Advertisement

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
  • 524 Downloads

Abstract

Background

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.

Results

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.

Conclusions

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

Keywords

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

Notes

Funding

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)

References

  1. 1.
    Topalian SL, Hodi FS, Brahmer JR, et al. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med. 2012;366(26):2443–54.CrossRefGoogle Scholar
  2. 2.
    Robert C, Long GV, Brady B, et al. Nivolumab in previously untreated melanoma without BRAF mutation. N Engl J Med. 2015;372(4):320–30.CrossRefGoogle Scholar
  3. 3.
    Reck M, Rodríguez-Abreu D, Robinson AG, et al. Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer. N Engl J Med. 2016;375(19):1823–33.CrossRefGoogle Scholar
  4. 4.
    Herbst RS, Baas P, Kim DW, et al. Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial. Lancet. 2016;387(10027):1540–50.CrossRefGoogle Scholar
  5. 5.
    Charles SF, Doi T, Raymond WJJ, et al. KEYNOTE-059 cohort 1: efficacy and safety of pembrolizumab (pembro) monotherapy in patients with previously treated advanced gastric cancer. J Clin Oncol. 2017;35(15_suppl):4003–3.CrossRefGoogle Scholar
  6. 6.
    Motzer RJ, Escudier B, McDermott DF, et al. Nivolumab versus Everolimus in advanced renal-cell carcinoma. N Engl J Med. 2015;373(19):1803–13.CrossRefGoogle Scholar
  7. 7.
    Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer. 2012;12(4):252–64.CrossRefGoogle Scholar
  8. 8.
    Kang YK, Boku N, Satoh T, et al. Nivolumab in patients with advanced gastric or gastro-oesophageal junction cancer refractory to, or intolerant of, at least two previous chemotherapy regimens (ONO-4538-12, ATTRACTION-2): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2017;390(10111):2461–71.CrossRefGoogle Scholar
  9. 9.
    Tumeh PC, Harview CL, Yearley JH, et al. PD-1 blockade induces responses by inhibiting adaptive immune resistance. Nature. 2014;515(7528):568–71.CrossRefGoogle Scholar
  10. 10.
    Eto S, Yoshikawa K, Nishi M, et al. Programmed cell death protein 1 expression is an independent prognostic factor in gastric cancer after curative resection. Gastric Cancer. 2016;19(2):466–71.CrossRefGoogle Scholar
  11. 11.
    Thompson ED, Zahurak M, Murphy A, et al. Patterns of PD-L1 expression and CD8 T cell infiltration in gastric adenocarcinomas and associated immune stroma. Gut. 2017;66(5):794–801.CrossRefGoogle Scholar
  12. 12.
    Kim JW, Nam KH, Ahn SH, et al. Prognostic implications of immunosuppressive protein expression in tumors as well as immune cell infiltration within the tumor microenvironment in gastric cancer. Gastric Cancer. 2016;19(1):42–52.CrossRefGoogle Scholar
  13. 13.
    Rimm DL, Han G, Taube JM, et al. A prospective, multi-institutional, pathologist-based assessment of 4 immunohistochemistry assays for PDL1 expression in non-small cell lung cancer. JAMA Oncol. 2017;3:1051–8, 2017.CrossRefGoogle Scholar
  14. 14.
    Hofmann M, Stoss O, Shi D, et al. Assessment of a HER2 scoring system for gastric cancer: results from a validation study. Histopathology. 2008;52:797–805.CrossRefGoogle Scholar
  15. 15.
    Bang YJ, Van Cutsem E, Feyereislova A, et al. Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial. Lancet. 2010;376:687–97.CrossRefGoogle Scholar
  16. 16.
  17. 17.
    Nishino M, Nikhil HR, Emily SC, et al. Immune-related response assessment during PD-1 inhibitor therapy in advanced non-small-cell lung cancer patients. J Immunother Cancer. 2016;4:84.CrossRefGoogle Scholar
  18. 18.
    Narita Y, Sugiyama K, Mitani S, et al. Peritoneum metastasis (PM) as a prognostic factor in metastatic gastric cancer (MGC) treated with anti-PD-1/PD-L1 monotherapy. J Clin Oncol. 2017;35(15_suppl): 3051–1.CrossRefGoogle Scholar
  19. 19.
    Le DT, Uram JN, Wang H, et al. PD-1 blockade in tumors with mismatch-repair deficiency. N Engl J Med. 2015;372(26):2509–20.CrossRefGoogle Scholar
  20. 20.
    Llosa NJ, Cruise M, Tam A, et al. The vigorous immune microenvironment of microsatellite instable colon cancer is balanced by multiple counter-inhibitory checkpoints. Cancer Discov. 2015;5(1):43–51.CrossRefGoogle Scholar
  21. 21.
    Cancer Genome Atlas Research Network. Comprehensive molecular characterization of gastric adenocarcinoma. Nature 2014;513(7517):202–9.CrossRefGoogle Scholar
  22. 22.
    Panda A, Mehnert JM, Hirshfield KM, et al. Immune activation and benefit from avelumab in EBV-positive gastric cancer. J Natl Cancer Inst. 2017 (Epub ahead of print).Google Scholar
  23. 23.
    Coelho MA, de Carné Trécesson S, et al. Oncogenic RAS Signaling Promotes Tumor Immunoresistance by Stabilizing PD-L1 mRNA. Immunity. 2017;47(6):1083–99.CrossRefGoogle Scholar
  24. 24.
    Taube JM, Anders RA, Young GD, et al. Colocalization of inflammatory response with B7-h1 expression in human melanocytic lesions supports an adaptive resistance mechanism of immune escape. Sci Transl Med. 2012;4(127):127ra37.CrossRefGoogle Scholar
  25. 25.
    Hamanishi J, Mandai M, Iwasaki M, et al. Programmed cell death 1 ligand 1 and tumorinfiltrating CD8 + T lymphocytes are prognostic factors of human ovarian cancer. Proc Natl Acad Sci USA. 2007;104(9):3360–5.CrossRefGoogle Scholar

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

Personalised recommendations