Genomic vulnerabilities and clinical behavior of metaplastic breast cancer through integrated registry and GENIE analysis

Background: Metaplastic breast cancer (MpBC) is a rare and highly heterogeneous subtype of breast cancer, predominantly triple-negative and characterized by chemoresistance, early relapse, and poor survival. Despite its classification within the triple-negative breast cancer (TNBC) spectrum, the clinical behavior and molecular landscape of MpBC remain poorly defined, limiting the development of targeted therapeutic strategies. Methods: Clinical MpBC cases from MD Anderson Cancer Center (2014-2025) were annotated for subtype, stage, and survival. Genomic data from the AACR GENIE MpBC cohort (v16.1; n=258) were evaluated for pathogenic mutations and copy-number alterations. Variant frequencies, hotspot patterns, and mutual exclusivity were assessed using Fisher's exact test. Analyses were performed in R, with statistical significance defined as p<0.05. Results: Among 105 MpBC cases in the MDACC registry, 92.9% were TNBC, with an overall mortality rate of 34.3%. HER2-positive disease was rare (3.5%) but demonstrated the highest proportional mortality (50%). ER-positive tumors ≥10% (3.5%) had a 25% mortality rate, whereas ER/PR low-positive (<10%) tumors exhibited clinical outcomes similar to TNBC. Notably, mortality was observed even among early-stage patients, underscoring aggressive tumor biology that is independent of stage. Genomic analysis of 258 MpBC cases (267 samples) from GENIE identified recurrent TP53 mutations (57%), including canonical hotspot variants (R248Q, R175H, R273C), consistent with pervasive genomic instability. PIK3CA alterations (34%), driven predominantly by H1047R, were frequently mutually exclusive with TP53 mutations (p=0.043), suggesting distinct molecular subclasses with differential oncogenic drivers. Additional recurrent alterations in chromatin regulators ( KMT2C 17.1%, KMT2D 10.5%) and copy-number gains involving AGO2 (22.9%), RAD21 (20.4%), RECQL4 (19.8%), and MYC (19.4%) highlight potential vulnerabilities in DNA repair, replication stress response, and transcriptional regulation. Genomic profiling of the institutional MpBC cohort is ongoing. Conclusion: These integrated clinical and molecular findings reinforce MpBC as a major contributor to mortality within the TNBC population despite its rarity and nominate PI3K/AKT pathway alterations, genomic instability, and epigenetic deregulation as potential therapeutic targets. These findings further support the need for biomarker-driven precision oncology trials, including basket-style designs and rare-tumor initiatives, to advance targeted therapies for rare, aggressive breast cancer subtypes.