CORRESPONDENCE

Tamoxifen May Be an Effective Adjuvant Treatment for BRCA1-Related Breast Cancer Irrespective of Estrogen Receptor Status

William D. Foulkes, John Goffin, Jean-Sébastien Brunet, Louis R. Bégin, Nora Wong, Pierre O. Chappuis

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 1Go. 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 1Go).


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Table 1. Proportional hazards models of the relative risk (RR) of death from breast cancer among 292 women who either received or did not receive adjuvant tamoxifen treatment*
 
These findings suggest that adjuvant tamoxifen might be an effective treatment for BRCA1-related breast cancer, irrespective of the ER status of the tumor. Recent data have indicated that wild-type BRCA1 protein may repress ER function, either directly (5) or indirectly (6). Therefore, tumors that lack functional BRCA1 protein may be particularly dependent on hormone therapy to limit estrogen-related cellular proliferation. In addition, tamoxifen can induce cell death via oxidative stress in ER-negative cancer cells (7), and this effect may be more prominent in BRCA1 null cells, which have profound defects in DNA repair. Thus, tumors that lack both ER and BRCA1 may respond differently to tamoxifen than those that lack only ER.

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.

REFERENCES

1 Johannsson OT, Idvall I, Anderson C, Borg A, Barkardottir RB, Egilsson V, et al. Tumour biological features of BRCA1-induced breast and ovarian cancer. Eur J Cancer 1997;33:362–71.[Medline]

2 Karp SE, Tonin PN, Bégin LR, Martinez JJ, Zhang JC, Pollak MN, et al. Influence of BRCA1 mutations on nuclear grade and estrogen receptor status of breast carcinoma in Ashkenazi Jewish women. Cancer 1997;80:435–41.[Medline]

3 King MC, Wieand S, Hale K, Lee M, Walsh T, Owens K, et al. Tamoxifen and breast cancer incidence among women with inherited mutations in BRCA1 and BRCA2: National Surgical Adjuvant Breast and Bowel Project (NSABP-P1) Breast Cancer Prevention Trial. JAMA 2001;286:2251–6.[Abstract/Free Full Text]

4 Narod SA, Brunet JS, Ghadirian P, Robson M, Heimdal K, Neuhausen SL, et al. Tamoxifen and risk of contralateral breast cancer in BRCA1 and BRCA2 mutation carriers: a case-control study. Hereditary Breast Cancer Clinical Study Group. Lancet 2000;356:1876–81.[Medline]

5 Fan S, Ma YX, Wang C, Yuan RQ, Meng Q, Wang JA, et al. Role of direct interaction in BRCA1 inhibition of estrogen receptor activity. Oncogene 2001;20:77–87.[Medline]

6 Fan S, Ma YX, Wang C, Yuan RQ, Meng Q, Wang JA, et al. p300 modulates the BRCA1 inhibition of estrogen receptor activity. Cancer Res 2002;62:141–51.[Abstract/Free Full Text]

7 Ferlini C, Scambia G, Marone M, Distefano M, Gaggini C, Ferrandina G, et al. Tamoxifen induces oxidative stress and apoptosis in oestrogen receptor-negative human cancer cell lines. Br J Cancer 1999;79:257–63.[Medline]


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