Association of tumor-infiltrating lymphocytes with distant disease-free survival in the ShortHER randomized adjuvant trial for patients with early HER2+ breast cancer

Background: There is the need to identify new prognostic markers to refine risk stratification for HER2-positive early breast cancer patients. The aim of this study was to evaluate the association of tumor-infiltrating lymphocytes (TILs) with distant disease-free survival (DDFS) in patients with HER2-positive early breast cancer enrolled in the ShortHER adjuvant trial which compared 9-weeks vs 1-year trastuzumab in addition to chemotherapy, and to test the interaction between TILs and treatment arm. Patients and Methods: Stromal TILs were assessed for 866 cases on centralized hematoxylin and eosin-stained tumor slides. The association of TILs as 10% increments with DDFS was assessed with Cox models. Kaplan Meier curves were estimated for patients with TILs≥20% and TILs<20%. Median follow up was 6.1 years. Results: Median TILs was 5% (Q1-Q3 1%-15%). Increased TILs were independently associated with better DDFS in multivariable model (HR 0.73, 95% CI 0.59-0.89, P=0.006, for each 10% TILs increment). 5-yrs DDFS rates were 91.1% for patients with TILs<20% and 95.7% for patients with TILs≥20% (P=0.025). The association between 10% TILs increments and DDFS was significant for patients randomized to 9 weeks of trastuzumab (HR 0.60, 95%CI 0.41-0.88) but not for patients treated with 1 year of trastuzumab (HR 0.89, 95%CI 0.71-1.12; test for interaction P=0.088). For patients with TILs<20%, the Hazard Ratio for the comparison between the short vs the long arm was 1.75 (95%CI 1.09-2.80, P=.021); whereas, for patients with TILs≥20% the Hazard Ratio for the comparison of short vs long arm was 0.23 (95% CI 0.05-1.09, P=0.064), resulting in a significant interaction (P=0.015). Conclusions: TILs are an independent prognostic factor for HER2-positive early breast cancer patients treated with adjuvant chemotherapy and trastuzumab and may refine the ability to identify patients at low risk of relapse eligible for de-escalated adjuvant therapy.