J Cancer 2019; 10(21):5130-5138. doi:10.7150/jca.34741

Research Paper

Comprehensive biomarker analyses identifies HER2, EGFR, MET RNA expression and thymidylate synthase 5'UTR SNP as predictors of benefit from S-1 adjuvant chemotherapy in Japanese patients with stage II/III gastric cancer

Takaki Yoshikawa1,2#, Toru Aoyama2#, Kentaro Sakamaki3, Takasi Oshima2, Joyce Lin4, Shenli Zhang5, Nur Sabrina Sapari6, Richie Soong6, Iain Tan7, Xiu Bin Chan8, Dan Bottomley9, Lindsay C Hewitt10, Tomio Arai11, Bin Tean Teh5, David Epstein5, Takashi Ogata2, Yoichi Kameda12, Yohei Miyagi13, Akira Tsuburaya2, Satoshi Morita14, Heike I Grabsch9,10*✉, Patrick Tan4,5,6*✉

1. Department of Gastric Surgery, National Cancer Center Hospital, Tokyo, Japan
2. Department of Gastrointestinal Surgery, Kanagawa Cancer Center, Yokohama, Japan
3. Department of Biostatistics and Epidemiology, Yokohama City University, Yokohama, Japan
4. Cancer Therapeutics and Stratified Oncology, Genome Institute of Singapore, Singapore
5. Cancer and Stem Cell Biology Program, Duke-NUS Graduate Medical School, Singapore
6. Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore
7. Department of Pathology, National University of Singapore, Singapore, Singapore
8. Cancer Therapeutics and Stratified Oncology, Genome Institute of Singapore, Singapore
9. Division of Pathology and Data Analytics, Leeds Institute of Medical Research at St James's, University of Leeds, Leeds, UK
10. Department of Pathology, GROW School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, NL
11. Department of Pathology, Tokyo Metropolitan Geriatric Hospital and Institute of Gerontology, Tokyo, Japan
12. Department of Pathology, Kanagawa Cancer Center, Yokohama, Japan
13. Molecular Pathology and Genetics Division, Kanagawa Cancer Center Research Institute, Yokohama, Japan
14. Department of Biomedical Statistics and Bioinformatics, Graduate School of Medicine, Kyoto University, Kyoto, Japan
#Takaki Yoshikawa and Toru Aoyama equally contributed this article.
* Joint senior authors

Abstract

Purpose: A comprehensive molecular analysis was conducted to identify prognostic and predictive markers for adjuvant S-1 chemotherapy in stage II/III Japanese gastric cancer (GC) patients and to evaluate their potential suitability for alternative cytotoxic or targeted drugs.

Experimental Design: We investigated genetic polymorphisms of enzymes potentially involved in 5-fluoruracil (5-FU) metabolism as well as platinum resistance, previously identified genomic subtypes potentially predicting 5-FU benefit, and mRNA expression levels of receptor tyrosine kinases and KRAS as potential treatment targets in a single institution cohort of 252 stage II/III GC patients treated with or without S-1 after D2 gastrectomy.

Results: 88% and 62% GC had a potentially 5-FU sensitive phenotype by SNP analyses of TS 3'UTR, and TS 5'UTR, respectively. 24%, 46%, 40%, 5%, and 44% GC had a potentially platinum sensitive phenotype by SNP analyses of GSTP1, ERCC1 rs11615, ERCC1 rs3212986, ERCC2, and XRCC1, respectively. High HER2, EGFR, FGFR2, or MET mRNA expression was observed in 49%, 66%, 72%, and 54% GC, respectively. High HER2 expression was the only significant prognosticator (HR=3.912, 95%CI: 1.706-8.973, p=0.0005). High HER2 (p=0.031), low EGFR (p=0.124), high MET (p=0.165) RNA expression, and TS 5'UTR subtype 2R/2R, 2R/3C, or 3C (p=0.058) were significant independent predictors for S-1 resistance.

Conclusions: The present study suggests that platinum-based or RTK targeted agents could be alternative treatment options for a substantial subgroup of Japanese GC patients currently treated with S-1. HER2, EGFR, MET, and TS 5'UTR SNP appear to be promising predictive markers for S-1 resistance warranting validation in an independent GC series.

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How to cite this article:
Yoshikawa T, Aoyama T, Sakamaki K, Oshima T, Lin J, Zhang S, Sapari NS, Soong R, Tan I, Chan XB, Bottomley D, Hewitt LC, Arai T, Teh BT, Epstein D, Ogata T, Kameda Y, Miyagi Y, Tsuburaya A, Morita S, Grabsch HI, Tan P. Comprehensive biomarker analyses identifies HER2, EGFR, MET RNA expression and thymidylate synthase 5'UTR SNP as predictors of benefit from S-1 adjuvant chemotherapy in Japanese patients with stage II/III gastric cancer. J Cancer 2019; 10(21):5130-5138. doi:10.7150/jca.34741. Available from http://www.jcancer.org/v10p5130.htm