
- Warner E, Hill K, Causer P, et al. Prospective study of breast cancer incidence in women with a BRCA1 or BRCA2 mutation under surveillance with and without magnetic resonance imaging. J Clin Oncol. 2011;29(13):1664–1669.
- Berg WA, Blume JD, Adams AM, et al. Reasons women at elevated risk of breast cancer refuse breast MR imaging screening: ACRIN 6666. Radiology. 2010;254(1):79–87.
- Kuhl CK, Schrading S, Strobel K, Schild HH, Hilgers RD, Bieling HB. Abbreviated breast magnetic resonance imaging (MRI): first postcontrast subtracted images and maximum-intensity projection—a novel approach to breast cancer screening with MRI. J Clin Oncol. 2014;32(22):2304–2310.
- Strahle DA, Pathak DR, Sierra A, Saha S, Strahle C, Devisetty K. Systematic development of an abbreviated protocol for screening breast magnetic resonance imaging. Breast Cancer Res Treat. 2017;162(2):283–295.
- Kuhl CK, Strobel K, Bieling H, Leutner C, Schild HH, Schrading S. Supplemental breast MR imaging screening of women with average risk of breast cancer. Radiology. 2017;283(2):361–370.
- Saslow D, Boetes C, Burke W, et al; American Cancer Society Breast Cancer Advisory Group. American Cancer Society guidelines for breast screening with MRI as an adjunct to mammography. CA Cancer J Clin. 2007;57(2):75–89.
- National Comprehensive Cancer Network. NCCN guidelines for detection, prevention, and risk reduction: breast cancer screening and diagnosis. https://www.nccn.org/professionals/physician_gls/pdf/breast-screening.pdf.
- Berg WA, Zhang Z, Lehrer D, et al; ACRIN 6666 Investigators. Detection of breast cancer with addition of annual screening ultrasound or a single screening MRI to mammography in women with elevated breast cancer risk. JAMA. 2012;307(13):1394–1404.
- Brennan S, Liberman L, Dershaw DD, Morris E. Breast MRI screening of women with a personal history of breast cancer. AJR Am J Roentgenol. 2010;195(2):510–516.
- Lehman CD, Lee JM, DeMartini WB, et al. Screening MRI in women with a personal history of breast cancer. J Natl Cancer Inst. 2016;108(3).
- Tagliafico AS, Calabrese M, Mariscotti G, et al. Adjunct screening with tomosynthesis or ultrasound in women with mammography-negative dense breasts: interim report of a prospective comparative trial [published online ahead of print March 9, 2016]. J Clin Oncol. JCO634147.
- Corsetti V, Houssami N, Ghirardi M, et al. Evidence of the effect of adjunct ultrasound screening in women with mammography-negative dense breasts: interval breast cancers at 1 year follow-up. Eur J Cancer. 2011;47(7):1021–1026.
- Ohuchi N, Suzuki A, Sobue T, et al; J-START Investigator Groups. Sensitivity and specificity of mammography and adjunctive ultrasonography to screen for breast cancer in the Japan Strategic Anti-Cancer Randomized Trial (J-START): a randomised controlled trial. Lancet. 2016;387(10016):341–348.
- Berg WA, Mendelson EB. Technologist-performed handheld screening breast US imaging: how is it performed and what are the outcomes to date? Radiology. 2014;272(1):12–27.
- Brem RF, Tabár L, Duffy SW, et al. Assessing improvement in detection of breast cancer with three-dimensional automated breast US in women with dense breast tissue: the SomoInsight study. Radiology. 2015;274(3):663–673.
- Kelly KM, Dean J, Comulada WS, Lee SJ. Breast cancer detection using automated whole breast ultrasound and mammography in radiographically dense breasts. Eur Radiol. 2010;20(3):734–742.
- Lehman CD, Arao RF, Sprague BL, et al. National performance benchmarks for modern screening digital mammography: update from the Breast Cancer Surveillance Consortium. Radiology. 2017;283(1):49–58.
- Kerlikowske K, Zhu W, Hubbard RA, et al; Breast Cancer Surveillance Consortium. Outcomes of screening mammography by frequency, breast density, and postmenopausal hormone therapy. JAMA Intern Med. 2013;173(9):807–816.
- Friedewald SM, Rafferty EA, Rose SL, et al. Breast cancer screening using tomosynthesis in combination with digital mammography. JAMA. 2014;311(24):2499–2507.
- Skaane P, Bandos AI, Gullien R, et al. Comparison of digital mammography alone and digital mammography plus tomosynthesis in a population-based screening program. Radiology. 2013;267(1):47–56.
- Ciatto S, Houssami N, Bernardi D, et al. Integration of 3D digital mammography with tomosynthesis for population breast-cancer screening (STORM): a prospective comparison study. Lancet Oncol. 2013;14(7):583–589.
- Bahl M, Lamb LR, Lehman CD. Pathologic outcomes of architectural distortion on digital 2D versus tomosynthesis mammography [published online ahead of print August 23, 2017]. AJR Am J Roentgenol. doi:10.2214/AJR.17.17979.
- Engmann NJ, Golmakani MK, Miglioretti DL, Sprague BL, Kerlikowske K; Breast Cancer Surveillance Consortium. Population-attributable risk proportion of clinical risk factors for breast cancer [published online ahead of print February 2, 2017]. JAMA Oncol. doi:10.1001/jamaoncol.2016.6326.
Dr. Berg is a Professor of Radiology at the University of Pittsburgh School of Medicine, the Magee-Womens Hospital of UPMC (University of Pittsburgh Medical Center), and the UPMC Hillman Cancer Institute, Pittsburgh, Pennsylvania.
The author reports no financial relationships relevant to this article.
Dr. Berg is a Professor of Radiology at the University of Pittsburgh School of Medicine, the Magee-Womens Hospital of UPMC (University of Pittsburgh Medical Center), and the UPMC Hillman Cancer Institute, Pittsburgh, Pennsylvania.
The author reports no financial relationships relevant to this article.
Dr. Berg is a Professor of Radiology at the University of Pittsburgh School of Medicine, the Magee-Womens Hospital of UPMC (University of Pittsburgh Medical Center), and the UPMC Hillman Cancer Institute, Pittsburgh, Pennsylvania.
The author reports no financial relationships relevant to this article.
MY STORY: Prologue
My aunt received a breast cancer diagnosis at age 40, and she died at age 60, in 1970. Then, in 1975, my mother’s breast cancer was found at age 55, but only after she was examined for nipple retraction; on mammography, the cancer had been obscured by dense breast tissue. Mom had 2 metastatic nodes but participated in the earliest clinical trials of chemotherapy and lived free of breast cancer for another 41 years. Naturally I thought that, were I to develop this disease, I would want it found earlier. Ironically, it was, but only because I had spent my career trying to understand the optimal screening approaches for women with dense breasts—women like me.
Cancers are masked on mammography in dense breasts
For women, screening mammography is an important step in reducing the risk of dying from breast cancer. The greatest benefits are realized by those who start annual screening at age 40, or 45 at the latest.1 As it takes 9 to 10 years to see a benefit from breast cancer screening at the population level, it is not logical to continue this testing when life expectancy is less than 10 years, as is the case with women age 85 or older, even those in the healthiest quartile.2–4 However, despite recent advances, the development of 3D mammography (tomosynthesis) (FIGURE 1) in particular, cancers can still be masked by dense breast tissue. Both 2D and 3D mammograms are x-rays; both dense tissue and cancers absorb x-rays and appear white.
Breast density is determined on mammography and is categorized as fatty, scattered fibroglandular, heterogeneously dense, or extremely dense (FIGURE 2).5 Tissue in the heterogeneous and extreme categories is considered dense. More than half of women in their 40s have dense breasts; with some fatty involution occurring around menopause, the proportion drops to 25% for women in their 60s.6 About half of breast cancers have calcifications, which on mammography are usually easily visible even in dense breasts. The problem is with noncalcified invasive cancers that can be hidden by dense tissue (FIGURE 3).
3D mammography improves cancer detection but is of minimal benefit in extremely dense breasts
Although 3D mammography improves cancer detection in most women, any benefit is minimal in women with extremely dense breasts, as there is no inherent soft-tissue contrast.7 Masked cancers are often only discovered because of a lump after a normal screening mammogram, as so-called “interval cancers.” Compared with screen-detected cancers, interval cancers tend to be more biologically aggressive, to have spread to lymph nodes, and to have worse prognoses. However, even some small screen-detected cancers are biologically aggressive and can spread to lymph nodes quickly, and no screening test or combination of screening tests can prevent this occurrence completely, regardless of breast density.
Related article:
Get smart about dense breasts
MRI provides early detection across all breast densities
In all tissue densities, contrast-enhanced magnetic resonance imaging (MRI) is far better than mammography in detecting breast cancer.8 Women at high risk for breast cancer caused by mutations in BRCA1, BRCA2, p53, and other genes have poor outcomes with screening mammography alone—up to 50% of cancers are interval cancers. Annual screening MRI reduces this percentage significantly, to 11% in women with pathogenic BRCA1 mutations and to 4% in women with BRCA2 mutations.9 Warner and colleagues found a decrease in late-stage cancers in high-risk women who underwent annual MRI screenings compared to high-risk women unable to have MRI.10
The use of MRI for screening is limited by availability, patient tolerance,11 and high cost. Research is being conducted to further validate approaches using shortened screening MRI times (so-called “abbreviated” or “fast” MRI) and, thereby, improve access, tolerance, and reduce associated costs; several investigators already have reported promising results, and a few centers offer this modality directly to patients willing to pay $300 to $350 out of pocket.12,13 Even in normal-risk women, MRI significantly increases detection of early breast cancer after a normal mammogram and ultrasound, and the cancer detection benefit of MRI is seen across all breast densities.14
Most health insurance plans cover screening MRI only for women who meet defined risk criteria, including women who have a known disease-causing mutation—or are suspected of having one, given a family history of breast cancer with higher than 20% to 25% lifetime risk by a model that predicts mutation carrier status—as well as women who had chest radiation therapy before age 30, typically for Hodgkin lymphoma, and at least 8 years earlier.15 In addition, MRI can be considered in women with atypical breast biopsy results or a personal history of lobular carcinoma in situ (LCIS).16
Screening MRI should start by age 25 in women with disease-causing mutations, or at the time of atypical or LCIS biopsy results, and should be performed annually unless the woman is pregnant or has a metallic implant, renal insufficiency, or another contraindication to MRI. MRI can be beneficial in women with a personal history of cancer, although annual mammography remains the standard of care.17–19
MRI and mammography can be performed at the same time or on an alternating 6-month basis, with mammography usually starting only after age 30 because of the small risk that radiation poses for younger women. There are a few other impediments to having breast MRI: The woman must lie on her stomach within a confined space (tunnel), the contrast that is injected may not be well tolerated, and insurance does not cover the test for women who do not meet the defined risk criteria.11
Read why mammography supplemented by US is best for women with dense breasts.
Ultrasonography supplements mammography
Mammography supplemented with ultrasonography (US) has been studied as a “Goldilocks” or best-fit solution for the screening of women with dense breasts, as detection of invasive cancers is improved with the 2 modalities over mammography alone, and US is less invasive, better tolerated, and lower in cost than the more sensitive MRI.
In women with dense breasts, US has been found to improve cancer detection over mammography alone, and early results suggest a larger cancer detection benefit from US than from 3D mammography, although research is ongoing.20 Adding US reduces the interval cancer rate in women with dense breasts to less than 10% of all cancers found—similar to results for women with fatty breasts.17,21,22
US can be performed by a trained technologist or a physician using a small transducer, which usually provides diagnostic images (so that most callbacks would be for a true finding), or a larger transducer and an automated system can be used to create more than a thousand images for radiologist review.23,24 Use of a hybrid system, a small transducer with an automated arm, has been validated as well.25 Screening US is not available universally, and with all these approaches optimal performance requires trained personnel. Supplemental screening US usually is covered by insurance but is nearly always subject to a deductible/copay.
Related article:
Educate patients about dense breasts and cancer risk
Reducing false-positives, callbacks, and additional testing
Mammography carries a risk of false-positives. On average, 11% to 12% of women are called back for additional testing after a screening mammogram, and in more than 95% of women brought back for extra testing, no cancer is found.26 Women with dense breasts are more likely than those with less dense breasts to be called back.27 US and MRI improve cancer detection and therefore yield additional positive, but also false-positive, findings. Notably, callbacks decrease after the first round of screening with any modality or combination of tests, as long as prior examinations are available for comparison.
One advantage of 3D over 2D mammography is a decrease in extra testing for areas of asymmetry, which are often recognizable on 3D mammography as representing normal superimposed tissue.28–30 Architectural distortion, which is better seen on 3D mammography and usually represents either cancer or a benign radial scar, can lead to false-positive biopsies, although the average biopsy rate is no higher for 3D than for 2D alone.31 Typically, the 3D and 2D examinations are performed together (slightly more than doubling the radiation dose), or synthetic 2D images can be created from the 3D slices (resulting in a total radiation dose almost the same as standard 2D alone).
Most additional cancers seen on 3D mammography or US are lower-grade invasive cancers with good prognoses. Some aggressive high-grade breast cancers go undetected even when mammography is supplemented with US, either because they are too small to be seen or because they resemble common benign masses and may not be recognized. MRI is particularly effective in depicting high-grade cancers, even small ones.
The TABLE summarizes the relative rates of cancer detection and additional testing by various breast screening tests or combinations of tests. Neither clinical breast examination by a physician or other health care professional nor routine breast self-examination reduces the number of deaths caused by breast cancer. Nevertheless, women should monitor any changes in their breasts and report these changes to their clinician. A new lump, skin or nipple retraction, or a spontaneous clear or bloody nipple discharge merits diagnostic breast imaging even if a recent screening mammogram was normal.
FIGURE 4 is an updated decision support tool that suggests strategies for optimizingcancer detection with widely available screening methods.
Read how to take advantage of today’s technology for breast density screening
MY STORY: Epilogue
My annual 3D mammograms were normal, even the year my cancer was present. In 2014, I entered my family history into the IBIS Breast Cancer Risk Evaluation Tool (Tyrer-Cuzick model of breast cancer risk) (http://www.ems-trials.org/riskevaluator/) and calculated my lifetime risk at 19.7%. That is when I decided to have a screening MRI. My invasive breast cancer was easily seen on MRI and then on US. The cancer was node-negative, easily confirmed with needle biopsy, and treated with lumpectomy and radiation. There was no need for chemotherapy.
My personal experience prompted me to join JoAnn Pushkin and Cindy Henke-Sarmento, RT(R)(M), BA, in developing a website, www.DenseBreast-info.org, to give women and their physicians easy access to information on making decisions about screening in dense breasts.
My colleagues and I are often asked what is the best way to order supplemental imaging for a patient who may have dense breasts. Even in cases in which a mammogram does not exist or is unavailable, the following prescription can be implemented easily at centers that offer US: “2D plus 3D mammogram if available; if dense, perform ultrasound as needed.”
Related article:
DenseBreast-info.org: What this resource can offer you, and your patients
Breast density screening: Take advantage of today’s technology
Breast screening and diagnostic imaging have improved significantly since the 1970s, when many of the randomized trials of mammography were conducted. Breast density is one of the most common and important risk factors for development of breast cancer and is now incorporated into the Breast Cancer Surveillance Consortium model (https://tools.bcsc-scc.org/BC5yearRisk/calculator.htm) and the Tyrer-Cuzick model (see also http://densebreast-info.org/explanation-of-dense-breast-risk-models.aspx).32 Although we continue to validate newer approaches, women should take advantage of the improved methods of early cancer detection, particularly if they have dense breasts or are at high risk for breast cancer.
Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.
MY STORY: Prologue
My aunt received a breast cancer diagnosis at age 40, and she died at age 60, in 1970. Then, in 1975, my mother’s breast cancer was found at age 55, but only after she was examined for nipple retraction; on mammography, the cancer had been obscured by dense breast tissue. Mom had 2 metastatic nodes but participated in the earliest clinical trials of chemotherapy and lived free of breast cancer for another 41 years. Naturally I thought that, were I to develop this disease, I would want it found earlier. Ironically, it was, but only because I had spent my career trying to understand the optimal screening approaches for women with dense breasts—women like me.
Cancers are masked on mammography in dense breasts
For women, screening mammography is an important step in reducing the risk of dying from breast cancer. The greatest benefits are realized by those who start annual screening at age 40, or 45 at the latest.1 As it takes 9 to 10 years to see a benefit from breast cancer screening at the population level, it is not logical to continue this testing when life expectancy is less than 10 years, as is the case with women age 85 or older, even those in the healthiest quartile.2–4 However, despite recent advances, the development of 3D mammography (tomosynthesis) (FIGURE 1) in particular, cancers can still be masked by dense breast tissue. Both 2D and 3D mammograms are x-rays; both dense tissue and cancers absorb x-rays and appear white.
Breast density is determined on mammography and is categorized as fatty, scattered fibroglandular, heterogeneously dense, or extremely dense (FIGURE 2).5 Tissue in the heterogeneous and extreme categories is considered dense. More than half of women in their 40s have dense breasts; with some fatty involution occurring around menopause, the proportion drops to 25% for women in their 60s.6 About half of breast cancers have calcifications, which on mammography are usually easily visible even in dense breasts. The problem is with noncalcified invasive cancers that can be hidden by dense tissue (FIGURE 3).
3D mammography improves cancer detection but is of minimal benefit in extremely dense breasts
Although 3D mammography improves cancer detection in most women, any benefit is minimal in women with extremely dense breasts, as there is no inherent soft-tissue contrast.7 Masked cancers are often only discovered because of a lump after a normal screening mammogram, as so-called “interval cancers.” Compared with screen-detected cancers, interval cancers tend to be more biologically aggressive, to have spread to lymph nodes, and to have worse prognoses. However, even some small screen-detected cancers are biologically aggressive and can spread to lymph nodes quickly, and no screening test or combination of screening tests can prevent this occurrence completely, regardless of breast density.
Related article:
Get smart about dense breasts
MRI provides early detection across all breast densities
In all tissue densities, contrast-enhanced magnetic resonance imaging (MRI) is far better than mammography in detecting breast cancer.8 Women at high risk for breast cancer caused by mutations in BRCA1, BRCA2, p53, and other genes have poor outcomes with screening mammography alone—up to 50% of cancers are interval cancers. Annual screening MRI reduces this percentage significantly, to 11% in women with pathogenic BRCA1 mutations and to 4% in women with BRCA2 mutations.9 Warner and colleagues found a decrease in late-stage cancers in high-risk women who underwent annual MRI screenings compared to high-risk women unable to have MRI.10
The use of MRI for screening is limited by availability, patient tolerance,11 and high cost. Research is being conducted to further validate approaches using shortened screening MRI times (so-called “abbreviated” or “fast” MRI) and, thereby, improve access, tolerance, and reduce associated costs; several investigators already have reported promising results, and a few centers offer this modality directly to patients willing to pay $300 to $350 out of pocket.12,13 Even in normal-risk women, MRI significantly increases detection of early breast cancer after a normal mammogram and ultrasound, and the cancer detection benefit of MRI is seen across all breast densities.14
Most health insurance plans cover screening MRI only for women who meet defined risk criteria, including women who have a known disease-causing mutation—or are suspected of having one, given a family history of breast cancer with higher than 20% to 25% lifetime risk by a model that predicts mutation carrier status—as well as women who had chest radiation therapy before age 30, typically for Hodgkin lymphoma, and at least 8 years earlier.15 In addition, MRI can be considered in women with atypical breast biopsy results or a personal history of lobular carcinoma in situ (LCIS).16
Screening MRI should start by age 25 in women with disease-causing mutations, or at the time of atypical or LCIS biopsy results, and should be performed annually unless the woman is pregnant or has a metallic implant, renal insufficiency, or another contraindication to MRI. MRI can be beneficial in women with a personal history of cancer, although annual mammography remains the standard of care.17–19
MRI and mammography can be performed at the same time or on an alternating 6-month basis, with mammography usually starting only after age 30 because of the small risk that radiation poses for younger women. There are a few other impediments to having breast MRI: The woman must lie on her stomach within a confined space (tunnel), the contrast that is injected may not be well tolerated, and insurance does not cover the test for women who do not meet the defined risk criteria.11
Read why mammography supplemented by US is best for women with dense breasts.
Ultrasonography supplements mammography
Mammography supplemented with ultrasonography (US) has been studied as a “Goldilocks” or best-fit solution for the screening of women with dense breasts, as detection of invasive cancers is improved with the 2 modalities over mammography alone, and US is less invasive, better tolerated, and lower in cost than the more sensitive MRI.
In women with dense breasts, US has been found to improve cancer detection over mammography alone, and early results suggest a larger cancer detection benefit from US than from 3D mammography, although research is ongoing.20 Adding US reduces the interval cancer rate in women with dense breasts to less than 10% of all cancers found—similar to results for women with fatty breasts.17,21,22
US can be performed by a trained technologist or a physician using a small transducer, which usually provides diagnostic images (so that most callbacks would be for a true finding), or a larger transducer and an automated system can be used to create more than a thousand images for radiologist review.23,24 Use of a hybrid system, a small transducer with an automated arm, has been validated as well.25 Screening US is not available universally, and with all these approaches optimal performance requires trained personnel. Supplemental screening US usually is covered by insurance but is nearly always subject to a deductible/copay.
Related article:
Educate patients about dense breasts and cancer risk
Reducing false-positives, callbacks, and additional testing
Mammography carries a risk of false-positives. On average, 11% to 12% of women are called back for additional testing after a screening mammogram, and in more than 95% of women brought back for extra testing, no cancer is found.26 Women with dense breasts are more likely than those with less dense breasts to be called back.27 US and MRI improve cancer detection and therefore yield additional positive, but also false-positive, findings. Notably, callbacks decrease after the first round of screening with any modality or combination of tests, as long as prior examinations are available for comparison.
One advantage of 3D over 2D mammography is a decrease in extra testing for areas of asymmetry, which are often recognizable on 3D mammography as representing normal superimposed tissue.28–30 Architectural distortion, which is better seen on 3D mammography and usually represents either cancer or a benign radial scar, can lead to false-positive biopsies, although the average biopsy rate is no higher for 3D than for 2D alone.31 Typically, the 3D and 2D examinations are performed together (slightly more than doubling the radiation dose), or synthetic 2D images can be created from the 3D slices (resulting in a total radiation dose almost the same as standard 2D alone).
Most additional cancers seen on 3D mammography or US are lower-grade invasive cancers with good prognoses. Some aggressive high-grade breast cancers go undetected even when mammography is supplemented with US, either because they are too small to be seen or because they resemble common benign masses and may not be recognized. MRI is particularly effective in depicting high-grade cancers, even small ones.
The TABLE summarizes the relative rates of cancer detection and additional testing by various breast screening tests or combinations of tests. Neither clinical breast examination by a physician or other health care professional nor routine breast self-examination reduces the number of deaths caused by breast cancer. Nevertheless, women should monitor any changes in their breasts and report these changes to their clinician. A new lump, skin or nipple retraction, or a spontaneous clear or bloody nipple discharge merits diagnostic breast imaging even if a recent screening mammogram was normal.
FIGURE 4 is an updated decision support tool that suggests strategies for optimizingcancer detection with widely available screening methods.
Read how to take advantage of today’s technology for breast density screening
MY STORY: Epilogue
My annual 3D mammograms were normal, even the year my cancer was present. In 2014, I entered my family history into the IBIS Breast Cancer Risk Evaluation Tool (Tyrer-Cuzick model of breast cancer risk) (http://www.ems-trials.org/riskevaluator/) and calculated my lifetime risk at 19.7%. That is when I decided to have a screening MRI. My invasive breast cancer was easily seen on MRI and then on US. The cancer was node-negative, easily confirmed with needle biopsy, and treated with lumpectomy and radiation. There was no need for chemotherapy.
My personal experience prompted me to join JoAnn Pushkin and Cindy Henke-Sarmento, RT(R)(M), BA, in developing a website, www.DenseBreast-info.org, to give women and their physicians easy access to information on making decisions about screening in dense breasts.
My colleagues and I are often asked what is the best way to order supplemental imaging for a patient who may have dense breasts. Even in cases in which a mammogram does not exist or is unavailable, the following prescription can be implemented easily at centers that offer US: “2D plus 3D mammogram if available; if dense, perform ultrasound as needed.”
Related article:
DenseBreast-info.org: What this resource can offer you, and your patients
Breast density screening: Take advantage of today’s technology
Breast screening and diagnostic imaging have improved significantly since the 1970s, when many of the randomized trials of mammography were conducted. Breast density is one of the most common and important risk factors for development of breast cancer and is now incorporated into the Breast Cancer Surveillance Consortium model (https://tools.bcsc-scc.org/BC5yearRisk/calculator.htm) and the Tyrer-Cuzick model (see also http://densebreast-info.org/explanation-of-dense-breast-risk-models.aspx).32 Although we continue to validate newer approaches, women should take advantage of the improved methods of early cancer detection, particularly if they have dense breasts or are at high risk for breast cancer.
Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.
- Oeffinger KC, Fontham ET, Etzioni R, et al; American Cancer Society. Breast cancer screening for women at average risk: 2015 guideline update from the American Cancer Society. JAMA. 2015;314(15):1599–1614.
- Tabar L, Yen MF, Vitak B, Chen HH, Smith RA, Duffy SW. Mammography service screening and mortality in breast cancer patients: 20-year follow-up before and after introduction of screening. Lancet. 2003;361(9367):1405–1410.
- Lee SJ, Boscardin WJ, Stijacic-Cenzer I, Conell-Price J, O’Brien S, Walter LC. Time lag to benefit after screening for breast and colorectal cancer: meta-analysis of survival data from the United States, Sweden, United Kingdom, and Denmark. BMJ. 2013;346:e8441.
- Walter LC, Covinsky KE. Cancer screening in elderly patients: a framework for individualized decision making. JAMA. 2001;285(21):2750–2756.
- Sickles EA, D’Orsi CJ, Bassett LW, et al. ACR BI-RADS mammography. In: D’Orsi CJ, Sickles EA, Mendelson EB, et al, eds. ACR BI-RADS Atlas, Breast Imaging Reporting and Data System. 5th ed. Reston, VA: American College of Radiology; 2013.
- Sprague BL, Gangnon RE, Burt V, et al. Prevalence of mammographically dense breasts in the United States. J Natl Cancer Inst. 2014;106(10).
- Rafferty EA, Durand MA, Conant EF, et al. Breast cancer screening using tomosynthesis and digital mammography in dense and nondense breasts. JAMA. 2016;315(16):1784–1786.
- Berg WA. Tailored supplemental screening for breast cancer: what now and what next? AJR Am J Roentgenol. 2009;192(2):390–399.
- Heijnsdijk EA, Warner E, Gilbert FJ, et al. Differences in natural history between breast cancers in BRCA1 and BRCA2 mutation carriers and effects of MRI screening—MRISC, MARIBS, and Canadian studies combined. Cancer Epidemiol Biomarkers Prev. 2012;21(9):1458–1468.
- Warner E, Hill K, Causer P, et al. Prospective study of breast cancer incidence in women with a BRCA1 or BRCA2 mutation under surveillance with and without magnetic resonance imaging. J Clin Oncol. 2011;29(13):1664–1669.
- Berg WA, Blume JD, Adams AM, et al. Reasons women at elevated risk of breast cancer refuse breast MR imaging screening: ACRIN 6666. Radiology. 2010;254(1):79–87.
- Kuhl CK, Schrading S, Strobel K, Schild HH, Hilgers RD, Bieling HB. Abbreviated breast magnetic resonance imaging (MRI): first postcontrast subtracted images and maximum-intensity projection—a novel approach to breast cancer screening with MRI. J Clin Oncol. 2014;32(22):2304–2310.
- Strahle DA, Pathak DR, Sierra A, Saha S, Strahle C, Devisetty K. Systematic development of an abbreviated protocol for screening breast magnetic resonance imaging. Breast Cancer Res Treat. 2017;162(2):283–295.
- Kuhl CK, Strobel K, Bieling H, Leutner C, Schild HH, Schrading S. Supplemental breast MR imaging screening of women with average risk of breast cancer. Radiology. 2017;283(2):361–370.
- Saslow D, Boetes C, Burke W, et al; American Cancer Society Breast Cancer Advisory Group. American Cancer Society guidelines for breast screening with MRI as an adjunct to mammography. CA Cancer J Clin. 2007;57(2):75–89.
- National Comprehensive Cancer Network. NCCN guidelines for detection, prevention, and risk reduction: breast cancer screening and diagnosis. https://www.nccn.org/professionals/physician_gls/pdf/breast-screening.pdf.
- Berg WA, Zhang Z, Lehrer D, et al; ACRIN 6666 Investigators. Detection of breast cancer with addition of annual screening ultrasound or a single screening MRI to mammography in women with elevated breast cancer risk. JAMA. 2012;307(13):1394–1404.
- Brennan S, Liberman L, Dershaw DD, Morris E. Breast MRI screening of women with a personal history of breast cancer. AJR Am J Roentgenol. 2010;195(2):510–516.
- Lehman CD, Lee JM, DeMartini WB, et al. Screening MRI in women with a personal history of breast cancer. J Natl Cancer Inst. 2016;108(3).
- Tagliafico AS, Calabrese M, Mariscotti G, et al. Adjunct screening with tomosynthesis or ultrasound in women with mammography-negative dense breasts: interim report of a prospective comparative trial [published online ahead of print March 9, 2016]. J Clin Oncol. JCO634147.
- Corsetti V, Houssami N, Ghirardi M, et al. Evidence of the effect of adjunct ultrasound screening in women with mammography-negative dense breasts: interval breast cancers at 1 year follow-up. Eur J Cancer. 2011;47(7):1021–1026.
- Ohuchi N, Suzuki A, Sobue T, et al; J-START Investigator Groups. Sensitivity and specificity of mammography and adjunctive ultrasonography to screen for breast cancer in the Japan Strategic Anti-Cancer Randomized Trial (J-START): a randomised controlled trial. Lancet. 2016;387(10016):341–348.
- Berg WA, Mendelson EB. Technologist-performed handheld screening breast US imaging: how is it performed and what are the outcomes to date? Radiology. 2014;272(1):12–27.
- Brem RF, Tabár L, Duffy SW, et al. Assessing improvement in detection of breast cancer with three-dimensional automated breast US in women with dense breast tissue: the SomoInsight study. Radiology. 2015;274(3):663–673.
- Kelly KM, Dean J, Comulada WS, Lee SJ. Breast cancer detection using automated whole breast ultrasound and mammography in radiographically dense breasts. Eur Radiol. 2010;20(3):734–742.
- Lehman CD, Arao RF, Sprague BL, et al. National performance benchmarks for modern screening digital mammography: update from the Breast Cancer Surveillance Consortium. Radiology. 2017;283(1):49–58.
- Kerlikowske K, Zhu W, Hubbard RA, et al; Breast Cancer Surveillance Consortium. Outcomes of screening mammography by frequency, breast density, and postmenopausal hormone therapy. JAMA Intern Med. 2013;173(9):807–816.
- Friedewald SM, Rafferty EA, Rose SL, et al. Breast cancer screening using tomosynthesis in combination with digital mammography. JAMA. 2014;311(24):2499–2507.
- Skaane P, Bandos AI, Gullien R, et al. Comparison of digital mammography alone and digital mammography plus tomosynthesis in a population-based screening program. Radiology. 2013;267(1):47–56.
- Ciatto S, Houssami N, Bernardi D, et al. Integration of 3D digital mammography with tomosynthesis for population breast-cancer screening (STORM): a prospective comparison study. Lancet Oncol. 2013;14(7):583–589.
- Bahl M, Lamb LR, Lehman CD. Pathologic outcomes of architectural distortion on digital 2D versus tomosynthesis mammography [published online ahead of print August 23, 2017]. AJR Am J Roentgenol. doi:10.2214/AJR.17.17979.
- Engmann NJ, Golmakani MK, Miglioretti DL, Sprague BL, Kerlikowske K; Breast Cancer Surveillance Consortium. Population-attributable risk proportion of clinical risk factors for breast cancer [published online ahead of print February 2, 2017]. JAMA Oncol. doi:10.1001/jamaoncol.2016.6326.
- Oeffinger KC, Fontham ET, Etzioni R, et al; American Cancer Society. Breast cancer screening for women at average risk: 2015 guideline update from the American Cancer Society. JAMA. 2015;314(15):1599–1614.
- Tabar L, Yen MF, Vitak B, Chen HH, Smith RA, Duffy SW. Mammography service screening and mortality in breast cancer patients: 20-year follow-up before and after introduction of screening. Lancet. 2003;361(9367):1405–1410.
- Lee SJ, Boscardin WJ, Stijacic-Cenzer I, Conell-Price J, O’Brien S, Walter LC. Time lag to benefit after screening for breast and colorectal cancer: meta-analysis of survival data from the United States, Sweden, United Kingdom, and Denmark. BMJ. 2013;346:e8441.
- Walter LC, Covinsky KE. Cancer screening in elderly patients: a framework for individualized decision making. JAMA. 2001;285(21):2750–2756.
- Sickles EA, D’Orsi CJ, Bassett LW, et al. ACR BI-RADS mammography. In: D’Orsi CJ, Sickles EA, Mendelson EB, et al, eds. ACR BI-RADS Atlas, Breast Imaging Reporting and Data System. 5th ed. Reston, VA: American College of Radiology; 2013.
- Sprague BL, Gangnon RE, Burt V, et al. Prevalence of mammographically dense breasts in the United States. J Natl Cancer Inst. 2014;106(10).
- Rafferty EA, Durand MA, Conant EF, et al. Breast cancer screening using tomosynthesis and digital mammography in dense and nondense breasts. JAMA. 2016;315(16):1784–1786.
- Berg WA. Tailored supplemental screening for breast cancer: what now and what next? AJR Am J Roentgenol. 2009;192(2):390–399.
- Heijnsdijk EA, Warner E, Gilbert FJ, et al. Differences in natural history between breast cancers in BRCA1 and BRCA2 mutation carriers and effects of MRI screening—MRISC, MARIBS, and Canadian studies combined. Cancer Epidemiol Biomarkers Prev. 2012;21(9):1458–1468.
- Warner E, Hill K, Causer P, et al. Prospective study of breast cancer incidence in women with a BRCA1 or BRCA2 mutation under surveillance with and without magnetic resonance imaging. J Clin Oncol. 2011;29(13):1664–1669.
- Berg WA, Blume JD, Adams AM, et al. Reasons women at elevated risk of breast cancer refuse breast MR imaging screening: ACRIN 6666. Radiology. 2010;254(1):79–87.
- Kuhl CK, Schrading S, Strobel K, Schild HH, Hilgers RD, Bieling HB. Abbreviated breast magnetic resonance imaging (MRI): first postcontrast subtracted images and maximum-intensity projection—a novel approach to breast cancer screening with MRI. J Clin Oncol. 2014;32(22):2304–2310.
- Strahle DA, Pathak DR, Sierra A, Saha S, Strahle C, Devisetty K. Systematic development of an abbreviated protocol for screening breast magnetic resonance imaging. Breast Cancer Res Treat. 2017;162(2):283–295.
- Kuhl CK, Strobel K, Bieling H, Leutner C, Schild HH, Schrading S. Supplemental breast MR imaging screening of women with average risk of breast cancer. Radiology. 2017;283(2):361–370.
- Saslow D, Boetes C, Burke W, et al; American Cancer Society Breast Cancer Advisory Group. American Cancer Society guidelines for breast screening with MRI as an adjunct to mammography. CA Cancer J Clin. 2007;57(2):75–89.
- National Comprehensive Cancer Network. NCCN guidelines for detection, prevention, and risk reduction: breast cancer screening and diagnosis. https://www.nccn.org/professionals/physician_gls/pdf/breast-screening.pdf.
- Berg WA, Zhang Z, Lehrer D, et al; ACRIN 6666 Investigators. Detection of breast cancer with addition of annual screening ultrasound or a single screening MRI to mammography in women with elevated breast cancer risk. JAMA. 2012;307(13):1394–1404.
- Brennan S, Liberman L, Dershaw DD, Morris E. Breast MRI screening of women with a personal history of breast cancer. AJR Am J Roentgenol. 2010;195(2):510–516.
- Lehman CD, Lee JM, DeMartini WB, et al. Screening MRI in women with a personal history of breast cancer. J Natl Cancer Inst. 2016;108(3).
- Tagliafico AS, Calabrese M, Mariscotti G, et al. Adjunct screening with tomosynthesis or ultrasound in women with mammography-negative dense breasts: interim report of a prospective comparative trial [published online ahead of print March 9, 2016]. J Clin Oncol. JCO634147.
- Corsetti V, Houssami N, Ghirardi M, et al. Evidence of the effect of adjunct ultrasound screening in women with mammography-negative dense breasts: interval breast cancers at 1 year follow-up. Eur J Cancer. 2011;47(7):1021–1026.
- Ohuchi N, Suzuki A, Sobue T, et al; J-START Investigator Groups. Sensitivity and specificity of mammography and adjunctive ultrasonography to screen for breast cancer in the Japan Strategic Anti-Cancer Randomized Trial (J-START): a randomised controlled trial. Lancet. 2016;387(10016):341–348.
- Berg WA, Mendelson EB. Technologist-performed handheld screening breast US imaging: how is it performed and what are the outcomes to date? Radiology. 2014;272(1):12–27.
- Brem RF, Tabár L, Duffy SW, et al. Assessing improvement in detection of breast cancer with three-dimensional automated breast US in women with dense breast tissue: the SomoInsight study. Radiology. 2015;274(3):663–673.
- Kelly KM, Dean J, Comulada WS, Lee SJ. Breast cancer detection using automated whole breast ultrasound and mammography in radiographically dense breasts. Eur Radiol. 2010;20(3):734–742.
- Lehman CD, Arao RF, Sprague BL, et al. National performance benchmarks for modern screening digital mammography: update from the Breast Cancer Surveillance Consortium. Radiology. 2017;283(1):49–58.
- Kerlikowske K, Zhu W, Hubbard RA, et al; Breast Cancer Surveillance Consortium. Outcomes of screening mammography by frequency, breast density, and postmenopausal hormone therapy. JAMA Intern Med. 2013;173(9):807–816.
- Friedewald SM, Rafferty EA, Rose SL, et al. Breast cancer screening using tomosynthesis in combination with digital mammography. JAMA. 2014;311(24):2499–2507.
- Skaane P, Bandos AI, Gullien R, et al. Comparison of digital mammography alone and digital mammography plus tomosynthesis in a population-based screening program. Radiology. 2013;267(1):47–56.
- Ciatto S, Houssami N, Bernardi D, et al. Integration of 3D digital mammography with tomosynthesis for population breast-cancer screening (STORM): a prospective comparison study. Lancet Oncol. 2013;14(7):583–589.
- Bahl M, Lamb LR, Lehman CD. Pathologic outcomes of architectural distortion on digital 2D versus tomosynthesis mammography [published online ahead of print August 23, 2017]. AJR Am J Roentgenol. doi:10.2214/AJR.17.17979.
- Engmann NJ, Golmakani MK, Miglioretti DL, Sprague BL, Kerlikowske K; Breast Cancer Surveillance Consortium. Population-attributable risk proportion of clinical risk factors for breast cancer [published online ahead of print February 2, 2017]. JAMA Oncol. doi:10.1001/jamaoncol.2016.6326.
GEICAM/2006-10: Adjuvant fulvestrant/anastrozole role in early breast cancer uncertain
MADRID – Until funders pulled the financial rug out from under them, investigators in the GEICAM/2006-10 trial thought they were going to find out whether adding fulvestrant (Faslodex) to anastrozole (Femara) could improve disease-free survival for postmenopausal women with early-stage hormone receptor–positive/human epidermal growth factor receptor 2–negative (HR+/HER2–) breast cancer.
But, when the results of the FACT trial were published, showing no advantage for fulvestrant and anastrozole over anastrozole alone as first-line therapy for postmenopausal women with HR+ breast cancer, recruitment in the GEICAM 2006-10 trial was halted midstream after only 872 of the planned 2852 patients were enrolled.
“Fulvestrant at the current recommended dose of 500 mg merits further testing as adjuvant endocrine therapy, either alone, in sequence, or in combination with aromatase inhibitors,” he said.
Invited discussant Nadia Harbeck, MD, PhD, from the University of Munich, agreed.
“I just want to urge you that you don’t take this as [evidence of] nonefficacy of a SERD in the adjuvant setting, but it’s a trial with an underdosed drug, and there could be better development in future with a novel compound to come or even with fulvestrant at a better dose,” she said.
Approximately 15% of patients with HR+ breast cancer treated with endocrine therapy have a relapse within the first 5 years of therapy, which led investigators to speculate whether incomplete suppression of estrogen receptors could lead to resistance to aromatase inhibitors (AIs), such as anastrozole.
The GEICAM/2006-10 trial was designed to see whether achieving a complete estrogen blockade with an AI, minimizing serum estradiol levels, and using the SERD fulvestrant to prevent activation of tumor estrogen receptors could prove a more effective treatment strategy than endocrine therapy with an AI alone, Dr. Ruíz-Borrego explained.
The investigators enrolled postmenopausal women with early-stage breast cancer who had undergone surgery with or without neoadjuvant or adjuvant chemotherapy, and – after stratification for number of lymph nodes, for chemotherapy, and for hormone receptor status (positive for estrogen and/or progesterone receptors) – randomly assigned them to oral anastrozole 1 mg daily or oral anastrozole 1mg daily plus fulvestrant delivered intramuscularly 500 mg on the first day of treatment, 250 mg on days 14 and 28, then 250 mg every 28 days thereafter for 3 years.
As noted, only 872 of the initial target of 2,825 patients were enrolled and randomized to both fulvestrant and anastrozole (435 patients) or to anastrozole alone (437).
After 5 years of follow-up, there were no significant differences in either the primary endpoint of disease-free survival between patients treated with the combination and those treated with anastrozole alone (90.97% vs. 90.76%, respectively). Similarly, there were no differences in the secondary endpoints of breast cancer–specific survival (93.17% vs. 92.39%) or overall survival (94.81% vs. 95.34%).
The trial results “reflect on the checkered history of the development of this drug [fulvestrant], which probably missed out on a great potential for patients to get access to a drug like this in the early breast cancer setting,” Dr. Harbeck remarked. The trial results were muddied by the abrupt closure of accrual and by the use of a fulvestrant dose half that of the currently recommended dose, she noted, adding that there is preclinical evidence to suggest that fulvestrant and anastrozole combined may be less effective than if the drugs were used in sequence.
“So maybe, for the further development of SERDs, we may want to go into more sequencing than combination strategies,” she said.
The trial was funded by AstraZeneca, although funding was withdrawn before full recruitment was completed. Dr. Ruíz-Borrego and Dr. Harbeck reported having no relevant disclosures.
MADRID – Until funders pulled the financial rug out from under them, investigators in the GEICAM/2006-10 trial thought they were going to find out whether adding fulvestrant (Faslodex) to anastrozole (Femara) could improve disease-free survival for postmenopausal women with early-stage hormone receptor–positive/human epidermal growth factor receptor 2–negative (HR+/HER2–) breast cancer.
But, when the results of the FACT trial were published, showing no advantage for fulvestrant and anastrozole over anastrozole alone as first-line therapy for postmenopausal women with HR+ breast cancer, recruitment in the GEICAM 2006-10 trial was halted midstream after only 872 of the planned 2852 patients were enrolled.
“Fulvestrant at the current recommended dose of 500 mg merits further testing as adjuvant endocrine therapy, either alone, in sequence, or in combination with aromatase inhibitors,” he said.
Invited discussant Nadia Harbeck, MD, PhD, from the University of Munich, agreed.
“I just want to urge you that you don’t take this as [evidence of] nonefficacy of a SERD in the adjuvant setting, but it’s a trial with an underdosed drug, and there could be better development in future with a novel compound to come or even with fulvestrant at a better dose,” she said.
Approximately 15% of patients with HR+ breast cancer treated with endocrine therapy have a relapse within the first 5 years of therapy, which led investigators to speculate whether incomplete suppression of estrogen receptors could lead to resistance to aromatase inhibitors (AIs), such as anastrozole.
The GEICAM/2006-10 trial was designed to see whether achieving a complete estrogen blockade with an AI, minimizing serum estradiol levels, and using the SERD fulvestrant to prevent activation of tumor estrogen receptors could prove a more effective treatment strategy than endocrine therapy with an AI alone, Dr. Ruíz-Borrego explained.
The investigators enrolled postmenopausal women with early-stage breast cancer who had undergone surgery with or without neoadjuvant or adjuvant chemotherapy, and – after stratification for number of lymph nodes, for chemotherapy, and for hormone receptor status (positive for estrogen and/or progesterone receptors) – randomly assigned them to oral anastrozole 1 mg daily or oral anastrozole 1mg daily plus fulvestrant delivered intramuscularly 500 mg on the first day of treatment, 250 mg on days 14 and 28, then 250 mg every 28 days thereafter for 3 years.
As noted, only 872 of the initial target of 2,825 patients were enrolled and randomized to both fulvestrant and anastrozole (435 patients) or to anastrozole alone (437).
After 5 years of follow-up, there were no significant differences in either the primary endpoint of disease-free survival between patients treated with the combination and those treated with anastrozole alone (90.97% vs. 90.76%, respectively). Similarly, there were no differences in the secondary endpoints of breast cancer–specific survival (93.17% vs. 92.39%) or overall survival (94.81% vs. 95.34%).
The trial results “reflect on the checkered history of the development of this drug [fulvestrant], which probably missed out on a great potential for patients to get access to a drug like this in the early breast cancer setting,” Dr. Harbeck remarked. The trial results were muddied by the abrupt closure of accrual and by the use of a fulvestrant dose half that of the currently recommended dose, she noted, adding that there is preclinical evidence to suggest that fulvestrant and anastrozole combined may be less effective than if the drugs were used in sequence.
“So maybe, for the further development of SERDs, we may want to go into more sequencing than combination strategies,” she said.
The trial was funded by AstraZeneca, although funding was withdrawn before full recruitment was completed. Dr. Ruíz-Borrego and Dr. Harbeck reported having no relevant disclosures.
MADRID – Until funders pulled the financial rug out from under them, investigators in the GEICAM/2006-10 trial thought they were going to find out whether adding fulvestrant (Faslodex) to anastrozole (Femara) could improve disease-free survival for postmenopausal women with early-stage hormone receptor–positive/human epidermal growth factor receptor 2–negative (HR+/HER2–) breast cancer.
But, when the results of the FACT trial were published, showing no advantage for fulvestrant and anastrozole over anastrozole alone as first-line therapy for postmenopausal women with HR+ breast cancer, recruitment in the GEICAM 2006-10 trial was halted midstream after only 872 of the planned 2852 patients were enrolled.
“Fulvestrant at the current recommended dose of 500 mg merits further testing as adjuvant endocrine therapy, either alone, in sequence, or in combination with aromatase inhibitors,” he said.
Invited discussant Nadia Harbeck, MD, PhD, from the University of Munich, agreed.
“I just want to urge you that you don’t take this as [evidence of] nonefficacy of a SERD in the adjuvant setting, but it’s a trial with an underdosed drug, and there could be better development in future with a novel compound to come or even with fulvestrant at a better dose,” she said.
Approximately 15% of patients with HR+ breast cancer treated with endocrine therapy have a relapse within the first 5 years of therapy, which led investigators to speculate whether incomplete suppression of estrogen receptors could lead to resistance to aromatase inhibitors (AIs), such as anastrozole.
The GEICAM/2006-10 trial was designed to see whether achieving a complete estrogen blockade with an AI, minimizing serum estradiol levels, and using the SERD fulvestrant to prevent activation of tumor estrogen receptors could prove a more effective treatment strategy than endocrine therapy with an AI alone, Dr. Ruíz-Borrego explained.
The investigators enrolled postmenopausal women with early-stage breast cancer who had undergone surgery with or without neoadjuvant or adjuvant chemotherapy, and – after stratification for number of lymph nodes, for chemotherapy, and for hormone receptor status (positive for estrogen and/or progesterone receptors) – randomly assigned them to oral anastrozole 1 mg daily or oral anastrozole 1mg daily plus fulvestrant delivered intramuscularly 500 mg on the first day of treatment, 250 mg on days 14 and 28, then 250 mg every 28 days thereafter for 3 years.
As noted, only 872 of the initial target of 2,825 patients were enrolled and randomized to both fulvestrant and anastrozole (435 patients) or to anastrozole alone (437).
After 5 years of follow-up, there were no significant differences in either the primary endpoint of disease-free survival between patients treated with the combination and those treated with anastrozole alone (90.97% vs. 90.76%, respectively). Similarly, there were no differences in the secondary endpoints of breast cancer–specific survival (93.17% vs. 92.39%) or overall survival (94.81% vs. 95.34%).
The trial results “reflect on the checkered history of the development of this drug [fulvestrant], which probably missed out on a great potential for patients to get access to a drug like this in the early breast cancer setting,” Dr. Harbeck remarked. The trial results were muddied by the abrupt closure of accrual and by the use of a fulvestrant dose half that of the currently recommended dose, she noted, adding that there is preclinical evidence to suggest that fulvestrant and anastrozole combined may be less effective than if the drugs were used in sequence.
“So maybe, for the further development of SERDs, we may want to go into more sequencing than combination strategies,” she said.
The trial was funded by AstraZeneca, although funding was withdrawn before full recruitment was completed. Dr. Ruíz-Borrego and Dr. Harbeck reported having no relevant disclosures.
AT ESMO 2017
Key clinical point: Adding fulvestrant to anastrozole did not improve outcomes in women with HR+/HER2– early-stage breast cancer, but the trial was hampered by early closure.
Major finding: There were no significant differences in disease-free, breast cancer–specific, or overall survival with fulvestrant/anastrozole vs. anastrozole alone.
Data source: Randomized phase 3 trial in 872 of 2,582 planned patients.
Disclosures: The trial was funded by AstraZeneca, although funding was withdrawn before full recruitment was completed. Dr. Ruíz-Borrego and Dr. Harbeck reported having no relevant disclosures.
‘Very daring study’ of neoadjuvant AI/CDKi combo in early BC is hypothesis generating
MADRID – For women with luminal breast cancer who are not initially candidates for breast-conserving surgery, neoadjuvant therapy with an aromatase inhibitor and a cyclin-dependent kinases 4/6 (CDK4/6) inhibitor offered a slightly higher residual cancer burden prior to surgery, but a significantly better safety profile than conventional chemotherapy with similar near-term safety outcomes, results of a phase 2 parallel group, noncomparative trial suggested.
Among 60 patients evaluable for response in an interim analysis of the UNICANCER NeoPAL trial, one patient (3.3%) treated with a combination of letrozole (Femara) and palbociclib (Ibrance) had a residual cancer burden (RCB) score of 0 (equivalent to a pathologic complete response; pCR), whereas three patients (10%) treated with FEC 100 chemotherapy (5-fluorouracil, epirubicin, and cyclophosphamide) had RCB 0 or I, reported Paul-Henri Cottu, MD, of the Institut Curie in Paris.
Following the interim analysis, the independent data monitoring committee for the NeoPAL trial recommended halting accrual; accrual was stopped in November 2016, after 106 patients had been randomized.
The IDMC also recommended that patients in the letrozole/palbociclib arm who did not have an RCB of 0 or I be offered adjuvant chemotherapy.
“Please note that 70% of those patients refused adjuvant chemotherapy,” Dr. Cottu said.
The investigators set out to test whether letrozole and palbociclib, which have been shown to have synergistic antiproliferative activity against advanced luminal breast cancer, could have similar benefits in the neoadjuvant setting.
They screened for women with luminal breast cancer who had newly diagnosed stage II or III breast cancer with biopsy-proven endocrine receptor–positive, human epidermal growth factor receptor 2–negative tumors, using the Prosigna test, based on the PAM50 gene signature assay. Women with node-positive luminal A or luminal B disease were enrolled and randomized to receive either letrozole 2.5 mg and palbociclib 125 mg daily for 3 out of every 4 weeks over 19 weeks, or three cycles of FEC 100, followed by three cycles of docetaxel 100 mg/m2 every 3 weeks, followed by surgery.
An interim analysis was planned after 30 patients were evaluable for RCB in the experimental arm, and, as prespecified, the trial was stopped for futility when fewer than five patients had an RCB of 0 or I.
The safety analysis, conducted with all 106 patients randomized, showed that letrozole/palbocilib was associated with more frequent grade 3 neutropenia (23% vs. 10% of patients with FEC), but less grade 4 neutropenia (1% vs. 11%, respectively), and no febrile neutropenia vs. 6% in the chemotherapy arm.
There were 2 serious adverse events with the AI/CDK-inhibitor combination vs. 17 with chemotherapy. Dose reductions or interruptions were less frequent with letrozole/palbociclib (10 and 16), and only two patients in the experimental arm required premature cessation of therapy vs. seven in the chemotherapy arm.
The final response analysis in 103 patients showed that the rate of RCB 0 or I was 7.7% with letrozole/palbociclib and 15.7% with chemotherapy. Respective rates of RCB II-III were 92.3% and 84.3%.
Clinical response rates were similar in each study arm, with approximately 30% complete responses and 44% partial responses.
In each arm, slightly less than one-third of patients underwent mastectomy, and a little more than two-thirds were able to have breast-conserving surgery after neoadjuvant therapy.
The patients will be followed out to at least 3 years to see whether those patients in the letrozole/palbociclib arm who turned down subsequent chemotherapy will have worse survival than patients who decided to undergo it, Dr. Cottu said.
Invited discussant Nadia Harbeck, MD, PhD, of the University of Munich called the NeoPAL trial “a very daring study.”
“This is not a practice-changing trial, but it’s a very, very interesting hypothesis-generating trial,” she said.
She said that the choice of RCB was probably not the best endpoint in a trial of endocrine-based therapy vs. chemotherapy.
“I think the challenge remains to identify those patients with luminal early breast cancer for whom an endocrine-based approach – not endocrine, but endocrine-based – will improve outcome, either replacing chemotherapy in the intermediate-risk setting or as an add-on in high-risk disease,” she said.
The study was funded by Pfizer and Nanostring. Dr. Cottu disclosed advisory board participation and travel support from Pfizer and others, and research support from Roche, Novartis, and AstraZeneca. Dr. Harbeck disclosed advising and consulting fees from Pfizer, Nanostring, and other companies.
MADRID – For women with luminal breast cancer who are not initially candidates for breast-conserving surgery, neoadjuvant therapy with an aromatase inhibitor and a cyclin-dependent kinases 4/6 (CDK4/6) inhibitor offered a slightly higher residual cancer burden prior to surgery, but a significantly better safety profile than conventional chemotherapy with similar near-term safety outcomes, results of a phase 2 parallel group, noncomparative trial suggested.
Among 60 patients evaluable for response in an interim analysis of the UNICANCER NeoPAL trial, one patient (3.3%) treated with a combination of letrozole (Femara) and palbociclib (Ibrance) had a residual cancer burden (RCB) score of 0 (equivalent to a pathologic complete response; pCR), whereas three patients (10%) treated with FEC 100 chemotherapy (5-fluorouracil, epirubicin, and cyclophosphamide) had RCB 0 or I, reported Paul-Henri Cottu, MD, of the Institut Curie in Paris.
Following the interim analysis, the independent data monitoring committee for the NeoPAL trial recommended halting accrual; accrual was stopped in November 2016, after 106 patients had been randomized.
The IDMC also recommended that patients in the letrozole/palbociclib arm who did not have an RCB of 0 or I be offered adjuvant chemotherapy.
“Please note that 70% of those patients refused adjuvant chemotherapy,” Dr. Cottu said.
The investigators set out to test whether letrozole and palbociclib, which have been shown to have synergistic antiproliferative activity against advanced luminal breast cancer, could have similar benefits in the neoadjuvant setting.
They screened for women with luminal breast cancer who had newly diagnosed stage II or III breast cancer with biopsy-proven endocrine receptor–positive, human epidermal growth factor receptor 2–negative tumors, using the Prosigna test, based on the PAM50 gene signature assay. Women with node-positive luminal A or luminal B disease were enrolled and randomized to receive either letrozole 2.5 mg and palbociclib 125 mg daily for 3 out of every 4 weeks over 19 weeks, or three cycles of FEC 100, followed by three cycles of docetaxel 100 mg/m2 every 3 weeks, followed by surgery.
An interim analysis was planned after 30 patients were evaluable for RCB in the experimental arm, and, as prespecified, the trial was stopped for futility when fewer than five patients had an RCB of 0 or I.
The safety analysis, conducted with all 106 patients randomized, showed that letrozole/palbocilib was associated with more frequent grade 3 neutropenia (23% vs. 10% of patients with FEC), but less grade 4 neutropenia (1% vs. 11%, respectively), and no febrile neutropenia vs. 6% in the chemotherapy arm.
There were 2 serious adverse events with the AI/CDK-inhibitor combination vs. 17 with chemotherapy. Dose reductions or interruptions were less frequent with letrozole/palbociclib (10 and 16), and only two patients in the experimental arm required premature cessation of therapy vs. seven in the chemotherapy arm.
The final response analysis in 103 patients showed that the rate of RCB 0 or I was 7.7% with letrozole/palbociclib and 15.7% with chemotherapy. Respective rates of RCB II-III were 92.3% and 84.3%.
Clinical response rates were similar in each study arm, with approximately 30% complete responses and 44% partial responses.
In each arm, slightly less than one-third of patients underwent mastectomy, and a little more than two-thirds were able to have breast-conserving surgery after neoadjuvant therapy.
The patients will be followed out to at least 3 years to see whether those patients in the letrozole/palbociclib arm who turned down subsequent chemotherapy will have worse survival than patients who decided to undergo it, Dr. Cottu said.
Invited discussant Nadia Harbeck, MD, PhD, of the University of Munich called the NeoPAL trial “a very daring study.”
“This is not a practice-changing trial, but it’s a very, very interesting hypothesis-generating trial,” she said.
She said that the choice of RCB was probably not the best endpoint in a trial of endocrine-based therapy vs. chemotherapy.
“I think the challenge remains to identify those patients with luminal early breast cancer for whom an endocrine-based approach – not endocrine, but endocrine-based – will improve outcome, either replacing chemotherapy in the intermediate-risk setting or as an add-on in high-risk disease,” she said.
The study was funded by Pfizer and Nanostring. Dr. Cottu disclosed advisory board participation and travel support from Pfizer and others, and research support from Roche, Novartis, and AstraZeneca. Dr. Harbeck disclosed advising and consulting fees from Pfizer, Nanostring, and other companies.
MADRID – For women with luminal breast cancer who are not initially candidates for breast-conserving surgery, neoadjuvant therapy with an aromatase inhibitor and a cyclin-dependent kinases 4/6 (CDK4/6) inhibitor offered a slightly higher residual cancer burden prior to surgery, but a significantly better safety profile than conventional chemotherapy with similar near-term safety outcomes, results of a phase 2 parallel group, noncomparative trial suggested.
Among 60 patients evaluable for response in an interim analysis of the UNICANCER NeoPAL trial, one patient (3.3%) treated with a combination of letrozole (Femara) and palbociclib (Ibrance) had a residual cancer burden (RCB) score of 0 (equivalent to a pathologic complete response; pCR), whereas three patients (10%) treated with FEC 100 chemotherapy (5-fluorouracil, epirubicin, and cyclophosphamide) had RCB 0 or I, reported Paul-Henri Cottu, MD, of the Institut Curie in Paris.
Following the interim analysis, the independent data monitoring committee for the NeoPAL trial recommended halting accrual; accrual was stopped in November 2016, after 106 patients had been randomized.
The IDMC also recommended that patients in the letrozole/palbociclib arm who did not have an RCB of 0 or I be offered adjuvant chemotherapy.
“Please note that 70% of those patients refused adjuvant chemotherapy,” Dr. Cottu said.
The investigators set out to test whether letrozole and palbociclib, which have been shown to have synergistic antiproliferative activity against advanced luminal breast cancer, could have similar benefits in the neoadjuvant setting.
They screened for women with luminal breast cancer who had newly diagnosed stage II or III breast cancer with biopsy-proven endocrine receptor–positive, human epidermal growth factor receptor 2–negative tumors, using the Prosigna test, based on the PAM50 gene signature assay. Women with node-positive luminal A or luminal B disease were enrolled and randomized to receive either letrozole 2.5 mg and palbociclib 125 mg daily for 3 out of every 4 weeks over 19 weeks, or three cycles of FEC 100, followed by three cycles of docetaxel 100 mg/m2 every 3 weeks, followed by surgery.
An interim analysis was planned after 30 patients were evaluable for RCB in the experimental arm, and, as prespecified, the trial was stopped for futility when fewer than five patients had an RCB of 0 or I.
The safety analysis, conducted with all 106 patients randomized, showed that letrozole/palbocilib was associated with more frequent grade 3 neutropenia (23% vs. 10% of patients with FEC), but less grade 4 neutropenia (1% vs. 11%, respectively), and no febrile neutropenia vs. 6% in the chemotherapy arm.
There were 2 serious adverse events with the AI/CDK-inhibitor combination vs. 17 with chemotherapy. Dose reductions or interruptions were less frequent with letrozole/palbociclib (10 and 16), and only two patients in the experimental arm required premature cessation of therapy vs. seven in the chemotherapy arm.
The final response analysis in 103 patients showed that the rate of RCB 0 or I was 7.7% with letrozole/palbociclib and 15.7% with chemotherapy. Respective rates of RCB II-III were 92.3% and 84.3%.
Clinical response rates were similar in each study arm, with approximately 30% complete responses and 44% partial responses.
In each arm, slightly less than one-third of patients underwent mastectomy, and a little more than two-thirds were able to have breast-conserving surgery after neoadjuvant therapy.
The patients will be followed out to at least 3 years to see whether those patients in the letrozole/palbociclib arm who turned down subsequent chemotherapy will have worse survival than patients who decided to undergo it, Dr. Cottu said.
Invited discussant Nadia Harbeck, MD, PhD, of the University of Munich called the NeoPAL trial “a very daring study.”
“This is not a practice-changing trial, but it’s a very, very interesting hypothesis-generating trial,” she said.
She said that the choice of RCB was probably not the best endpoint in a trial of endocrine-based therapy vs. chemotherapy.
“I think the challenge remains to identify those patients with luminal early breast cancer for whom an endocrine-based approach – not endocrine, but endocrine-based – will improve outcome, either replacing chemotherapy in the intermediate-risk setting or as an add-on in high-risk disease,” she said.
The study was funded by Pfizer and Nanostring. Dr. Cottu disclosed advisory board participation and travel support from Pfizer and others, and research support from Roche, Novartis, and AstraZeneca. Dr. Harbeck disclosed advising and consulting fees from Pfizer, Nanostring, and other companies.
AT ESMO 2017
Key clinical point:
Major finding: One patient (3.3%) assigned to letrozole/palbociclib had a residual cancer burden score of 0 or I, compared with three patients (10%) assigned to chemotherapy.
Data source: Interim analysis of a phase 2 parallel group trial with 60 patients evaluable for response and 106 evaluable for safety.
Disclosures: The study was funded by Pfizer and Nanostring. Dr. Cottu disclosed advisory board participation and travel support from Pfizer and others and research support from Roche, Novartis, and AstraZeneca. Dr. Harbeck disclosed advising and consulting fees from Pfizer, Nanostring, and other companies.
MONARCH 3: Abemaciclib plus AI boosts PFS in HR+/HER2- breast cancer
Madrid – A combination of the investigational cyclin-dependent kinase 4/6 (CDK4/6) agent abemaciclib and a nonsteroidal aromatase inhibitor (AI) was associated with a near doubling of progression-free survival in postmenopausal women with previously untreated hormone-receptor positive, human epidermal growth factor receptor 2–negative (HR+/HER2-) advanced breast cancer.
At a planned 18-month interim analysis of the MONARCH 3 trial, the median investigator-assessed progression free survival (PFS), the primary endpoint, had not been reached for 328 patients assigned to receive abemaciclib with either anastrozole (Arimidex) or letrozole (Femara). In contrast, the median PFS for 165 patients assigned to an AI and a placebo was 14.7 months, translating into a hazard ratio (HR) of 0.543 (P = .000021), reported Angelo Di Leo, MD, of Hospital of Prato, Istituto Toscano Tumori, Prato, Italy.
“Abemaciclib in combination with a nonsteroidal aromatase inhibitor is superior to a nonsteroidal aromatase inhibitor alone in terms of progression-free survival, but also in terms of the objective response rate as the initial treatment of HER2-negative, endocrine sensitive advanced breast cancer,” he said at a briefing prior to his presentation of the data in a presidential symposium at the European Society for Medical Oncology Congress.
The efficacy of abemaciclib was consistently seen across all subgroups.
“However, we have observed that the patients deriving the largest benefit from abemaciclib are those who have adverse prognostic factors such as, for instance, the presence of liver metastases, or the fact the disease has relapsed only after a few years from the end of adjuvant endocrine therapy,” he added.
The study was stopped for efficacy at the interim analysis.
Abemaciclib has previously been shown to be active as a monotherapy in treatment-refractory HR+/HER2- breast cancer, and in combination with fulvestrant (Faslodex) in patients who had disease progression on endocrine therapy.
Dr. Di Leo and his colleagues enrolled 493 postmenopausal women with metastatic or locally recurrent HR+/HER2- breast cancer who had not received systemic therapy in this setting. Patients who had prior neoadjuvant or adjuvant endocrine therapy were allowed if they had a disease-free interval of more than 1 year since completing endocrine therapy, The patients also had to have good performance status (Eastern Cooperative Oncology Group PS score 1 or less).
They were randomly assigned on a 2:1 basis to receive abemaciclib 150 mg b.i.d. on a continuous schedule plus either anastrozole 1 mg or letrozole 2.5 mg daily until disease progression, or to placebo plus either of the two AIs.
In addition to the superior PFS with abemaciclib added to an AI, as noted before, the CDK4/6 inhibitor was associated with a significantly better objective response rate (ORR), at 48.2% compared with 34.5% for placebo (P = .002). Among patients with measurable disease at baseline, the respective ORRs were 59.2% and 43.8% (P = .004). The clinical benefit rate in this subgroup was also better with abemaciclib, at 79.3% vs. 69.2% (P = .024).
In exploratory subgroup analyses, the investigators found that patients who had indicators of poor prognosis seemed to derive “substantial” benefit from the addition of abemaciclib. However, in an exploratory analysis in patients with disease only in bone, the investigators found that adding abemaciclib did not appear to improve PFS, suggesting that this subgroup could be treated effectively with endocrine therapy alone. Dr. Di Leo cautioned against overinterpreting this finding however, as only 109 patients had bone-only disease.
The safety analysis showed that patients were able to tolerate the combination fairly well. The incidence of grade 3 or 4 neutropenia was 21.1% with the combination compared with 1.2% with placebo, and grade 3 diarrhea occurred in 9.5% vs. 1.2% (no grade 4 diarrhea in either arm). The diarrhea tended to occur early in therapy and could be managed with dose adjustments and antidiarrheal medications, Dr. Di Leo said.
“What we would like to ask is, is this a practice-changing study? Do the results change standard first-line endocrine-based therapy, and then do these results change who we give endocrine therapy to?,” said invited discussant Nicholas Turner, PhD, of The Royal Marsden Hospital in London.
“The study stopped at the reported interim analysis, so at the moment the abemaciclib arm hasn’t reached the median PFS, but we can anticipate that with further follow-up we will see approximately a year improvement in median PFS by the addition of abemaciclib, which is really a substantial improvement in PFS for these patients. And importantly, this benefit was confirmed by a blinded independent central review of the investigator PFS,” he said.
Eli Lilly funded MONARCH 3. Dr. Di Leo and Dr. Turner reported receiving honoraria from the company.
Madrid – A combination of the investigational cyclin-dependent kinase 4/6 (CDK4/6) agent abemaciclib and a nonsteroidal aromatase inhibitor (AI) was associated with a near doubling of progression-free survival in postmenopausal women with previously untreated hormone-receptor positive, human epidermal growth factor receptor 2–negative (HR+/HER2-) advanced breast cancer.
At a planned 18-month interim analysis of the MONARCH 3 trial, the median investigator-assessed progression free survival (PFS), the primary endpoint, had not been reached for 328 patients assigned to receive abemaciclib with either anastrozole (Arimidex) or letrozole (Femara). In contrast, the median PFS for 165 patients assigned to an AI and a placebo was 14.7 months, translating into a hazard ratio (HR) of 0.543 (P = .000021), reported Angelo Di Leo, MD, of Hospital of Prato, Istituto Toscano Tumori, Prato, Italy.
“Abemaciclib in combination with a nonsteroidal aromatase inhibitor is superior to a nonsteroidal aromatase inhibitor alone in terms of progression-free survival, but also in terms of the objective response rate as the initial treatment of HER2-negative, endocrine sensitive advanced breast cancer,” he said at a briefing prior to his presentation of the data in a presidential symposium at the European Society for Medical Oncology Congress.
The efficacy of abemaciclib was consistently seen across all subgroups.
“However, we have observed that the patients deriving the largest benefit from abemaciclib are those who have adverse prognostic factors such as, for instance, the presence of liver metastases, or the fact the disease has relapsed only after a few years from the end of adjuvant endocrine therapy,” he added.
The study was stopped for efficacy at the interim analysis.
Abemaciclib has previously been shown to be active as a monotherapy in treatment-refractory HR+/HER2- breast cancer, and in combination with fulvestrant (Faslodex) in patients who had disease progression on endocrine therapy.
Dr. Di Leo and his colleagues enrolled 493 postmenopausal women with metastatic or locally recurrent HR+/HER2- breast cancer who had not received systemic therapy in this setting. Patients who had prior neoadjuvant or adjuvant endocrine therapy were allowed if they had a disease-free interval of more than 1 year since completing endocrine therapy, The patients also had to have good performance status (Eastern Cooperative Oncology Group PS score 1 or less).
They were randomly assigned on a 2:1 basis to receive abemaciclib 150 mg b.i.d. on a continuous schedule plus either anastrozole 1 mg or letrozole 2.5 mg daily until disease progression, or to placebo plus either of the two AIs.
In addition to the superior PFS with abemaciclib added to an AI, as noted before, the CDK4/6 inhibitor was associated with a significantly better objective response rate (ORR), at 48.2% compared with 34.5% for placebo (P = .002). Among patients with measurable disease at baseline, the respective ORRs were 59.2% and 43.8% (P = .004). The clinical benefit rate in this subgroup was also better with abemaciclib, at 79.3% vs. 69.2% (P = .024).
In exploratory subgroup analyses, the investigators found that patients who had indicators of poor prognosis seemed to derive “substantial” benefit from the addition of abemaciclib. However, in an exploratory analysis in patients with disease only in bone, the investigators found that adding abemaciclib did not appear to improve PFS, suggesting that this subgroup could be treated effectively with endocrine therapy alone. Dr. Di Leo cautioned against overinterpreting this finding however, as only 109 patients had bone-only disease.
The safety analysis showed that patients were able to tolerate the combination fairly well. The incidence of grade 3 or 4 neutropenia was 21.1% with the combination compared with 1.2% with placebo, and grade 3 diarrhea occurred in 9.5% vs. 1.2% (no grade 4 diarrhea in either arm). The diarrhea tended to occur early in therapy and could be managed with dose adjustments and antidiarrheal medications, Dr. Di Leo said.
“What we would like to ask is, is this a practice-changing study? Do the results change standard first-line endocrine-based therapy, and then do these results change who we give endocrine therapy to?,” said invited discussant Nicholas Turner, PhD, of The Royal Marsden Hospital in London.
“The study stopped at the reported interim analysis, so at the moment the abemaciclib arm hasn’t reached the median PFS, but we can anticipate that with further follow-up we will see approximately a year improvement in median PFS by the addition of abemaciclib, which is really a substantial improvement in PFS for these patients. And importantly, this benefit was confirmed by a blinded independent central review of the investigator PFS,” he said.
Eli Lilly funded MONARCH 3. Dr. Di Leo and Dr. Turner reported receiving honoraria from the company.
Madrid – A combination of the investigational cyclin-dependent kinase 4/6 (CDK4/6) agent abemaciclib and a nonsteroidal aromatase inhibitor (AI) was associated with a near doubling of progression-free survival in postmenopausal women with previously untreated hormone-receptor positive, human epidermal growth factor receptor 2–negative (HR+/HER2-) advanced breast cancer.
At a planned 18-month interim analysis of the MONARCH 3 trial, the median investigator-assessed progression free survival (PFS), the primary endpoint, had not been reached for 328 patients assigned to receive abemaciclib with either anastrozole (Arimidex) or letrozole (Femara). In contrast, the median PFS for 165 patients assigned to an AI and a placebo was 14.7 months, translating into a hazard ratio (HR) of 0.543 (P = .000021), reported Angelo Di Leo, MD, of Hospital of Prato, Istituto Toscano Tumori, Prato, Italy.
“Abemaciclib in combination with a nonsteroidal aromatase inhibitor is superior to a nonsteroidal aromatase inhibitor alone in terms of progression-free survival, but also in terms of the objective response rate as the initial treatment of HER2-negative, endocrine sensitive advanced breast cancer,” he said at a briefing prior to his presentation of the data in a presidential symposium at the European Society for Medical Oncology Congress.
The efficacy of abemaciclib was consistently seen across all subgroups.
“However, we have observed that the patients deriving the largest benefit from abemaciclib are those who have adverse prognostic factors such as, for instance, the presence of liver metastases, or the fact the disease has relapsed only after a few years from the end of adjuvant endocrine therapy,” he added.
The study was stopped for efficacy at the interim analysis.
Abemaciclib has previously been shown to be active as a monotherapy in treatment-refractory HR+/HER2- breast cancer, and in combination with fulvestrant (Faslodex) in patients who had disease progression on endocrine therapy.
Dr. Di Leo and his colleagues enrolled 493 postmenopausal women with metastatic or locally recurrent HR+/HER2- breast cancer who had not received systemic therapy in this setting. Patients who had prior neoadjuvant or adjuvant endocrine therapy were allowed if they had a disease-free interval of more than 1 year since completing endocrine therapy, The patients also had to have good performance status (Eastern Cooperative Oncology Group PS score 1 or less).
They were randomly assigned on a 2:1 basis to receive abemaciclib 150 mg b.i.d. on a continuous schedule plus either anastrozole 1 mg or letrozole 2.5 mg daily until disease progression, or to placebo plus either of the two AIs.
In addition to the superior PFS with abemaciclib added to an AI, as noted before, the CDK4/6 inhibitor was associated with a significantly better objective response rate (ORR), at 48.2% compared with 34.5% for placebo (P = .002). Among patients with measurable disease at baseline, the respective ORRs were 59.2% and 43.8% (P = .004). The clinical benefit rate in this subgroup was also better with abemaciclib, at 79.3% vs. 69.2% (P = .024).
In exploratory subgroup analyses, the investigators found that patients who had indicators of poor prognosis seemed to derive “substantial” benefit from the addition of abemaciclib. However, in an exploratory analysis in patients with disease only in bone, the investigators found that adding abemaciclib did not appear to improve PFS, suggesting that this subgroup could be treated effectively with endocrine therapy alone. Dr. Di Leo cautioned against overinterpreting this finding however, as only 109 patients had bone-only disease.
The safety analysis showed that patients were able to tolerate the combination fairly well. The incidence of grade 3 or 4 neutropenia was 21.1% with the combination compared with 1.2% with placebo, and grade 3 diarrhea occurred in 9.5% vs. 1.2% (no grade 4 diarrhea in either arm). The diarrhea tended to occur early in therapy and could be managed with dose adjustments and antidiarrheal medications, Dr. Di Leo said.
“What we would like to ask is, is this a practice-changing study? Do the results change standard first-line endocrine-based therapy, and then do these results change who we give endocrine therapy to?,” said invited discussant Nicholas Turner, PhD, of The Royal Marsden Hospital in London.
“The study stopped at the reported interim analysis, so at the moment the abemaciclib arm hasn’t reached the median PFS, but we can anticipate that with further follow-up we will see approximately a year improvement in median PFS by the addition of abemaciclib, which is really a substantial improvement in PFS for these patients. And importantly, this benefit was confirmed by a blinded independent central review of the investigator PFS,” he said.
Eli Lilly funded MONARCH 3. Dr. Di Leo and Dr. Turner reported receiving honoraria from the company.
AT ESMO 2017
Key clinical point: Adding the CDK4/6 inhibitor abemaciclib to an aromatase inhibitor significantly improved progression-free survival in the frontline for postmenopausal women with HR+/HER2- breast cancer.
Major finding: Median PFS was not reached with abemaciclib and letrozole or anastrozole, vs. 14.7 months for a placebo plus aromatase inhibitor.
Data source: Randomized phase 3 trial of 493 postmenopausal women with metastatic or locally recurrent HR+/HER2- breast cancer.
Disclosures: Eli Lilly funded MONARCH 3. Dr. Di Leo and Dr. Turner reported receiving honoraria from the company.