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. 2020 Jul 28;11(30):2906-2918.
doi: 10.18632/oncotarget.27658.

Biomarker analysis to predict the pathological response to neoadjuvant chemotherapy in locally advanced gastric cancer: An exploratory biomarker study of COMPASS, a randomized phase II trial

Takashi Oshima  1 , Takaki Yoshikawa  2 , Yohei Miyagi  3 , Satoshi Morita  4 , Michio Yamamoto  5 , Kazuaki Tanabe  6 , Kazuhiro Nishikawa  7 , Yuichi Ito  8 , Takanori Matsui  9 , Yutaka Kimura  10 , Tomoyuki Yokose  11 , Yukihiko Hiroshima  3 , Toru Aoyama  12 , Tsutomu Hayashi  2 , Takashi Ogata  1 , Haruhiko Cho  13 , Yasushi Rino  12 , Munetaka Masuda  12 , Akira Tsuburaya  14 , Junichi Sakamoto  15
Affiliations

Biomarker analysis to predict the pathological response to neoadjuvant chemotherapy in locally advanced gastric cancer: An exploratory biomarker study of COMPASS, a randomized phase II trial

Takashi Oshima et al. Oncotarget. .

Abstract

Background: The findings of COMPASS, a randomized phase II study, suggested that the regimens and courses of neoadjuvant chemotherapy (NAC) for locally advanced gastric cancer (GC) did not affect the pathological response. However, pathological complete response was achieved in 10% patients who received four courses of either S-1/cisplatin or paclitaxel/cisplatin. We hypothesized that if relevant biomarkers could be used to predict the suitable NAC regimen before treatment initiation, further improvements could be ensured in the outcomes of locally advanced GC.

Materials and methods: mRNA extraction, real-time polymerase chain reaction, and immunohistochemical analyses were performed using endoscopic biopsy specimens of primary tumors, collected prior to NAC, to determine the clinically relevant biomarkers.

Results: TIMP1, DSG2, RRM1, MUC2, EGFR, ZDHHC14, and CLDN18.2 were identified as biomarker candidates, since their expression was significantly associated with the pathological responses to each NAC regimen. Furthermore, TIMP1 and DSG2 were identified as predictive biomarkers of the pathological response to each NAC regimen.

Conclusions: The effective prediction of the pathological response to NAC regimens in locally advanced GC using biomarkers identified from endoscopic biopsy specimens indicates the possibility of personalizing NAC based on biomarker analysis.

Keywords: gastric cancer; neoadjuvant chemotherapy; pathological response; personalized therapy; predictive biomarkers.

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Conflict of interest statement

CONFLICTS OF INTEREST TO: Research Funding: Taiho pharmaceutical Co., Ltd, Chugai pharmaceutical Co., Ltd, Ono pharmaceutical Co., Ltd, Daiitisankyo pharmaceutical, Nippon Kayaku Co., Ltd, and Eli Lilly Japan K. K. Lecture fees: Nippon Kayaku Co., Ltd, Ono pharmaceutical Co.Ltd and Bristol-Myers Squibb K. K. Speaker Bureau: Taiho pharmaceutical Co., Ltd, Chugai pharmaceutical Co., Ltd, Ono pharmaceutical Co., Ltd, Bristol-Myers Squibb K. K and Eli Lilly Japan K. K. These are unrelated to the submitted work. TY: Lecture fees from: MSD, ONO, BMS, Taiho, Chugai, Daiichi-Sankyo, Lilly, Johnson and Johnson, Covidien, and Olympus. Personal grant from Lilly. These are unrelated to the submitted work. YM: Lecture fees from AstraZeneca, Taiho, Chugai, and Daiichi-Sankyo. Consigned research fund from Toso company, Limited, Japan. These are unrelated to the submitted work. YR: Speaker Bureau from; Daiichi-Sankyo, Johnson and Johnson, Otsuka, Lilly, Taiho pharmaceutical, Bristol-Myers Squibb. Research Funding: Taiho pharmaceutical, Abbott, Asahi Kasei, Daiichi-Sankyo, Tsumura & Co., Covidien, Zeria pharmaceutical, Otsuka, EA Pharma, Johnson and Johnson. These are unrelated to the submitted work. MM: Research Funding from Chugai pharmaceutical, Teijin pharmaceutical, Daiitisankyo pharmaceutical, Takeda pharmaceutical, Terumo Co.Ltd., Japan Lifeline Co.Ltd, Senko Co.Ltd. These are unrelated to the submitted work. The other co-authors declare no conflicts of interest relevant to this work. KY: Speaker Bureau from; Bristol-Myers Squibb K. K., Chugai pharmaceutical, EA Pharma, Eli Lilly Japan K. K., Ono pharmaceutical Co., Ltd, Taiho pharmaceutical Co. and Yakult. These are unrelated to the submitted work.

Figures

Figure 1
Figure 1. CONSORT diagram.
Among the 83 patients who participated in the COMPASS trial, mRNA extraction was performed successfully for 78 patients (94%) and the expression levels of 127 genes were measurable in 46 patients (55%). Twenty-three patients received SC; the remaining 23 received PC.
Figure 2
Figure 2. Immunohistochemical images for proteins encoded by seven biomarker candidate genes.
Immunohistochemical studies were performed for proteins encoded by seven biomarker candidate genes, ZDHHC14, TIMP1, CLDN18.2, EGFR, RRM1, MUC2 and DSG2 using formalin-fixed, paraffin-embedded biopsy specimens obtained from 24 patients. Immunohistochemical evaluation was performed based on the positive immunostained tumor cells with maximum intensity and the percentage of positive immunostained tumor cells. Representative images of high and low immunostaining of each biomarker candidate are shown.
Figure 3
Figure 3. The relationship between protein and gene expression determined by immunohistochemical and mRNA expression analysis in the same specimens.
The expression of proteins encoded by the biomarker candidates was examined at the mRNA level in the same samples. Based on the comparison of the mRNA expression levels of samples that were high immunoreactivity and low/negative immunoreactivity, significant differences were observed in the mRNA expression levels of TIMP1 (B), CLDN18.2 (C), and DSG2 (G). There was no significant difference in the expression levels of ZDHHC14 (A), EGFR (D), RRM1 (E), MUC2 (F).
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