A major step forward for BRCA1/2-related cancer risk management.

BRCA1 and BRCA2—identified in 1994 and 1995, respectively— are the most prevalent high-penetrance breast/ovarian cancer susceptibility genes identified to date. Mutations in these genes are associated with high lifetime risks of breast cancer, ovarian cancer, and to a lesser degree, a few other cancers. Deleterious mutations in these genes are associated with a 56% to 87% lifetime risk of developing breast cancer and up to 50% and 20% lifetime risk of ovarian cancer for BRCA1 and BRCA2, respectively. Breast cancer risk management options include intensive screening, chemoprevention, and risk-reducing surgery. Ovarian cancer risk management options are more limited, with no proven effective early detection method available. Riskreducing salpingo-oophorectomy (RRSO) has been shown to reduce the risk of developing breast cancer by approximately 50%, with higher benefits associated with earlier age at surgery, and that of ovarian/fallopian tube cancer by approximately 80% to 90%; however, there has only been one study showing a reduction in all-cause mortality associated with RRSO among BRCA mutation carriers. RRSO is recommended for BRCA mutation carriers by the age of 35 to 40 years once reproductive planning is complete, recognizing the lack of effective ovarian cancer screening, the significant post-RRSO reductions in both breast and ovarian cancer risk, and evidence suggesting a postoperative reduction in overall mortality. However, RRSO does not eliminate the risk of developing subsequent primary peritoneal carcinomatosis, a malignancy that is clinically similar to ovarian cancer. Furthermore, occult ovarian/fallopian tube cancers are found at the time of surgery in approximately 3% to 4% of mutation carriers in prospective studies. Even though occult cancers found at the time of RRSO tend to be of early stages, no clear survival benefit from this apparent downshift in stage has yet been demonstrated. Moreover, RRSO has the potential for significant short-term morbidity, especially symptoms related to acute estrogen deprivation and sexual dysfunction as well as long-term morbidity in premenopausal women as a result of premature surgical menopause. Given the complex relationship between RRSO-related cancer risk, mortality risk reduction, shortand long-term morbidity, surgical timing, and effects on quality of life, several important clinical questions remain unanswered. In the article that accompanies this editorial, Finch et al report on the impact of oophorectomy on breast and ovarian/fallopian tube/ peritoneal cancer incidence as well as disease-specific and overall mortality, and the 5-year survival of the ovarian/fallopian tube/peritoneal cancer cases among 5,783 women with BRCA1 or BRCA2 mutations who were observed prospectively for an average of 5.6 years (range, 0.001-16.8 years). This is an expansion of their previous publication, with significantly more patients and longer follow-up. In addition to confirming an 80% decrease in ovarian/fallopian tube/peritoneal cancer risk, the current article demonstrates a 69% reduction in all-cause mortality through age 70 years, with similar, statistically significant risk reductions observed in both BRCA1 and BRCA2 mutation carriers and greater risk reduction among women who had oophorectomy at or before age 60 years. The all-cause mortality reduction was also observed among those with a previous history of breast cancer, although the magnitude of this protective effect was somewhat smaller than that among women who had never had breast cancer (hazard ratio, 0.31 v 0.23). This represents the first time that a significant mortality reduction has been documented among BRCA2 mutation carriers, thus significantly strengthening the evidence supporting a role for oophorectomy in this subset of high-risk women. One hundred eight ovarian/fallopian tube/peritoneal cancers were diagnosed in the women with intact ovaries, 46 occult pelvic cancers were identified at the time of surgery, and 32 primary peritoneal cancers were diagnosed after oophorectomy. Determining the proportion of all ovarian cancers that is composed of fallopian tube cancer is one of the pressing scientific questions in hereditary breast/ ovarian cancer syndrome. Most of the information to date derives from analyses of the subsite distribution between ovary, fallopian tube, and peritoneum at the time of risk-reducing surgery. In this study, the subsite distribution, as abstracted from review of pathology reports and/or medical records, was reported for the occult cancers but not for those diagnosed clinically. Thirty-nine percent of the occult cancers in this series were classified as being of fallopian tube origin. This study did not include a central pathology review of the cancer cases; therefore, the site distribution of occult cancer must be regarded with caution. This remains a critical unanswered question. The 5-year survival was statistically significantly better for those with an occult cancer at risk-reducing oophorectomy compared with those who developed clinical ovarian cancer in the presence of intact ovaries or those with peritoneal cancer diagnosed after oophorectomy. The authors also reported an annual ovarian cancer incidence rate of 0.91%, with incidence peaking between the ages of 50 and 59 years for BRCA1 mutation carriers. The corresponding data for BRCA2 mutation carriers were 0.30% and ages 60 to 69 years. These results further substantiate the previous findings that the age at onset for BRCA1-related ovarian cancer is meaningfully younger than that JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 32 NUMBER 15 MAY 2