Abstract
BackgroundBase excision repair (BER) pathway is a DNA repair pathway that is important in carcinogenesis and in response to DNA-damaging chemotherapy. XRCC1 is one of important molecular markers for BER. So far, the role of XRCC1 polymorphisms with clinical outcomes of advanced NSCLC treated with platinum-based chemotherapy is inconclusive. To explore the relationship between XRCC1 polymorphisms and platinum-based chemotherapy in advanced NSCLC patients, we performed this meta-analysis.MethodsCrude odds ratios (ORs), Cox proportional hazard ratios (HRs) with the corresponding 95% confidence intervals (CIs) were adopted to assess the strength of association between XRCC1 polymorphisms and response rate, Overall survival (OS) and progression free survival (PFS) of advanced NSCLC treated with platinum-based chemotherapy. Q test and I2 test were used for the assessment of heterogeneity. Subgroup analyses were conducted when heterogeneity exists. Begg’s funnel plots and Egger’s linear regression test were used to estimate publication bias. Sensitivity analysis was performed to evaluate the stability of the result.ResultsA total of 19 studies including 2815 individuals were eligible for the analysis, results showed XRCC1 194Arg allele was negatively associated with the objective response rate relative to 194Trp, and results of homozygous model, dominant model and heterozygous model suggested a gene dosage effect negative correlation between 194Arg allele and objective response rate(ArgArg vs TrpTrp: OR = 0.64(95%CI: 0.44-0.91); ArgArg + TrpArg vs TrpTrp: OR = 0.79(95%CI: 0.57-1.11); TrpArg vs TrpTrp: OR = 1.05(95%CI: 0.73-1.51)). XRCC1 399Gln may indicate favorable overall survival (GlnGln + GlnArg vs ArgArg: HR = 0.65(95%CI: 0.43–0.98)) and favorable PFS (GlnGln vs ArgArg: HR = 0.72(95%CI: 0.48–0.97)) in Asian patients; while in Caucasian patients, XRCC1 399Gln indicated poorer overall survival (GlnGln vs ArgArg: HR = 2.29(95%CI: 1.25–3.33)).ConclusionsOur results indicated that in NSCLC patients treated with platinum-based regimen, XRCC1 194Arg allele suggest poor objective response rate, the GlnGln genotype of XRCC1 399 suggest poorer overall survival in Caucasian patients, and longer PFS in Asian patients.
Highlights
Base excision repair (BER) pathway is a DNA repair pathway that is important in carcinogenesis and in response to DNA-damaging chemotherapy
A study was excluded if any of the following cases occurred: (i) the study did not report any clinical outcome; (ii) studies using X-ray repair cross-complementing protein 1 (XRCC1) polymorphisms either to predict lung cancer’s risk or to predict treatment toxicity; (iii) studies reported with the same data or overlapping data by the same authors; (iv) the response rate or overall survival reported in the study was either not specific to polymorphism or could not be attributed to a specific polymorphism; (v) the response rate or overall survival stratified by Single nucleotide polymorphisms (SNP) was neither reported in nor derivable from the original article, and the principal investigator declined or was unable to provide this information on request
Studies were carried out to explore whether nonplatinum-based chemotherapy could achieve comparable efficacy as platinum-based chemotherapy. [36, 37] Metaanalysis’ results show gemcitabine plus docetaxel (GD) acquired similar survival with platinum-based regimens in first-line treatment of advanced non-small cell lung cancer (NSCLC), platinumbased regimens had an advantage in time to progression (TTP) and overall response rate (ORR) with more grade 3–4 nausea/vomiting, anemia, neutropenia and febrile neutropenia compared with GD
Summary
Base excision repair (BER) pathway is a DNA repair pathway that is important in carcinogenesis and in response to DNA-damaging chemotherapy. [2] For decades, platinum-based combination chemotherapy has been established as the cornerstone of advanced non-small cell lung cancer (NSCLC) treatment [3, 4]. Molecular-targeted therapy has been confirmed as first-line therapy option for those advanced NSCLC with driver gene mutations, including epidermal growth factor receptor (EGFR), anaplastic lymphoma receptor tyrosine kinase (ALK), and KRAS mutations in recent years, still majority of NSCLC patients are not indicated to adopt molecular-targeted therapy. For these patients, platinum-based combination remains the first choice. It is very important to select suitable treatment program for individualized treatment
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