Use of aromatase inhibitors in the adjuvant setting after diagnosis of hormone receptor–positive breast cancer seems to delay the development of contralateral breast cancer in all individuals … especially in BRCA1/2 mutation–positive patients.”
—Maryam Nemati Shafaee, MD
Given that BRCA1 and BRCA2 mutation carriers have an estimated 40% to 85% lifetime risk of breast cancer and an increased risk of developing contralateral breast cancer, risk reduction in this population remains essential. According to a study presented at the 2015 Breast Cancer Symposium, use of aromatase inhibitors may help accomplish this aim.1
“Use of aromatase inhibitors in the adjuvant setting after diagnosis of hormone receptor–positive breast cancer seems to delay the development of contralateral breast cancer in all individuals,” said Maryam Nemati Shafaee, MD, Hematology/Oncology Fellow at The University of Texas MD Anderson Cancer Center in Houston. “This effect was especially seen in BRCA1/2 mutation–positive patients. This gives patients an alternative option besides considering preventive mastectomy.”
In BRCA1/2 mutation carriers, the risk of contralateral breast cancer is approximately 2.5% per year, and the incidence of contralateral breast cancer is six times greater than in noncarriers. Current options for reducing risk of contralateral breast cancer in mutation carriers with a personal history of breast cancer, however, remain limited—either prophylactic contralateral mastectomy (rates between 20% and 80% have been reported) or surveillance.
“The role of chemoprevention remains relatively unknown at this time,” said Dr. Shafaee, “but there are data suggesting that endocrine therapy, especially tamoxifen in the adjuvant setting for estrogen receptor–positive breast cancer, may reduce the risk of [contralateral breast cancer] in this high-risk population.”
Although several studies have examined adjuvant tamoxifen use in BRCA1/2 mutation carriers, data remain inconclusive regarding its role in preventing contralateral breast cancer. Furthermore, Dr. Shafaee added, there are no data on the use of adjuvant aromatase inhibitors and contralateral breast cancer risk-reduction in this population.
Dr. Shafaee and colleagues sought to identify predictors of contralateral breast cancer in a cohort of patients with known BRCA status and personal history of breast cancer by reviewing a prospectively maintained research database of patients who underwent BRCA testing at MD Anderson Cancer Center between 2004 and 2014.
The following variables were included in the study: age at diagnosis, bilateral salpingo-oophorectomy, BRCA1/2 mutation status, HER2/neu amplification, TNM stage, nuclear grade, tamoxifen use, aromatase inhibitor use, or combined use of tamoxifen plus an aromatase inhibitor.
Investigators excluded male patients and those who had undergone contralateral prophylactic mastectomy, as well as those with the following features: noninvasive disease (ie, ductal carcinoma in situ), hormone receptor–negative tumors, synchronous breast cancer, variant BRCA mutation, metastatic disease at time of diagnosis or within 1 year from diagnosis, and development of gynecologic cancer during follow-up.
Of the 486 patients included for final analysis, the majority were diagnosed with primary breast cancer before age 50, were premenopausal at diagnosis, and had not undergone prophylactic bilateral salpingo-oophorectomy. BRCA1/2 mutation carriers formed 9% of the total population.
“In terms of adjuvant therapy,” said Dr. Shafaee, “the majority of our patients received tamoxifen only (60%). This was followed by a combination of aromatase inhibitor plus tamoxifen (21%). Patients receiving an aromatase inhibitor only represented 16% of the population, and 3% of the population did not receive any adjuvant endocrine therapy.”
The median follow-up of 8.6 years, although shorter than desired, was significant for identification of 43 contralateral breast cancers, Dr. Shafaee noted.
BRCA Mutation and Aromatase Inhibitors
The hazard ratio for developing contralateral breast cancer for BRCA1/2 mutation carriers vs noncarriers was 2.3 (P = .04) in both univariate and multivariate analyses.
Other factors, including age at diagnosis, prophylactic bilateral salpingo-oophorectomy, HER2/neu status, nuclear grade, and use of tamoxifen, were not significantly associated with increased risk of contralateral breast cancer.
“Interestingly,” said Dr. Shafaee, “aromatase inhibitor use in all patients was suggestive of decreased risk of contralateral breast cancer, but this was not statistically significant (P = .08). Among patients with BRCA1/2 mutations, however, aromatase-inhibitor use was significantly associated with a smaller hazard of developing [contralateral breast cancer] (P = .04).”
The hazard ratio for aromatase inhibitor use vs no use in the overall population was 0.54 (P = .08), a 46% reduction in risk that indicated a trend.
Of the 23 patients with BRCA1/2 mutations who did not receive aromatase inhibitors, 7 developed contralateral breast cancer. However, of the 18 patients with BRCA1/2 mutations who received aromatase inhibitors, none developed the disease.
“For future directions,” she concluded, “validation of our findings based on a larger cohort and longer follow-up of BRCA mutation carriers who have received endocrine therapy in the adjuvant setting are recommended.” ■
Disclosure: Dr. Shafaee reported no potential conflicts of interest.
1. Shafaee M, Gutierrez-Barrera A, Lin H, et al: Aromatase inhibitors and the risk of contralateral breast cancer in BRCA mutation carriers. 2015 Breast Cancer Symposium. Abstract 3. Presented September 25, 2015.
Discussant William J. Gradishar, MD, the Betsy Bramsen Professor of Breast Oncology at the Robert H. Lurie Comprehensive Cancer Center of Northwestern University in Chicago, endorsed Dr. Shafaee’s conclusions, while highlighting caution in interpreting the results.
“At first blush, it certainly is ...