INTEGRATED GENOMIC AND TRANSCRIPTOMIC PROFILING REVEALS THERAPEUTIC VULNERABILITIES IN METAPLASTIC BREAST CARCINOMA

Metaplastic breast carcinoma (MBC) remains refractory to conventional chemotherapy with limited targeted therapeutic options. We aimed to characterize the genomic and pathway-specific landscape underlying distinct MBC subtypes and to identify potentially actionable therapeutic vulnerabilities. TruSight RNA Pan-Cancer Panel (Illumina) was performed to identify novel transcripts, somatic variants, transcript variants and fusions in 7 squamous (SqC), 6 matrix-producing (Mp) and 10 spindle cells (SpC) MBCs compared with 12 triple-negative invasive ductal carcinomas of no special type (TNBC-NSTs) from our institutional cohort. Genomic and transcriptomic analyses were performed with OpenCravat and DESeq2. Statistical significance was set at p < 0.05. Funding: PNRR THE Spoke 6. CUP I53C22000780001. All 23 MBCs harbored recurrent somatic alterations in TP53 and chromatin remodeling genes, including KMT2C, EP300 and ARID1A. Compared to TNBC-NSTs, MBCs showed enrichment of alterations involving RTK-RAS, PI3K/AKT/mTOR, Hippo/Wnt, TGFβ and NOTCH signaling pathways, alongside subtype-specific molecular profiles. SpC MBCs were enriched in NOTCH, PI3K, JAK1 and Hippo/Wnt pathway alterations, whereas SqC MBCs more frequently harbored EGFR, TP53 and RTK-RAS alterations. Mp MBCs showed alterations involving metabolic and epigenetic regulators, including ACACA, together with DNA damage response (DDR)-related pathways. SqC and SpC MBCs displayed higher tumor mutational burden than NSTs and Mp MBCs, alongside stem-like, EMT-high, migratory and angiogenic programs, consistent with a more aggressive and potentially immunogenic phenotype. In contrast, TNBC-NSTs showed a simpler TP53- and PDE4DIP-driven pattern. Clinically actionable alterations involving EGFR, ATM, PI3K/PTEN and chromatin-remodeling pathways were identified. Notably, RP1-34H18.1-NAV3 gene fusion (68%) was detected across all MBC subtypes. MBC is a genetically complex and molecularly heterogeneous disease, distinct from TNBC-NST and characterized by subtype-specific genomic and transcriptomic differences. Our findings support tailored therapeutic strategies targeting EGFR/PI3K, Hippo/Wnt-EMT, immune and epigenetic/DDR pathways. Recurrent fusion transcripts previously unreported in MBC may have therapeutic relevance.