Dramatic Reduction in Cancer Risk After Salpingo-Oophorectomy in Women with BRCA Mutations

Nick Mulcahy

January 14, 2009

January 14, 2008 — Prophylactic salpingo-oophorectomy, or the surgical removal of the ovaries and fallopian tubes, reduces the risk for breast cancer by 50% and the risk for ovarian and fallopian tube cancer by 80% in women who carry mutations in the BRCA1 or BRCA2 gene, according to a new meta-analysis.

"It's really very clear that this surgery is protective. That's not controversial anymore. Our study quantifies the cancer risk reduction and is the most authoritative review to date," said Timothy R. Rebbeck, PhD, professor of epidemiology at the University of Pennsylvania School of Medicine, in Philadelphia, in an interview with Medscape Oncology.

Our study quantifies the cancer risk reduction and is the most authoritative review to date.

Dr. Rebbeck is the lead author of the study, which was published online January 13 in the Journal of the National Cancer Institute.

An editorial that accompanies the meta-analysis calls the study "meticulously executed" and calls the more accurate risk estimates "another important improvement in the management of high-risk women."

The new risk estimates should help women decide whether to undergo this surgery, suggest the editorialists, led by Mark H. Greene, MD, chief of the Clinical Genetics Branch of the National Cancer Institute. "We urge providers of cancer genetics counseling services to adopt the summary risk estimates developed by Rebbeck et al. as those most currently reliable when counseling BRCA mutation carriers."

However, Dr. Rebbeck reminded clinicians that the surgery is "risk-reducing and not 100% risk-eliminating," and that other prevention options might also be needed to address residual cancer risk.

Dr. Rebbeck also acknowledged that much remains to be learned about the surgery. "We only considered cancer end points here. We are also following other end points for future research," he said, citing a recent study that indicates that the removal of both ovaries before the age of 45 increases a woman's risk for cardiovascular death 20 to 30 years later (Menopause 2009;16:15-23), as reported by Medscape.

An Attempt to Differentiate Risk for BRCA1 vs BRCA2

Women with inherited mutations in the BRCA1 or BRCA2 genes have "substantially elevated" risks for breast and ovarian cancers, with a lifetime risk for breast cancer of 56% to 84%, according to the paper's authors. Carriers, particularly BRCA1 mutation carriers, develop breast cancer at an earlier age than noncarriers. The risk for ovarian cancer depends on BRCA status, with estimated risks ranging from 36% to 46% for BRCA1 mutation carriers and from 10% to 27% for BRCA2 mutation carriers.

One of the most commendable features of the current meta-analysis is that Dr. Rebbeck and colleagues "attempted to disentangle potential differences between BRCA1 and BRCA2 mutation carriers," write the editorialists. The 2 have important biologic differences that make a combined analysis "suboptimal."

Dr. Rebbeck and colleagues found a total of 10 studies that investigated breast or gynecologic cancer outcomes in BRCA1/2 mutation carriers who had undergone prophylactic salpingo-oophorectomy.

Breast cancer outcomes were investigated in 3 nonoverlapping studies of BRCA1/2 mutation carriers, 4 of BRCA1 mutation carriers, and 3 of BRCA2 mutation carriers. Gynecologic cancer outcomes were investigated in 3 nonoverlapping studies of BRCA1/2 mutation carriers and 1 study of BRCA1 mutation carriers.

Prophylactic salpingo-oophorectomy was associated with a statistically significant reduction in risk for breast cancer in BRCA1/2 mutation carriers (hazard ratio [HR], 0.49; 95% confidence interval [CI], 0.37 - 0.65). Similar risk reductions were observed in BRCA1 mutation carriers (HR, 0.47; 95% CI, 0.35 - 0.64) and in BRCA2 mutation carriers (HR, 0.47; 95% CI, 0.26 - 0.84).

Prophylactic salpingo-oophorectomy was also associated with a statistically significant reduction in the risk for BRCA1/2-associated ovarian or fallopian tube cancer (HR, 0.21; 95% CI, 0.12 - 0.39). Data were insufficient to obtain separate estimates for ovarian or fallopian tube cancer risk reduction with prophylactic salpingo-oophorectomy in BRCA1 or BRCA2 mutation carriers.

Improvements Needed, Questions Remain

Despite the fact that prophylactic salpingo-oophorectomy removes both the ovaries and fallopian tubes, the risk reduction for ovarian cancer in these mutation carriers is only 80%.

Dr. Rebbeck explains that residual ovarian (epithelial) cells remain in the peritoneum after surgery and apparently are sufficient to lead to ovarian cancer. "It's important for women to be aware that risk reduction is not complete, and for researchers and clinicians to find ways to improve the efficacy of this intervention by optimal timing and type of surgery," he told Medscape Oncology.

The effect of the timing of surgery and the age at which a women undergoes the procedure are unresolved but informed by a number of studies, write the meta-analysis authors.

In 1 study (J Clin Oncol. 2005;23:7491-7496), breast cancer risk reduction with prophylactic salpingo-oophorectomy was greater in BRCA1/2 mutation carriers who underwent surgery before age 50 than in women who underwent surgery after age 50. Among BRCA1 mutation carriers older than age 50, no risk reduction was evident with prophylactic salpingo-oophorectomy. No statistically significant association of the procedure at any age with risk reduction was observed in BRCA2 mutation carriers.

The importance of understanding the optimal age has been underscored by a number of studies, said Dr. Rebbeck, including the above-mentioned report published in Menopause that indicates that the removal of both ovaries before the age of 45 increases a woman's risk for cardiovascular death 20 to 30 years later.

Hormone replacement therapy (HRT) might help in younger women receiving the procedure. "It is possible that BRCA1/2 mutation carriers undergoing abrupt surgical menopause to reduce ovarian cancer risk who receive HRT may in fact derive important cardiovascular, bone-health, and quality-of-life benefits," write Dr. Rebbeck and colleagues.

However, many questions arise with the use of HRT, they note. " For example, it is not yet clear whether the long-term effects of long-term HRT in unaffected mutation BRCA1/2 carriers will ultimately be more beneficial in preventing noncancer mortality in these women or more harmful by increasing their risk of breast cancer (or potentially increasing cardiovascular events), compared with the general population," they write.

One of the coauthors of the meta-analysis, Noah D. Kauff, MD, from the Memorial Sloan-Kettering Cancer Center, reports receiving fees for legal defense work from Wyeth.

J Natl Cancer Inst. 2009;101:70-71, 80-87.

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