ILCness to stratify lobular-like breast cancer biology and as an outcome independent of <i>CDH1</i> mutation in early ER-positive/HER2-negative breast cancer.

576 Background: Invasive lobular carcinoma (ILC) represents a distinct histological subtype of breast cancer; however, its underlying molecular basis remains incompletely defined. Although loss-of-function mutations in CDH1 are considered a hallmark genetic event, substantial biological heterogeneity persists that cannot be fully explained by histology or mutation status alone. Methods: To address this limitation, we developed a continuous transcriptional framework, termed the ILCness score, to quantitatively capture lobular-like tumor biology. A tightly constrained principal component–based model was trained in the METABRIC cohort and fully fixed without retraining, enabling reproducible projection across independent datasets and expression platforms. Results: Unsupervised transcriptomic analyses demonstrated that invasive ductal carcinoma (IDC) and ILC did not form discrete expression clusters but instead distributed along a continuous molecular spectrum. The ILCness score robustly captured this continuum, with mixed-histology tumors occupying intermediate positions. Importantly, lobular-like transcriptional programs quantified by ILCness showed limited concordance with CDH1 mutation status. Across tumors, higher ILCness was consistently associated with reduced DNA repair and E2F target activity (Spearman |ρ| &gt; 0.4, P &lt; 0.001), whereas epithelial–mesenchymal transition displayed a context-dependent pattern. Tumor microenvironment analyses revealed that stromal and immune cell infiltration correlated more strongly with ILCness than with CDH1 mutation status. These associations were reproducibly validated in independent cohorts without model recalibration. Clinically, ILCness stratified prognostically distinct subgroups within histologically defined tumors, including IDC, independent of CDH1 mutation (disease-specific survival, P &lt; 0.01). Across multiple neoadjuvant and systemic therapy datasets, higher ILCness showed consistent directional associations with reduced pathological complete response to chemotherapy and differential response patterns to immune checkpoint inhibition and endocrine therapy. Conclusions: These findings establish lobular breast cancer as a continuum of transcriptional states rather than a discrete entity defined by histology or single-gene alterations. The ILCness score provides a scalable RNA-based framework for integrating molecular heterogeneity with tumor biology and clinical behavior, with potential implications for biologically informed patient stratification.