The P38α rs3804451 Variant Predicts Chemotherapy Response and Survival of Patients with Non–Small Cell Lung Cancer Treated with Platinum-Based Chemotherapy

Abstract

The JNK and P38α pathways play an important role in the sensitivity and outcomes of chemotherapy. We hypothesize that functional single nucleotide polymorphisms (SNPs) of genes of these pathways modulate outcomes of patients with advanced non–small cell lung cancer (NSCLC) treated with first-line platinum-based chemotherapy (PBC). We selectively genotyped 11 independent, potentially functional SNPs of 9 genes in the JNK and P38α pathways first in a discovery group of 355 patients with advanced NSCLC treated with PBC, and we evaluated their associations with progression-free survival (PFS) and overall survival (OS) by Cox proportional hazards regression analysis. Then, resultant significant SNPs were further validated in a replication group of 355 patients. In both discovery and validation groups as well as their combined analysis, the MAPK14 rs3804451GA/AA genotypes showed a strong association with a reduced PFS (adjusted hazards ratio [HR] = 1.39; 95% confidence interval [CI] = 1.16–1.66; P = .0003) and OS (adjusted HR = 1.41; 95% CI = 1.11-1.80; P = .005) compared with the wild-type GG genotype. In contrast, patients with or without the MAPK14 rs3804451A allele had no significant difference in OS in response to tyrosine-kinase inhibitor treatment (adjusted HR = 0.86; 95% CI = 0.56-1.33; P = .505). The present study provides evidence that the MAPK14 rs3804451 G>A variant may modulate survival outcomes in patients with advanced NSCLC treated with PBC. Larger studies of additional patient populations are needed to validate our findings.

Genetic variants in ERCC1 and XPC predict survival outcome of non-small cell lung cancer patients treated with platinum-based therapy

“…Furthermore, 219 (30.8%) and 257 (36.2%) of the patients received palliative radiotherapy and tyrosine-kinase inhibitor (TKI) treatment, respectively. The associations of these demographic characteristics and the known risk factors with NSCLC survival were also described in a previous publication 24 . The characteristics of demographic and clinical variables are described in Supplemental Table S2 .…”

“…The present study consisted of 710 patients diagnosed with NSCLC 24 , who had DNA samples, complete data on demographic, clinical characteristics, progression free survival (PFS) and overall survival (OS). Of all the patients, 508 were males and 202 were females, with a median age at diagnosis of 58 (a range of 23–83) years, and 334 (47%) were never, 41 (5.8%) former, and 335 (47.2%) current smokers.…”

An ERCC4 regulatory variant predicts grade‐3 or ‐4 toxicities in patients with advanced non‐small cell lung cancer treated by platinum‐based therapy

“…The discovery group included 355 patients recruited between February 2009 and February 2012, whereas the replication group consisted of 355 patients recruited from March 2012 to November 2013. Further details about the recruitment have been described elsewhere . In brief, the recruited patients were unrelated Han Chinese with inoperable TNM stages III to IV tumors of NSCLC without prior history of cancer other than in situ carcinoma; received PBC as the first‐line treatment; the Eastern Cooperative Oncology Group performance (ECOG) status 0 to 2 with normal blood and uronoscopy laboratory test results; no active infection, serious medical or psychological conditions that might affect adverse events; and at least two chemotherapy cycles except for those who developed severe toxicity after one cycle.…”

“…Further details about the recruitment have been described elsewhere. 17 In brief, the recruited patients were unrelated Han Chinese with inoperable TNM stages III to IV tumors of NSCLC without prior history of cancer other than in situ carcinoma; received PBC as the first-line treatment; the Eastern Cooperative Oncology Group performance (ECOG) status 0 to 2 with normal blood and uronoscopy laboratory test results; no active infection, serious medical or psychological conditions that might affect adverse events; and at least two chemotherapy cycles except for those who developed severe toxicity after one cycle. Clinical data, including age at treatment, sex, smoking status, ECOG performance, TNM stage, histological type and grade, chemotherapy regimen options and radiotherapy treatment, were collected from patients' medical records.…”