{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,10]],"date-time":"2026-07-10T05:13:39Z","timestamp":1783660419485,"version":"3.55.0"},"reference-count":59,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,7,10]],"date-time":"2026-07-10T00:00:00Z","timestamp":1783641600000},"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. Oncol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Outcomes in stage IV lung adenocarcinoma (LUAD) remain heterogeneous despite established genomic and immune biomarkers. We evaluated the prognostic and predictive value of soluble interleukin-2 receptor (sCD25), a marker of systemic inflammation and immune regulation.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>In this prospective observational real-world study (2020\u20132024), 133 consecutive patients with newly diagnosed stage IV LUAD, ECOG performance status 0\u20131, and survival \u22653 months were enrolled. Overall survival (OS) was the primary endpoint. Associations between sCD25 and OS were assessed using Kaplan\u2013Meier estimates, multivariable Cox regression, and propensity score matching. Treatment-by-biomarker interaction analyses evaluated EGFR tyrosine kinase inhibitors (TKIs), immune checkpoint inhibitors (ICIs), and antiangiogenic therapy.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>In the whole group, at a median follow-up of 24.1 months, 52 deaths occurred during follow-up. Elevated sCD25 (\u2265441 U\/mL) was associated with shorter OS (hazard ratio [HR], 5.70; 95% CI, 2.94\u201311.07; P &amp;lt;.0001) and remained prognostic in multivariable analysis (HR, 4.23; 95% CI, 2.01\u20138.91; P &amp;lt;.001) and after propensity score matching (HR, 4.61; 95% CI, 2.01\u201310.62; P &amp;lt;.001). One- and three-year OS rates were 97% and 78% for low sCD25 versus 68% and 27% for high sCD25. A significant treatment interaction was observed for EGFR\u2013TKIs, with benefit limited to the high-sCD25 subgroup (HR, 0.41; 95% CI, 0.19\u20130.88; P\u00a0= .02). No significant interactions were observed for ICIs or antiangiogenic therapy.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Baseline sCD25 is a biomarker in stage IV LUAD \u2014strongly prognostic and suggests differential benefit from EGFR\u2013TKIs\u2014and may help refine EGFR\u2013TKI selection. Multicenter validation is warranted.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fonc.2026.1810131","type":"journal-article","created":{"date-parts":[[2026,7,10]],"date-time":"2026-07-10T04:24:16Z","timestamp":1783657456000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Real-world evidence of baseline soluble CD25 as a prognostic biomarker and indicator of differential EGFR\u2013TKI benefit in stage IV lung adenocarcinoma"],"prefix":"10.3389","volume":"16","author":[{"given":"Huiru","family":"Guo","sequence":"first","affiliation":[{"name":"Department of Medical Oncology VI, Longhua University Hospital","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lingshuang","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology VI, Longhua University Hospital","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Veronika","family":"Lindberg","sequence":"additional","affiliation":[{"name":"Department of Statistics, Lintech AS","place":["Kristiansand, Norway"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yingjun","family":"Xue","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine, Longhua University Hospital","place":["Shanghai, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jan P. A.","family":"Baak","sequence":"additional","affiliation":[{"name":"Department of Molecular Digital Pathology, Stavanger University Hospital","place":["Stavanger, Norway"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,7,10]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"7","DOI":"10.3322\/caac.21708","article-title":"Cancer statistics, 2022","volume":"72","author":"Siegel","year":"2022","journal-title":"CA Cancer J Clin"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.3978\/j.issn.2218-6751.2014.09.01","article-title":"Lung cancer molecular epidemiology in China: recent trends","volume":"3","author":"Zhou","year":"2014","journal-title":"Transl Lung Cancer Res"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2021.761042","article-title":"How long have I got? In stage IV NSCLC patients with at least 3 months up to 10 years survival, accuracy of long-, intermediate-, and short-term survival prediction is not good enough to answer this question","volume":"11","author":"Guo","year":"2021","journal-title":"Front Oncol"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2022.837419","article-title":"Clinical and biological interpretation of survival curves of cancer patients, exemplified with stage IV non\u2013small-cell lung cancers with long follow-up","volume":"12","author":"Baak","year":"2022","journal-title":"Front Oncol"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1016\/j.lanepe.2024.100839","article-title":"Future perspective for the application of predictive biomarker testing in advanced-stage non\u2013small-cell lung cancer","volume":"38","author":"de Jager","year":"2024","journal-title":"Lancet Reg Health Eur"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2010.08.004","article-title":"Interleukin-2 receptor signalling: at the interface between tolerance and immunity","volume":"33","author":"Malek","year":"2010","journal-title":"Immunity"},{"key":"B7","doi-asserted-by":"publisher","first-page":"79","DOI":"10.1093\/imammb\/dqw021","article-title":"The effects of interleukin-2 on immune response regulation","volume":"35","author":"Waters","year":"2018","journal-title":"Math Med Biol"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1016\/j.clim.2020.108515","article-title":"The IL-2\u2013IL-2 receptor pathway in health and disease: the role of the soluble IL-2 receptor","volume":"218","author":"Damoiseaux","year":"2020","journal-title":"Clin Immunol"},{"key":"B9","doi-asserted-by":"publisher","first-page":"121","DOI":"10.1186\/s12943-023-01826-7","article-title":"Reigniting hope in cancer treatment: the promise and pitfalls of IL-2 and IL-2R targeting strategies","volume":"22","author":"Muhammad","year":"2023","journal-title":"Mol Cancer"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1038\/s12276-023-01150-6","article-title":"Soluble receptors in cancer: mechanisms, clinical significance, and therapeutic strategies","volume":"56","author":"Park","year":"2024","journal-title":"Exp Mol Med"},{"key":"B11","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/s0169-5002(98)00094-4","article-title":"Soluble interleukin 2 receptor (sIL2R) in monitoring advanced lung cancer during chemotherapy","volume":"23","author":"Brunetti","year":"1999","journal-title":"Lung Cancer"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.3390\/cancers13153702","article-title":"Serum sCD25 protein as a predictor of lack of long-term benefits from immunotherapy in non\u2013small-cell lung cancer: a pilot study","volume":"13","author":"Siemi\u0105tkowska","year":"2021","journal-title":"Cancers (Basel)"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1007\/s10637-023-01358-3","article-title":"Soluble interleukin-2 receptor as a predictive biomarker for poor efficacy of anti\u2013PD-1\/PD-L1 plus chemotherapy in NSCLC","volume":"41","author":"Tozuka","year":"2023","journal-title":"Invest New Drugs"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.12998\/wjcc.v10.i33.12230","article-title":"Prognostic role of pretreatment serum ferritin concentration in lung cancer patients: A meta-analysis","volume":"10","author":"Gao","year":"2022","journal-title":"World J Clin Cases"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.3892\/or.9.1.193","article-title":"The serum ferritin concentration is a significant prognostic indicator of survival in primary lung cancer","volume":"9","author":"Milman","year":"2002","journal-title":"Oncol Rep"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.4103\/0973-1482.139156","article-title":"Serum ferritin is elevated in advanced non\u2013small-cell lung cancer patients and is associated with efficacy of platinum-based chemotherapy","volume":"10","author":"Shi","year":"2014","journal-title":"J Cancer Res Ther"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1093\/intimm\/dxx031","article-title":"Hyperferritinemia and inflammation","volume":"29","author":"Kernan","year":"2017","journal-title":"Int Immunol"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2013.281053","article-title":"World Medical Association Declaration of Helsinki: ethical principles for medical research involving human subjects","volume":"310","year":"2013","journal-title":"JAMA"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.5867\/medwave.2018.02.7208","article-title":"Council for International Organizations of Medical Sciences (CIOMS) ethical guidelines: advancements and unsolved topics in 2016 upgrade","volume":"18","author":"Borgeat Meza","year":"2018","journal-title":"Medwave"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa011954","article-title":"Comparison of four chemotherapy regimens for advanced non\u2013small-cell lung cancer","volume":"346","author":"Schiller","year":"2002","journal-title":"N Engl J Med"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1002\/cam4.1776","article-title":"Radiotherapy improves the survival of patients with stage IV NSCLC: a propensity score matched analysis of the SEER database","volume":"7","author":"Zhang","year":"2018","journal-title":"Cancer Med"},{"key":"B22","doi-asserted-by":"publisher","first-page":"39","DOI":"10.1016\/j.jtho.2015.09.009","article-title":"The IASLC lung cancer staging project: proposals for revision of the TNM stage groupings in the forthcoming (eighth) edition of the TNM classification for lung cancer","volume":"11","author":"Goldstraw","year":"2016","journal-title":"J Thorac Oncol"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1097\/JTO.0b013e31829cf942","article-title":"Body mass index and its association with clinical outcomes for advanced non\u2013small-cell lung cancer patients enrolled on Eastern Cooperative Oncology Group clinical trials","volume":"8","author":"Dahlberg","year":"2013","journal-title":"J Thorac Oncol"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2012.45.2722","article-title":"Cancer cachexia in the age of obesity: skeletal muscle depletion is a powerful prognostic factor, independent of body mass index","volume":"31","author":"Martin","year":"2013","journal-title":"J Clin Oncol"},{"key":"B25","doi-asserted-by":"publisher","first-page":"41","DOI":"10.1093\/biomet\/70.1.41","article-title":"The central role of the propensity score in observational studies for causal effects","volume":"70","author":"Rosenbaum","year":"1983","journal-title":"Biometrika"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2019.21558","article-title":"Using propensity score methods to create target populations in observational clinical research","volume":"323","author":"Thomas","year":"2020","journal-title":"JAMA"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2019.21558","article-title":"Using propensity score methods to create target populations in observational clinical research","volume":"323","author":"Thomas","year":"2020","journal-title":"JAMA"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1093\/aje\/kwy201","article-title":"Addressing extreme propensity scores via the overlap weights","volume":"188","author":"Li","year":"2019","journal-title":"Am J Epidemiol"},{"key":"B29","doi-asserted-by":"publisher","first-page":"150","DOI":"10.1186\/s12874-016-0253-9","article-title":"Inverse probability weighting to estimate causal effect of a singular phase in a multiphase randomized clinical trial for multiple myeloma","volume":"16","author":"Pezzi","year":"2016","journal-title":"BMC Med Res Methodol"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1002\/sim.3697","article-title":"Balance diagnostics for comparing the distribution of baseline covariates between treatment groups in propensity score matched samples","volume":"28","author":"Austin","year":"2009","journal-title":"Stat Med"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1245\/s10434-023-14689-5","article-title":"Robotic versus thoracoscopic sub-lobar resection for octogenarians with clinical stage IA non-small cell lung cancer: a propensity score-matched real-world study","volume":"31","author":"Pan","year":"2024","journal-title":"Ann Surg Oncol"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1186\/s12911-024-02753-3","article-title":"A novel prediction model for the prognosis of non-small cell lung cancer with clinical routine laboratory indicators: a machine learning approach","volume":"24","author":"Wang","year":"2024","journal-title":"BMC Med Inform Decis Mak"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1007\/s10637-023-01358-3","article-title":"Soluble interleukin-2 receptor as a predictive biomarker for poor efficacy of combination treatment with anti-PD-1\/PD-L1 antibodies and chemotherapy in non-small cell lung cancer patients","volume":"41","author":"Tozuka","year":"2023","journal-title":"Invest New Drugs"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1080\/2162402X.2017.1356145","article-title":"EGFR mutation correlates with uninflamed phenotype and weak immunogenicity, causing impaired response to PD-1 blockade in non-small cell lung cancer","volume":"6","author":"Dong","year":"2017","journal-title":"Oncoimmunology"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1093\/annonc\/mdz133","article-title":"EGFR mutation subtypes and response to immune checkpoint blockade in NSCLC","volume":"30","author":"Hastings","year":"2019","journal-title":"Ann Oncol"},{"key":"B36","doi-asserted-by":"publisher","first-page":"118","DOI":"10.1186\/s12931-017-0604-z","article-title":"Hepatocyte growth factor produced in lung fibroblasts enhances non-small cell lung cancer cell survival and tumor progression","volume":"18","author":"Kanaji","year":"2017","journal-title":"Respir Res"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1038\/nature11183","article-title":"Tumour micro-environment elicits innate resistance to RAF inhibitors through HGF secretion","volume":"487","author":"Straussman","year":"2012","journal-title":"Nature"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1038\/ng.2330","article-title":"Activation of the AXL kinase causes resistance to EGFR-targeted therapy in lung cancer","volume":"44","author":"Zhang","year":"2012","journal-title":"Nat Genet"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-025-09071-2","article-title":"Concurrent loss of the Y chromosome in cancer and T cells impacts outcome","volume":"642","author":"Chen","year":"2025","journal-title":"Nature"},{"key":"B40","doi-asserted-by":"publisher","first-page":"243","DOI":"10.1186\/s12864-024-10168-7","article-title":"Loss of chromosome Y in regulatory T cells","volume":"25","author":"Mattisson","year":"2024","journal-title":"BMC Genomics"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-024-07943-7","article-title":"CTLA4 blockade abrogates KEAP1\/STK11-related resistance to PD-(L)1 inhibitors","volume":"635","author":"Skoulidis","year":"2024","journal-title":"Nature"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.22.00975","article-title":"Durvalumab with or without tremelimumab in combination with chemotherapy as first-line therapy for metastatic non\u2013small-cell lung cancer: the phase III POSEIDON study","volume":"41","author":"Johnson","year":"2023","journal-title":"J Clin Oncol"},{"key":"B43","doi-asserted-by":"crossref","DOI":"10.1136\/jitc-2025-011907","article-title":"Napsin A\u2013specific T-cell clonotypes are associated with improved clinical outcomes in patients receiving checkpoint immunotherapy for metastatic non\u2013small-cell lung cancer","volume-title":"J Immunother Cancer","author":"Miller","year":"2025"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1136\/jitc-2023-007310","article-title":"Increased interleukin-6\/C-reactive protein levels are associated with the upregulation of the adenosine pathway and serve as potential markers of therapeutic resistance to immune checkpoint inhibitor-based therapies in non\u2013small-cell lung cancer","volume":"11","author":"Naqash","year":"2023","journal-title":"J Immunother Cancer"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2403614","article-title":"Amivantamab plus lazertinib in previously untreated EGFR-mutated advanced non-small-cell lung cancer","volume":"391","author":"Cho","year":"2024","journal-title":"N Engl J Med"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2503001","article-title":"Overall survival with amivantamab-lazertinib in EGFR-mutated advanced NSCLC","volume":"393","author":"Yang","year":"2025","journal-title":"N Engl J Med"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.1016\/j.annonc.2023.10.117","article-title":"Amivantamab plus chemotherapy with and without lazertinib in EGFR-mutant advanced NSCLC after disease progression on osimertinib: primary results from the phase III MARIPOSA-2 study","volume":"35","author":"Passaro","year":"2024","journal-title":"Ann Oncol"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2024.113771","article-title":"Transcription factor ZNF263 enhances EGFR-targeted therapeutic response and reduces residual disease in lung adenocarcinoma","volume":"43","author":"Liang","year":"2024","journal-title":"Cell Rep"},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.1016\/j.canlet.2025.218069","article-title":"Targeting inosine metabolism to enhance EGFR-targeted therapy in lung adenocarcinoma","volume":"634","author":"Huang","year":"2025","journal-title":"Cancer Lett"},{"key":"B50","doi-asserted-by":"publisher","DOI":"10.1111\/imm.13847","article-title":"Unravelling CD24-Siglec-10 pathway: Cancer immunotherapy from basic science to clinical studies","volume":"173","author":"Hazra","year":"2024","journal-title":"Immunology"},{"key":"B51","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2028485","article-title":"Sacituzumab govitecan in metastatic triple-negative breast cancer","volume":"384","author":"Bardia","year":"2021","journal-title":"N Engl J Med"},{"key":"B52","doi-asserted-by":"publisher","DOI":"10.1002\/cac2.70068","article-title":"CD24 is a promising immunotherapeutic target for enhancing efficacy of third-generation EGFR-TKIs on EGFR-mutated lung cancer","volume":"45","author":"Liang","year":"2025","journal-title":"Cancer Commun (Lond)"},{"key":"B53","doi-asserted-by":"publisher","DOI":"10.1038\/s41571-020-0382-2","article-title":"The adenosine pathway in immuno-oncology","volume":"17","author":"Allard","year":"2020","journal-title":"Nat Rev Clin Oncol"},{"key":"B54","doi-asserted-by":"publisher","DOI":"10.1093\/aje\/kwv254","article-title":"Using big data to emulate a target trial when a randomized trial is not available","volume":"183","author":"Hern\u00e1n","year":"2016","journal-title":"Am J Epidemiol"},{"key":"B55","doi-asserted-by":"publisher","DOI":"10.1002\/pds.1357","article-title":"Immortal time bias in observational studies of drug effects","volume":"16","author":"Suissa","year":"2007","journal-title":"Pharmacoepidemiol Drug Saf"},{"key":"B56","doi-asserted-by":"publisher","DOI":"10.1002\/cncr.28273","article-title":"Dynamic prognostication using conditional survival estimates","volume":"119","author":"Zabor","year":"2013","journal-title":"Cancer"},{"key":"B57","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-019-1456-0","article-title":"CD24 signalling through macrophage Siglec-10 is a target for cancer immunotherapy","volume":"572","author":"Barkal","year":"2019","journal-title":"Nature"},{"key":"B58","doi-asserted-by":"publisher","DOI":"10.1200\/JCO-24-01349","article-title":"Datopotamab Deruxtecan in advanced or metastatic non-small cell lung cancer with actionable genomic alterations: Results from the phase II TROPION-Lung05 study","volume":"43","author":"Sands","year":"2025","journal-title":"J Clin Oncol"},{"key":"B59","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2008.16.1000","article-title":"Analysis of survival by tumor response and other comparisons of time-to-event by outcome variables","volume":"26","author":"Anderson","year":"2008","journal-title":"J Clin Oncol"}],"container-title":["Frontiers in Oncology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fonc.2026.1810131\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,10]],"date-time":"2026-07-10T04:24:18Z","timestamp":1783657458000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fonc.2026.1810131\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,10]]},"references-count":59,"alternative-id":["10.3389\/fonc.2026.1810131"],"URL":"https:\/\/doi.org\/10.3389\/fonc.2026.1810131","relation":{},"ISSN":["2234-943X"],"issn-type":[{"value":"2234-943X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,10]]},"article-number":"1810131"}}