Matrix-producing metaplastic carcinoma of the breast: clinicopathologic, germline, and genomic characterization of a distinct metaplastic carcinoma subtype

Matrix-producing metaplastic carcinoma (MPMC) is a rare subtype of metaplastic carcinoma (MC) characterized by invasive epithelial carcinoma with direct transition to chondromyxoid or cartilaginous matrix. Although MCs are recognized as aggressive triple-negative breast cancers, the clinicopathologic and genomic features of MPMC remain incompletely defined. We performed a clinicopathologic and genomic analysis of patients with MPMC diagnosed at a single tertiary cancer center between 2000 and 2025. All cases underwent centralized pathology review. Germline genetic testing results were reviewed. Associations with atypical microglandular adenosis (AMGA), treatment response, and clinical outcomes were evaluated. Targeted tumor-normal sequencing (MSK-IMPACT) results were retrospectively analyzed. A comparator cohort of MC without matrix-production (non-MPMC) (n = 37) was assembled for histologic, genomic, and hereditary predisposition analyses. A total of 77 patients with MPMC were included, of whom 94% had Nottingham grade 3 tumors and 91% had triple-negative disease. Among 21 patients treated with neoadjuvant chemotherapy, no pathologic complete responses were observed. The median follow-up was 56 months. During follow-up, locoregional recurrence occurred in 17% of patients, distant metastases developed in 33%, and 29% died of the disease. Germline pathogenic or likely pathogenic variants (P/LPVs) were identified in 32% (15/47) of tested patients, predominantly involving HRD-associated genes, including BRCA1/2 (23%). Compared with non-MPMC, MPMC demonstrated enrichment for germline P/LPVs (32% vs. 8%; P = 0.014), HRD-associated germline P/LPVs (28% vs. 3%; P = 0.002), and an increased prevalence of AMGA (22% vs. 0%; P = 0.0012). Sequencing demonstrated frequent TP53 alterations (90%) and recurrent chromosome 8q copy-number alterations, including MYC amplification (48%). Compared with non-MPMC, MPMC showed enrichment of multiple 8q-associated alterations, including MYC , as well as higher large-scale state transition and HRD-associated loss-of-heterozygosity scores. In contrast, PIK3CA , TERT , and CDKN2A/B alterations were less frequent in MPMC. MPMC is characterized by poor clinical outcomes, with one-third of patients developing distant metastases during follow-up, and by a distinct genomic profile that includes enrichment of germline HRD-associated pathogenic variants, frequent association with AMGA, selected HRD-associated genomic scar metrics, and recurrent chromosome 8q copy-number alterations compared with other metaplastic carcinoma subtypes. Although HRD-associated germline P/LPVs and AMGA were not significantly associated within the MPMC cohort, the enrichment of both features relative to non-MPMC supports further investigation of hereditary susceptibility and precursor lesion biology in this rare subtype. The absence of pathologic complete responses following neoadjuvant therapy highlights the need for improved treatment strategies and supports investigation of biomarker-driven therapeutic approaches.