BACKGROUND: Radiation-induced secondary breast cancer (BC) may be a concern after radiation therapy (RT) for primary breast cancer (PBC), especially in young patients with germline (g)BRCA-associated BC who already have high contralateral BC (CBC) risk and potentially increased genetic susceptibility to radiation. We sought to investigate whether adjuvant RT for PBC increases the risk of CBC in patients with gBRCA1/2-associated BC. METHODS: The gBRCA1/2 pathogenic variant carriers diagnosed with PBC were selected from the prospective International BRCA1/2 Carrier Cohort Study. We used multivariable Cox proportional hazards models to investigate the association between RT (yes vs no) and CBC risk. We further stratified for BRCA status and age at PBC diagnosis (<40 and >40 years). Statistical significance tests were 2-sided. RESULTS: Of 3602 eligible patients, 2297 (64%) received adjuvant RT. Median follow-up was 9.6 years. The RT group had more patients with stage III PBC than the non-RT group (15% vs 3%, P < .001), received chemotherapy more often (81% vs 70%, P < .001), and received endocrine therapy more often (50% vs 35%, P < .001). The RT group had an increased CBC risk compared with the non-RT group (adjusted hazard ratio [HR] = 1.44; 95% confidence interval [CI] = 1.12 to 1.86). Statistical significance was observed in gBRCA2 (HR = 1.77; 95% CI = 1.13 to 2.77) but not in gBRCA1 pathogenic variant carriers (HR = 1.29; 95% CI = 0.93 to 1.77; P = .39 for interaction). In the combined gBRCA1/2 group, patients irradiated when they were younger than or older than 40 years of age at PBC diagnosis showed similar risks (HR = 1.38; 95% CI = 0.93 to 2.04 and HR = 1.56; 95% CI = 1.11 to 2.19, respectively). CONCLUSIONS: RT regimens minimizing contralateral breast dose should be considered in gBRCA1/2 pathogenic variant carriers.

Center of Familial Breast and Ovarian Cancer and Center of Integrated Oncology University Hospital Cologne Cologne Germany

Centre for Cancer Genetic Epidemiology Department of Oncology University of Cambridge Cambridge UK

Centre for Cancer Genetic Epidemiology Department of Public Health and Primary Care University of Cambridge Cambridge UK

Centre for Personalized Response Monitoring in Oncology Odense University Hospital Odense Denmark

Département d'Anticipation et de Suivi des Cancers Oncogénétique Clinique Institut Paoli Calmettes Marseille France

Department for Clinical Genetics Radboud University Medical Centre Nijmegen the Netherlands

Department of Cancer Epidemiology and Genetics Masaryk Memorial Cancer Institute Brno Czech Republic

Department of Clinical Genetics Amsterdam UMC Vrije Universiteit Amsterdam Amsterdam the Netherlands

Department of Clinical Genetics Guy's and St Thomas' NHS Foundation Trust London UK

Department of Clinical Genetics Leiden University Medical Centre Leiden the Netherlands

Department of Clinical Genetics Odense University Hospital Odense Denmark

Department of Clinical Genetics Royal Devon and Exeter Hospital Exeter UK

Department of Clinical Research University of Southern Denmark Odense Denmark

Department of Epidemiology University Medical Center Groningen University of Groningen Groningen the Netherlands

Department of Genetics and Pathology Pomeranian Medical University Szczecin Poland

Department of Genetics Maastricht University Medical Centre Maastricht the Netherlands

Department of Medical Genetics National Institute for Health Research Cambridge Biomedical Research Centre University of Cambridge Cambridge UK

Department of Medical Oncology Erasmus MC Cancer Institute Rotterdam the Netherlands

Department of Molecular Genetics National Institute of Oncology Budapest Hungary

Department of Obstetrics and Gynecology Comprehensive Cancer Center Medical University of Vienna Vienna Austria

Department of Radiotherapy Erasmus MC Cancer Institute Erasmus University Medical Center Rotterdam the Netherlands

Division of Laboratories Pharmacy and Biomedical Genetics Department of Genetics University Medical Centre Utrecht Utrecht the Netherlands

Division of Molecular Pathology The Netherlands Cancer Institute Antoni Van Leeuwenhoek Hospital Amsterdam the Netherlands

Division of Psychosocial Research and Epidemiology Netherlands Cancer Institute Antoni van Leeuwenhoek Hospital Amsterdam the Netherlands

Genomic Medicine Division of Evolution and Genomic Sciences The University of Manchester St Mary's Hospital Manchester University NHS Foundation Trust Manchester UK

Genomics Center Centre Hospitalier Universitaire de Québec Université Laval Research Center Quebec City QC Canada

Independent Laboratory of Molecular Biology and Genetic Diagnostics Pomeranian Medical University Szczecin Poland

INSERM U900 Paris France

Institut Curie Paris France

Institut Paoli Calmettes and Aix Marseille University INSERM IRD SESSTIM Marseille France

Institute for Medical Informatics Statistics and Epidemiology University of Leipzig Leipzig Germany

Manchester Breast Centre Oglesby Cancer Research Centre The Christie University of Manchester Manchester UK

Mines ParisTech Fontainebleau France

Molecular Oncology Laboratory Hospital Clínico San Carlos Instituto de Investigación Sanitaria del Hospital Clínico San Carlos Madrid Spain

Program in Cancer Genetics Departments of Human Genetics and Oncology McGill University Montréal QC Canada

PSL Research University Paris France

The Prevent Breast Cancer Research Unit The Nightingale Centre Manchester University NHS Foundation Trust Manchester UK

J Natl Cancer Inst. 2023 Nov 8;115(11):1243-1245. doi: 10.1093/jnci/djad129. PubMed

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