Association Of Ca Repeat Number And R497k With Pfs To Egfr Tkis In Nsclc Patients Having Sensitive Mutation Of Egfr.

7592 Background: It has been well known that EGFR mutation on particular exons is 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 TKI might be related to specific single nucleotide polymorphisms (SNPs) regulating the expression of EGFR gene. Methods: In 165 advanced or metastatic NSCLC pts receiving gefitinib or erlotinib, we assayed mutation status of EGFR in paraffin embedded tumor tissue using direct sequencing and genotyped six different SNPs in genomic DNA extracted from peripheral blood; exon 191C>A, exon 216 G>T, CA repeat number, exon 13 R497K, exon 20 2607G>A, and exon 25 D994D. Results: Sex ratio was 80:85 and median age was 63.1 (35-82). Histological subtype was adenocarcinoma 131, squamous cell ca. 22, and BAC 3, etc. Objective response (CR+PR) was observed in 63pts (38.2%) and SD in 52 pts (31.5%). Median PFS was 4.3 months (95% CI 2.87-5.80). Analysis for EGFR mutation was done in 90 pts and 44 (48.9%) showed EGFR harboring sensitive mutation (mutEGFR). The pts having total number of CA repeat (38) was 100 (60.6%). In R497K, wild type (RR) was 36 (21.8%). Heterozygote (RK) and homozygote variants (KK) were 71 (43.0%) and 58 (35.2%), respectively. In D994D, wild type (GG) was 72 (43.6%) and heterozygote and homozygote variants (GA+AA) were 93 (56.4%). Statistically significant differences of PFS and OS were observed between wild and hetero-/homozygote variants of R497K (4.2 vs. 15.9 m, p=0.002 and 10.0 vs. 32.0 m, p=0.007, respectively). In the pts harboring mutEGFR, low (CA)N (and RK+KK variants of R497K demonstrated much longer PFS compared with high (CA)N and wild type (30.4 vs. 8.3 m, p=0.08 and 15.8 vs. 3.6 m, p=0.01, respectively). In the pts having wild type EGFR, GA+AA variants of D994D showed much longer PFS compared with wild type (12.6 vs. 3.8 m, p=0.09). Conclusions: Taken together, we suggest that (CA)N and R497K, germline genetic variations of EGFR gene, might be useful pharmacogenetic biomarker to predict longer PFS in NSCLC pts harboring mutEGFR.