Unwrapping the Implications of BRCA1 and BRCA2 Mutations in Ovarian Cancer

2][3] These trials have combined BRCA1 and BRCA2 mutation carriers because of the relative rarity of BRCA1 and BRCA2 mutations, which only account for approximately 10% and 5% of unselected cases of serous ovarian cancer, respectively. 4However, although both mutations are associated with hereditary breast and ovarian cancers, it has been suggested that these cancer predisposition syndromes represent related but clinically distinct entities. 5The lifetime risk of ovarian cancer is higher in BRCA1 than BRCA2 mutation carriers, estimated at 36-60% and 16-27%, respectively.6,7 BRCA1 mutation carriers tend to develop ovarian cancer on average about eight years earlier than BRCA2 mutation carriers. 1,4Microarrays of BRCA1 and BRCA2associated ovarian cancers also show significant differences in gene expression. 8Moreover, the protection conferred by risk-reducing salpingo-oophorectomy against breast and gynecologic cancers may differ between carriers of BRCA1 and BRCA2 mutations. 9In light of these observations, two recent reports have examined survival separately in BRCA1 and BRCA2-associated ovarian cancers in small cohorts. 10,11Both studies found significantly improved survival in BRCA2-associated ovarian cancers and smaller statistically non-significant improvement in survival in BRCA1-associated ovarian cancers.In this issue of JAMA, Bolton et al 12 report their analysis of patients with BRCA1 and BRCA2 ovarian cancer who were included in a large international dataset.Incident cases of ovarian cancer were pooled from 26 international prospective clinical genetics protocols, the majority of which were affiliated with either the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) or the Ovarian Cancer Association Consortium (OCAC).Baseline clinical characteristics such as year of diagnosis, age, stage, grade, and histology were controlled for, when available, with respect to overall survival.In their analysis of 3879 patients with ovarian cancer (2666 non-carriers, 909 BRCA1 mutation carriers, and 304 BRCA2 mutation carriers), the authors report fully adjusted hazard ratios for overall mortality at five years of 0.73 and 0.49 for BRCA1 and BRCA2 mutation carriers, respectively, compared to non-carriers.The differences in overall survival observed in BRCA1 and BRCA2 mutation carriers was statistically (and clinically) significant compared to both the sporadic cohort and each other.In a secondary analysis, the authors also found that the survival advantage conferred by BRCA1 mutations may be partially mitigated as the mutation site moved from the 5' to 3' end, suggesting that the site of BRCA1 mutation may have individual prognostic significance.