Skip to main content
Top
Published in: Gastric Cancer 1/2019

01-01-2019 | Original Article

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

Authors: Akihito Kawazoe, Kohei Shitara, Yasutoshi Kuboki, Hideaki Bando, Takashi Kojima, Takayuki Yoshino, Atsushi Ohtsu, Atsushi Ochiai, Yosuke Togashi, Hiroyoshi Nishikawa, Toshihiko Doi, Takeshi Kuwata

Published in: Gastric Cancer | Issue 1/2019

Login to get access

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.
Appendix
Available only for authorised users
Literature
1.
go back to reference 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.CrossRefPubMedPubMedCentral 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.CrossRefPubMedPubMedCentral
2.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
3.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
4.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
5.
go back to reference 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.CrossRef 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.CrossRef
6.
8.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
9.
10.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
11.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
12.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
13.
go back to reference 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.CrossRefPubMedPubMedCentral 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.CrossRefPubMedPubMedCentral
14.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
15.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
17.
go back to reference 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.CrossRefPubMedPubMedCentral 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.CrossRefPubMedPubMedCentral
18.
go back to reference 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.CrossRef 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.CrossRef
20.
go back to reference 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.CrossRefPubMed 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.CrossRefPubMed
21.
go back to reference Cancer Genome Atlas Research Network. Comprehensive molecular characterization of gastric adenocarcinoma. Nature 2014;513(7517):202–9.CrossRef Cancer Genome Atlas Research Network. Comprehensive molecular characterization of gastric adenocarcinoma. Nature 2014;513(7517):202–9.CrossRef
22.
go back to reference 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). 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).
23.
go back to reference 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.CrossRefPubMedPubMedCentral 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.CrossRefPubMedPubMedCentral
24.
go back to reference 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.CrossRefPubMedPubMedCentral 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.CrossRefPubMedPubMedCentral
25.
go back to reference 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.CrossRefPubMedPubMedCentral 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.CrossRefPubMedPubMedCentral
Metadata
Title
Clinicopathological features of 22C3 PD-L1 expression with mismatch repair, Epstein–Barr virus status, and cancer genome alterations in metastatic gastric cancer
Authors
Akihito Kawazoe
Kohei Shitara
Yasutoshi Kuboki
Hideaki Bando
Takashi Kojima
Takayuki Yoshino
Atsushi Ohtsu
Atsushi Ochiai
Yosuke Togashi
Hiroyoshi Nishikawa
Toshihiko Doi
Takeshi Kuwata
Publication date
01-01-2019
Publisher
Springer Japan
Published in
Gastric Cancer / Issue 1/2019
Print ISSN: 1436-3291
Electronic ISSN: 1436-3305
DOI
https://doi.org/10.1007/s10120-018-0843-9

Other articles of this Issue 1/2019

Gastric Cancer 1/2019 Go to the issue