Radiation Treatment, ATM, BRCA1/2, and CHEK2*1100delC Pathogenic Variants and Risk of Contralateral Breast Cancer

Area of Science:

• Oncology
• Genetics
• Radiation Oncology

Background:

• Contralateral breast cancer (CBC) risk is a concern for breast cancer survivors.
• The impact of radiation therapy (RT) on CBC risk in women with germline pathogenic variants in moderate- to high-penetrance breast cancer genes is not well understood.

Purpose of the Study:

• To investigate the association between RT, germline variants in ATM, BRCA1/2, or CHEK2*1100delC, and CBC risk.
• To determine if RT modifies the risk of CBC in carriers of these pathogenic variants.

Main Methods:

• A population-based case-control study.
• Analysis of 708 women with CBC and 1399 controls with unilateral breast cancer, diagnosed between 1985-2000 and aged <55 years.
• Screening for variants in breast cancer-associated genes and estimation of rate ratios (RR) using multivariable conditional logistic regression.

Main Results:

• RT did not modify the association between known pathogenic variants (BRCA1/2, CHEK2*1100delC) and CBC risk.
• BRCA1/2 pathogenic variant carriers with RT had an RR of 4.46 (95% CI = 2.96 to 6.71) for CBC.
• Rare ATM missense variants of uncertain significance were associated with increased RT-associated CBC risk (RR = 2.98, 95% CI = 1.31 to 6.80).

Conclusions:

• Current RT strategies appear safe for young women with BRCA1/2 or CHEK2 pathogenic variants regarding CBC risk.
• Rare ATM variants may confer increased risk for RT-associated CBC, suggesting a need for further research and potential clinical consideration.