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

Abstract

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.

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