In analyses of pooled information from cohorts of women with BRCA1 and BRCA2 mutations who have had a prior breast cancer diagnosis, Phillips and colleagues examined the association between tamoxifen use compared to nonuse on contralateral breast cancer risk.1 Tamoxifen use was associated with lower contralateral breast cancer risk for both BRCA1 and BRCA2 mutation carriers, with a suggested influence on both estrogen receptor (ER)-positive and -negative disease. Although the numbers of contralateral breast cancer events, especially among tamoxifen users, are limited, the report nonetheless provides the strongest evidence yet that tamoxifen may reduce breast cancer risk in both BRCA1 and BRCA2 mutation carriers.
Study Limitations
The analyses truncated at cohort recruitment are important, as they address the issue of guarantee-time bias.2 They yield suggestive, but not statistically significant, associations for tamoxifen use and breast cancer risk. The authors recognize the limitations of their nonrandomized design, as adjustments were needed for several factors generally associated with contralateral breast cancer risk--tamoxifen users were older and more commonly had an initial ER-positive cancer, received chemotherapy, and had bilateral salpingo-oophorectomy.
The potential for confounding is perhaps greatest in the population in which the initial breast cancer was ER-positive. In that setting, the decision against adjuvant tamoxifen use could be associated with potential confounding factors. As women with BRCA mutations who have climacteric symptoms may be current menopausal hormone therapy users,3 they should be aware of the mixed chemoprevention tamoxifen trial findings4 that has led the recent ASCO guideline update to find insufficient evidence to support a primary breast cancer risk-reduction role of tamoxifen in menopausal hormone therapy users.5
Clinical Considerations
As the authors outline, it is unlikely that a full-scale randomized clinical trial of tamoxifen in a BRCA mutation carrier population can successfully go forward. In addition to further follow-up of women in current cohorts, information from emerging, large electronic datasets may further inform this question in the future.
While the current study provides some evidence that tamoxifen is associated with reduced contralateral breast cancer risk in women with BRCA1 and BRCA2 mutations, given the nature of the available study population, questions remain. Therefore, discussion of these results in the clinic requires careful attention to potential adverse effects of tamoxifen use in the context of other available options to reduce breast cancer risk. ■
Dr. Chlebowski is Chief, Division of Medical Oncology and Hematology, Harbor-UCLA Medical Center, Los Angeles.
Disclosure: Dr. Chlebowski has served in a consultant or advisory role for AstraZeneca, Novartis, and Pfizer. He has received honoraria from Novartis and AstraZeneca and research funding from Amgen.
References
1. Phillips KA, Milne RL, Rookus MA, et al: Tamoxifen and risk of contralateral breast cancer for BRCA1 and BRCA2 mutation carriers. J Clin Oncol. August 5, 2013 (early release online).
2. Giobbie-Hurder A, Gelber RD, Regan MM: Challenges of guarantee-time bias. J Clin Oncol 31:2963-2969, 2013.
3. Finch A, Evans G, Narod SA: BRCA carriers, prophylactic salpingo-oophorectomy and menopause: Clinical management considerations and recommendations. Womens Health (Lond Engl) 8:543-555, 2012.
4. Visvanathan K, Chlebowski RT, Hurley P, et al: American Society of Clinical Oncology Clinical Practice Guideline update on the use of pharmacologic interventions including tamoxifen, raloxifene, and aromatase inhibition for breast cancer risk reduction. J Clin Oncol 27:3235-3258, 2009.
5. Visvanathan K, Hurley P, Bantug E, et al: Use of pharmacologic interventions for breast cancer risk reduction: American Society of Clinical Oncology Clinical Practice Guideline. J Clin Oncol 31:2942-2962, 2013.
