NBN, RAD51 and XRCC3 Polymorphisms as Potential Predictive Biomarkers of Adjuvant Radiotherapy Toxicity in Early HER2-Positive Breast Cancer.

Abstract

Simple SummaryAdjuvant radiotherapy for breast cancer patients significantly improves survival and causes side effects. It is known that the response to radiotherapy is individual, but we are not yet able to predict patients with high risk for acute or late radiotherapy adverse events. This study aimed to investigate the association between homologous recombination repair (HRR) polymorphisms and radiotherapy toxicity and thus contribute to the knowledge on potential predictive biomarkers of radiotherapy toxicity in early HER2-positive breast cancer. This study was among the first to evaluate the role of HRR genetic variability with cardiac toxicity. RAD51 polymorphisms were associated with cardiac adverse events, while XRCC3 polymorphisms were associated with skin adverse events. Our results suggest that polymorphisms in key HRR genes might be used as potential biomarkers of late treatment-related adverse events in early HER2-positive breast cancer treated with radiotherapy.Radiotherapy (RT) for breast cancer significantly impacts patient survival and causes adverse events. Double-strand breaks are the most harmful type of DNA damage associated with RT, which is repaired through homologous recombination (HRR). As genetic variability of DNA repair genes could affect response to RT, we aimed to evaluate the association of polymorphisms in HRR genes with tumor characteristics and the occurrence of RT adverse events in early HER2-positive breast cancer. Our study included 101 breast cancer patients treated with adjuvant RT and trastuzumab. All patients were genotyped for eight single nucleotide polymorphisms in NBN, RAD51 and XRCC3 using competitive allele-specific PCR. Carriers of XRCC3 rs1799794 GG genotype were less likely to have higher tumor differentiation grade (OR = 0.05, 95% CI = 0.01–0.44, p = 0.007). Carriers of RAD51 rs1801321 TT genotype were more likely to have higher NYHA class in univariable (OR = 10.0; 95% CI = 1.63–61.33; p = 0.013) and multivariable (OR = 9.27; 95% CI = 1.28–67.02; p = 0.027) analysis. Carriers of RAD51 rs12593359 GG genotype were less likely to have higher NYHA class in univariable (OR = 0.09; 95% CI = 0.01–0.79; p = 0.030) and multivariable (OR = 0.07; 95% CI = 0.01–0.81; p = 0.034) analysis. Carriers of XRCC3 rs1799794 GG genotypes experienced more skin adverse events based on LENT-SOMA scale in univariable (OR = 5.83; 95% CI = 1.22–28.00; p = 0.028) and multivariable (OR = 10.90; 95% CI = 1.61–73.72; p = 0.014) analysis. In conclusion, XRCC3 and RAD51 polymorphisms might contribute to RT adverse events in early HER2-positive breast cancer patients.