Preventing BRCA-related cancers: The case for oophorectomy
The team that conducted the recent prospective trial of risk-reducing surgery versus surveillance reviews the evidence, plus surgical technique, psychosocial factors, use of estrogen after surgery, and insurance issues.
In the sole prospective trial, salpingo-oophorectomy was associated with a 75% reduction in breast and gynecologic cancer.
Post-oophorectomy cancers identified. Possible limitations to the strategy became apparent in the early 1980s, when Tobacman and colleagues11 reported adenocarcinoma histologically indistinguishable from ovarian cancer after oophorectomy in a series of women with a strong family history.
In 1993, Piver et al12 reported a series of 6 cases of primary peritoneal cancer after prophylactic oophorectomy in 324 women from hereditary ovarian cancer families.
In 1997, the Cancer Genetics Studies Consortium reviewed all available data and concluded: “There is insufficient evidence to recommend for or against prophylactic oophorectomy as a measure for reducing ovarian cancer risk. Women with BRCA1 mutations should be counseled that this is an option available to them. Those considering prophylactic oophorectomy should be counseled that cancer has been documented to occur after the procedure.”13
Although the Cancer Genetics Studies Consortium did not specifically comment on prophylactic oophorectomy in carriers of BRCA2 mutations, most authorities interpreted these recommendations to apply to these women as well.
Predicting life expectancy. After these findings, several groups undertook decision analyses to evaluate the effect of prophylactic oophorectomy on life expectancy in women with BRCA mutations. Schrag et al14 reported that prophylactic oophorectomy in a 30-year-old with a BRCA mutation increased life expectancy by 0.3 to 1.7 years. This compares to 0.9 years for adjuvant chemotherapy in node-negative breast cancer.
A subsequent report by Grann and colleagues15 also suggested that prophylactic oophorectomy was associated with an increased life expectancy of 0.4 to 2.6 years. However, surgery was not cost-effective for quality-adjusted life-years saved.
Investigators cite need for prospective studies. In 1999, Rebbeck and colleagues16 conducted a retrospective case-control study of 43 women with BRCA1 mutations who underwent oophorectomy and 79 age-matched women with BRCA1 mutations who had ovaries in situ. In this series, oophorectomy was associated with a 47% decreased risk of subsequent breast cancer (hazard ratio 0.53). However, several investigators cited the need for prospective studies before incorporating oophorectomy into routine clinical practice for the prevention of cancer.17
The first prospective look at risk-reducing surgery
It was in this setting that our group launched a prospective trial to determine whether salpingo-oophorectomy offers any benefit over surveillance in preventing breast and gynecologic (ovarian, fallopian tube, and peritoneal) cancers in women with BRCA mutations.18
Proportional hazard analysis demonstrated that salpingo-oophorectomy was associated with a 75% reduction in subsequent breast and gynecologic cancer incidence in women with BRCA mutations (hazard ratio 0.25, 95% confidence interval 0.08 to 0.74). When the individual endpoints of breast and gynecologic cancer were observed, risk-reducing salpingo-oophorectomy (RRSO) was associated with an 85% reduction in subsequent ovarian cancer and a 68% reduction in subsequent breast cancer.
Methods. From June 1995 through May 2001, we enrolled 265 women with documented BRCA1 or BRCA2 mutations. Patients were followed by annual questionnaire, telephone contact, and medical-record review. Pathology reports were obtained for all new cancers diagnosed during follow-up.
After excluding women who underwent bilateral salpingo-oophorectomy before genetic testing, who were younger than 35 years at the time of testing, or who did not provide any follow-up information, 173 women with ovaries at risk and a documented BRCA mutation remained. These women participated in formal pre- and post-test genetic counseling and received uniform recommendations for cancer risk reduction, as detailed in the TABLE.
During follow-up, we calculated the incidence of new breast and gynecologic cancers diagnosed in the cohort who elected RRSO and compared it with the incidence of these cancers in women who chose surveillance.
Salpingo-oophorectomy was elected by 101 of the 173 women.
Findings. In 3 of these women, early-stage ovarian or fallopian-tube cancer that had not been detected during preoperative evaluation was found at the time of surgery. In the remaining 98 patients who underwent RRSO, 1 peritoneal cancer and 3 breast cancers were diagnosed during a mean 23 months of follow-up. In the 72 women who chose surveillance, 5 ovarian or peritoneal cancers and 8 breast cancers were diagnosed in a mean 25 months of follow-up.
Kaplan-Meier analysis of time to breast or BRCA-related gynecologic cancer is illustrated in FIGURE 1.
Other studies confirm findings. A second retrospective study by Rebbeck et al19 was released simultaneously with our findings and showed similar benefits. They found a 53% reduction in subsequent breast cancer risk and a 96% reduction in subsequent ovarian cancer risk. In the summer of 2003, a study from Israel by Rutter et al provided further confirmation of the substantially decreased incidence of cancer following risk-reducing surgery.20
