Associations of TILs and Genomic Alterations in HER2+ Early Breast Cancer
Shuangshuang Lu, Jiahui Huang, Yijin Gu, Chaofu Wang, Kunwei Shen, Xiaochun Fei, Xiaosong ChenAbstract
Background
This study investigated the associations between tumor-infiltrating lymphocytes (TILs), genomic features, and prognosis in HER2+ early breast cancer (EBC) patients receiving adjuvant trastuzumab.
Materials and Methods
We retrospectively analyzed 864 HER2+ EBC patients from Shanghai Ruijin Hospital (2009-2017). The optimal threshold of TILs for predicting disease free survival (DFS) and overall survival (OS) was explored. Whole-exome sequencing (WES) on 261 tumors assessed the mutational profiles, tumor mutational burden (TMB), and copy number alteration (CNA). Associations of these genomic features, TILs levels and prognosis were further evaluated.
Results
TILs showed a right-skewed distribution (median 15%, IQR 1-30%), and higher TILs were significantly associated with hormone receptor negativity and high histologic grade (p < 0.001). A 15% TILs threshold optimally predicted prognosis, with low TILs (≤15%, 63.0%) patients showing inferior DFS (HR 1.63, p = 0.009) and OS (HR 2.12, p = 0.037). WES identified frequent mutations in TP53 (62.8%), PIK3CA (34.5%), and BRCA2 (9.6%). Higher TILs density was observed in TP53-wild-type, low-TMB or low-CNA tumors (p < 0.05). PIK3CA mutations conferred a significant DFS advantage. Integrating TILs level with PIK3CA or BRCA2 mutational status yielded distinct DFS trajectories (log-rank p = 0.023 and 0.040, respectively); patients with both high TILs and either PIK3CA or BRCA2 mutations had the most favorable outcomes.
Discussion
Stromal TILs at a 15% cut-off provide robust prognostic information in trastuzumab-treated HER2+ EBC. Integrating TILs levels with PIK3CA or BRCA2 mutational status enables refined risk stratification, offering a practical framework for personalized treatment decisions.