{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,27]],"date-time":"2026-07-27T06:01:28Z","timestamp":1785132088860,"version":"3.55.0"},"reference-count":23,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,7,27]],"date-time":"2026-07-27T00:00:00Z","timestamp":1785110400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82303080, 82473488"],"award-info":[{"award-number":["82303080, 82473488"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Benefit from first-line immunotherapy-based treatment in advanced biliary tract cancer (BTC) is heterogeneous, and selection biomarkers are lacking. We investigated whether genomic features could stratify benefit from intensified immunotherapy-based treatment versus chemotherapy.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>This exploratory biomarker analysis included 58 patients from a randomized phase 2 trial of sintilimab, anlotinib, gemcitabine, and cisplatin (SAGC) versus gemcitabine plus cisplatin (GC) with baseline tumor tissue available for 425-gene targeted next-generation sequencing. Treatment-by-biomarker interactions for progression-free survival (PFS) were evaluated using Cox models. A genomic classifier was developed, and its feature selection robustness and internal stability were assessed by leave-one-out cross-validation (LOOCV) and bootstrap resampling.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Among 58 biomarker-evaluable patients, SAGC improved overall PFS versus GC (median 7.7 vs 6.3 months; HR 0.48, 95% CI 0.27\u20130.86; P\u00a0=\u00a00.011), with no overall survival (OS) difference (HR 0.98; P\u00a0=\u00a00.946). Evaluating these interactions identified DNA damage response (DDR) alteration and high tumor mutation burden (TMB-H) as the most robust predictors. Applied to both endpoints, the classifier stratified patients into SAGC-predominant (SP; either feature, n=40) and GC-predominant (GP; neither feature, n=18) subgroups, revealing diametrically opposed clinical trajectories (interaction P\u00a0=\u00a00.001 for PFS; P\u00a0=\u00a00.004 for OS). In SP, SAGC markedly prolonged PFS (10.7 vs 4.5 months; HR 0.26, 95% CI 0.12\u20130.55; P\u00a0=\u00a00.0002) and showed a favorable OS trend (16.9 vs 10.3 months; HR 0.55; P\u00a0=\u00a00.113). Conversely, in GP, SAGC yielded shorter PFS (5.8 vs 8.0 months; HR 2.70; P\u00a0=\u00a00.078) and significantly shorter OS (8.2 vs 13.9 months; HR 3.73, 95% CI 1.18\u201311.77; P\u00a0=\u00a00.017) compared to GC. LOOCV supported the reproducibility of feature prioritization and the internal stability of the final classifier, while bootstrap resampling supported the robustness of subgroup-specific treatment effects.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>An exploratory genomic classifier based on DDR alteration and TMB-H may help identify patients with advanced BTC more likely to benefit from the intensified first-line SAGC regimen, pending external validation.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2026.1878780","type":"journal-article","created":{"date-parts":[[2026,7,27]],"date-time":"2026-07-27T05:39:40Z","timestamp":1785130780000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Exploratory genomic stratification of benefit from first-line immunotherapy-based combination in advanced biliary tract cancer: a biomarker analysis of a randomized phase 2 trial"],"prefix":"10.3389","volume":"17","author":[{"given":"Yatong","family":"He","sequence":"first","affiliation":[{"name":"Postgraduate Training Base Alliance of Wenzhou Medical University (Zhejiang Cancer Hospital)","place":["Hangzhou, Zhejiang, China"]},{"name":"Department of Hepato-Pancreato-Biliary & Gastric Medical Oncology, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences","place":["Hangzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zeyu","family":"Ruan","sequence":"additional","affiliation":[{"name":"Postgraduate Training Base Alliance of Wenzhou Medical University (Zhejiang Cancer Hospital)","place":["Hangzhou, Zhejiang, China"]},{"name":"Department of Hepato-Pancreato-Biliary & Gastric Medical Oncology, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences","place":["Hangzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoqing","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Oncology, Hangzhou Xixi Hospital","place":["Hangzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yue","family":"Han","sequence":"additional","affiliation":[{"name":"Postgraduate Training Base Alliance of Wenzhou Medical University (Zhejiang Cancer Hospital)","place":["Hangzhou, Zhejiang, China"]},{"name":"Department of Hepato-Pancreato-Biliary & Gastric Medical Oncology, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences","place":["Hangzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junrong","family":"Yan","sequence":"additional","affiliation":[{"name":"Geneseeq Research Institute, Nanjing Geneseeq Technology Inc.","place":["Nanjing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiaojiao","family":"Ni","sequence":"additional","affiliation":[{"name":"Department of Hepato-Pancreato-Biliary & Gastric Medical Oncology, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences","place":["Hangzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qi","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Hepato-Pancreato-Biliary & Gastric Medical Oncology, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences","place":["Hangzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jieer","family":"Ying","sequence":"additional","affiliation":[{"name":"Postgraduate Training Base Alliance of Wenzhou Medical University (Zhejiang Cancer Hospital)","place":["Hangzhou, Zhejiang, China"]},{"name":"Department of Hepato-Pancreato-Biliary & Gastric Medical Oncology, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences","place":["Hangzhou, China"]},{"name":"Key Laboratory of Prevention, Diagnosis and Therapy of Upper Gastrointestinal Cancer of Zhejiang Province","place":["Hangzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shurui","family":"Zhou","sequence":"additional","affiliation":[{"name":"Postgraduate Training Base Alliance of Wenzhou Medical University (Zhejiang Cancer Hospital)","place":["Hangzhou, Zhejiang, China"]},{"name":"Department of Hepato-Pancreato-Biliary & Gastric Medical Oncology, Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences","place":["Hangzhou, China"]},{"name":"Key Laboratory of Prevention, Diagnosis and Therapy of Upper Gastrointestinal Cancer of Zhejiang Province","place":["Hangzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,7,27]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa0908721","article-title":"Cisplatin plus gemcitabine versus gemcitabine for biliary tract cancer","volume":"362","author":"Valle","year":"2010","journal-title":"N Engl J Med"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1056\/EVIDoa2200015","article-title":"Durvalumab plus gemcitabine and cisplatin in advanced biliary tract cancer","volume":"1","author":"Gandara","year":"2022","journal-title":"NEJM Evid"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(23)00727-4","article-title":"Pembrolizumab in combination with gemcitabine and cisplatin compared with gemcitabine and cisplatin alone for patients with advanced biliary tract cancer (KEYNOTE-966): a randomised, double-blind, placebo-controlled, phase 3 trial","volume":"401","author":"Kelley","year":"2023","journal-title":"Lancet"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2022.946861","article-title":"Lenvatinib plus programmed cell death protein-1 inhibitor beyond first-line systemic therapy in refractory advanced biliary tract cancer: a real-world retrospective study in China","volume":"13","author":"Shi","year":"2022","journal-title":"Front Immunol"},{"key":"B5","doi-asserted-by":"publisher","first-page":"65","DOI":"10.1002\/hep.32548","article-title":"Phase Ib study of anlotinib combined with TQB2450 in pretreated advanced biliary tract cancer and biomarker analysis","volume":"77","author":"Zhou","year":"2023","journal-title":"Hepatology"},{"key":"B6","doi-asserted-by":"publisher","first-page":"106","DOI":"10.1038\/s41392-023-01317-7","article-title":"Toripalimab combined with lenvatinib and GEMOX is a promising regimen as first-line treatment for advanced intrahepatic cholangiocarcinoma: a single-center, single-arm, phase 2 study","volume":"8","author":"Shi","year":"2023","journal-title":"Signal Transduct Target Ther"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1016\/j.tips.2019.07.001","article-title":"Tumor vasculatures: a new target for cancer immunotherapy","volume":"40","author":"Liu","year":"2019","journal-title":"Trends Pharmacol Sci"},{"key":"B8","doi-asserted-by":"publisher","first-page":"5559","DOI":"10.1038\/s41467-025-60119-3","article-title":"Sintilimab and anlotinib with gemcitabine plus cisplatin in advanced biliary tract cancer: SAGC a randomized phase 2 trial","volume":"16","author":"Li","year":"2025","journal-title":"Nat Commun"},{"key":"B9","doi-asserted-by":"publisher","first-page":"6450","DOI":"10.1038\/s41467-021-26806-7","article-title":"Genomic signatures define three subtypes of EGFR-mutant stage II-III non-small-cell lung cancer with distinct adjuvant therapy outcomes","volume":"12","author":"Liu","year":"2021","journal-title":"Nat Commun"},{"key":"B10","doi-asserted-by":"publisher","first-page":"435","DOI":"10.1186\/s12916-025-04263-z","article-title":"Multi-omics analysis uncovers predictive biomarkers for the efficacy and outcomes of chemoimmunotherapy in advanced unresectable biliary tract cancers","volume":"23","author":"Ni","year":"2025","journal-title":"BMC Med"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1016\/j.adro.2018.08.017","article-title":"The DNA damage response in immunotherapy and radiation","volume":"3","author":"Samstein","year":"2018","journal-title":"Adv Radiat Oncol"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2017.75.7740","article-title":"Alterations in DNA damage response and repair genes as potential marker of clinical benefit from PD-1\/PD-L1 blockade in advanced urothelial cancers","volume":"36","author":"Teo","year":"2018","journal-title":"J Clin Oncol"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1016\/j.apsb.2021.01.003","article-title":"Alterations of DNA damage response pathway: biomarker and therapeutic strategy for cancer immunotherapy","volume":"11","author":"Jiang","year":"2021","journal-title":"Acta Pharm Sin B"},{"key":"B14","doi-asserted-by":"publisher","first-page":"268","DOI":"10.1186\/s13046-022-02469-0","article-title":"The role of DNA damage repair (DDR) system in response to immune checkpoint inhibitor (ICI) therapy","volume":"41","author":"Shi","year":"2022","journal-title":"J Exp Clin Cancer Res"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.3390\/ijms262311271","article-title":"Targeting DNA damage response and immune crosstalk in cancer: mechanistic insights and therapeutic opportunities","volume":"26","author":"Marcut","year":"2025","journal-title":"Int J Mol Sci"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1016\/S1470-2045(20)30445-9","article-title":"Association of tumour mutational burden with outcomes in patients with advanced solid tumours treated with pembrolizumab: prospective biomarker analysis of the multicohort, open-label, phase 2 KEYNOTE-158 study","volume":"21","author":"Marabelle","year":"2020","journal-title":"Lancet Oncol"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-20-3054","article-title":"Tumor mutational burden as a predictor of immunotherapy response: is more always better","volume":"27","author":"Strickler","year":"2021","journal-title":"Clin Cancer Res"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1016\/j.esmoop.2021.100336","article-title":"Real-world application of tumor mutational burden-high (TMB-high) and microsatellite instability (MSI) confirms their utility as immunotherapy biomarkers","volume":"7","author":"Palmeri","year":"2022","journal-title":"ESMO Open"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1001\/jamanetworkopen.2023.11181","article-title":"Assessment of tumor mutational burden and outcomes in patients with diverse advanced cancers treated with immunotherapy","volume":"6","author":"Aggarwal","year":"2023","journal-title":"JAMA Netw Open"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1136\/jitc-2024-010311","article-title":"Tumor mutational burden and survival on immune checkpoint inhibition in >8000 patients across 24 cancer types","volume":"13","author":"Gandara","year":"2025","journal-title":"J Immunother Cancer"},{"key":"B21","doi-asserted-by":"publisher","first-page":"55","DOI":"10.1038\/s41698-025-01230-y","article-title":"Prospective tumour mutation burden and neoantigen profiling predicts immunotherapy response in metastatic melanoma","volume":"10","author":"Mao","year":"2026","journal-title":"NPJ Precis Oncol"},{"key":"B22","doi-asserted-by":"publisher","first-page":"S1457","DOI":"10.1016\/j.annonc.2022.10.104","article-title":"Impact of mutation status on efficacy outcomes in TOPAZ-1: a phase III study of durvalumab (D) or placebo (PBO) plus gemcitabine and cisplatin (+GC) in advanced biliary tract cancer (BTC)","volume":"33","author":"Valle","year":"2022","journal-title":"Ann Oncol"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2023.41.4_suppl.531","article-title":"Characterization of long-term survivors in the TOPAZ-1 study of durvalumab or placebo plus gemcitabine and cisplatin in advanced biliary tract cancer","volume":"41","author":"Bouattour","year":"2023","journal-title":"J Clin Oncol"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2026.1878780\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,27]],"date-time":"2026-07-27T05:39:42Z","timestamp":1785130782000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2026.1878780\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,27]]},"references-count":23,"alternative-id":["10.3389\/fimmu.2026.1878780"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2026.1878780","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,27]]},"article-number":"1878780"}}