Research article

Identification of women with an increased risk of developing radiation-induced breast cancer: a case only study

Annegien Broeks¹ , Linde M Braaf¹ , Angelina Huseinovic¹ , Anke Nooijen¹ , Jos Urbanus¹ , Frans BL Hogervorst² , Marjanka K Schmidt³ , Jan GM Klijn⁴ , Nicola S Russell⁵ , Flora E Van Leeuwen³ and Laura J Van 't Veer^1,2

¹Division of Experimental Therapy, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands

²Department of Pathology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands

³Department of Epidemiology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands

⁴Department of Medical Oncology, Dr Daniel den Hoed Cancer Centre, Groenehilledijk 301, 3075 EA, Rotterdam, The Netherlands

⁵Department of Radiotherapy, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands

author email corresponding author email

Breast Cancer Research 2007, 9:R26doi:10.1186/bcr1668

Published:	11 April 2007

See related editorial by Cardis et al., http://breast-cancer-research.com/content/9/3/106

Abstract

Introduction

Radiation exposure at a young age is one of the strongest risk factors for breast cancer. Germline mutations in genes involved in the DNA-damage repair pathway (DDRP) may render women more susceptible to radiation-induced breast cancer.

Methods

We evaluated the contribution of germline mutations in the DDRP genes BRCA1, BRCA2, CHEK2 and ATM to the risk of radiation-induced contralateral breast cancer (CBC). The germline mutation frequency was assessed, in a case-only study, in women who developed a CBC after they had a first breast cancer diagnosed before the age of 50 years, and who were (n = 169) or were not (n = 78) treated with radiotherapy for their first breast tumour.

Results

We identified 27 BRCA1, 5 BRCA2, 15 CHEK2 and 4 truncating ATM germline mutation carriers among all CBC patients tested (21%). The mutation frequency was 24.3% among CBC patients with a history of radiotherapy, and 12.8% among patients not irradiated for the first breast tumour (odds ratio 2.18 (95% confidence interval 1.03 to 4.62); p = 0.043). The association between DDRP germline mutation carriers and risk of radiation-induced CBC seemed to be strongest in women who developed their second primary breast tumour at least 5 years after radiotherapy. Those patients had an odds ratio of 2.51 (95% confidence interval 1.03 to 6.10; p = 0.049) of developing radiation-induced breast cancer, in comparison with non-carriers.

Conclusion

This study shows that carriers of germline mutations in a DDRP gene have an increased risk of developing (contralateral) breast cancer after radiotherapy; that is, over and above the risk associated with their carrier status. The increased risk indicates that knowledge of germline status of these DDRP genes at the time of breast cancer diagnosis may have important implications for the choice of treatment.