Risk-Reducing Bilateral Salpingo-Oophorectomy for Ovarian Cancer: A Review and Clinical Guide for Hereditary Predisposition Genes

Abstract

Pathogenic germline variants underlie up to 20% of ovarian cancer (OC) and are associated with varying degrees of risk for OC. For mutations in high-penetrance genes such as BRCA1/2, the role of risk-reducing bilateral salpingo-oophorectomy (RRSO) in cancer prevention is well-established and improves mortality. However, in moderate-penetrance genes where the degree of risk for OC is less precisely defined, the role of RRSO is more controversial. Although national guidelines have evolved to incorporate gene-specific recommendations, studies demonstrate significant variations in practice. Given this, our multidisciplinary group has reviewed the available literature on risk estimates for genes associated with OC, incorporated levels of evidence, and set thresholds for consideration of RRSO. We found that the benefit of RRSO is well-established for pathogenic variants in BRCA1/2 as well as BRIP1 and RAD51C/D where the risk of OC is elevated beyond our threshold for RRSO. In PALB2, RRSO is particularly controversial as newer studies consistently demonstrate an increased risk of OC that is dependent on family history, making uniform recommendations challenging. Additionally, new guidelines for Lynch syndrome provide gene-specific risks, questioning the role of RRSO, and even hysterectomy, for MSH6 and PMS2 mutation carriers. Given these uncertainties, shared decision making should be used around RRSO with discussion of individual risk factors, family history, and adverse effects of surgery and premature menopause. Herein, we provide a clinical guide and counseling points.

FIG 1.

Clinical guide for RRSO for OC by cancer susceptibility gene (decision aid for RRSO for OC in moderate-penetrance genes). This figure provides a clinical guide to assess benefit of RRSO for OC on the basis of the cancer susceptibility gene implicated. The y-axis represents estimated cumulative lifetime risk of OC, and the x-axis represents increasing risk for OC and evidence to support RRSO. Population risk for OC (1%-2%) and RRSO threshold (3%-4%) are plotted. Mutations in genes to the right of the dotted line represent clinical situations where there is likely benefit to RRSO for mutation status alone. Genes that overlap the RRSO threshold require careful consideration of risks and benefits of RRSO, considering family history, individual risk factors, risks of RRSO and premature menopause, and patient preference. Color coding indicates the age to consider RRSO on the basis of age at which increased risk starts to exceed population-level risk and areas of controversy and insufficient data. NOTE. It is reasonable to consider RRSO earlier than the recommended age in those with a significant family history of OC, typically 5-10 years before the earliest diagnosed OC. OC, ovarian cancer; RRSO, risk-reducing bilateral salpingo-oophorectomy.