Meta-analysis of Risk Reduction Estimates Associated With Risk-Reducing Salpingo-Oophorectomy in BRCA1 or BRCA2 Mutation Carriers

Timothy R. Rebbeck; Noah D. Kauff; Susan M. Domchek

Disclosures

J Natl Cancer Inst. 2009;101(2):80-87. 

In This Article

Abstract and Introduction

Abstract

Background: Risk-reducing salpingo-oophorectomy (RRSO) is widely used by carriers of BRCA1 or BRCA2 (BRCA1/2) mutations to reduce their risks of breast and ovarian cancer. To guide women and their clinicians in optimizing cancer prevention strategies, we summarized the magnitude of the risk reductions in women with BRCA1/2 mutations who have undergone RRSO compared with those who have not.
Methods: All reports of RRSO and breast and/or ovarian or fallopian tube cancer in BRCA1/2 mutation carriers published between 1999 and 2007 were obtained from a PubMed search. Hazard ratio (HR) estimates were identified directly from the original articles. Pooled results were computed from nonoverlapping studies by fixed-effects meta-analysis.
Results: Ten studies investigated breast or gynecologic cancer outcomes in BRCA1/2 mutation carriers who had undergone RRSO. Breast cancer outcomes were investigated in three nonoverlapping studies of BRCA1/2 mutation carriers, four of BRCA1 mutation carriers, and three of BRCA2 mutation carriers. Gynecologic cancer outcomes were investigated in three nonoverlapping studies of BRCA1/2 mutation carriers and one of BRCA1 mutation carriers. RRSO was associated with a statistically significant reduction in risk of breast cancer in BRCA1/2 mutation carriers (HR = 0.49; 95% confidence interval [CI] = 0.37 to 0.65). Similar risk reductions were observed in BRCA1 mutation carriers (HR = 0.47; 95% CI = 0.35 to 0.64) and in BRCA2 mutation carriers (HR = 0.47; 95% CI = 0.26 to 0.84). RRSO was also associated with a statistically significant reduction in the risk of BRCA1/2-associated ovarian or fallopian tube cancer (HR = 0.21; 95% CI = 0.12 to 0.39). Data were insufficient to obtain separate estimates for ovarian or fallopian tube cancer risk reduction with RRSO in BRCA1 or BRCA2 mutation carriers.
Conclusion: The summary estimates presented here indicate that RRSO is strongly associated with reductions in the risk of breast, ovarian, and fallopian tube cancers and should provide guidance to women in planning cancer risk reduction strategies.

Introduction

Women who have inherited mutations in the BRCA1 or BRCA2 (BRCA1/2) genes have substantially elevated risks of breast and ovarian cancer, with a lifetime risk of breast cancer of 56%-84%.[1,2,3,4] Breast cancer in BRCA1/2 mutation carriers also occurs at an earlier age, particularly among BRCA1 mutation carriers, than for noncarriers. The risk for ovarian cancer is dependent on whether the mutation has occurred in BRCA1 or BRCA2, with estimated risks ranging from 36% to 46% for BRCA1 mutation carriers and from 10% to 27% for BRCA2 mutation carriers.[1,2,5,6,7] Carriers of BRCA1/2 mutations are counseled to help them interpret the implications of these elevated risks, choose strategies to reduce these risks, and maximize early detection of cancers. The risk of breast cancer can be reduced either with risk-reducing oophorectomy and/or mastectomy or nonsurgically (ie, with screening and prevention techniques). However, due to the lack of effective screening for ovarian cancer, risk-reducing salpingo-oophorectomy (RRSO) is usually strongly recommended to BRCA1/2 mutation carriers once childbearing is complete.

RRSO has also been demonstrated to decrease the risk of both breast and ovarian cancer in BRCA1/2 mutation carriers.[8,9,10,11,12,13,14,15,16,17] However, studies examining the extent of risk reduction have used different designs; some are retrospective case-control studies, whereas others used a prospective cohort design [reviewed by Kauff and Barakat.[18] Even among prospective studies, the inclusion criteria and the definitions of follow-up time differ. In some studies, only unaffected mutation-positive women are included and followed up. In others, particularly when examining ovarian cancer risk, women with breast cancer are included. Such differences in study design can introduce biases (such as survival bias) and can have an impact on risk reduction estimates. For example, the reported efficacy of RRSO in reducing the risk of ovarian/fallopian tube cancers has varied from 71% to 96%.[8,10,11,13,16,17] Although these estimates imply a substantial reduction in risk, this variability may affect the decisions of premenopausal women who are making a decision about whether to undergo a treatment that will cause abrupt and premature menopause. Patients and their physicians need as much information as possible regarding the efficacy of RRSO in reducing cancer risk to balance this benefit with the health risks caused by premature entry into menopause. Hence, we identified the published studies pertaining to the benefits of RRSO in terms of reducing cancer risk, assembled information on their design, and calculated summary risk reduction estimates associated with RRSO in BRCA1/2 mutation carriers with the goal of aiding women and their clinicians in making cancer risk reduction decisions. Because randomized clinical trials of RRSO are likely not feasible and may not be ethically appropriate,[19] we report the results of all observational case-control and cohort studies in the literature.

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