Actionable gene-based classification toward precision medicine in gastric cancer

Hiroshi Ichikawa,Hitoshi Kameyama,Kohei Akazawa,Ryota Nakanishi,Takao Tanahashi ,Yuko Kitagawa,Shujiro Okuda,Yasuhiro Shimada ,Nobuaki Sato,Masayuki Nagahashi,Kazuaki Takabe,Takashi Ishikawa,Satoru Nakagawa,Takashi Kobayashi,Yiwei Ling,Eiji Oki,Hiroshi Yabusaki,Kazuhiro Yoshida,Dana Vuzman,Yuki Hirata,Takaaki Hanyu,Jun Sakata,Stephen Lyle,Toshifumi Wakai

doi:10.1186/s13073-017-0484-3

Abstract

BackgroundIntertumoral heterogeneity represents a significant hurdle to identifying optimized targeted therapies in gastric cancer (GC). To realize precision medicine for GC patients, an actionable gene alteration-based molecular classification that directly associates GCs with targeted therapies is needed.MethodsA total of 207 Japanese patients with GC were included in this study. Formalin-fixed, paraffin-embedded (FFPE) tumor tissues were obtained from surgical or biopsy specimens and were subjected to DNA extraction. We generated comprehensive genomic profiling data using a 435-gene panel including 69 actionable genes paired with US Food and Drug Administration-approved targeted therapies, and the evaluation of Epstein-Barr virus (EBV) infection and microsatellite instability (MSI) status.ResultsComprehensive genomic sequencing detected at least one alteration of 435 cancer-related genes in 194 GCs (93.7%) and of 69 actionable genes in 141 GCs (68.1%). We classified the 207 GCs into four The Cancer Genome Atlas (TCGA) subtypes using the genomic profiling data; EBV (N = 9), MSI (N = 17), chromosomal instability (N = 119), and genomically stable subtype (N = 62). Actionable gene alterations were not specific and were widely observed throughout all TCGA subtypes. To discover a novel classification which more precisely selects candidates for targeted therapies, 207 GCs were classified using hypermutated phenotype and the mutation profile of 69 actionable genes. We identified a hypermutated group (N = 32), while the others (N = 175) were sub-divided into six clusters including five with actionable gene alterations: ERBB2 (N = 25), CDKN2A, and CDKN2B (N = 10), KRAS (N = 10), BRCA2 (N = 9), and ATM cluster (N = 12). The clinical utility of this classification was demonstrated by a case of unresectable GC with a remarkable response to anti-HER2 therapy in the ERBB2 cluster.ConclusionsThis actionable gene-based classification creates a framework for further studies for realizing precision medicine in GC.

Highlights

Intertumoral heterogeneity represents a significant hurdle to identifying optimized targeted therapies in gastric cancer (GC)
Regarding 69 actionable genes which associated with Food and Drug Administration (FDA)-approved targeted therapies, at least one alteration was detected in 141 patients (68.1%)
Molecular classification according to The Cancer Genome Atlas (TCGA) subtype in Japanese GCs The 207 Japanese GCs were classified into four TCGA subtypes based on the genomic profiling data from the 435-gene panel (Fig. 1a)

Summary

Introduction

Intertumoral heterogeneity represents a significant hurdle to identifying optimized targeted therapies in gastric cancer (GC). To realize precision medicine for GC patients, an actionable gene alteration-based molecular classification that directly associates GCs with targeted therapies is needed. A number of clinical trials of targeted therapies have been conducted to improve the outcome of unresectable or recurrent GC [4]. The other targeted therapies failed to show any survival benefit in phase III clinical trials, deemed most likely due to the heterogeneous nature of GC and the lack of appropriate molecular biomarkers. A better understanding of the molecular profiles of GC and optimum patient selection based on the molecular alterations is necessary to facilitate targeted therapies for GC

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Results

Discussion

Conclusion