The Lynx Group

Large Study Supports Early Oophorectomy for BRCA Mutation Carriers

March 2014, Vol 5, No 2

Women who carry the BRCA1 or BRCA2 mutation had an 80% reduction in risk for ovarian, fallopian tube, or breast cancer if they underwent preventive oophorectomy, according to a large prospective study, and a 77% reduction in all-cause mortality (Finch AP, et al. J Clin Oncol. 2014 February 24 [Epub ahead of print]).

The majority of the risk reduction was among carriers of the more common BRCA1 mutation. Furthermore, the study results suggest that prophylactic oophorectomy should be done by age 35 years in all BRCA1 carriers, because waiting for a later age increases the risk for cancer.

“To me, waiting to have oophorectomy until age 35 is too much of a chance to take. These data are so striking that we believe prophylactic oophorectomy by age 35 should become a universal standard for women with BRCA1 mutations,” said study coinvestigator Steven A. Narod, MD, Professor of Epidemiology, University of Toronto, Ontario, Canada, in a statement commenting on the study. “Women with BRCA2 mutations, on the other hand, can safely delay oophorectomy until their 40s, since their ovarian cancer risk is not as strong,” Dr Narod added.

Current recommendations state that women with a BRCA mutation should consider prophylactic oophorectomy between the ages of 35 and 40 years.

The study results, as Dr Narod noted, were “striking.” Among women who were cancer free at baseline, preventive oophorectomy reduced the risk for death from any cause by 77%. Dr Narod noted that noncancer deaths would be rare in the study cohort, with an average age of 46 years at study enrollment. Over time, it is possible that the reduction in all-cause mortality associated with oophorectomy would be attenuated, because other causes of age-related death occur.

Study Details
This prospective study was based on a cohort of 5783 women who were carriers of the BRCA1 or BRCA2 mutation; of these, 2270 did not undergo oophorectomy and had intact ovaries, 2123 had undergone oophorectomy at baseline, and 1390 had the surgery after study enrollment. All women were identified from an international registry and completed a baseline questionnaire plus at least 1 follow-up questionnaire.

The mean age at enrollment was 46 years (range, 40.2 years for the no oophorectomy group and 50.5 years for those who had oophorectomy at baseline). Overall, 77.4% of the women were BRCA1 carriers, and 22.6% were BRCA2 carriers. Women who carried both mutations were excluded from the study.

At a mean follow-up of 5.6 years, 132 women developed ovarian cancer, 22 developed fallopian tube cancer, and 32 developed peritoneal (ie, breast) cancer; a total of 68 of these women died.

Among the women with intact ovaries, 98 cancers were diagnosed in BRCA1 mutation carriers and 10 cancers in BRCA2 mutation carriers. These cancers occurred approximately a decade earlier in BRCA1 mutation carriers, with the highest incidence between the ages of 50 and 59 years; for BRCA2 mutation carriers, the highest incidence was observed between the ages of 60 and 69 years.

At oophorectomy, 46 occult cancers were identified through pathology examinations: 27 ovarian cancers, 18 fallopian tube cancers, and 1 breast cancer. Of 44 cancers found in BRCA1 mutation carriers, 3 were in women aged ?40 years, and an additional 19 cancers were diagnosed between the ages of 40 and 49 years.

The 2 BRCA2-related cancers identified at oophorectomy were in women aged >60 years.

The remaining 32 cases were primary peritoneal cancers (28 in BRCA1 carriers and 4 in BRCA2 carriers); in these women, the mean age at diagnosis was 51.6 years (range, 36-69 years).

The 5-year survival rate was higher in women with occult ovarian cancer compared with those who had clinically detected ovarian cancer (91.6% vs 54.4%, respectively; P <.01). The 5-year survival rate for women with peritoneal cancer was 38.4%.

An adjusted analysis was performed to estimate the extent to which prophylactic oophorectomy reduced the risk for ovarian, fallopian tube, or peritoneal cancers in BRCA1 and BRCA2 carriers combined. The adjusted hazard ratio associated with oophorectomy was 0.20 (95% confidence interval, 0.13-0.30; P <.001).

Dissenting Opinion
“These data do not warrant changing the current recommendations regarding surgery for women who are BRCA1 and BRCA2 mutation carriers,” stated Noah D. Kauff, MD, Director, Ovarian Cancer Screening and Prevention Program, Memorial Sloan-Kettering Cancer Center, New York. “The study confirms prior data we have regarding the risk of ovarian cancer in women who are mutation carriers,” Dr Kauff said.

He pointed out that the actual rate of ovarian cancer in the study before age 40 years in women with BRCA1 mutations was 2.3%, as opposed to the 4% rate the investigators quoted in the Discussion section of the article.

“In women with intact ovaries, 8 of 979 women [0.8%] developed ovarian cancer by age 40; in an additional 202 women who had prophylactic oophorectomy prior to age 40, 3 had occult ovarian cancer [1.5%]. The 4% figure calculated by the authors was based on an assumption that the rate of ovarian cancer is constant from age 30-40, but that is not correct. The risk goes up after age 35,” Dr Kauff explained.

In his opinion, the evidence to date, including this study, supports current recommendations. The American Congress of Obstetricians and Gynecologists recommends that BRCA carriers have oophorectomy by age 40 years, or when childbearing is completed; the National Comprehensive Cancer Network guidelines recommend oophorectomy between the ages of 35 and 40 years, and when childbearing is completed.

“Oophorectomy 5 years earlier can be traumatic, especially in the US, where women are marrying later and often deferring childbearing until the late 30s. It is not clear to me that this study provides sufficient evidence to change current recommendations,” he said.

“Discussions with women who are BRCA1 or BRCA2 carriers should balance the risks versus benefits of preventive oophorectomy on cancer risks with its substantial costs on fertility, timing of menopause, and other symptoms that can markedly impact quality of life,” Dr Kauff said.

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