Multi-Institutional Study of Pathologist Reading of the Programmed Cell Death Ligand-1 Combined Positive Score Immunohistochemistry Assay for Gastric or Gastroesophageal Junction Cancer

Authors

Aileen I Fernandez
Charles J Robbins
Patricia Gaule
Diana Agostini-Vulaj
Robert A Anders
Andrew M Bellizzi
Wei Chen
Zongming Eric Chen
Purva Gopal
Lei Zhao
Mikhail Lisovsky
Xiuli Liu
Jinru Shia
Huamin Wang
Zhaohai Yang
Leena McCann
Yvonne G Chan
Jodi Weidler
Michael Bates
Xuchen Zhang
David L Rimm

Publication Date

5-1-2023

Journal

Modern Pathology

DOI

10.1016/j.modpat.2023.100128

PMID

36889057

PMCID

PMC10198879

PubMedCentral® Posted Date

5-1-2024

PubMedCentral® Full Text Version

Author MSS

Abstract

The assessment of the expression of programmed cell death ligand-1 (PD-L1) using immunohistochemistry (IHC) has been controversial since its introduction. The methods of assessment and the range of assays and platforms contribute to confusion. Perhaps the most challenging aspect of PD-L1 IHC is the combined positive score (CPS) method of interpretation of IHC results. Although the CPS method is prescribed for more indications than any other PD-L1 scoring system, its reproducibility has never been rigorously assessed. In this study, we collected a series of 108 gastric or gastroesophageal junction cancer cases, stained them using the Food and Drug Administration-approved 22C3 assay, scanned them, and then circulated them to 14 pathologists at 13 institutions for the assessment of interpretative concordance for the CPS system. We found that higher cut points (10 or 20) performed better than a CPS of < 1 or >1. We used the Observers Needed to Evaluate Subjective Tests algorithm to assess how the CPS system might perform in the real-world setting and found that the cut points of < 1 or >1 showed an overall percent agreement of only 30% among the pathologist raters, with a plateau occurring at 8 raters. The raters performed better at higher cut points. However, the best cut point of < 20 versus that of >20 was still disappointing, with a plateau at an overall percent agreement of 70% (at 7 raters). Although there is no ground truth for CPS, we compared the score with quantitative messenger RNA measurement and showed no relationship between the score (at any cut point) and messenger RNA amount. In summary, we showed that CPS shows high subjective variability among pathologist readers and is likely to perform poorly in the real-world setting. This system may be the root cause of the poor specificity and relatively low predictive value of IHC companion diagnostic tests for PD-1 axis therapies that use the CPS system.

Keywords

Humans, Apoptosis, B7-H1 Antigen, Biomarkers, Tumor, Esophageal Neoplasms, Esophagogastric Junction, Immunohistochemistry, Ligands, Pathologists, Reproducibility of Results, Stomach Neoplasms, CPS, GEJ, PD-L1, RNA, closed-system RT-qPCR, gastric cancer, immunohistochemistry

Published Open-Access

yes

Recommended Citation

Fernandez, Aileen I; Robbins, Charles J; Gaule, Patricia; et al., "Multi-Institutional Study of Pathologist Reading of the Programmed Cell Death Ligand-1 Combined Positive Score Immunohistochemistry Assay for Gastric or Gastroesophageal Junction Cancer" (2023). Faculty, Staff and Student Publications. 5120.
https://digitalcommons.library.tmc.edu/uthgsbs_docs/5120