Presentation Abstract

Abstract Number: 2752
Presentation Title: Genetic heterogeneity of ovarian cancer survival effects in BRCA1/2 germline mutations: a large, multi-center study
Presentation Time: Monday, Apr 04, 2011, 1:00 PM - 5:00 PM
Location: Exhibit Hall A4-C, Poster Section 35
Poster Section: 35
Poster Board Number: 15
Author Block: Kelly L. Bolton1, Cindy Goh2, Susan Ramus3, David Goldgar4, Javier Benitez5, Ana Osorio5, Douglas Easton2, Susan Peock2, Andrew Godwin6, Ava Kwong7, Ignacio Blanco8, kConFab Investigators, Ellen Goode9, Mark Greene10, Jennifer Loud10, Phuong Mai10, Amanda Toland11, Martin Gore12, Håkan Olsson13, Susan Neuhausen14, Kirsten Moysich15, Mary Beattie16, Lara Sucheston15, Marco Montagna17, Evelyn Despierre18, Diether Lambrechts19, Jenny Gross20, Christine Walsh20, Beth Karlan20, Georgia Chenevix-Trench21, Antonis Antoniou2, Paul Pharoah2. 1Division of Cancer Genetics and Epidemiology, National Cancer Institute, Rockville, MD; 2University of Cambridge, Cambridge, United Kingdom; 3Keck School of Medicine of the University of Southern California (USC), Los Angeles, CA; 4University of Utah, Salt Lake City, UT; 5Department of Human Genetics, Centro Nacional de Investigaciones Oncológicas, Madrid, Spain; 6University of Kansas, Lawrence, KS; 7Queen Mary Hospital,The University of Hong Kong, Hong Kong, Hong Kong; 8Hereditary Cancer Program, Catalan Institute of Oncology, Barcelona, Spain; 9Mayo Clinic, Rochester, MN; 10Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD; 11Ohio State University, Columbus, OH; 12Royal Marsden Hospital, London, United Kingdom; 13Department of Oncology, University Hospital Lund, Lund, Sweden; 14City of Hope, Duarte, CA; 15Roswell Park Cancer Institute, Buffalo, NY; 16Department of Medicine, UCSF, San Francisco, CA; 17Istituto Oncologico Veneto, UOC Immunologia e Diagnostica Molecolare Oncologica, Padova, Italy; 18Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University Hospitals Leuven, Leuven, Belgium; 19The Vesalius Research Center, K.U. Leuven and VIB, Leuven, Belgium; 20Cedars-Sinai Medical Center, Los Angeles, CA; 21The Queensland Institute of Medical Research, Brisbane, Australia
Abstract Body: 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=2x10-4, BRCA2; p=4x10-6), high grade (BRCA1; p=4x10-9, BRCA2; p=1x10-4), serous disease (BRCA1; p=3x10-6, BRCA2; p=0.003). BRCA1 carriers were younger at diagnosis (p=2x10-9) 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=2x10-14). 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=6x10-4) 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=5x10-4). 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.