Journal of Pathology and Translational Medicine

Review

Interpretation of PD-L1 expression in gastric cancer: summary of a consensus meeting of Korean gastrointestinal pathologists: Soomin Ahn, Yoonjin Kwak, Gui Young Kwon, Kyoung-Mee Kim, Moonsik Kim, Hyunki Kim, Young Soo Park, Hyeon Jeong Oh, Kyoungyul Lee, Sung Hak Lee, Hye Seung Lee; J Pathol Transl Med. 2024;58(3):103-116. Published online April 25, 2024; DOI: https://doi.org/10.4132/jptm.2024.03.15

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Nivolumab plus chemotherapy in the first-line setting has demonstrated clinical efficacy in patients with human epidermal growth factor receptor 2–negative advanced or metastatic gastric cancer, and is currently indicated as a standard treatment. Programmed death-ligand 1 (PD-L1) expression is an important biomarker for predicting response to anti–programmed death 1/PD-L1 agents in several solid tumors, including gastric cancer. In the CheckMate-649 trial, significant clinical improvements were observed in patients with PD-L1 combined positive score (CPS) ≥ 5, determined using the 28-8 pharmDx assay. Accordingly, an accurate interpretation of PD-L1 CPS, especially at a cutoff of 5, is important. The CPS method evaluates both immune and tumor cells and provides a comprehensive assessment of PD-L1 expression in the tumor microenvironment of gastric cancer. However, CPS evaluation has several limitations, one of which is poor interobserver concordance among pathologists. Despite these limitations, clinical indications relying on PD-L1 CPS are increasing. In response, Korean gastrointestinal pathologists held a consensus meeting for the interpretation of PD-L1 CPS in gastric cancer. Eleven pathologists reviewed 20 PD-L1 slides with a CPS cutoff close to 5, stained with the 28-8 pharmDx assay, and determined the consensus scores. The issues observed in discrepant cases were discussed. In this review, we present cases of gastric cancer with consensus PD-L1 CPS. In addition, we briefly touch upon current practices and clinical issues associated with assays used for the assessment of PD-L1 expression in gastric cancer.

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Adjuvant immunotherapy in patients with resected gastric and oesophagogastric junction cancer following preoperative chemotherapy with high risk for recurrence (ypN+ and/or R1): European Organisation of Research and Treatment of Cancer (EORTC) 1707 VESTIG
F. Lordick, M.E. Mauer, G. Stocker, C.A. Cella, I. Ben-Aharon, G. Piessen, L. Wyrwicz, G. Al-Haidari, T. Fleitas-Kanonnikoff, V. Boige, R. Lordick Obermannová, U.M. Martens, C. Gomez-Martin, P. Thuss-Patience, V. Arrazubi, A. Avallone, K.K. Shiu, P. Artru
Annals of Oncology.2025; 36(2): 197. CrossRef
PD-L1 as a Biomarker in Gastric Cancer Immunotherapy
Yunjoo Cho, Soomin Ahn, Kyoung-Mee Kim
Journal of Gastric Cancer.2025; 25(1): 177. CrossRef
PD-L1 importance in malignancies comprehensive insights into the role of PD-L1 in malignancies: from molecular mechanisms to therapeutic opportunities
Mojdeh Soltani, Mohammad Abbaszadeh, Hamed Fouladseresht, Mark J. M. Sullman, Nahid Eskandari
Clinical and Experimental Medicine.2025;[Epub] CrossRef
PD-L1 thresholds predict efficacy of immune checkpoint inhibition in first-line treatment of advanced gastroesophageal adenocarcinoma. A systematic review and meta-analysis of seven phase III randomized trials
V. Formica, C. Morelli, L. Fornaro, S. Riondino, M. Rofei, E. Fontana, E.C. Smyth, M. Roselli, H.-T. Arkenau
ESMO Open.2024; 9(11): 103967. CrossRef

Original Article

BRCA-mutated gastric adenocarcinomas are associated with chromosomal instability and responsiveness to platinum-based chemotherapy: Ji Hyun Oh, Chang Ohk Sung, Hyung-Don Kim, Sung-Min Chun, Jihun Kim; J Pathol Transl Med. 2023;57(6):323-331. Published online November 14, 2023; DOI: https://doi.org/10.4132/jptm.2023.10.22

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Abstract PDF Supplementary Material

Background
Homologous recombination defect is an important biomarker of chemotherapy in certain tumor types, and the presence of pathogenic or likely pathogenic mutations involving BRCA1 or BRCA2 (p-BRCA) mutations is the most well-established marker for the homologous recombination defect. Gastric cancer, one of the most prevalent tumor types in Asia, also harbors p-BRCA mutations.
Methods
To investigate the clinical significance of p-BRCA mutations, we analyzed 366 gastric cancer cases through next-generation sequencing. We determined the zygosity of p-BRCA mutations based on the calculated tumor purity through variant allelic fraction patterns and investigated whether the presence of p-BRCA mutations is associated with platinum-based chemotherapy and a certain molecular subtype.
Results
Biallelic p-BRCA mutation was associated with better response to platinum-based chemotherapy than heterozygous p-BRCA mutation or wild type BRCA genes. The biallelic p-BRCA mutations was observed only in the chromosomal instability subtype, while all p-BRCA mutations were heterozygous in microsatellite instability subtype.
Conclusions
In conclusion, patients with gastric cancer harboring biallelic p-BRCA mutations were associated with a good initial response to platinum-based chemotherapy and those tumors were exclusively chromosomal instability subtype. Further investigation for potential association with homologous recombination defect is warranted.

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Review

Molecular Testing for Gastrointestinal Cancer: Hye Seung Lee, Woo Ho Kim, Yoonjin Kwak, Jiwon Koh, Jeong Mo Bae, Kyoung-Mee Kim, Mee Soo Chang, Hye Seung Han, Joon Mee Kim, Hwal Woong Kim, Hee Kyung Chang, Young Hee Choi, Ji Y. Park, Mi Jin Gu, Min Jin Lhee, Jung Yeon Kim, Hee Sung Kim, Mee-Yon Cho; J Pathol Transl Med. 2017;51(2):103-121. Published online February 19, 2017; DOI: https://doi.org/10.4132/jptm.2017.01.24

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Abstract PDF

With recent advances in molecular diagnostic methods and targeted cancer therapies, several molecular tests have been recommended for gastric cancer (GC) and colorectal cancer (CRC). Microsatellite instability analysis of gastrointestinal cancers is performed to screen for Lynch syndrome, predict favorable prognosis, and screen patients for immunotherapy. The epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor has been approved in metastatic CRCs with wildtype RAS (KRAS and NRAS exon 2–4). A BRAF mutation is required for predicting poor prognosis. Additionally, amplification of human epidermal growth factor receptor 2 (HER2) and MET is also associated with resistance to EGFR inhibitor in metastatic CRC patients. The BRAF V600E mutation is found in sporadic microsatellite unstable CRCs, and thus is helpful for ruling out Lynch syndrome. In addition, the KRAS mutation is a prognostic biomarker and the PIK3CA mutation is a molecular biomarker predicting response to phosphoinositide 3-kinase/AKT/mammalian target of rapamycin inhibitors and response to aspirin therapy in CRC patients. Additionally, HER2 testing should be performed in all recurrent or metastatic GCs. If the results of HER2 immunohistochemistry are equivocal, HER2 silver or fluorescence in situ hybridization testing are essential for confirmative determination of HER2 status. Epstein-Barr virus–positive GCs have distinct characteristics, including heavy lymphoid stroma, hypermethylation phenotype, and high expression of immune modulators. Recent advances in next-generation sequencing technologies enable us to examine various genetic alterations using a single test. Pathologists play a crucial role in ensuring reliable molecular testing and they should also take an integral role between molecular laboratories and clinicians.

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