Copyright ©The Author(s) 2018. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Jul 7, 2018; 24(25): 2686-2697
Published online Jul 7, 2018. doi: 10.3748/wjg.v24.i25.2686
Advances in immuno-oncology biomarkers for gastroesophageal cancer: Programmed death ligand 1, microsatellite instability, and beyond
Emily M Lin, Jun Gong, Samuel J Klempner, Joseph Chao
Emily M Lin, Department of Internal Medicine, Harbor-UCLA Medical Center, Torrance, CA 90509, United States
Jun Gong, Joseph Chao, Department of Medical Oncology and Developmental Therapeutics, City of Hope Comprehensive Cancer Center, Duarte, CA 91010, United States
Samuel J Klempner, The Angeles Clinic and Research Institute, Los Angeles, CA 90404, United States
Samuel J Klempner, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, United States
Author contributions: Lin EM, Gong J and Chao J contributed to conception and design, provision of study materials, and collection and assembly of data; all authors contributed to data analysis and interpretation, manuscript writing, and final approval of manuscript.
Conflict-of-interest statement: Chao J has received research support (institutional), consulting, and speaker fees from Merck; Klempner SJ has received research support from Leap Therapeutics and Astellas (institutional), and consulting fees from Boston Biomedical and Lilly Oncology. The remaining authors declare no conflicts of interest.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See:
Correspondence to: Joseph Chao, MD, Assistant Professor, Department of Medical Oncology and Therapeutics Research, City of Hope Comprehensive Cancer Center, 1500 E. Duarte Rd., Duarte, CA 91010, United States.
Telephone: +1-626-4719200 Fax: +1-626-3018233
Received: March 30, 2018
Peer-review started: March 30, 2018
First decision: May 17, 2018
Revised: May 23, 2018
Accepted: June 16, 2018
Article in press: June 16, 2018
Published online: July 7, 2018

Blockade of the programmed death ligand 1 (PD-L1) and programmed cell death 1 (PD-1) receptor axis represents an effective form of cancer immunotherapy. Preclinical evidence initially suggested that gastric and gastroesophageal junction (GEJ) cancers are potentially immunotherapy-sensitive tumors. Early phase clinical trials have demonstrated promising antitumor activity with PD-1/PD-L1 blockade in advanced or metastatic gastric/GEJ cancer. Microsatellite instability (MSI) and PD-L1 expression have been shown to predict higher response to PD-1 inhibitors as highlighted by the recent approvals of pembrolizumab in treatment-refractory solid tumors with MSI status and the third-line or greater treatment of PD-L1 positive advanced gastric/GEJ cancers. However, predictive and prognostic biomarkers remain an ongoing need. In this review, we detail the preclinical evidence and early tissue biomarker analyses illustrating potential predictive biomarkers to PD-1/PD-L1 blockade in gastric/GEJ cancer. We also review the clinical development of PD-1/PD-L1 inhibitors in gastric/GEJ cancer and highlight several areas in need of future investigation in order to optimize the efficacy of PD-1/PD-L1 blockade in gastric/GEJ cancer.

Keywords: Immunotherapy, Programmed cell death 1, Programmed death ligand 1, Microsatellite instablility, Gastric cancer

Core tip: Programmed death ligand 1 (PD-L1) and microsatellite instability have recently entered into clinical practice as recommended biomarker testing for the use of immune checkpoint inhibitors in gastroesophageal cancer. However, PD-L1 still does not carry the highest sensitivity and specificity with variability in testing reported. Incorporation of PD-L1 expression from the tumor microenvironment with counting of immune cells appears to be the most effective strategy to date. Future efforts focusing on composite biomarkers in ongoing research from combinatorial immuno-oncology strategies are necessary to drive the field forward.