Abstract
BACKGROUND: Premenopausal women with triple-negative breast cancer (TNBC) exhibit considerable heterogeneity in their response to standard anthracycline and taxane-based chemotherapy, yet the underlying mechanisms remain poorly understood. We aimed to investigate the combined role of the tumour immune microenvironment and HER2-low status in predicting chemosensitivity and intrinsic resistance in this specific population. METHODS: We retrospectively analysed data from 767 premenopausal patients with TNBC across two Chinese medical centres. All patients underwent primary surgery followed by adjuvant chemotherapy based on anthracyclines and taxanes. Patients were randomly assigned to training and internal validation cohorts. Independent predictors of DFS were identified using multivariable Cox proportional hazards regression, and a nomogram was constructed accordingly. The model's discrimination was assessed using the concordance index (C-index) and time-dependent receiver operating characteristic (ROC) curve analysis, while calibration was evaluated with calibration curves. RESULTS: Multivariable analysis identified lower stromal tumour-infiltrating lymphocyte (sTIL) expression levels, and HER2 IHC 2+/FISH-negative status as independent factors associated with poorer DFS, besides that T3/T4 staging, higher N staging. A nomogram integrating these four variables demonstrated excellent predictive accuracy for DFS, with a C-index of 0.862 in the training set and 0.861 in the validation set. The area under the ROC curve (AUC) for predicting 3-year DFS was 0.907 and 0.908 in the training and validation sets, respectively. CONCLUSION: Our findings reveal that an immune-poor tumour microenvironment and HER2-low biology are key, complementary determinants of intrinsic resistance to standard chemotherapy in premenopausal TNBC. These readily available biomarkers provide a mechanistic rationale for patient stratification, suggesting that sTIL-low tumours might benefit from immunomodulatory strategies, while HER2-low tumours represent a candidate population for novel antibody-drug conjugates. This paradigm shift from empirical to biomarker-informed therapy could help overcome chemoresistance in this high-risk group.