Mutations May Improve Ovarian Cancer Survival

Among women with epithelial ovarian cancer (EOC), patients having a germline mutation in BRCA1 or BRCA2 was associated with improved 5-year overall survival, with BRCA2 carriers having the best prognosis, according to study results published in the Journal of the American Medical Association>/em> [2012;307(4):382-390]. A germline mutation is a gene change in a reproductive cell that can be passed to offspring. BRCA1 and BRCA2 are the strongest known genetic risk factors for both breast and EOC and are found in 6% to 15% of women with EOC. The relative prognosis of BRCA1/2 carriers and noncarriers is unclear. The study’s aim was to characterize the survival of BRCA carriers with EOC, compared with noncarriers and to determine whether BRCA1 and BRCA2 carriers show similar survival patterns. The findings are based on a pooled analysis of 26 observational studies on the survival of women with ovarian cancer, which included data from 1213 EOC cases with BRCA1 (n=909) or BRCA2 (n=304) and from 2666 noncarriers. All patients were followed up at variable times between 1987 and 2010. The median number of months from ascertainment to diagnosis for patients was 1 month; and the median year of diagnosis was 1998. Women were under active follow-up for a median of 38 months. During the 5 years following EOC diagnosis, 1766 deaths occurred. Data on tumor pathology, vital statistics, and treatment were obtained through a combination of medical records, local cancer registries, and death certificates. The primary end point was 5-year overall survival. The 5-year overall survival was 36% (95% confidence interval [CI], 34%-38%) for noncarriers, 44% (95% CI, 40%-48%) for BRCA1 carriers, and 52% (95% CI, 46%-58%) for BRCA2 carriers. After adjusting for study and year of diagnosis, BRCA1 and BRCA2 mutation carriers showed a more favorable survival than noncarriers (for BRCA1: hazard ratio [HR], 0.78; 95% CI, 0.68-0.89; P<.001; and for BRCA2: HR, 0.61; 95% CI, 0.50-0.76; P<.001). These survival differences remained after additional adjustment for stage, grade, histology, and age at diagnosis (for BRCA1: HR, 0.73; 95% CI, 0.64-0.84; P<.001; and for BRCA2: HR, 0.49; 95% CI, 0.39-0.61; P<.001). The BRCA1 HR estimates were significantly different from the BRCA2 HR estimates in unadjusted (P for heterogeneity=.05) and adjusted (P for heterogeneity=.003) models. The most notable advantage as well as disadvantage of the study was the fact that it was based on a heterogeneous population. The data was culled from studies containing different ethnic groups, using different mutation screening methodologies and case ascertainment. By including a wide variety of studies, however, the researchers were able to generate a large enough sample size to adequately address the issue of heterogeneity of the survival effect between BRCA1 and BRCA2. Yet, differences in study design and population may have limited the specificity of the study findings. Furthermore, varying levels of misclassification of BRCA status and other variables may have led to some bias of the investigators’ estimates toward the null. The researchers said that their study results have potentially important implications for the clinical management of patients with EOC. The findings can be utilized by clinicians for patient counseling regarding expected survival. “BRCA1 and BRCA2 carriers with EOC respond better than noncarriers to platinum-based chemotherapies and have improved survival despite the fact that the disease is generally diagnosed at a later stage and higher grade. If patients could be stratified based on their BRCA status, their treatment could be tailored to reflect this,” said the investigators. The data also provide further support that there may be different mechanisms involved in the etiology of different subtypes of EOCs, which result in different therapeutic targets based on germline and somatic genetic variation. Furthermore, given the prognostic information provided by BRCA1 and BRCA2 and the potential for personalized cancer treatments, the researchers concluded that routine testing of women presenting with high-grade cancer might be warranted.