Impact of single‐nucleotide polymorphisms in DNA repair pathway genes on response to chemoradiotherapy in rectal cancer patients: Results from ACCORD‐12/PRODIGE‐2 phase III trial

Abstract

We examined whether 66 germline single-nucleotide polymorphisms (SNPs) in 10 candidate genes would predict clinical outcome in 316 patients with resectable locally advanced rectal cancer (LARC) enrolled in the ACCORD-12 phase III trial who were randomly treated with preoperative radiotherapy plus capecitabine (CAP45; n = 155) or dose-intensified radiotherapy plus capecitabine and oxaliplatin (CAPOX50; n = 161). The primary endpoint was tumor response according to the Dworak score. Multivariate logistic regression models adjusted on treatment arm and T stage determined the SNPs prognostic and predictive values for tumor response. In univariate analysis, five SNPs in ERCC2, XPA, MTHFR and ERCC1 were associated with the Dworak score in the CAPOX50 arm. In the overall population, interaction with treatment arm was significant for ERCC2 rs1799787 (p interaction = 0.05) and XPA rs3176683 (p interaction = 0.008), suggesting a predictive effect for response to oxaliplatin-based chemoradiotherapy (CRT). All but XPA rs3176683 had a prognostic effect on tumor response. In a multivariate model, interaction remained significant for XPA rs3176683 ([OR 7.33, 95% CI 1.40-38.23], p interaction = 0.018) and the prognostic effect significant for ERCC2 rs1799787 ([OR 0.55, 95%CI 0.32-0.93], p = 0.027) and ERCC1 rs10412761 ([OR 0.57, 95%CI 0.34-0.98], p = 0.042). Patients with the T/G haplotype of rs1799787 and rs10412761 had a 60% decrease in odds of response (p < 0.001). None of the five SNPs were associated with toxicity, overall and disease-free survival. These data suggest that genetic variation in DNA repair genes influences response to preoperative CRT in LARC and identify patients who benefit from the addition of oxaliplatin to CRT.

DNA repair genes are associated with tumor tissue differentiation and immune environment in lung adenocarcinoma: a bioinformatics analysis based on big data

“…Clinical studies have found that different individuals with the same clinical characteristics show great heterogeneity in clinical manifestations, treatment sensitivity, disease recurrence, and survival outcomes. We have previously reported on individual differences in genetic susceptibility, (31)(32)(33). However, a large number of research results are inconsistent, and there is no consensus on whether differences in DNA repair gene expression can be used as prognostic indicators.…”

Biomarkers for Predicting the Response to Radiation-Based Neoadjuvant Therapy in Rectal Cancer

“…Sixtysix germline SNPs were found in 10 candidate DNA repair genes. Boige et al [31] concluded that 5 SNPs located in ERCC1, MTHFR, excision repair cross-complementing group 2 (ERCC2) and XPA were closely related to the Dworak score. XPA rs3176683 was valuable for predicting the response to nCRT, while the ERCC2 rs1799787 and ERCC1 rs10412761 variants were reported to be promising prognostic markers.…”

Cellular Mechanisms Accounting for the Refractoriness of Colorectal Carcinoma to Pharmacological Treatment

“…A study carried out in 126 patients with advanced CRC, treated with a first-line oxaliplatin/5-FU chemotherapeutic regimen, showed that rs11615 and rs13181 SNPs were significantly correlated with clinical response and OS [ 134 ]. Patients with the T/G haplotype of the ERCC2 rs1799787 (c.1832-70C > T) and ERCC1 rs10412761 (c.-22 + 1089T > G) SNPs had a 60% decrease in odds of response to preoperative capecitabine and oxaliplatin-based chemoradiotherapy in locally advanced rectal cancer [ 135 ]. ERCC5 polymorphisms at the promoter region (c.-763A > G (rs2016073) and c.25G > A (rs751402)) may also be predictors of response to oxaliplatin-based chemotherapy in advanced CRC, as patients with the -763A/+25G haplotype had a higher risk of non-response to this pharmacological regimen [ 136 ].…”