Refined histopathological predictors of BRCA1 and BRCA2mutation status: a large-scale analysis of breast cancer characteristics from the BCAC, CIMBA, and ENIGMA consortia
Authors: Spurdle Amanda B , Couch Fergus J , Parsons Michael T , McGuffog Lesley , Barrowdale Daniel , Bolla Manjeet K , Wang Qin , Healey Sue , Schmutzler Rita Katharina , Wappenschmidt Barbara , Rhiem Kerstin , Hahnen Eric , Engel Christoph , Meindl Alfons , Ditsch Nina , Arnold Norbert , Plendl Hansjoerg , Niederacher Dieter , Sutter Christian , Wang-Gohrke Shan , Steinemann Doris , Preisler-Adams Sabine , Kast Karin , Varon-Mateeva Raymonda , Ellis Steve , Frost Debra , Platte Radka , Perkins Jo , Evans D Gareth , Izatt Louise , Eeles Ros , Adlard Julian , Davidson Rosemarie , Cole Trevor , Scuvera Giulietta , Manoukian Siranoush , Bonanni Bernardo , Mariette Frederique , Fortuzzi Stefano , Viel Alessandra , Pasini Barbara , Papi Laura , Varesco Liliana , Balleine Rosemary , Nathanson Katherine L , Domchek Susan M , Offitt Kenneth , Jakubowska Anna , Lindor Noralane , Thomassen Mads , Jensen Uffe Birk , Rantala Johanna , Borg Åke , Andrulis Irene L , Miron Alexander , Hansen Thomas VO , Caldes Trinidad , Neuhausen Susan L , Toland Amanda E , Nevanlinna Heli , Montagna Marco , Garber Judy , Godwin Andrew K , Osorio Ana , Factor Rachel E , Terry Mary B , Rebbeck Timothy R , Karlan Beth Y , Southey Melissa , Rashid Muhammad Usman , Tung Nadine , Pharoah Paul DP , Blows Fiona M , Dunning Alison M , Provenzano Elena , Hall Per , Czene Kamila , Schmidt Marjanka K , Broeks Annegien , Cornelissen Sten , Verhoef Senno , Fasching Peter A , Beckmann Matthias W , Ekici Arif B , Slamon Dennis J , Bojesen Stig E , Nordestgaard Børge G , Nielsen Sune F , Flyger Henrik , Chang-Claude Jenny , Flesch-Janys Dieter , Rudolph Anja , Seibold Petra , Aittomäki Kristiina , Muranen Taru A , Heikkilä Päivi , Blomqvist Carl , Figueroa Jonine , Chanock Stephen J , Brinton Louise , Lissowska Jolanta , Olson Janet E , Pankratz Vernon S , John Esther M , Whittemore Alice S , West Dee W , Hamann Ute , Torres Diana , Ulmer Hans Ulrich , Rüdiger Thomas , Devilee Peter , Tollenaar Robert AEM , Seynaeve Caroline , Van Asperen Christi J , Eccles Diana M , Tapper William J , Durcan Lorraine , Jones Louise , Peto Julian , dos-Santos-Silva Isabel , Fletcher Olivia , Johnson Nichola , Dwek Miriam , Swann Ruth , Bane Anita L , Glendon Gord , Mulligan Anna M , Giles Graham G , Milne Roger L , Baglietto Laura , McLean Catriona , Carpenter Jane , Clarke Christine , Scott Rodney , Brauch Hiltrud , Brüning Thomas , Ko Yon-Dschun , Cox Angela , Cross Simon S , Reed Malcolm WR , Lubinski Jan , Jaworska-Bieniek Katarzyna , Durda Katarzyna , Gronwald Jacek , Dörk Thilo , Bogdanova Natalia , Park-Simon Tjoung-Won , Hillemanns Peter , Haiman Christopher A , Henderson Brian E , Schumacher Fredrick , Le Marchand Loic , Burwinkel Barbara , Marme Frederik , Surovy Harald , Yang Rongxi , Anton-Culver Hoda , Ziogas Argyrios , Hooning Maartje J , Collée J Margriet , Martens John WM , Tilanus-Linthorst Madeleine MA , Brenner Hermann , Dieffenbach Aida Karina , Arndt Volke , Stegmaier Christa , Winqvist Robert , Pylkäs Katri , Jukkola-Vuorinen Arja , Grip Mervi , Lindblom Annika , Margolin Sara , Joseph Vijai , Robson Mark , Rau-Murthy Rohini , González-Neira Anna , Arias José Ignacio , Zamora Pilar , Benítez Javier , Mannermaa Arto , Kataja Vesa , Kosma Veli-Matti , Hartikainen Jaana M , Peterlongo Paolo , Zaffaroni Daniela , Barile Monica , Capra Fabio , Radice Paolo , Teo Soo H , Easton Douglas F , Antoniou Antonis C , Chenevix-Trench Georgia , Goldgar David E ,   EMBRACE Group,   GENICA Network,   HEBON Group,   kConFab Investigators
Published: December 2014

Abstract
Introduction
The distribution of histopathological features of invasive breast tumors in BRCA1 or BRCA2 germline mutation carriers differs from that of individuals with no known mutation. Histopathological features thus have utility for mutation prediction, including statistical modeling to assess pathogenicity of BRCA1 or BRCA2 variants of uncertain clinical significance. We analyzed large pathology datasets accrued by the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) and the Breast Cancer Association Consortium (BCAC) to reassess histopathological predictors of BRCA1 and BRCA2 mutation status, and provide robust likelihood ratio (LR) estimates for statistical modeling.

Methods
Selection criteria for study/center inclusion were estrogen receptor (ER) status or grade data available for invasive breast cancer diagnosed younger than 70 years. The dataset included 4,477 BRCA1 mutation carriers, 2,565 BRCA2 mutation carriers, and 47,565 BCAC breast cancer cases. Country-stratified estimates of the likelihood of mutation status by histopathological markers were derived using a Mantel-Haenszel approach.

Results
ER-positive phenotype negatively predicted BRCA1 mutation status, irrespective of grade (LRs from 0.08 to 0.90). ER-negative grade 3 histopathology was more predictive of positive BRCA1 mutation status in women 50 years or older (LR = 4.13 (3.70 to 4.62)) versus younger than 50 years (LR = 3.16 (2.96 to 3.37)). For BRCA2, ER-positive grade 3 phenotype modestly predicted positive mutation status irrespective of age (LR = 1.7-fold), whereas ER-negative grade 3 features modestly predicted positive mutation status at 50 years or older (LR = 1.54 (1.27 to 1.88)). Triple-negative tumor status was highly predictive of BRCA1 mutation status for women younger than 50 years (LR = 3.73 (3.43 to 4.05)) and 50 years or older (LR = 4.41 (3.86 to 5.04)), and modestly predictive of positive BRCA2 mutation status in women 50 years or older (LR = 1.79 (1.42 to 2.24)).

Conclusions
These results refine likelihood-ratio estimates for predicting BRCA1 and BRCA2 mutation status by using commonly measured histopathological features. Age at diagnosis is an important variable for most analyses, and grade is more informative than ER status for BRCA2 mutation carrier prediction. The estimates will improve BRCA1 and BRCA2 variant classification and inform patient mutation testing and clinical management.