Pathology of breast and ovarian cancers among BRCA1 and BRCA2 mutation carriers: Results from the consortium of investigators of modifiers of BRCA1/2 (CIMBA)

Nasim Mavaddat, Daniel Barrowdale, Irene L. Andrulis, Susan M. Domchek, Diana Eccles, Heli Nevanlinna, Susan J. Ramus, Amanda Spurdle, Mark Robson, Mark Sherman, Anna Marie Mulligan, Fergus J. Couch, Christoph Engel, Lesley McGuffog, Sue Healey, Olga M. Sinilnikova, Melissa C. Southey, Mary Beth Terry, David Goldgar, Frances O'MalleyEsther M. John, Ramunas Janavicius, Laima Tihomirova, Thomas V.O. Hansen, Finn C. Nielsen, Ana Osorio, Alexandra Stavropoulou, Javier Benítez, Siranoush Manoukian, Bernard Peissel, Monica Barile, Sara Volorio, Barbara Pasini, Riccardo Dolcetti, Anna Laura Putignano, Laura Ottini, Paolo Radice, Ute Hamann, Muhammad U. Rashid, Frans B. Hogervorst, Mieke Kriege, Rob B. Van Der Luijt, for HEBON, Susan Peock, Debra Frost, D. Gareth Evans, Carole Brewer, Lisa Walker, Mark T. Rogers, Lucy E. Side, Catherine Houghton, for EMBRACE, Jo Ellen Weaver, Andrew K. Godwin, Rita K. Schmutzler, Barbara Wappenschmidt, Alfons Meindl, Karin Kast, Norbert Arnold, Dieter Niederacher, Christian Sutter, Helmut Deissler, Doroteha Gadzicki, Sabine Preisler-Adams, Raymonda Varon-Mateeva, Ines Schönbuchner, Heidrun Gevensleben, Dominique Stoppa-Lyonnet, Muriel Belotti, Laure Barjhoux, for GEMO Study Collaborators, Claudine Isaacs, Beth N. Peshkin, Trinidad Caldes, Miguel De Al Hoya, Carmen Cañadas, Tuomas Heikkinen, Päivi Heikkilä, Kristiina Aittomäki, Ignacio Blanco, Conxi Lazaro, Joan Brunet, Bjarni A. Agnarsson, Adalgeir Arason, Rosa B. Barkardottir, Martine Dumont, Jacques Simard, Marco Montagna, Simona Agata, Emma D'Andrea, Max Yan, Stephen Fox, Timothy R. Rebbeck, Wendy Rubinstein, Nadine Tung, Judy E. Garber, Xianshu Wang, Zachary Fredericksen, Vernon S. Pankratz, Noralane M. Lindor, Csilla Szabo, Kenneth Offit, Rita Sakr, Mia M. Gaudet, Christian F. Singer, Muy Kheng Tea, Christine Rappaport, Phuong L. Mai, Mark H. Greene, Anna Sokolenko, Evgeny Imyanitov, Amanda Ewart Toland, Leigha Senter, Kevin Sweet, Mads Thomassen, Anne Marie Gerdes, Torben Kruse, Maria Caligo, Paolo Aretini, Johanna Rantala, Anna Von Wachenfeld, Karin Henriksson, Linda Steele, Susan L. Neuhausen, Robert Nussbaum, Mary Beattie, Kunle Odunsi, Lara Sucheston, Simon A. Gayther, Kate Nathanson, Jenny Gross, Christine Walsh, Beth Karlan, Georgia Chenevix-Trench, Douglas F. Easton, Antonis C. Antoniou, for the Consortium of Investigators of Modifiers of BRCA1/2

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330 Citations (Scopus)

Abstract

Background: Previously, small studies have found that BRCA1 and BRCA2 breast tumors differ in their pathology. Analysis of larger datasets of mutation carriers should allow further tumor characterization. Methods: We used data from 4,325 BRCA1 and 2,568 BRCA2 mutation carriers to analyze the pathology of invasive breast, ovarian, and contralateral breast cancers. Results: There was strong evidence that the proportion of estrogen receptor (ER)-negative breast tumors decreased with age at diagnosis among BRCA1 (P-trend = 1.2 × 10-5), but increased with age at diagnosis among BRCA2, carriers (P-trend = 6.8 × 10-6). The proportion of triple-negative tumors decreased with age at diagnosis in BRCA1 carriers but increased with age at diagnosis of BRCA2 carriers. In both BRCA1 and BRCA2 carriers, ER-negative tumors were of higher histologic grade than ER-positive tumors (grade 3 vs. grade 1; P = 1.2 × 10-13 for BRCA1 and P = 0.001 for BRCA2). ER and progesterone receptor (PR) expression were independently associated with mutation carrier status [ER-positive odds ratio (OR) for BRCA2 = 9.4, 95% CI: 7.0-12.6 and PR-positive OR = 1.7, 95% CI: 1.3-2.3, under joint analysis]. Lobular tumors were more likely to be BRCA2-related (OR for BRCA2 = 3.3, 95% CI: 2.4-4.4; P = 4.4 × 10-14), and medullary tumors BRCA1-related (OR for BRCA2 = 0.25, 95% CI: 0.18-0.35; P = 2.3 × 10-15). ER-status of the first breast cancer was predictive of ER-status of asynchronous contralateral breast cancer (P = 0.0004 for BRCA1; P = 0.002 for BRCA2). There were no significant differences in ovarian cancer morphology between BRCA1 and BRCA2 carriers (serous: 67%; mucinous: 1%; endometrioid: 12%; clear-cell: 2%). Conclusions/Impact: Pathologic characteristics of BRCA1 and BRCA2 tumors may be useful for improving risk-prediction algorithms and informing clinical strategies for screening and prophylaxis.

Original languageEnglish
Pages (from-to)134-147
Number of pages14
JournalCancer Epidemiology, Biomarkers & Prevention
Volume21
Issue number1
DOIs
Publication statusPublished - 1 Jan 2012
Externally publishedYes

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