{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T14:02:47Z","timestamp":1789999367276,"version":"4.0.1"},"reference-count":45,"publisher":"MDPI AG","issue":"18","license":[{"start":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T00:00:00Z","timestamp":1789948800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Background\/Objectives: Standard guidelines for treating locally advanced and metastatic gastroesophageal cancer (GEC) involve combination regimens of chemotherapy and immunotherapy. Patient eligibility for these treatments is primarily guided by the programmed cell death ligand 1 (PD-L1) combined positive score (CPS). This approach assumes that a single baseline biopsy accurately reflects a stable, tumor-wide PD-L1 status, an assumption increasingly challenged by spatial and temporal heterogeneity. This systematic review aims to synthesize existing data on PD-L1 expression dynamics before and after systemic therapy in GEC, and to evaluate whether these changes differ between neoadjuvant and metastatic settings. Methods: We systematically searched PubMed\/MEDLINE (up to May 2026) for studies reporting paired pre- and post-treatment PD-L1 status in gastric and gastroesophageal junction cancers. This systematic review was conducted in accordance with the PRISMA 2020 guidelines. Narrative synthesis and qualitative data transformation were structured following the Synthesis Without Meta-analysis (SWiM) reporting framework. Study-level risk of bias was assessed using the Newcastle-Ottawa Scale (NOS). Results: Eleven studies were included in this systematic review, stratified into neoadjuvant (n = 6) and metastatic (n = 5) settings. Our findings suggest that changes in PD-L1 expression in gastroesophageal cancer depend heavily on the clinical setting. Specifically, an upward trend in post-treatment PD-L1 expression was evident in the neoadjuvant setting, with 5 of 6 studies reporting a prevalence of PD-L1 gain ranging from 6.3% to 33.3%. Conversely, PD-L1 downregulation was consistently reported across all metastatic studies, with loss rates ranging from 19.3% to 44.4%. Conclusions: PD-L1 status in gastroesophageal cancer changes dynamically after treatment. These findings highlight the limitations of relying on archival tissue and support the use of repeat biopsies to track evolving tumor phenotypes. This study is primarily limited by small sample sizes of paired biopsies, technical heterogeneity in PD-L1 scoring and treatment regimens, potential publication bias, and the lack of prospective registration.<\/jats:p>","DOI":"10.3390\/cancers18183065","type":"journal-article","created":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T12:50:03Z","timestamp":1789995003000},"page":"3065","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Treatment-Induced PD-L1 Dynamics and Temporal Heterogeneity in Locally Advanced and Metastatic Gastroesophageal Cancer\u2014A Systematic Review"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0009-0001-4641-2911","authenticated-orcid":false,"given":"Marharyta","family":"Khaustova","sequence":"first","affiliation":[{"name":"Medical Oncology Division, ASST Sette Laghi, 21100 Varese, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elisabetta","family":"Liberanome","sequence":"additional","affiliation":[{"name":"Department of Medicine and Technological Innovation (DiMIT), University of Insubria, 21100 Varese, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annamaria","family":"De Giorgi","sequence":"additional","affiliation":[{"name":"Medical Oncology Division, ASST Sette Laghi, 21100 Varese, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1475-3252","authenticated-orcid":false,"given":"Luigi Pio","family":"Guerrera","sequence":"additional","affiliation":[{"name":"Medical Oncology Division, ASST Sette Laghi, 21100 Varese, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fausto","family":"Petrelli","sequence":"additional","affiliation":[{"name":"Oncology Unit, ASST Bergamo Ovest, 24047 Treviglio, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gianluca","family":"Tomasello","sequence":"additional","affiliation":[{"name":"Oncology Unit, ASST Crema, Largo Dossena 2, 26013 Crema, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michele","family":"Ghidini","sequence":"additional","affiliation":[{"name":"Medical Oncology Division, ASST Sette Laghi, 21100 Varese, Italy"},{"name":"Department of Medicine and Technological Innovation (DiMIT), University of Insubria, 21100 Varese, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,21]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Lu, B., Zhang, D., Liu, Q., Zuo, X., and Chen, Y. (Res. Sq., 2025). Global epidemiology of gastric cancer in 2022 and projections for 2050: A comprehensive analysis and forecasts based on GLOBOCAN data, Res. Sq., preprint.","DOI":"10.21203\/rs.3.rs-8058648\/v1"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1016\/S0140-6736(21)00797-2","article-title":"First-Line Nivolumab plus Chemotherapy versus Chemotherapy Alone for Advanced Gastric, Gastro-Oesophageal Junction, and Oesophageal Adenocarcinoma (CheckMate 649): A Randomised, Open-Label, Phase 3 Trial","volume":"398","author":"Janjigian","year":"2021","journal-title":"Lancet"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1181","DOI":"10.1016\/S1470-2045(23)00515-6","article-title":"Pembrolizumab plus Chemotherapy versus Placebo plus Chemotherapy for HER2-Negative Advanced Gastric Cancer (KEYNOTE-859): A Multicentre, Randomised, Double-Blind, Phase 3 Trial","volume":"24","author":"Rha","year":"2023","journal-title":"Lancet Oncol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1056\/NEJMoa2503701","article-title":"Perioperative Durvalumab in Gastric and Gastroesophageal Junction Cancer","volume":"393","author":"Janjigian","year":"2025","journal-title":"N. Engl. J. Med."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1948","DOI":"10.1016\/S0140-6736(18)32557-1","article-title":"Perioperative Chemotherapy with Fluorouracil plus Leucovorin, Oxaliplatin, and Docetaxel versus Fluorouracil or Capecitabine plus Cisplatin and Epirubicin for Locally Advanced, Resectable Gastric or Gastro-Oesophageal Junction Adenocarcinoma (FLOT4): A Randomised, Phase 2\/3 Trial","volume":"393","author":"Homann","year":"2019","journal-title":"Lancet"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"2197","DOI":"10.1016\/S0140-6736(23)02033-0","article-title":"Pembrolizumab plus Trastuzumab and Chemotherapy for HER2-Positive Gastric or Gastro-Oesophageal Junction Adenocarcinoma: Interim Analyses from the Phase 3 KEYNOTE-811 Randomised Placebo-Controlled Trial","volume":"402","author":"Janjigian","year":"2023","journal-title":"Lancet"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"e078876","DOI":"10.1136\/bmj-2023-078876","article-title":"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","volume":"385","author":"Qiu","year":"2024","journal-title":"BMJ"},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Zhou, Y., Wei, L., Wang, L., Zhang, B., and Liang, J. (2026). Unlocking the Potential: Current Landscape and Future Directions of Immunotherapy in Gastric Cancer. Front. Immunol., 17.","DOI":"10.3389\/fimmu.2026.1742723"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"100154","DOI":"10.1016\/j.modpat.2023.100154","article-title":"High Interobserver Variability Among Pathologists Using Combined Positive Score to Evaluate PD-L1 Expression in Gastric, Gastroesophageal Junction, and Esophageal Adenocarcinoma","volume":"36","author":"Robert","year":"2023","journal-title":"Mod. Pathol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"330","DOI":"10.5858\/arpa.2018-0043-OA","article-title":"Clinical Utility of the Combined Positive Score for Programmed Death Ligand-1 Expression and the Approval of Pembrolizumab for Treatment of Gastric Cancer","volume":"143","author":"Kulangara","year":"2019","journal-title":"Arch. Pathol. Lab. Med."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"4003","DOI":"10.1200\/JCO.2017.35.15_suppl.4003","article-title":"KEYNOTE-059 Cohort 1: Efficacy and Safety of Pembrolizumab (Pembro) Monotherapy in Patients with Previously Treated Advanced Gastric Cancer","volume":"35","author":"Fuchs","year":"2017","journal-title":"J. Clin. Oncol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"153338","DOI":"10.1016\/j.prp.2020.153338","article-title":"PD-L1 Expression in Paired Biopsies and Surgical Specimens in Gastric Adenocarcinoma: A Digital Image Analysis Study","volume":"218","author":"Heo","year":"2021","journal-title":"Pathol. Res. Pract."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"278","DOI":"10.1038\/s41416-019-0515-5","article-title":"Can PD-L1 Expression Evaluated by Biopsy Sample Accurately Reflect Its Expression in the Whole Tumour in Gastric Cancer?","volume":"121","author":"Yamashita","year":"2019","journal-title":"Br. J. Cancer"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"192","DOI":"10.5230\/jgc.2025.25.e3","article-title":"Spatial and Temporal Tumor Heterogeneity in Gastric Cancer: Discordance of Predictive Biomarkers","volume":"25","author":"Lee","year":"2025","journal-title":"J. Gastric Cancer"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"6453","DOI":"10.1158\/1078-0432.CCR-20-2085","article-title":"Spatial and Temporal Heterogeneity of PD-L1 Expression and Tumor Mutational Burden (TMB) in Gastroesophageal Adenocarcinoma (GEA) at Baseline Diagnosis and after Chemotherapy","volume":"26","author":"Zhou","year":"2020","journal-title":"Clin. Cancer Res."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1007\/s10120-018-0842-x","article-title":"Discordancy and Changes in the Pattern of Programmed Death Ligand 1 Expression before and after Platinum-Based Chemotherapy in Metastatic Gastric Cancer","volume":"22","author":"Yang","year":"2019","journal-title":"Gastric Cancer"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1023","DOI":"10.1038\/s41591-024-02877-z","article-title":"Neoadjuvant Nivolumab or Nivolumab plus LAG-3 Inhibitor Relatlimab in Resectable Esophageal\/Gastroesophageal Junction Cancer: A Phase Ib Trial and ctDNA Analyses","volume":"30","author":"Kelly","year":"2024","journal-title":"Nat. Med."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1038\/s41467-022-35431-x","article-title":"Neoadjuvant Therapy with Immune Checkpoint Blockade, Antiangiogenesis, and Chemotherapy for Locally Advanced Gastric Cancer","volume":"14","author":"Li","year":"2023","journal-title":"Nat. Commun."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1476","DOI":"10.1158\/1078-0432.CCR-24-3528","article-title":"Determinants of Response to Sequential Pembrolizumab with Trastuzumab plus Platinum\/5-FU in HER2-Positive Gastric Cancer: A Phase II Chemoimmunotherapy Trial","volume":"31","author":"Lim","year":"2025","journal-title":"Clin. Cancer Res."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"258","DOI":"10.1007\/s13577-023-00990-8","article-title":"Tracking Circulating PD-L1-Positive Cells to Monitor the Outcome of Patients with Gastric Cancer Receiving Anti-HER2 plus Anti-PD-1 Therapy","volume":"37","author":"Chong","year":"2024","journal-title":"Hum. Cell"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"e12378","DOI":"10.1002\/2056-4538.12378","article-title":"Gastric Cancer Immune Microenvironment Score Predicts Neoadjuvant Chemotherapy Efficacy and Prognosis","volume":"10","author":"Zhao","year":"2024","journal-title":"J. Pathol. Clin. Res."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"150","DOI":"10.1002\/jso.26929","article-title":"PD-L1 Expression in Gastric and Gastroesophageal Junction Cancer Patients Treated with Perioperative Chemotherapy","volume":"126","author":"Ribeiro","year":"2022","journal-title":"J. Surg. Oncol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"282","DOI":"10.1002\/path.5832","article-title":"Tumor-immune Landscape Patterns before and after Chemoradiation in Resectable Esophageal Adenocarcinomas","volume":"256","author":"Soeratram","year":"2022","journal-title":"J. Pathol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"737","DOI":"10.1007\/s10120-026-01737-8","article-title":"Diagnostic Discordance and Treatment-Associated Change of PD-L1 and CLDN18.2 in Gastric Cancer: A Real-World Analysis of Paired Biopsy-Resection Samples","volume":"29","author":"Yu","year":"2026","journal-title":"Gastric Cancer"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"100089","DOI":"10.1016\/j.esmogo.2024.100089","article-title":"Concordance of PD-L1 Status in Primary Gastroesophageal Adenocarcinoma and Matched Peritoneal Metastases: A Single Institution Study","volume":"5","author":"Massa","year":"2024","journal-title":"ESMO Gastrointest. Oncol."},{"key":"ref_26","unstructured":"Pouw, R.E. (2026, September 11). Endoscopic Tissue Sampling\u2014Part 1: Upper Gastrointestinal and Hepatopancreatobiliary Tracts|ESGE. Available online: https:\/\/www.esge.com\/endoscopic-tissue-sampling-part1-esge-guideline."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Ahn, S., Hwang, I., Kim, Y., Lee, S., Cho, Y., Kang, S.Y., Kim, D.G., Lee, J., and Kim, K.-M. (2025). Best Practice PD-L1 Staining and Interpretation in Gastric Cancer Using PD-L1 IHC PharmDx 22C3 and PD-L1 IHC PharmDx 28-8 Assays, with Reference to Common Issues and Solutions. Biomedicines, 13.","DOI":"10.3390\/biomedicines13112824"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"186","DOI":"10.1186\/s12935-020-01273-0","article-title":"Heterogeneous Programmed Death-Ligand 1 Expression in Gastric Cancer: Comparison of Tissue Microarrays and Whole Sections","volume":"20","author":"Ye","year":"2020","journal-title":"Cancer Cell Int."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"86","DOI":"10.3892\/br.2021.1462","article-title":"The Role of Immunogenic Cell Death in Gastrointestinal Cancer Immunotherapy (Review)","volume":"15","author":"Songjang","year":"2021","journal-title":"Biomed. Rep."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Ibrahim, D., Sim\u00f3, C., Brown, E.L., Shmuel, S., Panikar, S.S., Benton, A., DeWeerd, R., Dehdashti, F., Park, H., and Pereira, P.M.R. (2024). PD-L1 Has a Heterogeneous and Dynamic Expression in Gastric Cancer with Implications for immunoPET. Front. Immunol., 15.","DOI":"10.3389\/fimmu.2024.1405485"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"17810","DOI":"10.1038\/s41598-017-18132-0","article-title":"IFN\u03b3 Induces PD-L1 Overexpression by JAK2\/STAT1\/IRF-1 Signaling in EBV-Positive Gastric Carcinoma","volume":"7","author":"Moon","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"2754","DOI":"10.7150\/jca.31755","article-title":"Changes in Expression of Multiple Checkpoint Molecules and Infiltration of Tumor Immune Cells after Neoadjuvant Chemotherapy in Gastric Cancer","volume":"10","author":"Yu","year":"2019","journal-title":"J. Cancer"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"e010041","DOI":"10.1136\/jitc-2024-010041","article-title":"Multiomics Reveals Tumor Microenvironment Remodeling in Locally Advanced Gastric and Gastroesophageal Junction Cancer Following Neoadjuvant Immunotherapy and Chemotherapy","volume":"12","author":"Ji","year":"2024","journal-title":"J. Immunother. Cancer"},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Desimpel, P.-H., Petit, P.-F., Van den Eynde, B.J., and Zhu, J. (2025). Unlocking the Mystery of the PD-1\/PD-L1 Axis: Beyond the Checkpoint Hype. Front. Immunol., 16.","DOI":"10.3389\/fimmu.2025.1708873"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"12632","DOI":"10.1038\/ncomms12632","article-title":"Glycosylation and Stabilization of Programmed Death Ligand-1 Suppresses T-Cell Activity","volume":"7","author":"Li","year":"2016","journal-title":"Nat. Commun."},{"key":"ref_36","first-page":"727","article-title":"PD-1\/PD-L1 Pathway: Current Researches in Cancer","volume":"10","author":"Han","year":"2020","journal-title":"Am. J. Cancer Res."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"301","DOI":"10.1111\/pin.13427","article-title":"Molecular Classification and Intratumoral Heterogeneity of Gastric Adenocarcinoma","volume":"74","author":"Kuwata","year":"2024","journal-title":"Pathol. Int."},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Ramos, A., Sadeghi, S., and Tabatabaeian, H. (2021). Battling Chemoresistance in Cancer: Root Causes and Strategies to Uproot Them. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22179451"},{"key":"ref_39","first-page":"e1291","article-title":"Molecular and Cellular Paradigms of Multidrug Resistance in Cancer","volume":"5","author":"Vaidya","year":"2022","journal-title":"Cancer Rep."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"692","DOI":"10.1186\/s12967-025-06660-7","article-title":"Heterogeneous Tissue-Specific Macrophages Orchestrate Metastatic Organotropism of Breast Cancer: Implications for Promising Therapeutics","volume":"23","author":"Wang","year":"2025","journal-title":"J. Transl. Med."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1384","DOI":"10.1053\/j.gastro.2024.08.007","article-title":"Spatially Resolved Niche and Tumor Microenvironmental Alterations in Gastric Cancer Peritoneal Metastases","volume":"167","author":"Zhao","year":"2024","journal-title":"Gastroenterology"},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Mirzabeigi, Y., Youssef, J., Gonzalez, J., Martinez, T., Avellan, R., Wong, A., Perez, M., Carvajal, L.L., Abou-Kheir, W., and Bahmad, H.F. (2026). Cancer-Associated Fibroblast Heterogeneity and Extracellular Matrix Remodeling as Orchestrators of Drug Resistance in Upper Gastrointestinal Cancers: Insights from Spatial Multi-Omics and Therapeutic Implications. Cancers, 18.","DOI":"10.3390\/cancers18142358"},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Han, X., Zhang, J., Li, W., Huang, X., Wang, X., Wang, B., Gao, L., and Chen, H. (2025). The Role of B2M in Cancer Immunotherapy Resistance: Function, Resistance Mechanism, and Reversal Strategies. Front. Immunol., 16.","DOI":"10.3389\/fimmu.2025.1512509"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1779","DOI":"10.1007\/s00262-019-02410-z","article-title":"Clinicopathologic Significance of Human Leukocyte Antigen Class I Expression in Patients with Stage II and III Gastric Cancer","volume":"68","author":"Park","year":"2019","journal-title":"Cancer Immunol. Immunother."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"n71","DOI":"10.1136\/bmj.n71","article-title":"The PRISMA 2020 statement: An updated guideline for reporting systematic reviews","volume":"372","author":"Page","year":"2021","journal-title":"BMJ"}],"container-title":["Cancers"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6694\/18\/18\/3065\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T13:16:00Z","timestamp":1789996560000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6694\/18\/18\/3065"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,21]]},"references-count":45,"journal-issue":{"issue":"18","published-online":{"date-parts":[[2026,9]]}},"alternative-id":["cancers18183065"],"URL":"https:\/\/doi.org\/10.3390\/cancers18183065","relation":{},"ISSN":["2072-6694"],"issn-type":[{"value":"2072-6694","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,21]]}}}