Genetic Variants Of Dna Repair Genes As Predictors Of Late Radiotoxicity And Treatment Outcome In Oropharyngeal Carcinoma

PurposeTo investigate the impact of genetic variants of DNA repair genes on the severity of late radiotoxicities and treatment outcome in oropharyngeal carcinoma. MethodsPatients of oropharyngeal carcinoma were enrolled in the study from March 2015 to December 2017. They were treated with 2-D radical radiotherapy at a dose of 66Gy in 33 fractions and were followed up for the development of late radiotoxicities, namely, xerostomia and subcutaneous fibrosis; and the treatment outcome. Toxicities were graded according to the RTOG/EORTC grading system and maximum grade was recorded over the length of the patients9 follow-up. Treatment response, disease-free survival and overall survival were analysed. Six Single Nucleotide Polymorphisms of DNA repair genes, namely, XRCC1 1196G\u003eA, XRCC3 722C\u003eT, ERCC4 Ex8 1244G\u003eA, ERCC4 Ex11 2505T\u003eC, XRCC5 1401G\u003eT and Rad51 172G\u003eT were analysed by PCR-RFLP and correlated with the severity of radiotoxicities and the treatment outcome using Chi-square test and binary logistic regression analysis. Survival curves were plotted according to the Kaplan-Meier method and statistically compared using log-rank test. Results179 patients of oropharyngeal carcinoma were included in the study. The median follow-up was 16 months (13-48 months). 36 patients developed severe (≥grade 2) subcutaneous fibrosis and 72 developed severe (≥grade 2) xerostomia. Homo CC genotype of XRCC3 722C\u003eT (p=0.013*, OR 2.350, 95% CI 1.089-5.382), Homo AA genotype of ERCC4 Ex8 1244G\u003eA (p=0.001**, OR 11.626, 95% CI 2.490-275.901) and Homo TT genotype of XRCC5 1401G\u003eT (p=0.020*, OR 2.188, 95% CI 1.652-7.334) were independent predictive factors for the risk of severe subcutaneous fibrosis on multivariate logistic regression analysis.Likewise, Homo CC genotype of ERCC4 Exon11 2505T\u003eC (p=0.020*, OR=2.717, 95% CI 1.754-3.910) and HomoTT genotype of Rad51 172G\u003eT (p=0.040*, OR=2.135, 95% CI 1.035-4.407) were significant risk factors for the development of severe late-onset xerostomia.In addition, on univariate analysis, variants which correlated with poor response to treatment were; Homo AA genotype of ERCC4 Ex8 1244G\u003eA(p=0.016*, OR=5.652, 95% CI 2.501-63.811), Homo CC genotype of ERCC4 Exon11 2505T\u003eC (p=0.020*, OR=3.011, 95% CI 1.502-5.039) and HomoTT genotype of Rad51 172G\u003eT(p=0.004*, OR=2.689, 95% CI 1.364-5.300).The median relapse-free survival and overall survival were 14 (13-41) and 15 (13-48) months respectively. A poor relapse-free survival was seen in patients harboring the Homo TT genotype of XRCC5 1401G\u003eT (p=0.018*, OR 2.105, 95% CI 1.545-5.239) and HomoTT genotype of Rad51 172G\u003eT (p=0.031*, OR=1.981, 95% CI 1.063-3.694).Homo CC genotype of XRCC3 722C\u003eT (p=0.012*, OR 2.497, 95% CI 1.828-4.708), Homo AA genotype of ERCC4 Ex8 1244G\u003eA (p=0.017*, OR 1.745, 95% CI 1.155-19.594) and HomoTT genotype of Rad51 172G\u003eT (p=0.041*, OR 1.192, 95% CI 1.026-3.564) were significantly associated with a poor overall survival. ConclusionsOur findings demonstrate the role of Single Nucleotide Polymorphisms in candidate genes of DNA repair as predictive and prognostic biomarkers in oropharyngeal carcinoma treated by radiotherapy. These genetic variants can be incorporated into predictive models of normal tissue toxicity and radioresponse, thereby, guiding individualised radiation therapy protocols. Citation Format: Ankita Gupta, Don Mathew, Arnab Pal, Sushmita Ghoshal. Genetic variants of DNA repair genes as predictors of late radiotoxicity and treatment outcome in oropharyngeal carcinoma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 6515.