Abstract 2752: Genetic heterogeneity of ovarian cancer survival effects in BRCA1/2 germline mutations: a large, multi-center study

Abstract

Rare germline mutations in the breast and ovarian cancer predisposition genes BRCA1 and BRCA2 are present in roughly 5 percent of ovarian cancer patients. Both genes play key roles in DNA damage repair but appear to have distinct, although often complementary, functions. The risks of breast and ovarian cancer have been shown to differ between BRCA1 and BRCA2 carriers, and mutation-specific effects have also been suggested for both groups. Published reports comparing the survival of ovarian cancer patients with and without BRCA1/2 mutations generally show a survival advantage among mutation carriers. This is thought to be related to an improved response of carriers to platinum-based therapies. Since it is not known whether BRCA1 and BRCA2 carriers show similar survival patterns, we have performed a large, multicenter study to investigate the impact of germline BRCA1 and BRCA2 mutations on ovarian cancer survival. 3,531 invasive epithelial ovarian cancer cases (1,178 BRCA1, 367 BRCA2 and 1,986 BRCA-negative) with survival time data from twenty-four studies in the U.S.A, Europe, Israel and Asia were included. In our main analysis, we excluded patients who were known or who were likely to have not received platinum-based therapy. Compared to non-carriers, BRCA1 and BRCA2 carriers were more likely to present with advanced stage (BRCA1; p=2×10−4, BRCA2; p=4×10−6), high grade (BRCA1; p=4×10−9, BRCA2; p=1×10−4), serous disease (BRCA1; p=3×10−6, BRCA2; p=0.003). BRCA1 carriers were younger at diagnosis (p=2×10−9) and BRCA2 slightly older at diagnosis (p=0.002) than non-carriers. BRCA1 and BRCA2 carriers did not differ in terms of tumor stage, grade or histology but did show differences in the age at diagnosis (p=2×10−14). In an unadjusted analysis, neither BRCA1 nor BRCA2 carriers differed from non-carriers in overall survival (BRCA1: HR=1.02, p=0.77, BRCA2: HR=0.89, p=0.36). After adjusting for stage, grade, histology and age at diagnosis, BRCA1 carriers showed a modest, non-significant, survival advantage (HR=0.84, p=0.12) while BRCA2 carriers showed a marked improvement (HR=0.57, p=6×10−4) compared to non-carriers. This survival advantage was also seen when comparing BRCA2 carriers to BRCA1 carriers after adjustment for age at diagnosis (HR=0.69, p=5×10−4). Similar results were obtained when we restricted the analysis to high grade, advanced stage, serous cases. The survival differences we observed between BRCA1 and BRCA2 carriers could be related to differences in tumor biology or chemo-sensitivity. Additional analyses investigating the later will be presented in addition to mutation-specific effects within BRCA1 and BRCA2. In this study, we provide strong evidence for genetic heterogeneity of survival effects in ovarian cancer patients with BRCA mutations. This could be applied to both clinical prediction and to aid our understanding of the complex biology of BRCA mutations. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2752. doi:10.1158/1538-7445.AM2011-2752

BRCA1 and BRCA2 mutations correlate with TP53 abnormalities and presence of immune cell infiltrates in ovarian high-grade serous carcinoma

“…A recent report on patients from 27 international studies demonstrated improved survival of BRCA1 and BRCA2 mutation carriers relative to non-carriers. 57 Unlike previous series (and the current case series) where the number of BRCA1 and BRCA2-null patients from which conclusions were drawn was relatively small, Bolton's multi-center study had outcome data on over 1400 BRCA1 and BRCA2 mutation carriers and B2400 non-carriers, allowing them to take into account clinical factors known to influence outcome. The recently published data from The Cancer Genome Atlas has confirmed the association of BRCA mutations with a favorable prognosis, and also showed no prognostic effect with BRCA1 promoter methylation (compared with tumors lacking BRCA mutations or methylation).…”

BRCA 1/BRCA 2 Pathogenic/Likely Pathogenic Variant Patients with Breast, Ovarian, and Other Cancers

“…It is not clear whether age at diagnosis in ovarian cancer patients who harbor BRCA 1/BRCA 2 pathogenic/likely pathogenic variants differs from non-carriers. It was shown that BRCA1 pathogenic/likely pathogenic variant ovarian cancer patients were younger compared with non-carriers, but it was not observed for BRCA2 carriers [25]. Another study showed that age at diagnosis in ovarian cancer patients who harbor the BRCA 1/BRCA 2 pathogenic/likely pathogenic variant was comparable to non-carriers [27].…”

“…BRCA 1/BRCA 2 pathogenic/likely pathogenic variant status affects both progression-free survival and overall survival [24]. Firstly, it was shown that ovarian cancers in BRCA 1/BRCA 2 pathogenic/likely pathogenic variant carriers had favorable survival outcomes, compared with non-carrier patients [25][26][27]. Platinium sensitivity, repeatedly responded to platin-based regimens and longer duration of response, might play important role in favorable survival advantage in BRCA 1/BRCA 2 carriers with ovarian cancer patients.…”