MA13.01 A Validation Study on DNA Repair Gene Variant for Lung Cancer Survival Prediction after Chemoradiation: A Secondary Analysis for RTOG-0617 Study

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We previously reported that important genetic variants in DNA repair pathway genes particularly rs238406 in ERCC2 may be a predictive biomarker of radiation dose in patients with locally-advanced non-small cell lung cancer (LA-NSCLC) treated with chemoradiation (Wang et al, 2012; Jin et al, 2015). This study aimed to validate these findings using an independent cohort of NSCLC patients treated with high and standard doses of radiotherapy (RT). The study population was from RTOG-0617 clinical trial, a phase III trial comparing overall survival between high and standard RT doses with concurrent chemotherapy, with or without cetuximab, in stage III NSCLC. Patients with blood samples available for analysis were eligible to this study. DNA samples for genotyping were extracted from buffy-coat that were collected before commencement of treatment. Over two dozens functionally important SNPs of DNA repair pathway were tested using MassArray System. According to our previous study, this validation study focused solely on rs11615, rs3212948 in ERCC1 and rs238406 in ERCC2 in the nucleotide excision repair (NER) pathway, which were significant prognostic factors with respect to survival. The primary endpoint was OS, calculated from randomization to death due to any cause or last follow-up. Log-rank test and Cox proportional hazards model were used to examine the effects of genotypes on OS. The interaction term between respective SNP and RT dose groups was of primary interest. 321 patients met the selection criteria. Similar to findings of our previous study, Cox models found neither rs11615 nor rs3212948 in ERCC1 had a significant interaction effect with RT dose group (P>0.05). Notably, there was a statistically significant interaction between ERCC2: rs238406 (GT/TT vs. GG) and radiation dose (P for interaction=0.011). Specifically, in standard dose RT group patients carrying chemoradiation sensitive genotypes (GT/TT) had a better OS than chemoradiation resistant genotypes (GG) (median survival time [MST] 30 vs. 20 months [mo], hazard ratio [HR] = 0.628, 95% confidence interval [CI] 0.420-0.940, P=0.023). In contrast, among those treated with high dose RT, patients with chemoradiation sensitive genotypes (GT/TT) had a numerically worse OS than those with chemoradiation resistant genotypes (GG) (MST 22 vs. 31 mo, HR=1.57, 95% CI 0.86-2.83, P=0.13). Similar results were also found among patients received concurrent chemoradiation without cetuximab. This study validated our previous findings that ERCC2: rs238406 is a predictive biomarker of radiation dose with respect to OS in patients with NSCLC treated with concurrent chemoradiotherapy. Dose escalation may have worse survival in patients carrying chemoradiation sensitive genotypes. Genetic variants and their interaction with radiation dose may potentially guide individualized dose escalation in NSCLC radiotherapy.