Immunohistochemistry-based molecular subtypes and stromal tumor-infiltrating lymphocytes in triple-negative breast cancer: a chemotherapy-only cohort
Jesus Edgardo Hernandez-Hernandez, Alejandro Mohar, César Octavio Lara-Torres, Daniela Vazquez-Juarez, Tamara Palacios, Lourdes Peña-Torres, Guadalupe Moncada-Claudio, Areli Velazquez-Martinez, Paula Cabrera-Galeana, Gabriela Sofía Gómez-Macías, Fany Iris Porras-Reyes, Víctor Manuel Pérez-Sánchez, Alejandro Aranda-Gutierrez, Cynthia Villarreal-GarzaAbstract
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 = 0.049), 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.