Predictive power of tertiary lymphoid structure for prognosis and neoadjuvant chemotherapy response in HER2-positive breast cancer

This study evaluated the prognostic significance of tertiary lymphoid structures (TLS) in human epidermal growth factor receptor 2 (HER2)-positive breast cancer (BC), focusing on their associations with survival outcomes, response to neoadjuvant therapy, and potential as a biomarker for personalized treatment strategies. Data from patients with HER2-positive BC in the METABRIC and The Cancer Genome Atlas databases were analyzed. TLS expression scores were calculated using gene set variation analysis, and their associations with survival outcomes were assessed. Immune cell infiltration, immune checkpoint expression, tumor mutational burden, and pathway enrichment were also evaluated. Data from the I-SPY2 clinical trial and a clinicopathological cohort of 19 patients from Xiangya Hospital were used to assess the relationship between TLS expression and pathological complete response following neoadjuvant therapy. High TLS expression was associated with improved survival and increased infiltration of antitumor immune cells. TLS-high tumors were enriched in immune-related pathways, whereas TLS-low tumors showed activation of proliferation and metabolism pathways. Patients with high TLS expression had better responses to neoadjuvant therapy, while those with low TLS expression derived greater benefit from dual-targeted treatments. TLS represents a promising biomarker for predicting survival and response to neoadjuvant therapy in HER2-positive BC, with potential to support personalized treatment strategies.