Immunohistochemistry-based molecular subtypes and stromal tumor-infiltrating lymphocytes in triple-negative breast cancer: a chemotherapy-only cohort
Academic Article in Scopus
Background: Triple-negative breast cancer (TNBC) is a biologically heterogeneous, aggressive disease where immunohistochemistry (IHC)-based algorithms, defining luminal androgen receptor (LAR), immunomodulatory (IM), basal-like immunosuppressed (BLIS), mesenchymal (MES), and unclassifiable (UC) subtypes, offer a pragmatic alternative to transcriptomics. This study evaluated clinical trajectories and survival outcomes associated with IHC-based molecular subtypes and stromal tumor-infiltrating lymphocytes (sTILs) across distinct subgroups. Methods: A retrospective analysis of 289 women with TNBC treated with chemotherapy-only regimens analyzed molecular subtypes across four clinical groups: non-recurrent, recurrent, progression during neoadjuvant chemotherapy, and de novo metastatic disease. IHC-based subclassification included androgen receptor (AR), CD8, FOXC1, and DCLK1 biomarkers. Overall survival (OS) and disease-free survival (DFS) were estimated using the Kaplan-Meier method, and multivariable Cox proportional hazards models. Results: The cohort included non-recurrent (43.9%), recurrent (26.3%), neoadjuvant progressors (11.5%), and de novo stage IV (18.3%) cases. IM subtype (16.3%) was enriched in non-recurrent cases with the highest median sTILs levels (20.0%). BLIS (26.3%) and UC (39.4%) subtypes predominated in recurrent and metastatic disease, while MES subtype (9.0%) predominated in neoadjuvant chemotherapy progressors. In early-stage disease, sTILs ¿10% independently predicted superior OS (HR 0.63, 95% CI, 0.40-1.0; P = .049), showing no prognostic role in the de novo stage IV group. Molecular subtypes lost independent significance in multivariable models. Conclusions: Clinicopathological factors and sTILs remain primary prognostic determinants in TNBC. Although IHC-based molecular subtypes were not independent survival predictors, their differential clinical distribution validates their biological relevance to identify therapeutic vulnerabilities, and to guide precision medicine and de-escalation strategies.
