{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T20:04:00Z","timestamp":1790193840128,"version":"4.1.0"},"reference-count":19,"publisher":"American Medical Association (AMA)","issue":"4","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JAMA Oncol"],"published-print":{"date-parts":[[2025,4,1]]},"abstract":"Importance<\/jats:title>For patients with early ERBB2 <\/jats:italic>(formerly HER2<\/jats:italic>)\u2013positive breast cancer, there is a need to identify biomarkers to guide treatment de-escalation.<\/jats:p><\/jats:sec>Objective<\/jats:title>To evaluate the association of tumor-infiltrating lymphocytes (TILs) with distant disease-free (DDFS) and overall survival (OS) for patients with ERBB2<\/jats:italic>-positive early breast cancer.<\/jats:p><\/jats:sec>Design, Setting, and Participants<\/jats:title>The ShortHER randomized clinical trial was a multicentric trial in Italy that enrolled patients with ERBB2<\/jats:italic>-positive breast cancer from December 2007 to October 2013. Patients received 9 weeks or 1 year of adjuvant trastuzumab combined with chemotherapy. Tumor samples were evaluated for TILs. Herein, patients were evaluated at a median follow-up of 9 years, and data were analyzed from February 2023 to August 2024.<\/jats:p><\/jats:sec>Intervention<\/jats:title>Four cycles of anthracycline-based chemotherapy followed by 4 courses of taxanes combined with trastuzumab for 1 year (long arm) or 3 courses of taxanes combined with trastuzumab for 9 weeks followed by reduced-dose anthracycline-based chemotherapy for 3 courses (short arm).<\/jats:p><\/jats:sec>Main Outcomes and Measures<\/jats:title>The association of TILs with DDFS and OS was assessed with Cox models.<\/jats:p><\/jats:sec>Results<\/jats:title>Of 1253 patients enrolled in the ShortHER trial, 866 women (median [IQR] age, 56 [48-64] years) had evaluable TILs. In Cox models with relevant factors, each 5% TIL increment was associated with improved DDFS (hazard ratio [HR], 0.87; 95% CI, 0.80-0.95; P<\/jats:italic>\u2009=\u2009.001) and OS (HR, 0.89; 95% CI, 0.81-0.98; P<\/jats:italic>\u2009=\u2009.01). The 10-year OS rate was 91.3% for patients with TILs 20% or higher, 93.3% for patients with TILs 30% or higher, and 98.1% for patients with TILs 50% or higher, resulting higher vs lower TIL counterparts. Patients with TILs lower than 20% showed a better outcome with the long vs short treatment (10-year DDFS, 88.7% vs 81.0%), whereas patients with TILs 20% or higher showed the opposite (10-year DDFS, 87.1% vs 92.2%; P <\/jats:italic>for interaction\u2009=\u2009.01). Similarly, patients with TILs 20% or higher had a 10-year OS rate of 89.3% in the long arm vs 93.1% in the short arm (HR, 0.36; 95% CI, 0.10-1.36); patients with TILs lower than 20% had a 10-year OS rate of 91.3% in the long arm vs 86.9% in the short arm (HR, 1.36; 95% CI, 0.82-2.23; P <\/jats:italic>for interaction\u2009=\u2009.06).<\/jats:p><\/jats:sec>Conclusions and Relevance<\/jats:title>This follow-up analysis of the ShortHER randomized clinical trial is, to our knowledge, the first demonstration of an independent effect of TILs in terms of OS for patients with ERBB2<\/jats:italic>-positive early breast cancer treated with adjuvant chemotherapy and anti-ERBB2<\/jats:italic> therapy. Patients with TILs 20% or higher who de-escalated trastuzumab duration and chemotherapy dose were not exposed to an excess risk of distant relapse or death.<\/jats:p><\/jats:sec>Trial Registration<\/jats:title>EudraCT: 2007-004326-25<\/jats:ext-link><\/jats:p><\/jats:sec>","DOI":"10.1001\/jamaoncol.2024.6872","type":"journal-article","created":{"date-parts":[[2025,2,13]],"date-time":"2025-02-13T16:14:45Z","timestamp":1739463285000},"page":"386","source":"Crossref","is-referenced-by-count":21,"title":["Tumor-Infiltrating Lymphocytes and Survival Outcomes in Early ERBB2<\/i>-Positive Breast Cancer"],"prefix":"10.1001","volume":"11","author":[{"given":"Maria Vittoria","family":"Dieci","sequence":"first","affiliation":[{"name":"Department of Surgery, Oncology and Gastroenterology (DiSCOG), University of Padova, Padova, Italy"},{"name":"Oncology 2, Veneto Institute of Oncology IOV-IRCCS, Padova, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giancarlo","family":"Bisagni","sequence":"additional","affiliation":[{"name":"Department of Oncology and Advanced Technologies, Azienda USL-IRCCS, Reggio Emilia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefania","family":"Bartolini","sequence":"additional","affiliation":[{"name":"Department of Nervous System Medical Oncology, IRCCS Istituto delle Scienze Neurologiche di Bologna, Bologna, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessio","family":"Schirone","sequence":"additional","affiliation":[{"name":"S. Anna University Hospital, Ferrara, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luigi","family":"Cavanna","sequence":"additional","affiliation":[{"name":"Internal Medicine and Oncology, Clinica Piacenza, Piacenza, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonino","family":"Musolino","sequence":"additional","affiliation":[{"name":"Medical Oncology, Breast and GYN Unit, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) \u201cDino Amadori,\u201d Meldola, Italy"},{"name":"Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesco","family":"Giotta","sequence":"additional","affiliation":[{"name":"IRCCS Istituto Tumori \u201cGiovanni Paolo II,\u201d Bari, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anita","family":"Rimanti","sequence":"additional","affiliation":[{"name":"Carlo Poma Hospital, ASST Mantova, Mantova, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ornella","family":"Garrone","sequence":"additional","affiliation":[{"name":"Medical Oncology Unit, Fondazione IRCCS Ca\u2019 Granda Ospedale Maggiore Policlinico, Milano, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elena","family":"Bertone","sequence":"additional","affiliation":[{"name":"Medical Oncology, S. Anna Hospital, Torino, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katia","family":"Cagossi","sequence":"additional","affiliation":[{"name":"Breast Unit Ausl Modena, Ramazzini Hospital, Carpi, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samanta","family":"Sarti","sequence":"additional","affiliation":[{"name":"IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) \u201cDino Amadori,\u201d Meldola, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonella","family":"Ferro","sequence":"additional","affiliation":[{"name":"Rete Clinica Senologica-Oncologia Medica S. Chiara, APSS, Trento, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Federico","family":"Piacentini","sequence":"additional","affiliation":[{"name":"Department of Medical and Surgical Sciences for Children and Adults, University Hospital of Modena, Modena, Italy"},{"name":"Azienda Ospedaliero-Universitaria di Modena, Modena, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Enrico","family":"Orvieto","sequence":"additional","affiliation":[{"name":"Pathology Unit, Ulss 5 Polesana, Rovigo, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melinda","family":"Sanders","sequence":"additional","affiliation":[{"name":"Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Federica","family":"Miglietta","sequence":"additional","affiliation":[{"name":"Department of Surgery, Oncology and Gastroenterology (DiSCOG), University of Padova, Padova, Italy"},{"name":"Oncology 2, Veneto Institute of Oncology IOV-IRCCS, Padova, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Davide","family":"Massa","sequence":"additional","affiliation":[{"name":"Department of Surgery, Oncology and Gastroenterology (DiSCOG), University of Padova, Padova, Italy"},{"name":"Oncology 2, Veneto Institute of Oncology IOV-IRCCS, Padova, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara","family":"Balduzzi","sequence":"additional","affiliation":[{"name":"University of Modena and Reggio Emilia, Modena, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pierfranco","family":"Conte","sequence":"additional","affiliation":[{"name":"Department of Surgery, Oncology and Gastroenterology (DiSCOG), University of Padova, Padova, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roberto","family":"D\u2019Amico","sequence":"additional","affiliation":[{"name":"Department of Medical and Surgical Sciences for Children and Adults, University Hospital of Modena, Modena, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valentina","family":"Guarneri","sequence":"additional","affiliation":[{"name":"Department of Surgery, Oncology and Gastroenterology (DiSCOG), University of Padova, Padova, Italy"},{"name":"Oncology 2, Veneto Institute of Oncology IOV-IRCCS, Padova, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"10","reference":[{"issue":"12","key":"coi240081r1","doi-asserted-by":"publisher","first-page":"2328","DOI":"10.1093\/annonc\/mdy414","article-title":"Nine weeks versus 1 year adjuvant trastuzumab in combination with chemotherapy: final results of the phase III randomized Short-HER study.","volume":"29","author":"Conte","year":"2018","journal-title":"Ann Oncol"},{"issue":"32","key":"coi240081r2","doi-asserted-by":"publisher","first-page":"4976","DOI":"10.1200\/JCO.23.00790","article-title":"Nine-week versus one-year trastuzumab for early human epidermal growth factor receptor 2-positive breast cancer: 10-year update of the ShortHER phase III randomized trial.","volume":"41","author":"Conte","year":"2023","journal-title":"J Clin Oncol"},{"issue":"3","key":"coi240081r3","doi-asserted-by":"publisher","first-page":"418","DOI":"10.1093\/annonc\/mdz007","article-title":"Association of tumor-infiltrating lymphocytes with distant disease-free survival in the ShortHER randomized adjuvant trial for patients with early HER2+ breast cancer.","volume":"30","author":"Dieci","year":"2019","journal-title":"Ann Oncol"},{"key":"coi240081r4","doi-asserted-by":"publisher","first-page":"8","DOI":"10.1016\/j.ctrv.2017.04.005","article-title":"Tumor-infiltrating lymphocytes in patients with HER2-positive breast cancer treated with neoadjuvant chemotherapy plus trastuzumab, lapatinib or their combination: a meta-analysis of randomized controlled trials.","volume":"57","author":"Solinas","year":"2017","journal-title":"Cancer Treat Rev"},{"issue":"1","key":"coi240081r5","doi-asserted-by":"publisher","first-page":"29","DOI":"10.1038\/s41523-024-00636-4","article-title":"Tumor-infiltrating lymphocytes in HER2-positive breast cancer treated with neoadjuvant chemotherapy and dual HER2-blockade.","volume":"10","author":"Liefaard","year":"2024","journal-title":"NPJ Breast Cancer"},{"issue":"4","key":"coi240081r6","doi-asserted-by":"publisher","first-page":"490","DOI":"10.1001\/jamaoncol.2022.6288","article-title":"Prognostic and predictive value of immune-related gene expression signatures vs tumor-infiltrating lymphocytes in early-stage ERBB2\/HER2-positive breast cancer: a correlative analysis of the CALGB 40601 and PAMELA trials.","volume":"9","author":"Fernandez-Martinez","year":"2023","journal-title":"JAMA Oncol"},{"issue":"1","key":"coi240081r7","doi-asserted-by":"publisher","first-page":"69","DOI":"10.1093\/jnci\/djy076","article-title":"Tumor-infiltrating lymphocytes in patients receiving trastuzumab\/pertuzumab-based chemotherapy: a TRYPHAENA substudy.","volume":"111","author":"Ignatiadis","year":"2019","journal-title":"J Natl Cancer Inst"},{"issue":"4","key":"coi240081r8","doi-asserted-by":"publisher","first-page":"448","DOI":"10.1001\/jamaoncol.2015.0830","article-title":"Tumor-infiltrating lymphocytes and associations with pathological complete response and event-free survival in HER2-positive early-stage breast cancer treated with lapatinib and trastuzumab: a secondary analysis of the NeoALTTO trial.","volume":"1","author":"Salgado","year":"2015","journal-title":"JAMA Oncol"},{"issue":"1","key":"coi240081r9","doi-asserted-by":"publisher","first-page":"105","DOI":"10.1200\/JCO.2009.23.7370","article-title":"Tumor-associated lymphocytes as an independent predictor of response to neoadjuvant chemotherapy in breast cancer.","volume":"28","author":"Denkert","year":"2010","journal-title":"J Clin Oncol"},{"issue":"8","key":"coi240081r10","doi-asserted-by":"publisher","first-page":"1544","DOI":"10.1093\/annonc\/mdu112","article-title":"Tumor infiltrating lymphocytes are prognostic in triple negative breast cancer and predictive for trastuzumab benefit in early breast cancer: results from the FinHER trial.","volume":"25","author":"Loi","year":"2014","journal-title":"Ann Oncol"},{"issue":"1","key":"coi240081r11","doi-asserted-by":"publisher","first-page":"56","DOI":"10.1001\/jamaoncol.2015.3239","article-title":"Association of stromal tumor-infiltrating lymphocytes with recurrence-free survival in the N9831 adjuvant trial in patients with early-stage HER2-positive breast cancer.","volume":"2","author":"Perez","year":"2016","journal-title":"JAMA Oncol"},{"issue":"8","key":"coi240081r12","doi-asserted-by":"publisher","first-page":"867","DOI":"10.1093\/jnci\/djz032","article-title":"Stromal tumor-infiltrating lymphocytes in NRG Oncology\/NSABP B-31 adjuvant trial for early-stage HER2-positive breast cancer.","volume":"111","author":"Kim","year":"2019","journal-title":"J Natl Cancer Inst"},{"issue":"5","key":"coi240081r13","doi-asserted-by":"publisher","first-page":"873","DOI":"10.1093\/annonc\/mdv106","article-title":"Guidelines for time-to-event end point definitions in breast cancer trials: results of the DATECAN initiative (Definition for the Assessment of Time-to-event Endpoints in CANcer trials).","volume":"26","author":"Gourgou-Bourgade","year":"2015","journal-title":"Ann Oncol"},{"issue":"2","key":"coi240081r14","doi-asserted-by":"publisher","first-page":"27","DOI":"10.3390\/cells10020223","article-title":"Immune infiltrates in breast cancer: recent updates and clinical implications.","volume":"10","author":"Dieci","year":"2021","journal-title":"Cells"},{"issue":"1","key":"coi240081r15","doi-asserted-by":"publisher","first-page":"150","DOI":"10.1038\/s41523-021-00346-1","article-title":"The tale of TILs in breast cancer: a report from the International Immuno-Oncology Biomarker Working Group.","volume":"7","author":"El Bairi","year":"2021","journal-title":"NPJ Breast Cancer"},{"issue":"16","key":"coi240081r16","doi-asserted-by":"publisher","first-page":"508","DOI":"10.1200\/JCO.2023.41.16_suppl.508","article-title":"Do tumor infiltrating lymphocytes (TILs) predict benefits from trastuzumab therapy for HER2 positive breast cancer? meta-analysis of individual patient data from 4097 women in 5 trials.","volume":"41","author":"Hills","year":"2023","journal-title":"J Clin Oncol"},{"issue":"2","key":"coi240081r17","doi-asserted-by":"publisher","first-page":"159","DOI":"10.1016\/j.annonc.2023.11.016","article-title":"Early breast cancer: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up.","volume":"35","author":"Loibl","year":"2024","journal-title":"Ann Oncol"},{"issue":"16","key":"coi240081r18","doi-asserted-by":"publisher","first-page":"1816","DOI":"10.1200\/JCO.22.00069","article-title":"Biomarkers for adjuvant endocrine and chemotherapy in early-stage breast cancer: ASCO guideline update.","volume":"40","author":"Andre","year":"2022","journal-title":"J Clin Oncol"},{"issue":"1","key":"coi240081r19","doi-asserted-by":"publisher","first-page":"17","DOI":"10.1038\/s41523-020-0156-0","article-title":"Pitfalls in assessing stromal tumor infiltrating lymphocytes (sTILs) in breast cancer.","volume":"6","author":"Kos","year":"2020","journal-title":"NPJ Breast Cancer"}],"container-title":["JAMA Oncology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/jamanetwork.com\/journals\/jamaoncology\/articlepdf\/2830196\/jamaoncology_dieci_2025_oi_240081_1744202993.14381.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,4,17]],"date-time":"2025-04-17T15:01:42Z","timestamp":1744902102000},"score":1,"resource":{"primary":{"URL":"https:\/\/jamanetwork.com\/journals\/jamaoncology\/fullarticle\/2830196"}},"subtitle":["10-Year Analysis of the ShortHER Randomized Clinical Trial"],"short-title":[],"issued":{"date-parts":[[2025,4,1]]},"references-count":19,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2025,4,1]]}},"URL":"https:\/\/doi.org\/10.1001\/jamaoncol.2024.6872","relation":{},"ISSN":["2374-2437"],"issn-type":[{"value":"2374-2437","type":"print"}],"subject":[],"published":{"date-parts":[[2025,4,1]]}}}