Characterization of the Cancer Spectrum in Men With Germline BRCA1 and BRCA2 Pathogenic Variants: Results From the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA).

The limited data on cancer phenotypes in men with germline BRCA1 and BRCA2 pathogenic variants (PVs) have hampered the development of evidence-based recommendations for early cancer detection and risk reduction in this population.

To compare the cancer spectrum and frequencies between male BRCA1 and BRCA2 PV carriers.

Retrospective cohort study of 6902 men, including 3651 BRCA1 and 3251 BRCA2 PV carriers, older than 18 years recruited from cancer genetics clinics from 1966 to 2017 by 53 study groups in 33 countries worldwide collaborating through the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Clinical data and pathologic characteristics were collected.

BRCA1/2 status was the outcome in a logistic regression, and cancer diagnoses were the independent predictors. All odds ratios (ORs) were adjusted for age, country of origin, and calendar year of the first interview.

Among the 6902 men in the study (median [range] age, 51.6 [18-100] years), 1634 cancers were diagnosed in 1376 men (19.9%), the majority (922 of 1,376 [67%]) being BRCA2 PV carriers. Being affected by any cancer was associated with a higher probability of being a BRCA2, rather than a BRCA1, PV carrier (OR, 3.23; 95% CI, 2.81-3.70; P < .001), as well as developing 2 (OR, 7.97; 95% CI, 5.47-11.60; P < .001) and 3 (OR, 19.60; 95% CI, 4.64-82.89; P < .001) primary tumors. A higher frequency of breast (OR, 5.47; 95% CI, 4.06-7.37; P < .001) and prostate (OR, 1.39; 95% CI, 1.09-1.78; P = .008) cancers was associated with a higher probability of being a BRCA2 PV carrier. Among cancers other than breast and prostate, pancreatic cancer was associated with a higher probability (OR, 3.00; 95% CI, 1.55-5.81; P = .001) and colorectal cancer with a lower probability (OR, 0.47; 95% CI, 0.29-0.78; P = .003) of being a BRCA2 PV carrier.

Significant differences in the cancer spectrum were observed in male BRCA2, compared with BRCA1, PV carriers. These data may inform future recommendations for surveillance of BRCA1/2-associated cancers and guide future prospective studies for estimating cancer risks in men with BRCA1/2 PVs.

JAMA oncology. 2020 Jul 02 [Epub ahead of print]

Valentina Silvestri, Goska Leslie, Daniel R Barnes, and the CIMBA Group , Bjarni A Agnarsson, Kristiina Aittomäki, Elisa Alducci, Irene L Andrulis, Rosa B Barkardottir, Alicia Barroso, Daniel Barrowdale, Javier Benitez, Bernardo Bonanni, Ake Borg, Saundra S Buys, Trinidad Caldés, Maria A Caligo, Carlo Capalbo, Ian Campbell, Wendy K Chung, Kathleen B M Claes, Sarah V Colonna, Laura Cortesi, Fergus J Couch, Miguel de la Hoya, Orland Diez, Yuan Chun Ding, Susan Domchek, Douglas F Easton, Bent Ejlertsen, Christoph Engel, D Gareth Evans, Lidia Feliubadalò, Lenka Foretova, Florentia Fostira, Lajos Géczi, Anne-Marie Gerdes, Gord Glendon, Andrew K Godwin, David E Goldgar, Eric Hahnen, Frans B L Hogervorst, John L Hopper, Peter J Hulick, Claudine Isaacs, Angel Izquierdo, Paul A James, Ramunas Janavicius, Uffe Birk Jensen, Esther M John, Vijai Joseph, Irene Konstantopoulou, Allison W Kurian, Ava Kwong, Elisabetta Landucci, Fabienne Lesueur, Jennifer T Loud, Eva Machackova, Phuong L Mai, Keivan Majidzadeh-A, Siranoush Manoukian, Marco Montagna, Lidia Moserle, Anna Marie Mulligan, Katherine L Nathanson, Heli Nevanlinna, Joanne Ngeow Yuen Ye, Liene Nikitina-Zake, Kenneth Offit, Edith Olah, Olufunmilayo I Olopade, Ana Osorio, Laura Papi, Sue K Park, Inge Sokilde Pedersen, Pedro Perez-Segura, Annabeth H Petersen, Pedro Pinto, Berardino Porfirio, Miquel Angel Pujana, Paolo Radice, Johanna Rantala, Muhammad U Rashid, Barak Rosenzweig, Maria Rossing, Marta Santamariña, Rita K Schmutzler, Leigha Senter, Jacques Simard, Christian F Singer, Angela R Solano, Melissa C Southey, Linda Steele, Zoe Steinsnyder, Dominique Stoppa-Lyonnet, Yen Yen Tan, Manuel R Teixeira, Soo H Teo, Mary Beth Terry, Mads Thomassen, Amanda E Toland, Sara Torres-Esquius, Nadine Tung, Christi J van Asperen, Ana Vega, Alessandra Viel, Jeroen Vierstraete, Barbara Wappenschmidt, Jeffrey N Weitzel, Greet Wieme, Sook-Yee Yoon, Kristin K Zorn, Lesley McGuffog, Michael T Parsons, Ute Hamann, Mark H Greene, Judy A Kirk, Susan L Neuhausen, Timothy R Rebbeck, Marc Tischkowitz, Georgia Chenevix-Trench, Antonis C Antoniou, Eitan Friedman, Laura Ottini

Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy., Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom., Department of Pathology, Landspitali University Hospital, Reykjavik, Iceland., Department of Clinical Genetics, Helsinki University Hospital, University of Helsinki, Helsinki, Finland., Immunology and Molecular Oncology Unit, Veneto Institute of Oncology IOV-IRCCS, Padua, Italy., Lunenfeld-Tanenbaum Research Institute, Fred A. Litwin Center for Cancer Genetics, Mount Sinai Hospital, Toronto, Ontario, Canada., Human Genetics Group, Human Cancer Genetics Programme, Spanish National Cancer Research Centre, Madrid, Spain., Human Genetics Group and Genotyping Unit, CEGEN, Human Cancer Genetics Programme, Spanish National Cancer Research Centre, Madrid, Spain., Division of Cancer Prevention and Genetics-IEO, European Institute of Oncology IRCCS, Milan, Italy., Department of Oncology, Lund University, Skåne University Hospital, Lund, Sweden., Huntsman Cancer Institute, Department of Internal Medicine, University of Utah Health, Salt Lake City., Instituto de Investigación Sanitaria San Carlos (IdISSC), Centro Investigación Biomédica en Red de Cáncer (CIBERONC), Medical Oncology Department, Hospital Clínico San Carlos, Madrid, Spain., Section of Molecular Genetics, Department of Laboratory Medicine, University Hospital of Pisa, Pisa, Italy., Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, Victoria, Australia., Departments of Pediatrics and Medicine, Columbia University, New York, New York., Centre for Medical Genetics, Ghent University, Gent, Belgium., Department of Oncology and Haematology, University of Modena and Reggio Emilia, Modena, Italy., Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota., Hereditary Cancer Genetics Group, Vall d'Hebron Institute of Oncology, Barcelona, Spain., Department of Population Sciences, Beckman Research Institute of City of Hope, Duarte, California., Abramson Cancer Center, Perelman School of Medicine, Department of Medicine, University of Pennsylvania, Philadelphia., Department of Oncology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark., Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, Leipzig, Germany., Genomic Medicine, Manchester Academic Health Sciences Centre, Division of Evolution and Genomic Science, Manchester University, Manchester University Hospitals NHS Foundation Trust, Manchester, United Kingdom., Molecular Diagnostic Unit, Hereditary Cancer Program, IDIBELL (Bellvitge Biomedical Research Institute), Catalan Institute of Oncology, CIBERONC, Barcelona, Spain., Department of Cancer Epidemiology and Genetics, Masaryk Memorial Cancer Institute, Brno, Czech Republic., Molecular Diagnostics Laboratory, INRASTES, National Centre for Scientific Research "Demokritos", Athens, Greece., Medical Oncology Center, National Institute of Oncology, Budapest, Hungary., Department of Clinical Genetics, Rigshospitalet, Copenhagen, Denmark., Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City., Huntsman Cancer Institute, Department of Dermatology, University of Utah School of Medicine, Salt Lake City., Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany., Family Cancer Clinic, Netherlands Cancer Institute, Amsterdam, the Netherlands., Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Victoria, Australia., Center for Medical Genetics, NorthShore University HealthSystem, Evanston, Illinois., Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC., Genetic Counseling Unit, Hereditary Cancer Program, IDIBGI (Institut d'Investigació Biomèdica de Girona), Catalan Institute of Oncology, CIBERONC, Girona, Spain., Hematology, Oncology and Transfusion Medicine Center, Department of Molecular and Regenerative Medicine, Vilnius University Hospital Santariskiu Clinics, Vilnius, Lithuania., Department of Clinical Genetics, Aarhus University Hospital, Aarhus, Denmark., Department of Epidemiology and Population Health, Division of Oncology, Department of Medicine, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, California., Clinical Genetics Research Lab, Department of Cancer Biology and Genetics, Memorial Sloan Kettering Cancer Center, New York, New York., Hong Kong Hereditary Breast Cancer Family Registry, Cancer Genetics Centre, Happy Valley, Hong Kong., UO Oncologia Medica, Azienda Ospedaliero Universitaria Pisana, Pisa, Italy., Genetic Epidemiology of Cancer Team, Inserm, U900, Paris, France., Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland., Magee-Womens Hospital, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania., Breast Cancer Research Center, Genetics Department, Motamed Cancer Institute, ACECR, Tehran, Iran., Unit of Medical Genetics, Department of Medical Oncology and Hematology, Fondazione IRCCS Istituto Nazionale dei Tumori (INT), Milan, Italy., Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada., Department of Obstetrics and Gynecology, Helsinki University Hospital, University of Helsinki, Helsinki, Finland., Cancer Genetics Service, National Cancer Centre Singapore, Singapore., Latvian Biomedical Research and Study Centre, Riga, Latvia., Department of Molecular Genetics, National Institute of Oncology, Budapest, Hungary., Center for Clinical Cancer Genetics, The University of Chicago, Chicago, Illinois., Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence, Italy., Department of Preventive Medicine, Seoul National University College of Medicine, Seoul, Korea., Molecular Diagnostics, Department of Clinical Medicine, Aalborg University Hospital, Aalborg University, Aalborg, Denmark., Department of Clinical Genetics, Vejle Hospital, Vejle, Denmark., Department of Genetics, Portuguese Oncology Institute, Porto, Portugal., ProCURE, Catalan Institute of Oncology, IDIBELL (Bellvitge Biomedical Research Institute), Barcelona, Spain., Unit of Molecular Bases of Genetic Risk and Genetic Testing, Department of Research, Fondazione IRCCS Istituto Nazionale dei Tumori (INT), Milan, Italy., Clinical Genetics, Karolinska Institutet, Stockholm, Sweden., Molecular Genetics of Breast Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany., Male High Risk Clinic, Uro-Oncology Service, Urology Department, Chaim Sheba Medical Center, Tel-Hashomer, Israel., Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark., Fundación Pública Galega Medicina Xenómica-SERGAS, Santiago de Compostela, Spain., Clinical Cancer Genetics Program, The Comprehensive Cancer Center, Division of Human Genetics, Department of Internal Medicine, The Ohio State University, Columbus., Genomics Center, Centre Hospitalier Universitaire de Québec-Université Laval, Research Centre, Québec City, Québec, Canada., Comprehensive Cancer Center, Department of OB/GYN, Medical University of Vienna, Vienna, Austria., INBIOMED, Faculty of Medicine/UBA-CONICET and Genotyping Laboratory, Department of Clinical Chemistry, Centro de Educacion Medica e Investigaciones Clinicas, CABA, Argentina., Precision Medicine, School of Clinical Sciences at Monash Health, Monash University, Clayton, Victoria, Australia., Service de Génétique, Institut Curie, Paris, France., Department of OB/GYN, Medical University of Vienna, Vienna, Austria., Cancer Research Malaysia, Subang Jaya, Selangor, Malaysia., Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, New York., Department of Clinical Genetics, Odense University Hospital, Odense, Denmark., Department of Cancer Biology and Genetics, The Ohio State University, Columbus., Department of Medical Oncology, Beth Israel Deaconess Medical Center, Boston, Massachusetts., Department of Clinical Genetics, Leiden University Medical Center, Leiden, the Netherlands., Division of Functional onco-genomics and genetics, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, Aviano, Italy., Clinical Cancer Genetics, City of Hope, Duarte, California., Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia., Centre for Cancer Research, University of Sydney at The Westmead Institute for Medical Research, and Familial Cancer Service, Westmead Hospital, New South Wales, Australia., Harvard T.H. Chan School of Public Health, Boston, Massachusetts., Program in Cancer Genetics, Departments of Human Genetics and Oncology, McGill University, Montréal, Quebec, Canada., Sackler Faculty of Medicine, Tel Aviv University, Ramat Aviv, Israel.