{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,20]],"date-time":"2026-07-20T12:01:56Z","timestamp":1784548916947,"version":"3.55.0"},"reference-count":21,"publisher":"MDPI AG","issue":"14","license":[{"start":{"date-parts":[[2026,7,20]],"date-time":"2026-07-20T00:00:00Z","timestamp":1784505600000},"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: Left ventricular (LV) dysfunction is a clinically important complication of anthracycline- and trastuzumab-based treatment in breast cancer. Inflammatory pathways may contribute to cancer therapy-related cardiac dysfunction, and the CD40\/CD40 ligand (CD40L) axis has been implicated in vascular inflammation and myocardial injury. This study assessed longitudinal changes in CD40 and CD40L during adjuvant treatment and their association with LV dysfunction. Methods: Twenty-eight women with operable breast cancer receiving adjuvant anthracycline-based chemotherapy with or without trastuzumab were prospectively evaluated. Blood samples were collected at baseline, 6 months, and treatment completion at 15 months to measure CD40 and CD40L. Cardiac function was assessed by transthoracic echocardiography, including left ventricular ejection fraction and global longitudinal strain, at baseline and every 3 months. Repeated-measures analysis of variance examined temporal biomarker changes and interactions with LV dysfunction. Results: Participants had a mean age of 52.6 \u00b1 10.7 years and a mean BMI of 25.8 \u00b1 4.8 kg\/m2; 64% were postmenopausal, 76% had HER2-positive disease, and 79.3% received radiotherapy and trastuzumab. During follow-up, 15 patients (53.6%) developed LV dysfunction. CD40 levels remained stable overall (p = 0.31), whereas CD40L increased significantly over time (p &lt; 0.001). Baseline CD40 did not differ by LV dysfunction status (p = 0.79). However, CD40 showed a significant time-by-LV dysfunction interaction (p = 0.022), increasing late in patients with LV dysfunction and declining in those without it. CD40L showed no such interaction (p = 0.85). Conclusions: In this small exploratory cohort, CD40 demonstrated differential longitudinal patterns according to subsequent LV dysfunction, whereas CD40L increased over time without a clear association with LV dysfunction. These findings should be interpreted as hypothesis-generating and require validation in larger prospective cohorts.<\/jats:p>","DOI":"10.3390\/cancers18142340","type":"journal-article","created":{"date-parts":[[2026,7,20]],"date-time":"2026-07-20T10:44:02Z","timestamp":1784544242000},"page":"2340","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Evaluation of Longitudinal CD40 and CD40L Changes During Adjuvant Breast Cancer Therapy and Their Association with Left Ventricular Dysfunction"],"prefix":"10.3390","volume":"18","author":[{"given":"Georgia","family":"Efthymiou","sequence":"first","affiliation":[{"name":"Laboratory of Biology, Department of Basic Medical Sciences, National and Kapodistrian University of Athens Medical School, 11527 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0047-8090","authenticated-orcid":false,"given":"Maria","family":"Anastasiou","sequence":"additional","affiliation":[{"name":"Section of Medical Oncology, 2nd Propaedeutic Department of Internal Medicine and Clinical Research Institute, Attikon University Hospital, National and Kapodistrian University of Athens Medical School, 12461 Haidari, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8079-0599","authenticated-orcid":false,"given":"Evangelos","family":"Oikonomou","sequence":"additional","affiliation":[{"name":"3rd Cardiology Department, \u201cSotiria\u201d General Hospital of Chest Diseases of Athens, Athina Ioanni Martinou Endowed Chair, National and Kapodistrian University of Athens Medical School, 11527 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9260-6306","authenticated-orcid":false,"given":"Panagiotis","family":"Theofilis","sequence":"additional","affiliation":[{"name":"1st Cardiology Department, \u201cHippokration\u201d Athens General Hospital, National and Kapodistrian University of Athens Medical School, 11527 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5741-4288","authenticated-orcid":false,"given":"Hector","family":"Katifelis","sequence":"additional","affiliation":[{"name":"Laboratory of Biology, Department of Basic Medical Sciences, National and Kapodistrian University of Athens Medical School, 11527 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elias","family":"Giallafos","sequence":"additional","affiliation":[{"name":"3rd Department of Cardiology, Sotiria Chest Disease Hospital, National and Kapodistrian University of Athens Medical School, 11527 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3295-6811","authenticated-orcid":false,"given":"Maria","family":"Gazouli","sequence":"additional","affiliation":[{"name":"Laboratory of Biology, Department of Basic Medical Sciences, National and Kapodistrian University of Athens Medical School, 11527 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2508-500X","authenticated-orcid":false,"given":"Anastasia","family":"Kotanidou","sequence":"additional","affiliation":[{"name":"1st Department of Critical Care Medicine and Pulmonary Services, Evangelismos Hospital, National and Kapodistrian University of Athens Medical School, 10676 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gerasimos","family":"Siasos","sequence":"additional","affiliation":[{"name":"3rd Department of Cardiology, Sotiria Chest Disease Hospital, National and Kapodistrian University of Athens Medical School, 11527 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"634","DOI":"10.1136\/heartjnl-2012-303151","article-title":"Trastuzumab-induced cardiotoxicity in early breast cancer patients: A retrospective study of possible risk and protective factors","volume":"99","author":"Farolfi","year":"2013","journal-title":"Heart"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1981","DOI":"10.1161\/CIRCULATIONAHA.114.013777","article-title":"Early detection of anthracycline cardiotoxicity and improvement with heart failure therapy","volume":"131","author":"Cardinale","year":"2015","journal-title":"Circulation"},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Theofilis, P., Vlachakis, P.K., Oikonomou, E., Drakopoulou, M., Karakasis, P., Apostolos, A., Pamporis, K., Tsioufis, K., and Tousoulis, D. (2024). Cancer Therapy-Related Cardiac Dysfunction: A Review of Current Trends in Epidemiology, Diagnosis, and Treatment. Biomedicines, 12.","DOI":"10.3390\/biomedicines12122914"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"576","DOI":"10.1016\/j.recesp.2016.12.032","article-title":"Early Diagnosis and Prediction of Anticancer Drug-induced Cardiotoxicity: From Cardiac Imaging to \u201cOmics\u201d Technologies","volume":"70","author":"Madonna","year":"2017","journal-title":"Rev. Esp. Cardiol. (Engl. Ed.)"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"471","DOI":"10.2217\/fca.15.16","article-title":"Current and emerging modalities for detection of cardiotoxicity in cardio-oncology","volume":"11","author":"Khouri","year":"2015","journal-title":"Future Cardiol."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Anastasiou, M., Oikonomou, E., Theofilis, P., Gazouli, M., Psyrri, A., Zagouri, F., Siasos, G., and Tousoulis, D. (2025). The Role of miRNAs in Chemotherapy-Induced Cardiotoxicity. Biomedicines, 13.","DOI":"10.3390\/biomedicines13102331"},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Daub, S., Lutgens, E., Munzel, T., and Daiber, A. (2020). CD40\/CD40L and Related Signaling Pathways in Cardiovascular Health and Disease-The Pros and Cons for Cardioprotection. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21228533"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1007\/s12265-020-09994-3","article-title":"The CD40-CD40L Dyad as Immunotherapeutic Target in Cardiovascular Disease","volume":"14","author":"Bosmans","year":"2021","journal-title":"J. Cardiovasc. Transl. Res."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1101","DOI":"10.1093\/eurheartj\/ehi132","article-title":"Soluble CD40 ligand in acute and chronic heart failure","volume":"26","author":"Ueland","year":"2005","journal-title":"Eur. Heart J."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"2192","DOI":"10.1161\/01.ATV.0000182904.08513.60","article-title":"Associations between soluble CD40 ligand, atherosclerosis risk factors, and subclinical atherosclerosis: Results from the Dallas Heart Study","volume":"25","author":"Zirlik","year":"2005","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"458","DOI":"10.1038\/s44161-025-00633-1","article-title":"The immune checkpoint regulator CD40 potentiates myocardial inflammation","volume":"4","author":"Jimenez","year":"2025","journal-title":"Nat. Cardiovasc. Res."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"886","DOI":"10.1016\/j.jaccao.2025.10.003","article-title":"Biomarkers and Cardiotoxicity in Breast Cancer: A Step Forward and More Studies Needed","volume":"7","author":"Baik","year":"2025","journal-title":"JACC CardioOncol"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"4229","DOI":"10.1093\/eurheartj\/ehac244","article-title":"2022 ESC Guidelines on cardio-oncology developed in collaboration with the European Hematology Association (EHA), the European Society for Therapeutic Radiology and Oncology (ESTRO) and the International Cardio-Oncology Society (IC-OS)","volume":"43","author":"Lyon","year":"2022","journal-title":"Eur. Heart J."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Ciappina, G., Colarusso, L., Maiorana, E., Ottaiano, A., Franchina, T., Picone, A., Facchini, G., Barraco, C., Ieni, A., and Cusma Piccione, M. (2025). Cardiotoxicity Induced by Anticancer Therapies: A Call for Integrated Cardio-Oncology Practice. Pharmaceuticals, 18.","DOI":"10.3390\/ph18091399"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1945","DOI":"10.1002\/ejhf.1920","article-title":"Baseline cardiovascular risk assessment in cancer patients scheduled to receive cardiotoxic cancer therapies: A position statement and new risk assessment tools from the Cardio-Oncology Study Group of the Heart Failure Association of the European Society of Cardiology in collaboration with the International Cardio-Oncology Society","volume":"22","author":"Lyon","year":"2020","journal-title":"Eur. J. Heart Fail."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1007\/s11886-016-0731-z","article-title":"Curing Cancer, Saving the Heart: A Challenge That Cardioncology Should Not Miss","volume":"18","author":"Cardinale","year":"2016","journal-title":"Curr. Cardiol. Rep."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"ehaf784.4034","DOI":"10.1093\/eurheartj\/ehaf784.4034","article-title":"Comparison of cardiac magnetic resonance imaging and echocardiography for early definition of chemotherapeutic cardiotoxicity in children and adolescents: A systematic review and meta-analysis","volume":"46","author":"Fante","year":"2025","journal-title":"Eur. Heart J."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Getie, M., Mekonnen, B.A., Seifu, D., Mulugeta, Y., Tebeje, S., Tafere, C., and Amuamuta, A. (2025). Serum cardiac and inflammatory biomarker levels following chemotherapy among female patients with breast cancer attending at Tikur Anbessa Specialized Hospital, Addis Ababa, Ethiopia. BMC Cancer, 25.","DOI":"10.1186\/s12885-025-13583-5"},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Borowiec, A., Ozdowska, P., Rosinska, M., Zebrowska, A.M., Jasek, S., Kotowicz, B., Makowka, A., Waniewska, J., Kosela-Paterczyk, H., and Lampka, E. (2025). Interleukin-6 in Anthracycline-Related Cardiac Dysfunction: A Comparison with Myeloperoxidase and TNF-Alpha. Int. J. Mol. Sci., 26.","DOI":"10.3390\/ijms26094071"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"530","DOI":"10.1016\/j.molmed.2008.09.006","article-title":"CD40-CD40 ligand interactions in oxidative stress, inflammation and vascular disease","volume":"14","author":"Rizvi","year":"2008","journal-title":"Trends Mol. Med."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1104","DOI":"10.1056\/NEJMoa022600","article-title":"Soluble CD40 ligand in acute coronary syndromes","volume":"348","author":"Heeschen","year":"2003","journal-title":"N. Engl. J. Med."}],"container-title":["Cancers"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6694\/18\/14\/2340\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,20]],"date-time":"2026-07-20T11:07:46Z","timestamp":1784545666000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6694\/18\/14\/2340"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,20]]},"references-count":21,"journal-issue":{"issue":"14","published-online":{"date-parts":[[2026,7]]}},"alternative-id":["cancers18142340"],"URL":"https:\/\/doi.org\/10.3390\/cancers18142340","relation":{},"ISSN":["2072-6694"],"issn-type":[{"value":"2072-6694","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,20]]}}}