Predictive assessment in pharmacogenetics of XRCC1 gene on clinical outcomes of advanced lung cancer patients treated with platinum-based chemotherapy

Abstract

Published data have shown inconsistent results about the pharmacogenetics of XRCC1 gene on clinical outcomes of advanced lung cancer patients treated with platinum-based chemotherapy. This meta-analysis aimed to summarize published findings and provide more reliable association. A total of 53 eligible studies including 7433 patients were included. Patients bearing the favorable TrpTrp and TrpArg genotypes of Arg194Trp were more likely to better response rates to platinum-based chemotherapy compared to those with the unfavorable ArgArg genotype (TrpTrp+TrpArg vs. ArgArg: odds ratio (OR) = 2.02, 95% CI, 1.66–2.45). The GlnGln and GlnArg genotypes of Arg399Gln were significantly associated with the poorer response rates compared to those with the ArgArg genotype (GlnGln +GlnArg vs. ArgArg: OR = 0.68, 95% CI, 0.54–0.86). The GlnGln genotype might be more closely associated with shorter survival time and higher risks of death for patients (GlnGln vs. ArgArg: hazard ratio (HR) = 1.14, 95% CI, 0.75–1.75). Our cumulative meta-analyses indicated a distinct apparent trend toward a better response rate for Arg194Trp, but a poorer response rate in Arg399Gln. These findings indicate a predictive role of XRCC1 polymorphisms in clinical outcomes. The use of XRCC1 polymorphisms as predictive factor of clinical outcomes in personalized chemotherapy treatment requires further verification from large well-designed pharmacogenetics studies.

XRCC1 polymorphism and overall survival in ovarian cancer patients treated with platinum-based chemotherapy

“…These polymorphisms, which lead to the encoded amino acid changes that might affect the normal function of XRCC1 protein, might alter the efficiency of DNA repair and result in carcinogenesis development. [ 10 ] But, in our study, we did not find a significant association between these 2 genes and OC, which showed good agreement with 2 previous studies conducted in Russia and Korea. [ 31 , 32 ] Only in further stratified analysis by disease status, 399GlnGln was shown to be predictive in OS when different percentage of patients with stage III and IV were analyzed.…”

“…[ 36 , 37 ] Genetic polymorphisms of drug target genes, genes involving in detoxification pathways and DNA repair pathways may influence the anticancer therapeutic efficacy of platinum drugs and reveal platinum sensitivity in patients. [ 10 ] Therefore, other genetic variations may also be significantly associated with outcomes, and combined analysis of various genes for prognosis of platinum-based chemotherapy should be considered. Furthermore, the sample size and ethnic factor may be another reason.…”

Targeting DNA Damage Response in the Radio(Chemo)therapy of Non-Small Cell Lung Cancer

“…Evidence from lung cancer patients showed that XRCC1 (rs25487, Arg399Gln) might influence radiation and platinum-based chemotherapy wherein patients with the ancestral allele (G) were found to be more radiosensitive and have a higher overall survival [ 38 ], while the XRCC1 399Arg/Arg genotype carriers had a higher response rate than that of the Gln genotype carriers (OR = 4.81, 95% CI = 1.778–13.013, p = 0.002) [ 39 , 40 ] and a poor overall survival in a short-term period (HR = 1.718, p = 0.003; HR = 1.691, p = 0.003, respectively) in a treatment with platinum-based chemotherapy for NSCLC patients [ 41 ]. As for the XRCC1 Arg194Trp polymorphism, it was found to be significantly associated with better response rates to platinum-based chemotherapy in advanced NSCLC [ 36 , 42 , 43 ].…”

Interaction of Arg194Trp and Arg399Gln genotypes with the risk of radiation on cancer patients

“…The main function of XRCC1 is associated with its role in the path of single-strand breaks (SSBs) damage and base excision repair (BER) pathways through the enzymatic stage (Campalans et al 2015;Norjmaa et al 2016). XRCC1 gene polymorphism that occurs in DNA repair genes resulting in decreased DNA repair ability, increased mutation rate and cancer risk such as breast, prostate cancer, cervical cancer, and lung cancer (Moullan et al 2003;Rybicki et al 2004;Ochiai 2015;Yuan et al 2015;Meng et al 2017).…”