Data from Pathology of Breast and Ovarian Cancers among <i>BRCA1</i> and <i>BRCA2</i> Mutation Carriers: Results from the Consortium of Investigators of Modifiers of <i>BRCA1</i>/<i>2</i> (CIMBA)
Authors: Mavaddat Nasim , Barrowdale Daniel , Andrulis Irene L. , Domchek Susan M. , Eccles Diana , Nevanlinna Heli , Ramus Susan J. , Spurdle Amanda , Robson Mark , Sherman Mark , Mulligan Anna Marie , Couch Fergus J. , Engel Christoph , McGuffog Lesley , Healey Sue , Sinilnikova Olga M. , Southey Melissa C. , Terry Mary Beth , Goldgar David , O'Malley Frances , John Esther M. , Janavicius Ramunas , Tihomirova Laima , Hansen Thomas V. O. , Nielsen Finn C. , Osorio Ana , Stavropoulou Alexandra , Benítez Javier , Manoukian Siranoush , Peissel Bernard , Barile Monica , Volorio Sara , Pasini Barbara , Dolcetti Riccardo , Putignano Anna Laura , Ottini Laura , Radice Paolo , Hamann Ute , Rashid Muhammad U. , Hogervorst Frans B. , Kriege Mieke , van der Luijt Rob B. , Peock Susan , Frost Debra , Evans D. Gareth , Brewer Carole , Walker Lisa , Rogers Mark T. , Side Lucy E. , Houghton Catherine , Weaver JoEllen , Godwin Andrew K. , Schmutzler Rita K. , Wappenschmidt Barbara , Meindl Alfons , Kast Karin , Arnold Norbert , Niederacher Dieter , Sutter Christian , Deissler Helmut , Gadzicki Doroteha , Preisler-Adams Sabine , Varon-Mateeva Raymonda , Schönbuchner Ines , Gevensleben Heidrun , Stoppa-Lyonnet Dominique , Belotti Muriel , Barjhoux Laure , Isaacs Claudine , Peshkin Beth N. , Caldes Trinidad , de la Hoya Miguel , Cañadas Carmen , Heikkinen Tuomas , Heikkilä Päivi , Aittomäki Kristiina , Blanco Ignacio , Lazaro Conxi , Brunet Joan , Agnarsson Bjarni A. , Arason Adalgeir , Barkardottir Rosa B. , Dumont Martine , Simard Jacques , Montagna Marco , Agata Simona , D'Andrea Emma , Yan Max , Fox Stephen , Rebbeck Timothy R. , Rubinstein Wendy , Tung Nadine , Garber Judy E. , Wang Xianshu , Fredericksen Zachary , Pankratz Vernon S. , Lindor Noralane M. , Szabo Csilla , Offit Kenneth , Sakr Rita , Gaudet Mia M. , Singer Christian F. , Tea Muy-Kheng , Rappaport Christine , Mai Phuong L. , Greene Mark H. , Sokolenko Anna , Imyanitov Evgeny , Toland Amanda Ewart , Senter Leigha , Sweet Kevin , Thomassen Mads , Gerdes Anne-Marie , Kruse Torben , Caligo Maria , Aretini Paolo , Rantala Johanna , von Wachenfeld Anna , Henriksson Karin , Steele Linda , Neuhausen Susan L. , Nussbaum Robert , Beattie Mary , Odunsi Kunle , Sucheston Lara , Gayther Simon A. , Nathanson Kate , Gross Jenny , Walsh Christine , Karlan Beth , Chenevix-Trench Georgia , Easton Douglas F. , Antoniou Antonis C. 
Published: April 2023

<div>Abstract<p><b>Background:</b> Previously, small studies have found that <i>BRCA1</i> and <i>BRCA2</i> breast tumors differ in their pathology. Analysis of larger datasets of mutation carriers should allow further tumor characterization.</p><p><b>Methods:</b> We used data from 4,325 <i>BRCA1</i> and 2,568 <i>BRCA2</i> mutation carriers to analyze the pathology of invasive breast, ovarian, and contralateral breast cancers.</p><p><b>Results:</b> There was strong evidence that the proportion of estrogen receptor (ER)-negative breast tumors decreased with age at diagnosis among <i>BRCA1</i> (<i>P-</i>trend = 1.2 × 10<sup>−5</sup>), but increased with age at diagnosis among <i>BRCA2</i>, carriers (<i>P-</i>trend = 6.8 × 10<sup>−6</sup>). The proportion of triple-negative tumors decreased with age at diagnosis in <i>BRCA1</i> carriers but increased with age at diagnosis of <i>BRCA2</i> carriers. In both <i>BRCA1</i> and <i>BRCA2</i> carriers, ER-negative tumors were of higher histologic grade than ER-positive tumors (grade 3 vs. grade 1; <i>P</i> = 1.2 × 10<sup>−13</sup> for <i>BRCA1</i> and <i>P</i> = 0.001 for <i>BRCA2</i>). ER and progesterone receptor (PR) expression were independently associated with mutation carrier status [ER-positive odds ratio (OR) for <i>BRCA2</i> = 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 <i>BRCA2-</i>related (OR for <i>BRCA2</i> = 3.3, 95% CI: 2.4–4.4; <i>P</i> = 4.4 × 10<sup>−14</sup>), and medullary tumors <i>BRCA1</i>-related (OR for <i>BRCA2</i> = 0.25, 95% CI: 0.18–0.35; <i>P</i> = 2.3 × 10<sup>−15</sup>). ER-status of the first breast cancer was predictive of ER-status of asynchronous contralateral breast cancer (<i>P</i> = 0.0004 for <i>BRCA1</i>; <i>P</i> = 0.002 for <i>BRCA2</i>). There were no significant differences in ovarian cancer morphology between <i>BRCA1</i> and <i>BRCA2</i> carriers (serous: 67%; mucinous: 1%; endometrioid: 12%; clear-cell: 2%).</p><p><b>Conclusions/Impact:</b> Pathologic characteristics of <i>BRCA1</i> and <i>BRCA2</i> tumors may be useful for improving risk-prediction algorithms and informing clinical strategies for screening and prophylaxis. <i>Cancer Epidemiol Biomarkers Prev; 21(1); 134–47. ©2011 AACR</i>.</p></div>