Pharmacogenetic Association between XRCC1 Polymorphisms and Response to Platinum-Based Chemotherapy in Asian Patients with NSCLC: A Meta-Analysis

Abstract

Background. Platinum-based chemotherapy plays an antitumor role by damaging DNA. X-ray repair crosscomplementing protein 1 (XRCC1) participates in DNA repair and thus affects the sensitivity to platinum drugs. Two polymorphisms of XRCC1, rs25487 (Arg399Gln) and rs1799782 (Arg194Trp), have been widely studied for the association with clinical outcomes of platinum-based chemotherapy in Asian patients with non-small-cell lung cancer (NSCLC), but the results remain inconclusive. Thus, we performed the present meta-analysis. Methods. Literature search was performed in PubMed, Web of Science, and EMBASE up to June 2019. Odds ratios (ORs) for objective response ratio (ORR), Cox proportional hazard ratios (HRs) of overall survival (OS) and progression-free survival (PFS), and the corresponding 95% confidence intervals (95% CIs) were calculated to assess the association strengths between XRCC1 polymorphisms and clinical outcomes. Comparisons were performed in homozygous, heterozygous, dominant, and recessive models. Results. Finally, a total of 23 studies involving 5567 patients were included in the meta-analysis. Compared to ArgArg of rs25487, GlnGln ( OR = 1.71 , 95% CI: 1.16-2.52, p = .007 , I 2 = 56.8 % ) and GlnArg ( OR = 1.23 , 95% CI: 1.07-1.40, p = .003 , I 2 = 29.0 % ) were associated with higher ORR. Meanwhile, GlnGln indicated a favorable OS ( HR = 0.60 , 95% CI: 0.40-0.88) and PFS ( HR = 0.64 , 95% CI: 0.46-0.90). We also found positive associations between rs1799782 and ORR in all comparison models with low between-study heterogeneity. The association strength increased with the number of variant alleles (TrpTrp vs. ArgArg: OR = 1.73 , 95% CI:1.31-2.27; TrpArg vs. ArgArg: OR = 1.28 , 95% CI: 1.06-1.55), suggesting a gene dosage effect. In addition, TrpTrp predicted a longer OS. Conclusion. Our results showed that rs25487 and rs1799782 of XRCC1 are potential markers to predict clinical outcomes of platinum-based chemotherapy in Asian patients with NSCLC.

Association between XRCC1 Arg399Gln polymorphism with prognosis of head and neck squamous cell carcinomas: A meta-analysis

“…The results of the present meta-analysis regarding the non-existence of a significant relationship between survival and XRCC1 Arg 399Gln polymorphism are somewhat inconsistent with the results of the some meta-analyses conducted on cancers of other parts of the body [ 23 , 25 , 26 , 27 ]. This inconsistency can indicate the different impact of the polymorphism on the prognosis of cancers in different parts of the body, which can be due to different etiological factors and carcinogenesis processes of cancers of different parts of the body, or because of the use of different chemotherapy drugs with different mechanisms which consequently will determine the impact of such a polymorphism on the patient prognosis.…”

Genetic Variants Associated With Response to Platinum-Based Chemotherapy in Non-Small Cell Lung Cancer Patients: A Field Synopsis and Meta‐Analysis

“…Instead, the ERCC2 rs1799793 may indirectly contribute to platinum chemoresistance by dysregulating apoptosis, as the resulting Asp-to-Asn substitution led to a 2.5-fold increased apoptotic response in a lymphoblastoid cell line [ 70 ]. Similarly, the variant allele of XRCC1 rs25487 also showed associations with PBC chemoresistance, consistent with a recent meta-analysis by Zhang et al [ 61 ]. Bioinformatics analyses predicted that the XRCC1 rs25487 variants are benign and tolerated, suggesting that the genetic variant also does not directly affect DNA repair to result in PBC chemoresistance.…”

Correlations between pathogenic variants in DNA repair genes and anticancer treatment efficacy in stage IV non‐small cell lung cancer: A large real‐world cohort and review of the literature

“…Many studies have evaluated the effect of DDR gene pathogenic variants on the efficacy of platinum‐based chemotherapy, with conflicting results 27 , 28 , 29 , 30 , 31 (Table 5 ). We did not find a statistically significant difference in ORR, PFS, and OS between the pDDR and wtDDR groups in the present study.…”