. 2023 Nov 8;115(11):1318-1328.

doi: 10.1093/jnci/djad116.

Contralateral breast cancer risk in patients with breast cancer and a germline-BRCA1/2 pathogenic variant undergoing radiation

Mark van Barele¹, Delal Akdeniz¹, Bernadette A M Heemskerk-Gerritsen¹; Genepso; Nadine Andrieu^{2

3

4

5}, Catherine Noguès^{6

7}; HEBON; Christi J van Asperen⁸, Marijke Wevers⁹, Margreet G E M Ausems¹⁰, Geertruida H de Bock¹¹, Charlotte J Dommering¹², Encarnacion B Gómez-García¹³, Flora E van Leeuwen¹⁴, Thea M Mooij¹⁴; EMBRACE; Douglas F Easton^{15

16}, Antonis C Antoniou¹⁵, D Gareth Evans^{17

18

19}, Louise Izatt²⁰, Marc Tischkowitz^{21

22}, Debra Frost¹⁵, Carole Brewer²³, Edit Olah²⁴, Jacques Simard²⁵, Christian F Singer²⁶, Mads Thomassen^{27

28

29}, Karin Kast³⁰, Kerstin Rhiem³⁰, Christoph Engel³¹, Miguel de la Hoya³², Lenka Foretová³³, Anna Jakubowska^{34

35}, Agnes Jager¹, Margriet G A Sattler³⁶, Marjanka K Schmidt^{14

37}, Maartje J Hooning¹

Affiliations

¹ Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, the Netherlands.
² INSERM, U900, Paris, France.
³ Institut Curie, Paris, France.
⁴ PSL Research University, Paris, France.
⁵ Mines ParisTech, Fontainebleau, France.
⁶ Département d'Anticipation et de Suivi des Cancers, Oncogénétique Clinique, Institut Paoli-Calmettes, Marseille, France.
⁷ Institut Paoli-Calmettes & Aix Marseille University, INSERM, IRD, SESSTIM, Marseille, France.
⁸ Department of Clinical Genetics, Leiden University Medical Centre, Leiden, the Netherlands.
⁹ Department for Clinical Genetics, Radboud University Medical Centre, Nijmegen, the Netherlands.
¹⁰ Division of Laboratories, Pharmacy and Biomedical Genetics, Department of Genetics, University Medical Centre Utrecht, Utrecht, the Netherlands.
¹¹ Department of Epidemiology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.
¹² Department of Clinical Genetics, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands.
¹³ Department of Genetics, Maastricht University Medical Centre, Maastricht, the Netherlands.
¹⁴ Division of Psychosocial Research and Epidemiology, Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital, Amsterdam, the Netherlands.
¹⁵ Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
¹⁶ Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK.
¹⁷ The Prevent Breast Cancer Research Unit, The Nightingale Centre, Manchester University NHS Foundation Trust, Manchester, UK.
¹⁸ Genomic Medicine, Division of Evolution and Genomic Sciences, The University of Manchester, St Mary's Hospital, Manchester University NHS Foundation Trust, Manchester, UK.
¹⁹ Manchester Breast Centre, Oglesby Cancer Research Centre, The Christie, University of Manchester, Manchester, UK.
²⁰ Department of Clinical Genetics, Guy's and St Thomas' NHS Foundation Trust, London, UK.
²¹ Department of Medical Genetics, National Institute for Health Research Cambridge Biomedical Research Centre, University of Cambridge, Cambridge, UK.
²² Program in Cancer Genetics, Departments of Human Genetics and Oncology, McGill University, Montréal, QC, Canada.
²³ Department of Clinical Genetics, Royal Devon & Exeter Hospital, Exeter, UK.
²⁴ Department of Molecular Genetics, National Institute of Oncology, Budapest, Hungary.
²⁵ Genomics Center, Centre Hospitalier Universitaire de Québec, Université Laval Research Center, Quebec City, QC, Canada.
²⁶ Department of Obstetrics and Gynecology, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria.
²⁷ Department of Clinical Genetics, Odense University Hospital, Odense, Denmark.
²⁸ Department of Clinical Research, University of Southern Denmark, Odense, Denmark.
²⁹ Centre for Personalized Response Monitoring in Oncology (PREMIO), Odense University Hospital, Odense, Denmark.
³⁰ Center of Familial Breast and Ovarian Cancer and Center of Integrated Oncology, University Hospital Cologne, Cologne, Germany.
³¹ Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, Leipzig, Germany.
³² Molecular Oncology Laboratory, Hospital Clínico San Carlos, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), Madrid, Spain.
³³ Department of Cancer Epidemiology and Genetics, Masaryk Memorial Cancer Institute, Brno, Czech Republic.
³⁴ Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland.
³⁵ Independent Laboratory of Molecular Biology and Genetic Diagnostics, Pomeranian Medical University, Szczecin, Poland.
³⁶ Department of Radiotherapy, Erasmus MC Cancer Institute, Erasmus University Medical Center, Rotterdam, the Netherlands.
³⁷ Division of Molecular Pathology, The Netherlands Cancer Institute-Antoni Van Leeuwenhoek Hospital, Amsterdam, the Netherlands.

PMID: 37369040
PMCID: PMC10637040
DOI: 10.1093/jnci/djad116

Contralateral breast cancer risk in patients with breast cancer and a germline-BRCA1/2 pathogenic variant undergoing radiation

Mark van Barele et al. J Natl Cancer Inst. 2023.

. 2023 Nov 8;115(11):1318-1328.

doi: 10.1093/jnci/djad116.

Authors

Affiliations

¹ Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, the Netherlands.
² INSERM, U900, Paris, France.
³ Institut Curie, Paris, France.
⁴ PSL Research University, Paris, France.
⁵ Mines ParisTech, Fontainebleau, France.
⁶ Département d'Anticipation et de Suivi des Cancers, Oncogénétique Clinique, Institut Paoli-Calmettes, Marseille, France.
⁷ Institut Paoli-Calmettes & Aix Marseille University, INSERM, IRD, SESSTIM, Marseille, France.
⁸ Department of Clinical Genetics, Leiden University Medical Centre, Leiden, the Netherlands.
⁹ Department for Clinical Genetics, Radboud University Medical Centre, Nijmegen, the Netherlands.
¹⁰ Division of Laboratories, Pharmacy and Biomedical Genetics, Department of Genetics, University Medical Centre Utrecht, Utrecht, the Netherlands.
¹¹ Department of Epidemiology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.
¹² Department of Clinical Genetics, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands.
¹³ Department of Genetics, Maastricht University Medical Centre, Maastricht, the Netherlands.
¹⁴ Division of Psychosocial Research and Epidemiology, Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital, Amsterdam, the Netherlands.
¹⁵ Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
¹⁶ Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK.
¹⁷ The Prevent Breast Cancer Research Unit, The Nightingale Centre, Manchester University NHS Foundation Trust, Manchester, UK.
¹⁸ Genomic Medicine, Division of Evolution and Genomic Sciences, The University of Manchester, St Mary's Hospital, Manchester University NHS Foundation Trust, Manchester, UK.
¹⁹ Manchester Breast Centre, Oglesby Cancer Research Centre, The Christie, University of Manchester, Manchester, UK.
²⁰ Department of Clinical Genetics, Guy's and St Thomas' NHS Foundation Trust, London, UK.
²¹ Department of Medical Genetics, National Institute for Health Research Cambridge Biomedical Research Centre, University of Cambridge, Cambridge, UK.
²² Program in Cancer Genetics, Departments of Human Genetics and Oncology, McGill University, Montréal, QC, Canada.
²³ Department of Clinical Genetics, Royal Devon & Exeter Hospital, Exeter, UK.
²⁴ Department of Molecular Genetics, National Institute of Oncology, Budapest, Hungary.
²⁵ Genomics Center, Centre Hospitalier Universitaire de Québec, Université Laval Research Center, Quebec City, QC, Canada.
²⁶ Department of Obstetrics and Gynecology, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria.
²⁷ Department of Clinical Genetics, Odense University Hospital, Odense, Denmark.
²⁸ Department of Clinical Research, University of Southern Denmark, Odense, Denmark.
²⁹ Centre for Personalized Response Monitoring in Oncology (PREMIO), Odense University Hospital, Odense, Denmark.
³⁰ Center of Familial Breast and Ovarian Cancer and Center of Integrated Oncology, University Hospital Cologne, Cologne, Germany.
³¹ Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, Leipzig, Germany.
³² Molecular Oncology Laboratory, Hospital Clínico San Carlos, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), Madrid, Spain.
³³ Department of Cancer Epidemiology and Genetics, Masaryk Memorial Cancer Institute, Brno, Czech Republic.
³⁴ Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland.
³⁵ Independent Laboratory of Molecular Biology and Genetic Diagnostics, Pomeranian Medical University, Szczecin, Poland.
³⁶ Department of Radiotherapy, Erasmus MC Cancer Institute, Erasmus University Medical Center, Rotterdam, the Netherlands.
³⁷ Division of Molecular Pathology, The Netherlands Cancer Institute-Antoni Van Leeuwenhoek Hospital, Amsterdam, the Netherlands.

PMID: 37369040
PMCID: PMC10637040
DOI: 10.1093/jnci/djad116

Abstract

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.

PubMed Disclaimer

Conflict of interest statement

All authors have completed and submitted the Form for Disclosure of Potential Conflicts of interest.

D. Gareth Evans reports potential conflict of interest from AstraZeneca and AmGen; Karin Kast from Roche Pharma AG; Jacques Simard reports holding BRCA1 and BRCA2 patents. The other authors report no conflicts of interest.

Figures

**Figure 1.**
Example of 3D-CRT planning, showing 1% to 5% of the total prescribed dosage (darkest shaded area, **white arrow**) on the contralateral breast as a result of the breast anatomy or tumor localization (more likely if medial). 3D-CRT = 3-dimensional–conformal radiation therapy.

**Figure 2.**
Flow diagram of patient inclusion. CBC = contralateral breast cancer; DCIS = ductal carcinoma in situ; HEBON = Hereditary Breast and Ovarian cancer research Netherlands; IBCCS = International *BRCA1/2* Carrier Cohort Study; PBC = primary breast cancer; RRM = risk-reducing mastectomy; RT, radiation therapy.

**Figure 3.**
Fine and Gray competing risks model–derived CBC cumulative incidence curves, by RT. Cumulative incidences at 5-year intervals for both groups displayed in the table below the graph. CBC = contralateral breast cancer; CI = confidence interval; RT = radiation therapy.

See this image and copyright information in PMC

Comment in

Contralateral breast cancer risk with radiation therapy in BRCA mutation carriers: what do we tell patients?
Lee MK, Robson ME. Lee MK, et al. J Natl Cancer Inst. 2023 Nov 8;115(11):1243-1245. doi: 10.1093/jnci/djad129. J Natl Cancer Inst. 2023. PMID: 37603726 Free PMC article. No abstract available.

References

1. Sung H, Ferlay J, Siegel RL, et al.Global Cancer Statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021;71(3):209-249. - PubMed
1. Cancer stat facts: female breast cancer. National Cancer Institute Surveillance, Epidemiology, and End Results Program. https://seer.cancer.gov/statfacts/html/breast.html. Accessed October 9, 2021.
1. Clarke M, Collins R, Darby S, et al.; Early Breast Cancer Trialists’ Collaborative Group (EBCTCG). Effects of radiotherapy and of differences in the extent of surgery for early breast cancer on local recurrence and 15-year survival: an overview of the randomised trials. Lancet. 2005;366(9503):2087-2106. - PubMed
1. Darby S, McGale P, Correa C, et al.; Early Breast Cancer Trialists’ Collaborative Group (EBCTCG). Effect of radiotherapy after breast-conserving surgery on 10-year recurrence and 15-year breast cancer death: meta-analysis of individual patient data for 10,801 women in 17 randomised trials. Lancet. 2011;378(9804):1707-1716. - PMC - PubMed
1. Nickoloff JA, Sharma N, Taylor L.. Clustered DNA double-strand breaks: biological effects and relevance to cancer radiotherapy. Genes (Basel). 2020;11(1):99. - PMC - PubMed

Publication types

Actions

MeSH terms

Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

Contralateral breast cancer risk in patients with breast cancer and a germline-BRCA1/2 pathogenic variant undergoing radiation

Affiliations

Contralateral breast cancer risk in patients with breast cancer and a germline-BRCA1/2 pathogenic variant undergoing radiation

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

Comment in

References

Publication types

MeSH terms

Substances

Grants and funding

LinkOut - more resources

Full Text Sources