Association Between <emph type="ital">BRCA1</emph> and <emph type="ital">BRCA2</emph> Mutations and Survival in Women With Invasive Epithelial Ovarian Cancer

Abstract

Context Approximately 10 percent of women with invasive epithelial ovarian cancer (EOC) carry deleterious germline mutations in BRCA1 or BRCA2. A recent report 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 to non-carriers and to determine whether BRCA1 and BRCA2 carriers show similar survival patterns. Design, Setting, and Participants We pooled data from 26 studies on the survival of women with ovarian cancer. This included data on 1,213 EOC cases with pathogenic germline mutations in BRCA1 (909) or BRCA2 (304) and 2,666 non-carriers recruited and followed for variable times between 1987 and 2010; the median year of diagnosis was 1998. Main Outcome Measures Five year overall mortality. Results The five-year overall survival was 36 percent (95% CI: 34–38) for non-carriers, 44 percent (95% CI: 40–48) for BRCA1 carriers and 52 percent (95% CI: 46–58) for BRCA2 carriers. After adjusting for study and year of diagnosis, BRCA1 and BRCA2 carriers showed a more favorable survival than non-carriers (BRCA1, HR=0.78; 95% CI=0.68–0.89, P=2×10−4; BRCA2, HR = 0.61; 95% CI=0.50–0.76, P=6×10−6). These survival differences remained after additional adjustment for stage, grade, histology and age at diagnosis (BRCA1, HR=0.73, 95% CI=0.64–0.84, P=2×10−5; BRCA2, HR = 0.49, 95% CI=0.39–0.61, P=3×10−10). Conclusions Among patients with invasive epithelial ovarian cancer, having a germline mutation in BRCA1 or BRCA2 was associated with improved 5-year overall survival.

Variants in Notch signalling pathway genes, PSEN1 and MAML2, predict overall survival in Chinese patients with epithelial ovarian cancer

“…In addition to clinical and demographic factors, molecular biomarkers could be promising prognostic or predictive factors for EOC. For example, molecular epidemiological studies have demonstrated that the altered expression levels of BRCA1 and BRCA2 as a result of mutations are associated with individual variation of clinical outcomes of EOC patients 4, 5. The genomewide association study (GWAS) approach has also been used to identify susceptibility loci associated with clinical outcomes in European EOC patients 6.…”

Morphologic correlates of molecular alterations in extrauterine Müllerian carcinomas

“…30 Since that time, Soslow et al 23 validated the significance of different histologic patterns by describing variant morphologies (SET) in tumors with BRCA germline mutations that are associated with a better prognosis and a better response to chemotherapy. 3,4,[12][13][14][15][16][17][18][19] We previously reported on a separate cohort of high-grade serous carcinomas, showing an association between BRCA-positivity and variant histology (SET-like), younger age, a lower frequency of serous tubal intraepithelial carcinoma, and trends toward improved survival. 24 In this current study, we found that mutations in homologous recombination genes were 6 times more likely to be associated with nonclassic high-grade serous carcinoma histology (70%) than with classic high-grade serous carcinoma histology (28%) (P o0.001), and BRCA1 mutations were 10 times more likely to be associated with nonclassic high-grade serous carcinoma histology (P o 0.001) than classic histology.…”

“…10,11 The reliance on alternative end-joining repair pathways subsequently renders homologous recombination-deficient tumors more sensitive to chemotherapy as well as to PARPi. 3,4,[12][13][14][15][16][17][18][19] Only one PARPi has been FDA approved for the treatment of ovarian cancer, olaparib, and this is only in the setting of BRCA mutation and at least three prior lines of chemotherapy. Our findings further support the work of Pennington et al, 21 suggesting that a broader population of women with ovarian cancer may benefit from PARPi therapy.…”

“…[6][7][8][9] Homologous recombination-deficient high-grade serous carcinomas (including BRCA1/2 mutations) depend on alternative, error-prone mechanisms for doublestrand break repair, such as the Polθ/PARP1-mediated alternative end-joining pathway for DNA repair, 10,11 and subsequently have been shown to have increased sensitivity to platinum chemotherapy and to poly ADP-ribose polymerase inhibitors (PARPi), and improved overall survival. 3,4,[12][13][14][15][16][17][18][19] Studies from The Cancer Genome Atlas Research Network (TCGA) demonstrated that nearly one-third of ovarian high-grade serous carcinomas had BRCA1-/2 alterations, which included 20% with either germline or somatic mutations in BRCA1/2 and an additional 11% with BRCA1 epigenetic silencing via hypermethylation. 20 Interestingly, they found that improved survival was limited to high-grade serous carcinomas with mutations in BRCA1/2, and was not seen in high-grade serous carcinomas with epigenetically silenced BRCA1.…”

Effectiveness and Safety of Poly (ADP-ribose) Polymerase Inhibitors in Cancer Therapy: A Systematic Review and Meta-analysis

“…Individuals with BRCA mutation are at an increased risk of developing breast, ovarian, and other cancers [34]. More than 1 million women develop breast or ovarian cancer every year worldwide, and about 10% of them have a BRCA mutation [35][36][37], moreover that cancer patients with BRCA mutation have better outcomes than non-BRCA carriers [38,39]. And a recent study [40] suggested that BRCA mutation should be taken into account when devising therapeutic strategies.…”