Affiliations of authors: W. D. Foulkes (Program in Cancer Genetics, Departments of Oncology and Human Genetics), J. Goffin (Department of Oncology), L. R. Bégin (Department of Pathology), N. Wong (Cancer Prevention Centre, Sir M. B. Davis-Jewish General Hospital), P. O. Chappuis (Department of Medicine, Research Institute of the McGill University Health Centre), McGill University, Montreal, Quebec, Canada; J.-S. Brunet, Algorithme Pharma, Montreal.
Correspondence to: William D. Foulkes, M.B.B.S., Ph.D., Montreal General Hospital, Division of Medical Genetics, 1650 Cedar Ave., Montreal, Quebec H3G 1A4, Canada (e-mail: william.foulkes{at}mcgill.ca).
One of the most important questions in the management of women with BRCA1-related breast cancer is whether tamoxifen will be an effective treatment. This area of research is controversial because most BRCA1-related breast cancers are estrogen receptor (ER)-negative (1,2) and, for women in the general population, tamoxifen can provide neither prevention against nor treatment for ER-negative breast cancers. In a recent analysis of the National Surgical Adjuvant Breast and Bowel Project breast cancer prevention trial (NSABP-P1), King et al. (3) suggested that tamoxifen was less effective in preventing the development of ER-negative BRCA1-related breast cancers than it was in preventing the development of ER-positive BRCA2-related breast cancers. However, Narod et al. (4) demonstrated a statistically significantly reduced risk of contralateral breast cancer following tamoxifen treatment in BRCA1 mutation carriers, irrespective of the ER status of the primary tumor. There are currently no data available on the effectiveness of tamoxifen in reducing mortality from breast cancer in BRCA1 mutation carriers.
To study the impact of BRCA1 mutation status on the response to adjuvant tamoxifen treatment, we performed a proportional hazards breast-cancer-specific survival analysis using a retrospective cohort of 292 Ashkenazi Jewish women with first primary invasive breast cancer diagnosed between 1980 and 1995 who had been tested for the founder mutations in BRCA1 and BRCA2 that are common in this population. The median follow-up time of survivors was 8.9 years, and 31 women were identified as BRCA1 mutation carriers. Seven of these women developed ER-positive breast cancer, four of whom had received tamoxifen, and 23 women developed ER-negative breast cancer, five of whom had received tamoxifen. One BRCA1 mutation carrier developed a breast cancer of unknown ER status.
Because tamoxifen treatment was not randomly assigned, we cannot directly compare survival between the women who did or did not receive tamoxifen. Instead, we created proportional hazards models for women who used or did not use tamoxifen. Tumor size, ER status, axillary lymph node involvement, and BRCA1 mutation status were included as variables in the two models. The relative risk (RR) of death for the group of women who had not received tamoxifen is shown in Table 1. Notably, BRCA1 mutation status was a poor prognostic factor for breast-cancer-specific survival in multivariable analysis (RR = 2.16, 95% confidence interval [CI] = 1.0 to 4.68; P = .05). In comparison, the negative impact of BRCA1 mutations was lost in women who had received tamoxifen, with an RR of death associated with a BRCA1 mutation of 0.3 (95% CI = 0.04 to 2.49; P = .27). In addition, when the multivariable analysis was repeated with chemotherapy as an additional variable, the RR of death changed only marginally (Table 1
).
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In conclusion, our data support the idea that the ER-negative status of breast cancers that occur in BRCA1 mutation carriers may not have the same effect on the response to tamoxifen as it does for women with breast cancer in the general population. Prospective studies of the effect of tamoxifen on BRCA1 mutation carriers who develop ER-negative breast cancer will be required to validate these findings. Nevertheless, these preliminary observations indicate that it may be premature to conclude that tamoxifen has no role in the prevention or treatment of ER-negative BRCA1-related breast cancer.
NOTES
Funded by the Department of Defense, Fonds de la Recherche en Santé du Québec, and the Canadian Genetic Diseases Network.
We thank Nancy Hamel and Ann-Josée Paradis for technical assistance.
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