Purpose: Metaplastic breast cancer (MpBC) is a rare subtype of breast cancer that is commonly triple-negative and poorly responsive to neoadjuvant therapy (NAT) in retrospective studies. Experimental Design: To better define clinical outcomes and correlates of response, we analyzed the rate of pathological complete response (pCR) to NAT, survival outcomes, and genomic and transcriptomic profiles of the pre-treatment tumors in a prospective clinical trial (NCT02276443). 211 patients with triple-negative breast cancer (TNBC), including 39 with MpBC, received doxorubicin-cyclophosphamide-based NAT. Results: Although not meeting the threshold for statistical significance, patients with MpBCs were less likely to experience a pCR (23% vs 40%; p=0.07), had shorter event-free survival (29.4 vs 32.2 months, p=0.15), metastasis-free survival (30.3 vs 32.4 months, p=0.22) and overall survival (32.6 vs 34.3 months, p=0.21). This heterogeneity is mirrored in the molecular profiling. Mutations in PI3KCA (23% vs 9%, p=0.07) and its pathway (41% vs 18%, p=0.02), were frequently observed and enriched in MpBCs. The gene expression profiles of each histologically defined subtype were distinguishable, and characterized by distinctive gene signatures. Among non-Mp TNBCs, 10% possessed a metaplastic-like gene expression signature and had pCR rates and survival outcomes similar to MpBC. Conclusions: Further investigations will determine if metaplastic-like tumors should be treated more similarly to MpBC in the clinic. The 23% pCR rate in this study suggests that patients with MpBC should be considered for NAT. To improve this rate, a pathway analysis predicted enrichment of HDAC and RTK/MAPK pathways in MpBC, which may serve as new targetable vulnerabilities.
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