Germline Polymorphisms in EGFR and Survival in Patients With Lung Cancer Receiving Gefitinib

Abstract

The purpose of this study was to evaluate associations between germline epidermal growth factor receptor (EGFR) variants involved in transcriptional regulation and overall survival in white patients with non-small-cell lung cancer (NSCLC) treated with the EGFR tyrosine kinase inhibitor, gefitinib. Of 175 consecutive patients treated with oral gefitinib (250 mg/day), 170 (median age: 67 years; 72% men) were evaluable for genotyping and survival. Fifty-five patients (33%) had stable disease and 17 (10%) had an objective response. The most common of four haplotypes was G-C (EGFR*1) at the EGFR -216G>T and -191C>A loci (frequency, 0.45). After adjusting for performance status, previous platinum-containing chemotherapy and occurrence of skin rash or diarrhea during the first treatment cycle in patients with performance status 0 or 1 (N=139), the absence of EGFR*1 was associated with significantly better survival (hazard ratio: 0.54; 95% confidence interval: 0.32-0.91; P=0.015). The results may help identify patients with NSCLC who can benefit from gefitinib treatment.

Association of Polymorphisms inAKT1andEGFRwith Clinical Outcome and Toxicity in Non–Small Cell Lung Cancer Patients Treated with Gefitinib

“…All polymorphisms followed the Hardy-Weinberg's equilibrium (Table 2), as calculated with the SNP analyzer software, 11 and allelic frequencies for the EGFR polymorphisms were comparable with those reported in previous studies in Caucasian-predominant NSCLC patients (25,28), whereas the frequencies of AKT1-SNP3 and SNP4 were similar to those observed in Caucasian populations (36,37). No significant correlations were detected between genotype and baseline demographic characteristics.…”

“…The length of a CA-repeat in intron-1 was associated with gefitinib response and/or time-to-progression(TTP)/OS in several retrospective studies (22)(23)(24)(25)(26). However, this polymorphism was not correlated with EGFR expression in cell lines and NSCLC tissues (24,27), and no association with clinical outcome was observed in the largest pharmacogenetic analysis in NSCLC Caucasian patients treated with gefitinib (28). Interethnic differences in CA-intron-1-repeat frequency and linkage disequilibrium with other polymorphisms may explain these controversial results (29,30).…”

“…The CA repeat length in the intron-1 (CA)n and the −216G/T (dbSNP-ID: rs712829) EGFR polymorphisms were studied as previously described (28,32). The EGFR −191C/A (dbSNP-ID:rs712830) and R497K (G/A, dbSNP-ID:rs11543848), and the AKT1-SNP3 C/T (dbSNP-ID:rs3730350) and SNP4 G/A (dbSNP-ID:rs1130233) were studied with Taqman probe-based assays using the ABI PRISM-7500HT.…”

Overview of molecular testing in non-small-cell lung cancer: mutational analysis, gene copy number, protein expression and other biomarkers of EGFR for the prediction of response to tyrosine kinase inhibitors

“…Asian patients tend to have longer CA repeat lengths. Two Asian studies (Han et al, 2007;Nie et al, 2007) and one American study found associations with lung cancer survival or toxicity with gefitinib, whereas others found no significant association (Ichihara et al, 2007;Gregorc et al, 2008). Shorter CA repeat lengths were associated with poorer survival in the absence of therapy with an EGFR TKI, which is a reversal of expectations in TKI-treated patients (Dubey et al, 2006).…”

“…Both the EGFR -216G/T and -191C/A polymorphisms are located in the transcriptional start site region of the promoter, wherein multiple nuclear regulatory affinity sites are located (Liu et al, 2005). Two studies in Caucasian patients reported that the -216G/T variant, alone or in combination with -191C/A, was associated with improved outcome, greater toxicity to gefitinib or both (Cusatis et al, 2006;Liu et al, 2008), whereas a third found no association (Gregorc et al, 2008). Among Asians, these variants are rare (Ichihara et al, 2007).…”