Breast Neuroendocrine Carcinoma: Molecular Insights Beyond Histology.

PURPOSE: Primary breast neuroendocrine carcinomas (NECs) are rare, high-grade malignancies that are frequently grouped with invasive breast carcinomas with neuroendocrine differentiation (IBC-NED), despite uncertain biological equivalence. We sought to define the clinicopathologic, immunophenotypic, and genomic features of breast NEC and to determine whether they represent a biologically distinct entity. METHODS: We performed a retrospective analysis of 24 primary breast NECs and compared them with 28 grade-matched IBC-NEDs. Clinicopathologic features, treatment response, and outcomes were evaluated. Immunohistochemical profiling included neuroendocrine and breast lineage markers and retinoblastoma (Rb) expression. Targeted tumor-normal next-generation sequencing was performed in a subset of NEC (n = 10) and IBC-NED (n = 7) to characterize genomic alterations and pathway-level differences. RESULTS: Breast NECs were predominantly estrogen receptor (ER)-negative/human epidermal growth factor receptor-2-negative (63%) and frequently exhibited small cell morphology. Despite radiographic response to neoadjuvant chemotherapy, no patients achieved pathologic complete response. Immunophenotypically, NECs demonstrated diffuse neuroendocrine marker expression and frequent loss of Rb protein (93%), consistent with RB pathway disruption. Compared with IBC-NED, NECs showed significantly lower ER expression and reduced GATA3 positivity. Genomically, NECs were enriched for TP53 alterations (90% v 33%, P < .05) and more frequently harbored RB1 alterations (60% v 14%), with concurrent TP53/RB1 alterations in 50% of cases. Alterations in the PI3K pathway were also observed in NECs. By contrast, IBC-NED demonstrated recurrent luminal-type copy-number alterations, including amplifications in FGFR1 and CCND1. CONCLUSION: Breast NEC is characterized by a distinct clinicopathologic and molecular profile compared with grade-matched IBC-NED, defined by frequent TP53 and RB1 alterations, RB pathway disruption, and limited response to neoadjuvant therapy. These findings support classification of breast NEC as a biologically distinct subtype and highlight potential avenues for biomarker-driven therapeutic strategies in this rare malignancy.