Tumor-Infiltrating Lymphocytes and Survival Outcomes in Early ERBB2-Positive Breast Cancer: 10-Year Analysis of the ShortHER Randomized Clinical Trial.

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.