PD-L1 CPS in gastroesophageal cancer: differences in routine care versus Checkmate 649 and implications for biopsy-site choice and assay standardisation

Janjigian YY, Ajani JA, Moehler M, Shen L, Garrido M, Gallardo C, et al. First-Line Nivolumab Plus Chemotherapy for Advanced Gastric, Gastroesophageal Junction, and Esophageal Adenocarcinoma: 3-Year Follow-Up of the Phase III CheckMate 649 Trial. J Clin Oncol, 2024: Jco2301601.

Rha SY, Oh DY, Yañez P, Bai Y, Ryu MH, Lee J, et al. Pembrolizumab plus chemotherapy versus placebo plus chemotherapy for HER2-negative advanced gastric cancer (KEYNOTE-859): a multicentre, randomised, double-blind, phase 3 trial. Lancet Oncol. 2023;24:1181–95.

Article 
CAS 
PubMed 

Google Scholar 

Yamashita K, Iwatsuki M, Harada K, Eto K, Hiyoshi Y, Ishimoto T, et al. Prognostic impacts of the combined positive score and the tumor proportion score for programmed death ligand-1 expression by double immunohistochemical staining in patients with advanced gastric cancer. Gastric Cancer. 2020;23:95–104.

Article 
CAS 
PubMed 

Google Scholar 

Svensson MC, Borg D, Zhang C, Hedner C, Nodin B, Uhlén M, et al. Expression of PD-L1 and PD-1 in Chemoradiotherapy-Naïve Esophageal and Gastric Adenocarcinoma: Relationship With Mismatch Repair Status and Survival. Front Oncol. 2019;9:136.

Article 
PubMed 
PubMed Central 

Google Scholar 

Yoshida T, Ogura G, Tanabe M, Hayashi T, Ohbayashi C, Azuma M, et al. Clinicopathological features of PD-L1 protein expression, EBV positivity, and MSI status in patients with advanced gastric and esophagogastric junction adenocarcinoma in Japan. Cancer Biol Ther. 2022;23:191–200.

Article 
CAS 
PubMed 
PubMed Central 

Google Scholar 

Liu X, Choi MG, Kim K, Kim KM, Kim ST, Park SH, et al. High PD-L1 expression in gastric cancer (GC) patients and correlation with molecular features. Pathol Res Pr. 2020;216:152881.

Article 
CAS 

Google Scholar 

Chen T-H, Chen M-H, Hung Y-P, Chiang N-J, Huang K-H, Lin Y-H, et al. Elevated PD-L1 Expression and Microsatellite Instability in Elderly Patients With Gastric Cancer. J Immunother. 2023;46:111–9.

Article 
CAS 
PubMed 

Google Scholar 

Zhou KI, Peterson B, Serritella A, Thomas J, Reizine N, Moya S, et al. Spatial and Temporal Heterogeneity of PD-L1 Expression and Tumor Mutational Burden in Gastroesophageal Adenocarcinoma at Baseline Diagnosis and after Chemotherapy. Clin Cancer Res. 2020;26:6453–63.

Article 
CAS 
PubMed 
PubMed Central 

Google Scholar 

Gao Y, Li S, Xu D, Chen S, Cai Y, Jiang W, et al. Prognostic value of programmed death-1, programmed death-ligand 1, programmed death-ligand 2 expression, and CD8(+) T cell density in primary tumors and metastatic lymph nodes from patients with stage T1-4N+M0 gastric adenocarcinoma. Chin J Cancer. 2017;36:61.

Article 
PubMed 
PubMed Central 

Google Scholar 

Zhang M, Dong Y, Liu H, Wang Y, Zhao S, Xuan Q, et al. The clinicopathological and prognostic significance of PD-L1 expression in gastric cancer: a meta-analysis of 10 studies with 1,901 patients. Sci Rep. 2016;6:37933.

Article 
CAS 
PubMed 
PubMed Central 

Google Scholar 

Fernandez AI, Gaule P, Rimm DL. Tissue Age Affects Antigenicity and Scoring for the 22C3 Immunohistochemistry Companion Diagnostic Test. Mod Pathol. 2023;36:100159.

Article 
CAS 
PubMed 
PubMed Central 

Google Scholar 

Yanagihara K, Nagata K, Yamakawa T, Kato S, Tamura M, Yoshida M. Decline of PD-L1 Immunoreactivity with Storage Duration in Formalin-Fixed Paraffin-Embedded Breast Cancer Specimens: Implications for Diagnostic Accuracy and Immunotherapy Eligibility in Triple-Negative Breast Cancer. Cancers. 2025;17:3103.

Article 
CAS 
PubMed 
PubMed Central 

Google Scholar 

Inc, AT PD-L1 IHC 28-8 pharmDx interpretation manual–gastric adenocarcinoma, gastroesophageal junction (GEJ) adenocarcinoma, and esophageal adenocarcinoma, version 29546. 2021; Available from: https://www.agilent.com/cs/library/usermanuals/public/29456-d68866-pd-l1-28-8-gastric-interpretation-manual-en-eu.pdf.

Klempner SJ, Cowden ES, Cytryn SL, Fassan M, Kawakami H, Shimada H, et al. PD-L1 Immunohistochemistry in Gastric Cancer: Comparison of Combined Positive Score and Tumor Area Positivity Across 28-8, 22C3, and SP263 Assays. JCO Precision Oncol. 2024; e2400230.

West NP, Mansoor W, Taniere P, Smyth E, Rodriguez-Justo M, Oniscu A, et al. Best-Practice Biomarker Testing of Oesophago-Gastric Cancer in the UK: Expert Consensus Recommendations Developed Using a Modified Delphi. Clin Oncol (R Coll Radio). 2024;36:701–09.

Article 
CAS 

Google Scholar 

Rodriguez-Justo M, Mansoor W, Bird T, Eatock M, Starling N, Taniere P. Results of a modified Delphi consensus on the optimal testing pathway for oesophago-gastric cancer care in the UK. BMJ Open. 2025;15:e094343.

Article 
PubMed 
PubMed Central 

Google Scholar 

Qiu M-Z, Oh D-Y, Kato K, Arkenau T, Tabernero J, Correa MC, et al. Tislelizumab plus chemotherapy versus placebo plus chemotherapy as first line treatment for advanced gastric or gastro-oesophageal junction adenocarcinoma: RATIONALE-305 randomised, double blind, phase 3 trial. BMJ. 2024;385:e078876.

Article 
CAS 
PubMed 

Google Scholar 

Pham T, Liu Y, Sharpnack M, Lum J, Koralek DO, Thakur MD. Concordance between PD-L1 assays 28-8 and SP263 and their respective scoring algorithms in procured upper gastrointestinal adenocarcinoma samples. J Clin Oncol. 2025;43:479–9.

Article 

Google Scholar 

Shah Y, Verma A, Marderstein AR, White J, Bhinder B, Garcia Medina JS, et al. Pan-cancer analysis reveals molecular patterns associated with age. Cell Rep. 2021;37:110100.

Article 
CAS 
PubMed 

Google Scholar 

Chalmers ZR, Connelly CF, Fabrizio D, Gay L, Ali SM, Ennis R, et al. Analysis of 100,000 human cancer genomes reveals the landscape of tumor mutational burden. Genome Med. 2017;9:34.

Article 
PubMed 
PubMed Central 

Google Scholar 

Rizvi NA, Hellmann MD, Snyder A, Kvistborg P, Makarov V, Havel JJ, et al. Mutational landscape determines sensitivity to PD-1 blockade in non–small cell lung cancer. Science. 2015;348:124–8.

Article 
CAS 
PubMed 
PubMed Central 

Google Scholar 

Sha D, Jin Z, Budczies J, Kluck K, Stenzinger A, Sinicrope FA. Tumor Mutational Burden as a Predictive Biomarker in Solid Tumors. Cancer Discov. 2020;10:1808–1825.

Article 
CAS 
PubMed 
PubMed Central 

Google Scholar 

Al-Batran S-E, Hofheinz RD, Pauligk C, Kopp H-G, Haag GM, Luley KB, et al. Histopathological regression after neoadjuvant docetaxel, oxaliplatin, fluorouracil, and leucovorin versus epirubicin, cisplatin, and fluorouracil or capecitabine in patients with resectable gastric or gastro-oesophageal junction adenocarcinoma (FLOT4-AIO): results from the phase 2 part of a multicentre, open-label, randomised phase 2/3 trial. Lancet Oncol. 2016;17:1697–1708.

Article 
CAS 
PubMed 

Google Scholar 

Jiménez Fonseca P, Carmona-Bayonas A, Hernández R, Custodio A, Cano JM, Lacalle A, et al. Lauren subtypes of advanced gastric cancer influence survival and response to chemotherapy: real-world data from the AGAMENON National Cancer Registry. Br J Cancer. 2017;117:775–82.

Article 
PubMed 
PubMed Central 

Google Scholar 

van der Kaaij RT, Koemans WJ, van Putten M, Snaebjornsson P, Luijten JCHBM, van Dieren JM, et al. A population-based study on intestinal and diffuse type adenocarcinoma of the oesophagus and stomach in the Netherlands between 1989 and 2015. Eur J Cancer. 2020;130:23–31.

Article 
PubMed 

Google Scholar 

Kubota Y, Kawazoe A, Mishima S, Nakamura Y, Kotani D, Kuboki Y, et al. Comprehensive clinical and molecular characterization of claudin 18.2 expression in advanced gastric or gastroesophageal junction cancer. ESMO Open. 2023;8:100762.

Article 
CAS 
PubMed 
PubMed Central 

Google Scholar 

Massa V, Salani F, Grelli G, Genovesi V, Vivaldi C, Signorini F, et al. Concordance of PD-L1 combined positive score (CPS) analysis between primary gastric cancer and matched peritoneal metastasis. J Clin Oncol. 2024;42:e16068.

Article 

Google Scholar