Tumor-Infiltrating Lymphocytes and Survival Outcomes in Early <i>ERBB2</i>-Positive Breast Cancer
Authors: Maria Vittoria Dieci, Giancarlo Bisagni, Stefania Bartolini, Alessio Schirone, Luigi Cavanna, Antonino Musolino, Francesco Giotta, Anita Rimanti, Ornella Garrone, Elena Bertone, Katia Cagossi, Samanta Sarti, Antonella Ferro, Federico Piacentini, Enrico Orvieto, Melinda Sanders, Federica Miglietta, Davide Massa, Sara Balduzzi, Pierfranco Conte, Roberto D’Amico, Valentina Guarneri
Journal: JAMA Oncology (2025)

Importance For patients with early ERBB2 (formerly HER2 )–positive breast cancer, there is a need to identify biomarkers to guide treatment de-escalation. Objective To evaluate the association of tumor-infiltrating lymphocytes (TILs) with distant disease-free (DDFS) and overall survival (OS) for patients with ERBB2 -positive early breast cancer. Design, Setting, and Participants The ShortHER randomized clinical trial was a multicentric trial in Italy that enrolled patients with ERBB2 -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. Intervention 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). Main Outcomes and Measures The association of TILs with DDFS and OS was assessed with Cox models. Results 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 = .001) and OS (HR, 0.89; 95% CI, 0.81-0.98; P = .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 for interaction = .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 for interaction = .06). Conclusions and Relevance 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 -positive early breast cancer treated with adjuvant chemotherapy and anti- ERBB2 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. Trial Registration EudraCT: 2007-004326-25