Refined histopathological predictors of BRCA1 and BRCA2 mutation status: a large-scale analysis of breast cancer characteristics from the BCAC, CIMBA, and ENIGMA consortia

Spurdle AB, Couch FJ, Parsons MT, Mcguffog L, Barrowdale D, Bolla MK, Wang Q, Healey S, Schmutzler RK, Wappenschmidt B, Rhiem K, Hahnen E, Engel C, Meindl A, Ditsch N, Arnold N, Plendl H, Niederacher D, Sutter C, Wang-Gohrke S, Steinemann D, Preisler-Adams S, Kast K, Varon-Mateeva R, Ellis S, Frost D, Platte R, Perkins J, Evans DG, Izatt L, Eeles R, Adlard J, Davidson R, Cole T, Scuvera G, Manoukian S, Bonanni B, Mariette F, Fortuzzi S, Viel A, Pasini B, Papi L, Varesco L, Balleine R, Nathanson KL, Domchek SM, Offitt K, Jakubowska A, Lindor N, Thomassen M, Jensen UB, Rantala J, Borg A, Andrulis IL, Miron A, Hansen TVO, Caldes T, Neuhausen SL, Toland AE, Nevanlinna H, Montagna M, Garber J, Godwin AK, Osorio A, Factor RE, Terry MB, Rebbeck TR, Karlan BY, Southey M, Rashid MU, Tung N, Pharoah PDP, Blows FM, Dunning AM, Provenzano E, Hall P, Czene K, Schmidt MK, Broeks A, Cornelissen S, Verhoef S, Fasching PA, Beckmann M, Ekici AB, Slamon DJ, Bojesen SE, Nordestgaard BG, Nielsen SF, Flyger H, Chang-Claude J, Flesch-Janys D, Rudolph A, Seibold P, Aittomaki K, Muranen TA, Heikkila P, Blomqvist C, Figueroa J, Chanock SJ, Brinton L, Lissowska J, Olson JE, Pankratz VS, John EM, Whittemore AS, West DW, Hamann U, Torres D, Ulmer HU, Rudiger T, Devilee P, Tollenaar RAEM, Seynaeve C, Van Asperen CJ, Eccles DM, Tapper WJ, Durcan L, Jones L, Peto J, Dos-Santos-Silva I, Fletcher O, Johnson N, Dwek M, Swann R, Bane AL, Glendon G, Mulligan AM, Giles GG, Milne RL, Baglietto L, Mclean C, Carpenter J, Clarke C, Scott R, Brauch H, Bruning T, Ko YD, Cox A, Cross SS, Reed MWR, Lubinski J, Jaworska-Bieniek K, Durda K, Gronwald J, Dork T, Bogdanova N, Park-Simon TW, Hillemanns P, Haiman CA, Henderson BE, Schumacher F, Le Marchand L, Burwinkel B, Marme F, Surovy H, Yang R, Anton-Culver H, Ziogas A, Hooning MJ, Collee JM, Martens JWM, Tilanus-Linthorst MMA, Brenner H, Dieffenbach AK, Arndt V, Stegmaier C, Winqvist R, Pylkas K, Jukkola-Vuorinen A, Grip M, Lindblom A, Margolin S, Joseph V, Robson M, Rau-Murthy R, Gonzalez-Neira A, Arias JI, Zamora P, Benitez J, Mannermaa A, Kataja V, Kosma VM, Hartikainen JM, Peterlongo P, Zaffaroni D, Barile M, Capra F, Radice P, Teo SH, Easton DF, Antoniou AC, Chenevix-Trench G, Goldgar DE (2014)

Publication Type: Journal article

Publication year: 2014

Journal

Publisher: BioMed Central

Book Volume: 16

Pages Range: 3419

Journal Issue: 6

DOI: 10.1186/s13058-014-0474-y

Abstract

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.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.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)).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.

Authors with CRIS profile

Involved external institutions

Spanish National Cancer Research Centre / Centro Nacional de Investigaciones Oncológicas (CNIO) Spain (ES) QIMR Berghofer Medical Research Institute (früher: the Queensland Institute of Medical Research) Australia (AU) University of Cambridge United Kingdom (GB) Technische Universität München (TUM) Germany (DE) University of California Los Angeles (UCLA) United States (USA) (US) Ruprecht-Karls-Universität Heidelberg Germany (DE) Erasmus University Rotterdam (EUR) / Erasmus Universiteit Rotterdam Netherlands (NL) Deutsches Krebsforschungszentrum (DKFZ) Germany (DE) Oulun Yliopisto / University of Oulo Finland (FI) Universität zu Köln Germany (DE) Universität Leipzig Germany (DE) Ludwig-Maximilians-Universität (LMU) Germany (DE) Christian-Albrechts-Universität zu Kiel Germany (DE) Charité - Universitätsmedizin Berlin Germany (DE) Universitätsklinikum Ulm Germany (DE) Medizinische Hochschule Hannover (MHH) / Hannover Medical School Germany (DE) Westfälische Wilhelms-Universität (WWU) Münster Germany (DE) Technische Universität Dresden Germany (DE) Central Manchester University Hospitals United Kingdom (GB) Guy's and St Thomas' (NHS Foundation Trust) United Kingdom (GB) Chapel Allerton Hospital United Kingdom (GB) Southern General Hospital United Kingdom (GB) Birmingham Women's and Children's NHS Foundation Trust United Kingdom (GB) Fondazione IRCCS: Istituto Nazionale dei Tumori Italy (IT) European Institute of Oncology / Istituto Europeo di Oncologia (IEO) Italy (IT) IFOM - FIRC Institute of Molecular Oncology Italy (IT) Centro di Riferimento Oncologico (CRO) Italy (IT) University of Turin / Università degli Studi di Torino (UNITO) Italy (IT) Università degli Studi di Firenze / University of Florence Italy (IT) Ospedale San Martino (IRCCS AOU) Italy (IT) University of Sydney (USYD) Australia (AU) University of Pennsylvania United States (USA) (US) Memorial Sloan Kettering Cancer Center United States (USA) (US) Mayo Clinic United States (USA) (US) Odense Universitetshospital (OUH) Denmark (DK) Aarhus University Hospital / Aarhus Universitetshospital Denmark (DK) Karolinska University Hospital / Karolinska Universitetssjukhuset Sweden (SE) Lund University / Lunds universitet Sweden (SE) University of Toronto Canada (CA) Case Western Reserve University United States (USA) (US) Heinrich-Heine-Universität Düsseldorf Germany (DE) Hospital Clínico San Carlos Spain (ES) The University of Melbourne Australia (AU) University of Kansas (KU) United States (USA) (US) Istituto Oncologico Veneto (IOV), IRCCS Italy (IT) Dana–Farber Cancer Institute United States (USA) (US) University of Utah United States (USA) (US) Columbia University United States (USA) (US) Copenhagen University Hospital Denmark (DK) City of Hope Medical Center United States (USA) (US) Antoni van Leeuwenhoek Netherlands (NL) Helsingin yliopisto / University of Helsinki Finland (FI) University Health Network (UHN) Canada (CA) National Cancer Institute (NCI) United States (USA) (US) Klinikum Mittelbaden Baden-Baden Balg Germany (DE) Cancer Prevention Institute of California (CPIC) United States (USA) (US) Städtisches Klinikum Karlsruhe Germany (DE) Leiden University Netherlands (NL) University of Southampton United Kingdom (GB) Queen Mary, University of London United Kingdom (GB) London School of Hygiene and Tropical Medicine United Kingdom (GB) University of Westminster United Kingdom (GB) Hamilton Health Sciences (HHS) Canada (CA) Mount Sinai Hospital (MSH) Canada (CA) Cancer Council Victoria Australia (AU) The Alfred Hospital Australia (AU) University of Newcastle (UoN) Australia (AU) Institut für Prävention und Arbeitsmedizin der Deutschen Gesetzlichen Unfallversicherung (IPA) Germany (DE) Evangelische Kliniken Bonn gGmbH Germany (DE) Eberhard Karls Universität Tübingen Germany (DE) Pomeranian Medical University / Pomorski Uniwersytet Medyczny w Szczecinie (PMU) Poland (PL) Hospital Monte Naranco Spain (ES) Hospital Universitario La Paz Spain (ES) University of Eastern Finland Finland (FI) Ramsay Sime Darby Health Care (RSDHC) Malaysia (MY) Stanford University United States (USA) (US) Erasmus University Medical Center (MC) Netherlands (NL) University of California Irvine United States (USA) (US) Ohio State University United States (USA) (US) Maria Skłodowska-Curie Institute of Oncology / Centrum Onkologii–Instytut im. Marii Skłodowskiej-Curie w Warszawie Poland (PL) Krebsregister Saarland / Saarland Cancer Registry Germany (DE) Karolinska Institute Sweden (SE) University of Hawaii (U.H.) United States (USA) (US) University of Southern California (USC) United States (USA) (US) University of Sheffield United Kingdom (GB) Universitätsklinikum Hamburg-Eppendorf (UKE) Germany (DE) Cedars-Sinai Medical Center United States (USA) (US) Universitätsklinikum Heidelberg Germany (DE)

How to cite

APA:

Spurdle, A.B., Couch, F.J., Parsons, M.T., Mcguffog, L., Barrowdale, D., Bolla, M.K.,... Goldgar, D.E. (2014). Refined histopathological predictors of BRCA1 and BRCA2 mutation status: a large-scale analysis of breast cancer characteristics from the BCAC, CIMBA, and ENIGMA consortia. Breast Cancer Research, 16(6), 3419. https://dx.doi.org/10.1186/s13058-014-0474-y

MLA:

Spurdle, Amanda B., et al. "Refined histopathological predictors of BRCA1 and BRCA2 mutation status: a large-scale analysis of breast cancer characteristics from the BCAC, CIMBA, and ENIGMA consortia." Breast Cancer Research 16.6 (2014): 3419.

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