Protective Effect of Salpingo-oophorectomy in At-Risk Women: Best Evidence Yet
Protective Effect of Salpingo-oophorectomy in At-Risk Women: Best Evidence Yet
Abstract & Commentary
By Robert L. Coleman, MD, Associate Professor, University of Texas; M.D., Anderson Cancer Center, Houston, is Associate Editor for OB/GYN Clinical Alert.
Dr. Coleman is on the speaker's bureau for GlaxoSmithKline, Bristol-Myers Squibb, and Ortho Biotech.
Synopsis: Oophorectomy is associated with reduced risk of ovarian and fallopian tube cancer in high-risk women, although there is a substantial residual risk for peritoneal cancer in BRCA1 and BRCA2 mutation carriers following prophylactic salpingo-oophorectomy.
Source: Finch A, et al. Salpingo-oophorectomy and the risk of ovarian, fallopian tube, and peritoneal cancers in women with a BRCA1 or BRCA2 Mutation. JAMA. 2006;296:185-192.
It is well recognized that women in whom a BRCA1 or BRCA2 mutation is identified have an accelerated risk of breast and/or ovarian cancer. Known cases generally undergo heightened surveillance and consider prophylactic salpingo-oophorectomy to reduce their risk of either or both cancers. Previous estimates of the efficacy of surgery are based on data obtained from retrospective, case-control cohort or small prospective studies. Finch and colleagues in the Hereditary Ovarian Cancer Clinical Study Group evaluated this efficacy in a large prospective, international study over a 10-year enrollment period. All women in this study were confirmed BRCA1 or BRCA2 carriers and underwent serial questionnaires to identify incident cancer and, if not performed prior to study entry, prophylactic salpingo-oophorectomy. From nearly 2900 women enrolled, 1828 women provided follow-up data in which risk could be estimated by BRCA mutation and following prophylactic salpingo-oophorectomy, if performed. After a mean follow-up of 3.5 years, 50 incident cancers were reported in the cohort. Approximately 57% of women underwent prophylactic salpingo-oophorectomy; about half prior to study entry. Cancer (ovarian, fallopian tube, and peritoneal) was diagnosed in 32 women with intact ovaries compared to 7 following prophylactic salpingo-oophorectomy. Eleven women (2.2%) had occult cancer at the time of surgery. The estimated cumulative incidence of peritoneal cancer following prophylactic salpingo-oophorectomy was 4.3% at 20 years—approximately 9 times the background risk (non-BRCA women). The overall adjusted reduction in cancer risk following prophylactic salpingo-oophorectomy is 80%. The authors conclude that while cancer risk is not eliminated following prophylactic salpingo-oophorectomy, it is substantially reduced in these high-risk women.
Commentary
From a clinician's perspective, the data presented in this most recent report are essentially "icing on the cake." In essence, prophylactic salpingo-oophorectomy appears to confer a significant protective effect against the development of peritoneal cancer in "at-risk" women. While the message even antedates identification of the genes responsible for this condition, the current report provides the clearest insight into the qualifiers surrounding this risk as well as providing important information in cumulative risk (incidence) to assist in making sound recommendations in surveillance of these women. There are several key features of the current report that distinguish it from others in the literature. First, the trial is sufficiently large enough to have a critical mass of incident cancers. This helps to more correctly quantify risk stratified by surgery. The 80% protective effect is within the estimated range of other reports, but the number has varied widely. Second, the trial is prospective in nature. While there is (obvious) lack of randomization, this design helps to avoid under- and over-estimation of cancer protection and allows for the best estimates of age-specific cumulative incidence. The authors found that, similar to the general population, annual incidence of cancer increases with age. For mutation carriers, this risk peaks between 60 and 70—about 10 years earlier than the general population. The mean age of cancer diagnosis was 42 years with the youngest incident cancer at age 38. Third, all women in this study were confirmed mutation carriers by genetic analysis. Previous reports have identified case subjects by inconsistent testing or by family history alone.1-4 Knowledge of mutational status standardizes the risk across statistical cohorts and allows for risk/intervention effects by mutation type. In addition, more accurate estimates of penetrance can be generated. The authors demonstrate that the penetrance of ovarian cancer is 62% to age 75 for BRCA1 and 18% to age 75 for BRCA2 carriers. These numbers are slightly higher than previously estimated but are distinguished from other reports where inconsistent data on family members undergoing risk-reducing surgery may have been included artificially lowering penetrance estimates. Of note, nearly 70% of women in the current report had a personal history of breast cancer. If there are common risk features of breast and ovarian cancer, this inclusion may over-estimate true penetrance in these women.
All in all, the data reported here should provide confidence in the recommendation to remove unaffected fallopian tubes and ovaries at age 35 or completion of childbearing in women harboring a mutation in the BRCA genes. While a clear statement on the merits of hysterectomy in this setting cannot be made from the current report, removal of the fallopian tubes are an important element given the observation of incident cancer. In addition, careful sectioning of the normal removed organs is critical as occult disease is not uncommon and undiagnosed cancer is often lethal.
References
- Paley PJ, et al. Occult cancer of the fallopian tube in BRCA-1 germline mutation carriers at prophylactic oophorectomy: a case for recommending hysterectomy at surgical prophylaxis. Gynecol Oncol. 2001;80:176-180.
- Schmeler KM, et al. Prophylactic bilateral salpingo-oophorectomy compared with surveillance in women with BRCA mutations. Obstet Gynecol. 2006;108:515-520.
- Kramer JL, et al. Prophylactic oophorectomy reduces breast cancer penetrance during prospective, long-term follow-up of BRCA1 mutation carriers. J Clin Oncol. 2005;23:8629-8635.
- Kauff ND, et al: Risk-reducing salpingo-oophorectomy in women with a BRCA1 or BRCA2 mutation. N Engl J Med. 2002;346:1609-1615.
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