Abstract
PurposeDespite discrepant results on clinical utility, several trials are already prospectively randomizing non-small cell lung cancer (NSCLC) patients by ERCC1 status. We aimed to characterize the prognostic and predictive effect of ERCC1 by systematic review and meta-analysis.MethodsEligible studies assessed survival and/or chemotherapy response in NSCLC or SCLC by ERCC1 status. Effect measures of interest were hazard ratio (HR) for survival or relative risk (RR) for chemotherapy response. Random-effects meta-analyses were used to account for between-study heterogeneity, with unadjusted/adjusted effect estimates considered separately.Results23 eligible studies provided survival results in 2,726 patients. Substantial heterogeneity was observed in all meta-analyses (I2 always >30%), partly due to variability in thresholds defining ‘low’ and ‘high’ ERCC1. Meta-analysis of unadjusted estimates showed high ERCC1 was associated with significantly worse overall survival in platinum-treated NSCLC (average unadjusted HR = 1.61, 95%CI:1.23–2.1, p = 0.014), but not in NSCLC untreated with chemotherapy (average unadjusted HR = 0.82, 95%CI:0.51–1.31). Meta-analysis of adjusted estimates was limited by variable choice of adjustment factors and potential publication bias (Egger's p<0.0001). There was evidence that high ERCC1 was associated with reduced response to platinum (average RR = 0.80; 95%CI:0.64–0.99). SCLC data were inadequate to draw firm conclusions.ConclusionsCurrent evidence suggests high ERCC1 may adversely influence survival and response in platinum-treated NSCLC patients, but not in non-platinum treated, although definitive evidence of a predictive influence is lacking. International consensus is urgently required to provide consistent, validated ERCC1 assessment methodology. ERCC1 assessment for treatment selection should currently be restricted to, and evaluated within, clinical trials.
Highlights
Lung cancer is the commonest cause of cancer death globally, accounting for around 1.3 million deaths per year [1]
Rosell et al [38] stratified patients into groups who received three different chemotherapy regimes, one of which overlapped with a larger cohort [39] and was excluded; Olaussen et al [36] reported separately on patients randomised to either chemotherapy or observation following resection; Okuda et al [28] presented separate outcome data from non-randomised cohorts who underwent either peri-operative chemotherapy or surgery alone; and Fujii et al [32] separately analysed outcomes for patients undergoing neoadjuvant chemotherapy or chemoradiotherapy, but datapoints were not extractable for the chemoradiotherapy group and this dataset was excluded
Meta-analysis of three studies in SCLC (292 patients), provided evidence of a trend towards increased response to platinum-containing chemotherapy in high excision repair cross-complementation group 1 (ERCC1) expressing tumours, this was not statistically significant
Summary
Lung cancer is the commonest cause of cancer death globally, accounting for around 1.3 million deaths per year [1]. Survival from both major subtypes (nonsmall cell lung cancer (NSCLC) and SCLC) remain poor, with only around 5% of all patients reaching 5 years. ERCC1 is the rate-limiting member of the nucleotide excision repair pathway (NER), one of at least 5 overlapping biochemical pathways by which altered DNA sequences can be restored to base-line. Abrogation of these pathways has been both associated with carcinogenesis [5], and targeted as a therapeutic mechanism [6]. Mechanisms of platinum cytotoxicity include forming bulky DNA adducts leading to both inter-and intrastrand cross-link generation, which results in apoptosis unless repaired
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