Publications (2)60.05 Total impact
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Article: Association between BRCA1 and BRCA2 mutations and survival in women with invasive epithelial ovarian cancer.
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ABSTRACT: Approximately 10% of women with invasive epithelial ovarian cancer (EOC) carry deleterious germline mutations in BRCA1 or BRCA2. A recent article suggested that BRCA2-related EOC was associated with an improved prognosis, but the effect of BRCA1 remains unclear. To characterize the survival of BRCA carriers with EOC compared with noncarriers and to determine whether BRCA1 and BRCA2 carriers show similar survival patterns. A pooled analysis of 26 observational studies on the survival of women with ovarian cancer, which included data from 1213 EOC cases with pathogenic germline mutations in BRCA1 (n = 909) or BRCA2 (n = 304) and from 2666 noncarriers recruited and followed up at variable times between 1987 and 2010 (the median year of diagnosis was 1998). Five-year overall mortality. The 5-year overall survival was 36% (95% 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 estimate was significantly different from the HR estimated in the adjusted model (P for heterogeneity = .003). Among patients with invasive EOC, having a germline mutation in BRCA1 or BRCA2 was associated with improved 5-year overall survival. BRCA2 carriers had the best prognosis.JAMA The Journal of the American Medical Association 01/2012; 307(4):382-90. · 30.03 Impact Factor -
Article: Association Between BRCA1 and BRCA2 Mutations and Survival in Women With Invasive Epithelial Ovarian Cancer
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ABSTRACT: Context Approximately 10% of women with invasive epithelial ovarian cancer (EOC) carry deleterious germline mutations in BRCA1 or BRCA2. A recent article suggested that BRCA2 -related EOC was associated with an improved prognosis, but the effect of BRCA1 remains unclear.Objective To characterize the survival of BRCA carriers with EOC compared with noncarriers and to determine whether BRCA1 and BRCA2 carriers show similar survival patterns.Design, Setting, and Participants A pooled analysis of 26 observational studies on the survival of women with ovarian cancer, which included data from 1213 EOC cases with pathogenic germline mutations in BRCA1 (n = 909) or BRCA2 (n = 304) and from 2666 noncarriers recruited and followed up at variable times between 1987 and 2010 (the median year of diagnosis was 1998).Main Outcome Measure Five-year overall mortality.Results The 5-year overall survival was 36% (95% 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 estimate was significantly different from the HR estimated in the adjusted model (P for heterogeneity = .003).Conclusion Among patients with invasive EOC, having a germline mutation in BRCA1 or BRCA2 was associated with improved 5-year overall survival. BRCA2 carriers had the best prognosis. Figures in this Article Germline mutations in the tumor suppressor genes BRCA1 (NCBIEntrezGene672) and BRCA2 (NCBIEntrezGene 675) are the strongest known genetic risk factors for both breast and epithelial ovarian cancer (EOC) and are found in 6% to 15% of women with EOC.1- 3BRCA1 is involved in DNA repair, cell-cycle checkpoint control, chromatin remodeling, transcriptional regulation, and mitosis, and BRCA2 has an important role in homologous recombination.4 The clinical characteristics of EOCs among BRCA1/2 carriers differ from that of noncarriers. BRCA1 -related disease is more likely to be of serous histology,5 high grade,6 and advanced stage.3 Less data are available for BRCA2 -related EOC due to their lower prevalence and lower EOC penetrance relative to BRCA1, but a similar pattern is generally reported.5,7 The relative prognosis of BRCA1/2 carriers and noncarriers is unclear. A recent article8 found a more favorable outcome for BRCA2 mutation carriers, with no significant difference in outcome for BRCA1 mutation carriers compared with noncarriers. However, some studies have demonstrated a more favorable prognosis for BRCA1 and BRCA2 carriers6- 7,9 compared with noncarriers, whereas other studies have reported no significant difference.10- 11 Several factors may account for these divergent results. Most studies contained less than 50 carriers and all contained less than 250 carriers, resulting in imprecise survival estimates. Small sample sizes have also resulted in the grouping of BRCA1 and BRCA2 carriers together for analysis, despite potential prognostic differences. In addition, adjustment for prognostic factors known to differ by carrier status has varied among studies. In addition, few studies used appropriate statistical methods to account for the potential bias resulting from the inclusion of prevalent cases.12 The mechanism driving the association between BRCA1/2 mutations and survival is not known but some retrospective studies suggested that the survival advantage of carriers could be mediated through improved response to platinum-based agents.7,13 This is consistent with in vitro studies showing that BRCA1 and BRCA2 deficient cells are hypersensitive to drugs, which induce double-strand DNA breaks such as platinum-based agents.14 The goal of our study was to collate the data from multiple EOC case series with data on BRCA1 and BRCA2 mutation status to provide definitive evidence of the relative effect of germline BRCA1 and BRCA2 mutations on prognosis. The results could provide insight into the biology of BRCA1/2 mutations, improve clinical management of mutation carriers, and have implications for clinical trial design, particularly for agents targeting BRCA1/2 dysfunction, such as poly (ADP-ribose) polymerase inhibitors.15JAMA The Journal of the American Medical Association 307(4):382-389. · 30.03 Impact Factor
