{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,5]],"date-time":"2026-11-05T12:43:17Z","timestamp":1793882597061,"version":"4.7.0"},"reference-count":31,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,2,12]],"date-time":"2026-02-12T00:00:00Z","timestamp":1770854400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>Current biomarkers for immunochemotherapy in HER2-negative advanced gastric cancer (AGC) exhibit inadequate predictive accuracy. Therefore, the development of innovative methodologies is imperative for improving patient selection.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>In this retrospective biomarker study, a cohort of 107 patients with HER2-negative AGC undergoing first-line immunochemotherapy was examined. Serum biomarkers were serially assessed at baseline and after two treatment cycles. Univariate and multivariate Cox regression analyses, as well as ROC curve analysis, were employed to identify prognostic serum dynamics. A composite biomarker integrating dynamic changes in lactate dehydrogenase (LDH) and a combined positive score (CPS) was developed and validated. Additionally, exploratory genomic profiling was performed.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>In this study, dynamic changes in LDH were identified as an independent prognostic factor. An increase in LDH of \u226526% after two treatment cycles was associated with significantly poorer progression-free survival (PFS: 5.33 vs. 8.93 months; HR: 2.585, P&amp;lt; 0.001) and overall survival (OS: 13.13 vs. 19.63 months; HR: 2.689, P&amp;lt; 0.001). Consistent results were observed in landmark analyses at the two-cycle timepoint, with significant differences in PFS-landmark (PFS-landmark: 5.17 vs. 8.40 months; HR: 2.450, P&amp;lt; 0.001) and OS-landmark (OS-landmark: 11.76 vs. 19.20 months; HR: 2.538, P&amp;lt; 0.001). Combining LDH dynamics with baseline CPS overcame the predictive limitations observed in patients with CPS&amp;lt;5. The subgroup within the composite biomarker (baseline CPS&amp;lt;5 plus LDH elevation \u226526% after two cycles) demonstrated poor prognosis and high risk of early disease progression in survival analysis (median PFS: 4.43 months; median OS: 12.26 months). The robustness of this biomarker was supported by ROC and calibration curves. Additionally, exploratory genomic analysis suggested potential prognostic implications of specific KRAS mutant subtypes and co-mutation patterns. However, validation of these findings is warranted through prospective, multi-center-controlled cohort studies due to constraints related to sample size.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>In HER2-negative advanced gastric cancer, a \u226526% increase in LDH following two treatment cycles serves as an independent prognostic risk factor. Combining baseline CPS with early LDH dynamics improves the identification of patients with aggressive disease and poor initial treatment response, thereby facilitating closer monitoring and prompt therapeutic reassessment for more personalized management.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2026.1659007","type":"journal-article","created":{"date-parts":[[2026,2,12]],"date-time":"2026-02-12T06:46:39Z","timestamp":1770878799000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["A composite biomarker based on early dynamic changes in lactate dehydrogenase and PD-L1 expression enhances outcome prediction for immunochemotherapy in HER2-negative advanced gastric cancer"],"prefix":"10.3389","volume":"17","author":[{"given":"Yue","family":"Zhang","sequence":"first","affiliation":[{"name":"Department of Gastrointestinal Medical Oncology, Harbin Medical University Cancer Hospital","place":["Harbin, Heilongjiang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang","family":"Tian","sequence":"additional","affiliation":[{"name":"Department of Endoscopy, Harbin Medical University Cancer Hospital","place":["Harbin, Heilongjiang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoli","family":"Wei","sequence":"additional","affiliation":[{"name":"Department of Gastrointestinal Medical Oncology, Harbin Medical University Cancer Hospital","place":["Harbin, Heilongjiang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lu","family":"Bai","sequence":"additional","affiliation":[{"name":"Department of Gastrointestinal Medical Oncology, Harbin Medical University Cancer Hospital","place":["Harbin, Heilongjiang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meiqi","family":"Song","sequence":"additional","affiliation":[{"name":"Department of Gastrointestinal Medical Oncology, Harbin Medical University Cancer Hospital","place":["Harbin, Heilongjiang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuanzhi","family":"Guo","sequence":"additional","affiliation":[{"name":"Department of Gastrointestinal Medical Oncology, Harbin Medical University Cancer Hospital","place":["Harbin, Heilongjiang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tianlai","family":"Liu","sequence":"additional","affiliation":[{"name":"Affiliated Cancer Hospital of Inner Mongolia Medical University","place":["Hohhot, Inner Mongolia, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xing","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Gastrointestinal Medical Oncology, Harbin Medical University Cancer Hospital","place":["Harbin, Heilongjiang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weiqi","family":"Shan","sequence":"additional","affiliation":[{"name":"Department of Gastrointestinal Medical Oncology, Harbin Medical University Cancer Hospital","place":["Harbin, Heilongjiang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huaxing","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Endoscopy, Harbin Medical University Cancer Hospital","place":["Harbin, Heilongjiang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu","family":"Han","sequence":"additional","affiliation":[{"name":"Department of Gastrointestinal Medical Oncology, Harbin Medical University Cancer Hospital","place":["Harbin, Heilongjiang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,2,12]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.3322\/caac.21834","article-title":"Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries","volume":"74","author":"Bray","year":"2024","journal-title":"CA Cancer J Clin"},{"key":"B2","doi-asserted-by":"publisher","first-page":"392","DOI":"10.1200\/JCO.2025.43.4_suppl.392","article-title":"First-line (1L) nivolumab (NIVO) plus chemotherapy (chemo) vs chemo in patients (pts) with advanced gastric cancer, gastroesophageal junction cancer, and esophageal adenocarcinoma (GC\/GEJC\/EAC): 5-year (y) follow-up of Chinese pts from CheckMate 649","volume":"43","author":"Shen","year":"2025","journal-title":"J Clin Oncol"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2023.19918","article-title":"Sintilimab plus chemotherapy for unresectable gastric or gastroesophageal junction cancer: the ORIENT-16 randomized clinical trial","volume":"330","author":"Xu","year":"2023","journal-title":"Jama"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1016\/j.pathol.2020.10.007","article-title":"Programmed death ligand-1 (PD-L1) as a predictive marker for immunotherapy in solid tumours: a guide to immunohistochemistry implementation and interpretation","volume":"53","author":"Paver","year":"2021","journal-title":"Pathology"},{"key":"B5","doi-asserted-by":"publisher","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":"B6","doi-asserted-by":"publisher","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":"B7","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.CD-23-0857","article-title":"Early immune remodeling steers clinical response to first-line chemoimmunotherapy in advanced gastric cancer","volume":"14","author":"An","year":"2024","journal-title":"Cancer Discov"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.CD-23-1060","article-title":"Early changes in tumor-naive cell-free methylomes and fragmentomes predict outcomes in pembrolizumab-treated solid tumors","volume":"14","author":"Stutheit-Zhao","year":"2024","journal-title":"Cancer Discov"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2024.1327449","article-title":"Serum albumin and derived neutrophil-to-lymphocyte ratio are potential predictive biomarkers for immune checkpoint inhibitors in small cell lung cancer","volume":"15","author":"Kuang","year":"2024","journal-title":"Front Immunol"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.3390\/nu15194290","article-title":"The prognostic value of the prognostic nutritional index in patients with advanced or metastatic gastric cancer treated with immunotherapy","volume":"15","author":"Pan","year":"2023","journal-title":"Nutrients"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2024.1408700","article-title":"Prognostic value of inflammatory markers NLR, PLR, and LMR in gastric cancer patients treated with immune checkpoint inhibitors: a meta-analysis and systematic review","volume":"15","author":"Tan","year":"2024","journal-title":"Front Immunol"},{"key":"B12","doi-asserted-by":"publisher","first-page":"e70199","DOI":"10.1002\/mco2.70199","article-title":"Platelet-to-neutrophil ratio: A novel prognostic indicator for anti-PD-1-based therapy in relapsed\/refractory hodgkin lymphoma and solid tumors","volume":"6","author":"Pan","year":"2025","journal-title":"MedComm (2020)"},{"key":"B13","doi-asserted-by":"publisher","first-page":"797","DOI":"10.1111\/j.1365-2559.2008.03028.x","article-title":"Assessment of a HER2 scoring system for gastric cancer: results from a validation study","volume":"52","author":"Hofmann","year":"2008","journal-title":"Histopathology"},{"key":"B14","doi-asserted-by":"publisher","first-page":"1121","DOI":"10.1186\/s12885-024-12813-6","article-title":"Measurement of changes in serum-based inflammatory indicators to monitor response to nivolumab monotherapy in advanced gastric cancer: a multicenter retrospective study","volume":"24","author":"Inukai","year":"2024","journal-title":"BMC Cancer"},{"key":"B15","doi-asserted-by":"publisher","first-page":"264","DOI":"10.1186\/s12876-025-03883-2","article-title":"Dynamic variations in peripheral blood indices and their association with efficacy and adverse reactions of pd- 1 inhibitor combined chemotherapy in patients with advanced gastric cancer","volume":"25","author":"Wang","year":"2025","journal-title":"BMC Gastroenterol"},{"key":"B16","doi-asserted-by":"publisher","first-page":"102926","DOI":"10.1016\/j.eclinm.2024.102926","article-title":"Contraception with levonorgestrel-releasing intrauterine system versus copper intrauterine device: a meta-analysis of randomized controlled trials","volume":"78","author":"Liu","year":"2024","journal-title":"EClinicalMedicine"},{"key":"B17","doi-asserted-by":"publisher","first-page":"51","DOI":"10.1186\/s13613-025-01471-x","article-title":"Comparison of all-cause mortality with different blood glucose control strategies in patients with diabetes in the ICU: a network meta-analysis of randomized controlled trials","volume":"15","author":"Li","year":"2025","journal-title":"Ann Intensive Care"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1038\/s41416-018-0167-x","article-title":"S100B and LDH as early prognostic markers for response and overall survival in melanoma patients treated with anti-PD-1 or combined anti-PD-1 plus anti-CTLA-4 antibodies","volume":"119","author":"Wagner","year":"2018","journal-title":"Br J Cancer"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejca.2022.11.032","article-title":"Rationale for LDH-targeted cancer immunotherapy","volume":"181","author":"Miholjcic","year":"2023","journal-title":"Eur J Cancer"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2025.02.008","article-title":"Lactate: A key regulator of the immune response","volume":"58","author":"Llibre","year":"2025","journal-title":"Immunity"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1038\/s41571-022-00686-2","article-title":"The multiple roles of LDH in cancer","volume":"19","author":"Claps","year":"2022","journal-title":"Nat Rev Clin Oncol"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1016\/j.lungcan.2020.12.027","article-title":"Immunotherapy in advanced Non-Small Cell Lung Cancer patients with poor performance status: The role of clinical-pathological variables and inflammatory biomarkers","volume":"152","author":"Lobefaro","year":"2021","journal-title":"Lung Cancer"},{"key":"B23","doi-asserted-by":"publisher","first-page":"80","DOI":"10.1016\/j.ejca.2022.08.034","article-title":"High serum LDH and liver metastases are the dominant predictors of primary cancer resistance to anti-PD(L)1 immunotherapy","volume":"177","author":"Dercle","year":"2022","journal-title":"Eur J Cancer"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1097\/JS9.0000000000001119","article-title":"Efficacy and safety of neoadjuvant sintilimab in combination with FLOT chemotherapy in patients with HER2-negative locally advanced gastric or gastroesophageal junction adenocarcinoma: an investigator-initiated, single-arm, open-label, phase II study","volume":"110","author":"Li","year":"2024","journal-title":"Int J Surg"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1200\/EDBK_200643","article-title":"Patterns of response and progression to immunotherapy","volume":"38","author":"Borcoman","year":"2018","journal-title":"Am Soc Clin Oncol Educ Book"},{"key":"B26","doi-asserted-by":"publisher","first-page":"87","DOI":"10.1148\/radiol.2020200443","article-title":"Incidence of pseudoprogression during immune checkpoint inhibitor therapy for solid tumors: A systematic review and meta-analysis","volume":"297","author":"Park","year":"2020","journal-title":"Radiology"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1038\/s43018-021-00184-x","article-title":"The Metabolic Landscape of RAS-Driven Cancers from biology to therapy","volume":"2","author":"Mukhopadhyay","year":"2021","journal-title":"Nat Cancer"},{"key":"B28","doi-asserted-by":"publisher","first-page":"102317","DOI":"10.1016\/j.tranon.2025.102317","article-title":"Efficacy of first-line chemotherapy combined with immunotherapy or anti-angiogenic therapy in advanced KRAS-mutant non-small cell lung cancer","volume":"53","author":"Qiang","year":"2025","journal-title":"Transl Oncol"},{"key":"B29","doi-asserted-by":"publisher","first-page":"4933","DOI":"10.3390\/cancers14194933","article-title":"Clinical and molecular features of KRAS-mutated lung cancer patients treated with immune checkpoint inhibitors","volume":"14","author":"Zhao","year":"2022","journal-title":"Cancers (Basel)"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1016\/j.jtho.2023.12.015","article-title":"Outcome of first-line treatment with pembrolizumab according to KRAS\/TP53 mutational status for nonsquamous programmed death-ligand 1-high (\u226550%) NSCLC in the german national network genomic medicine lung cancer","volume":"19","author":"Bischoff","year":"2024","journal-title":"J Thorac Oncol"},{"key":"B31","doi-asserted-by":"publisher","first-page":"54","DOI":"10.1136\/jcp-2022-208574","article-title":"Prognostic value of KRAS mutations, TP53 mutations and PD-L1 expression among lung adenocarcinomas treated with immunotherapy","volume":"77","author":"T\u00f8nnesen","year":"2023","journal-title":"J Clin Pathol"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2026.1659007\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,2,24]],"date-time":"2026-02-24T10:26:36Z","timestamp":1771928796000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2026.1659007\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,2,12]]},"references-count":31,"alternative-id":["10.3389\/fimmu.2026.1659007"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2026.1659007","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,2,12]]},"article-number":"1659007"}}