Tamoxifen Inhibits Second Breast Cancers in Women with BRCA Mutations
Tamoxifen Inhibits Second Breast Cancers in Women with BRCA Mutations
ABSTRACT & COMMENTARY
Synopsis: In a matched, case-control study of women with BRCA1 or BRCA2 mutations and primary, invasive breast cancer, the occurrence of a second breast cancer was significantly reduced if tamoxifen had been used in the treatment of the primary cancer.
Source: Narod SA, et al. Lancet 2000;356:1876-1881.
Women with brca1 or brca2 mutations have a higher incidence of primary breast cancer and of contralateral breast cancer than in those with earlier breast cancer.1 Tamoxifen protects against contralateral breast cancer in the general population,2 but it remains to be established whether tamoxifen will reduce the incidence of contralateral breast cancer in patients with BRCA-associated primary breast cancer. In the study of women with breast cancer and mutations of BRCA1 or BRCA2, tamoxifen use was examined for those who went on to develop a second breast cancer (n = 209) and for those who remained free of a second breast cancer (n = 384). This was a matched, case-control study and tamoxifen use was determined either by interview or by self-administered questionnaire.
The multivariate odds ratio for contralateral breast cancer associated with tamoxifen use was 0.50 (95% confidence interval [CI] 0.28-0.89). Tamoxifen protected against contralateral breast cancer for carriers of BRCA1 mutations (odds ratio 0.38, 95% CI 0.19-0.74) and for those with BRCA2 mutations (0.63, 0.20-1.50). Thus, in women who used tamoxifen for 2-4 years, the risk of contralateral breast cancer was reduced by 75%. As expected, the risk of contralateral breast cancer was also reduced by oophorectomy (0.42, 0.22-0.83) and by chemotherapy (0.40, 0.26-0.60).
COMMENT by William B. Ershler, MD
This was a multi-institutional investigation from the Hereditary Breast Cancer Clinical Study Group and there were 1243 living patients with invasive breast cancer in carriers of pathogenic BRCA1 or BRCA2 mutations. Of these, 24% had bilateral breast cancer. A quarter of those with bilateral breast disease were removed from further analysis, primarily because the diagnoses were either synchronous or very close in time, making it impossible to judge the effect of tamoxifen on the second tumor. The remaining 209 cases were matched with others of similar age (within 5 years) with similar mutation (BRCA1 or BRCA2) and similar length of follow-up evaluation. The frequency and mean duration of tamoxifen use were compared between bilateral disease cases and controls. Only 22 (11%) of those with bilateral disease had used tamoxifen compared to 21% of those in the control (unilateral) group.
The findings are important but not unexpected. It has been reported that oophorectomy in patients with BRCA1 mutations and breast cancer reduces the risk of second breast cancer,3 and that pregnancy increases the risk of cancer for these individuals.4 However, it is interesting to note that in this analysis, tamoxifen seemed to have a protective effect, even in women who had previous oophorectomy, suggesting an additive effect that may even be independent of receptor-mediated estrogen blockade.
The question remains as to what is the optimal treatment for women with hereditary breast cancer associated with BRCA1 or BRCA2 mutations. It appears from this study that tamoxifen alone will prevent (or, at least delay) the onset of a second breast cancer. Whether the effect is truly additive to that of chemotherapy in this setting, and for how long tamoxifen should be continued are questions that remain unanswered. The latter is indeed one that needs prompt attention with the apparent increased risk of endometrial cancers in long-term tamoxifen users.4
References
1. Narod SA, et al. Am J Hum Genet 1995;56:254-264.
2. Fisher B, et al. J Natl Cancer Inst 1998;90:1371-1388.
3. Rebbeck TR, et al. J Natl Cancer Inst 1999;91: 1475-1479.
4. Bergman L, et al. Lancet 2000;356:881-887.
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