Prognostic impact of KRAS mutant type and MET amplification in metastatic and recurrent gastric cancer patients treated with first-line S-1 plus cisplatin chemotherapy.

Satoshi Matsusaka,Yuichi Ishikawa,Noriko Yamamoto,Takashi Kobunai,Toshiharu Yamaguchi,Nobuyuki Mizunuma,Keisho Chin,Gotaro Tanaka,Kazuaki Matsuoka,Mariko Ogura

doi:10.18632/genesandcancer.96

Satoshi Matsusaka, Yuichi Ishikawa + Show 8 more

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https://doi.org/10.18632/genesandcancer.96

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Abstract

Receptor tyrosine kinase (RTK)-related genes, including HER2, EGFR, MET, FGFR2 and KRAS, are target molecules that are clinically beneficial in gastric cancer (GC). We investigated the correlation between RTK-related genes and the curative effect of first-line S-1 plus cisplatin (SP) combination chemotherapy in metastatic and recurrent GC. We enrolled 150 patients with histopathologically confirmed metastatic and recurrent GC treated with SP. KRAS mutation was detected using direct sequencing. DNA copy number was measured by real-time PCR. Formalin-fixed paraffin-embedded specimens were examined immunohistochemically for HER2, EGFR, FGFR2 and MET. Among 144 patients, KRAS mutation was detected in five (3.5%) at codon 12 and one (0.7%) at codon 13. FGFR2, EGFR, HER2, MET and KRAS gene amplification was suggested in 4.4%, 5.9%, 9%, 3.7% and 10.3% of patients, respectively. KRAS mutation, but not KRAS amplification, was associated with significantly shorter overall and progression-free survival. MET membranous overexpression was associated with a significantly higher tumor response. MET amplification was associated with significantly shorter overall survival. We show for the first time that KRAS mutation and MET amplification are promising predictive markers in metastatic and recurrent GC patients treated with SP. KRAS status may be a useful prognostic marker in patients treated with SP.

Highlights

We enrolled 150 patients with metastatic and recurrent gastric cancer (GC) treated with first-line S-1 plus cisplatin (SP) combination chemotherapy
To the best of our knowledge, we are the first to demonstrate that KRAS mutation in tumors independently predicts worse progression-free survival (PFS) and overall survival (OS) in patients with metastatic and recurrent GC treated with SP
It is reported that GC cell lines, which have MEK1 mutation or MEK1 and KRAS mutations, are hypersensitive to MEK1 inhibitors [20]

Summary

Introduction

We enrolled 150 patients with metastatic and recurrent GC treated with first-line SP combination chemotherapy. One tumor exhibited high-level amplification of a component with two low-level amplifications (high FGFR2/low KRAS and EGFR amplification in one case). The distribution of FGFR2 and MET expression was observed diffusely in tumors (Supplementary Figure 1A, B). FGFR2 membranous (FGFR2-m) overexpression (more than median H score) was observed in 55% of tumors. FGFR2 cytoplasmic (FGFR2-c) overexpression was observed in 47% of tumors. MET membranous (MET-m) overexpression was observed in 51% of tumors. MET cytoplasmic (MET-c) overexpression was observed in 49% of tumors. The distribution of EGFR and HER2 expression was observed locally in tumors.

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