Gastric Cancer

, Volume 22, Issue 1, pp 69–76 | Cite as

Clinicopathological features of 22C3 PD-L1 expression with mismatch repair, Epstein–Barr virus status, and cancer genome alterations in metastatic gastric cancer

  • Akihito Kawazoe
  • Kohei ShitaraEmail author
  • Yasutoshi Kuboki
  • Hideaki Bando
  • Takashi Kojima
  • Takayuki Yoshino
  • Atsushi Ohtsu
  • Atsushi Ochiai
  • Yosuke Togashi
  • Hiroyoshi Nishikawa
  • Toshihiko Doi
  • Takeshi Kuwata
Original Article



Recently, the U.S. Food and Drug Administration approved pembrolizumab for patients (pts) with PD-L1-positive metastatic gastric cancer (MGC) based on 22C3 immunohistochemistry (IHC) assay. However, little is known about detailed clinicopathological features of 22C3 PD-L1 expression in MGC.

Patients and methods

Pts with histologically confirmed MGC were eligible for this prospective observational study. PD-L1 expression (22C3) on tumor cell (TC) or immune cell (IC) and mismatch repair (MMR) were analyzed by IHC. Epstein–Barr virus (EBV) was detected by in situ hybridization. The expressions of tyrosine kinase receptors (RTKs) and cancer genome alterations were evaluated by IHC or next-generation sequencing.


A total of 225 pts were analyzed in this study. PD-L1 expression on TC, PD-L1 on IC, MMR-deficient (D-MMR), and EBV positivity were identified in 8.4, 65.3, 6.2, and 6.2% cases, respectively. PD-L1 expression in TC was more frequently observed in pts with D-MMR (P < 0.001), PIK3CA mutation (P = 0.020), and KRAS mutation (P = 0.002), and PD-L1 on IC was associated with EBV positivity (P = 0.034), and lymph-node metastasis (P < 0.001). PD-L1 expression on either IC or TC was less frequently observed in pts with peritoneal metastasis and Borrmann Type 4. A significant association was not observed between PD-L1 expression and RTKs expression or presence of other gene alterations. PD-L1 expression on either TC or IC was not prognostic factor.


22C3 PD-L1 expression in MGC was associated with distinct clinicopathological features, but was not a prognostic factor.


22C3 PD-L1 expression Metastatic gastric cancer Mismatch repair Epstein–Barr virus Cancer genome alterations 



This study was supported by a research funding from National Cancer Center Hospital East (none apply).

Compliance with ethical standards

Conflict of interest

KS has received personal fees from Astellas, Bristol-Myers Squibb, Takeda, Pfizer, Novartis, Abbvie and Yakult; grants and personal fees from Eli Lilly and Ono Pharma; grants from Sumitomo Dainippon Pharma, MSD, Daiichi-Sankyo, Taiho Pharma, and Chugai Pharma. All remaining authors have declared no conflicts of interest. YK has received personal fees from Taiho Pharma, Bayer, and Eli Lilly; grants from Takeda, AstraZeneca, Daiichi-Sankyo, and Incyte. TY has received personal fees from Eli Lilly; grants from GlaxoSmithKline K.K and Nippon Boehringer Ingelheim Co., Ltd. AO has received grants from Bristol-Myers Squibb. YT has received personal fees and grants from Ono Pharma, personal fees from MSD, Chugai Pharmaceutical Co., Ltd, AstraZeneca, Boehringer Ingelheim Japan Inc, Novartis Pharma, and Eli Lilly Japan. HN has received grants from Ono Pharma, Kyowa Hakko Kirin, Sysmex, Taiho Pharma, Zenyaku-kogyo, and Daiichi-Sankyo. TD has received personal fees from Amgen; grants and personal fees from Eli Lilly, Chugai Pharma, Kyowa Hakko Kirin, MSD, and Daiichi Sankyo; grants from Taiho Pharma, Novartis, Merck Serono, Astellas Pharma Janssen, Boehringer Ingelheim, Takeda, Pfizer and Sumitomo Group, Celegene and Bristo Myers Squibb, Abbvie, and Quintiles. TK has received personal fees from Chugai Pharma and grants from government. All remaining authors have declared no conflicts of interest.

Human rights statement

All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1964 and later versions.

Informed consent

Informed consent or substitute was obtained from all patients for being included in the study.

Supplementary material

10120_2018_843_MOESM1_ESM.docx (40 kb)
Supplementary material 1 (DOCX 40 KB)


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Copyright information

© The International Gastric Cancer Association and The Japanese Gastric Cancer Association 2018

Authors and Affiliations

  • Akihito Kawazoe
    • 1
  • Kohei Shitara
    • 1
    Email author
  • Yasutoshi Kuboki
    • 1
  • Hideaki Bando
    • 1
  • Takashi Kojima
    • 1
  • Takayuki Yoshino
    • 1
  • Atsushi Ohtsu
    • 1
  • Atsushi Ochiai
    • 2
  • Yosuke Togashi
    • 3
  • Hiroyoshi Nishikawa
    • 3
  • Toshihiko Doi
    • 1
  • Takeshi Kuwata
    • 2
  1. 1.Department of Gastroenterology and Gastrointestinal OncologyNational Cancer Center Hospital EastKashiwaJapan
  2. 2.Department of Pathology and Clinical LaboratoriesNational Cancer Center Hospital EastKashiwaJapan
  3. 3.Division of Immunology, Research Cancer for Innovative OncologyNational Cancer Center Hospital EastKashiwaJapan

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