Two genetic polymorphisms of EGFR as useful predictive biomarkers for NSCLC patients receiving EGFR TKIs

e18050 Background: The EGFR mutation on particular exons has been known as a strong predictive biomarker to EGFR TKIs (tyrosine kinase inhibitors) in NSCLC pts. However, some pts having wild type EGFR do not infrequently show clinically favorable outcome to EGFR TKIs. Accordingly, we hypothesized that clinical outcome and skin toxicity to EGFR TKIs might be related to specific single nucleotide polymorphisms regulating the expression of EGFR gene as well as EGFR sensitive mutation. Methods: In 211 advanced or metastatic NSCLC pts receiving gefitinib or erlotinib, we assayed mutation status of EGFR in paraffin embedded tumor tissue using PNA clamping method and direct sequencing. Six different SNPs in genomic DNA extracted from peripheral blood were analyzed; promoter 191C>A, 216 G>T, CA repeat number, exon 13 R497K, exon 20 2607G>A, and exon 25 D994D. Results: M:F ratio was 106:105 and mean age was 63.2 (35.0-82.0). Histological subtypes are as follows: 175 adenocarcinoma, 32 squamous cell ca. and 3 large cell ca. Objective response (CR+PR) was observed in 78 pts (36.9%) and SD in 69 pts (32.7%). Median PFS and OS were 8.7 ± 11.3 and 15.9 ± 14.8 months, respectively. Of 167 pts in whom EGFR mutation was analyzed, 68 pts (40.7%) had EGFR harboring sensitive mutation. In R497K, wild type (RR) was 35 (21.0%) and K alleles (RK + KK) were 132 (79.0%). In D994D, wild type (GG) was 76 (45.5%) and heterozygote and homozygote variants (GA+AA) were 91(54.5%). Statistically significant differences of PFS and OS were observed between wild and hetero-/homozygote variants of R497K (11.9 m vs. 36.2 m, p=0.037 and 23.7 m vs. 39.1 m, p=0.054, respectively) in the pts harboring mutant type EGFR. Meanwhile, in the pts harboring wild type EGFR, GA+ AA genotype of D994D demonstrated much longer PFS and OS compared with GG genotype (PFS: 18.5 vs. 3.7 m, p=0.013 and 37.6 vs. 15.2 m, p=0.035, respectively). In addition, skin rash showed statistically significant association with R497K polymorphism (P=0.031). Conclusions: Our data suggest that two germline genetic variations of EGFR gene, R497K and D994D, be useful pharmacogenetic biomarker to predict longer PFS and OS for EGFR TKIs in advanced NSCLC pts harboring mutant type and wild type EGFR, respectively.