Molecular Characterization and Prospective Evaluation of Pathologic Response and Outcomes with Neoadjuvant Therapy in Metaplastic Triple-Negative Breast Cancer

• Type of Material: Article
• Authors: Clinton Yam, The University of Texas MD Anderson Cancer Center; Nour Abuhadra, The University of Texas MD Anderson Cancer Center; Ryan Sun, The University of Texas MD Anderson Cancer Center; Beatriz E Adrada, Univ Texas MD Anderson Canc Ctr; Qing-Qing Ding, The University of Texas MD Anderson Cancer Center; Jason B White, The University of Texas MD Anderson Cancer Center; Elizabeth E Ravenberg, The University of Texas MD Anderson Cancer Center; Alyson R Clayborn, The University of Texas MD Anderson Cancer Center; Vicente Valero, The University of Texas MD Anderson Cancer Center; Debu Tripathy, The University of Texas MD Anderson Cancer Center; Senthilkumar Damodaran, The University of Texas MD Anderson Cancer Center; Banu K Arun, The University of Texas MD Anderson Cancer Center; Jennifer K Litton, The University of Texas MD Anderson Cancer Center; Naoto T Ueno, The University of Texas MD Anderson Cancer Center; Rashmi K Murthy, The University of Texas MD Anderson Cancer Center; Bora Lim, Baylor College of Medicine; Luis Baez, University of Puerto Rico; Xiaoxian Li, Emory University; Aman U Buzdar, The University of Texas MD Anderson Cancer Center; Gabriel N Hortobagyi, The University of Texas MD Anderson Cancer Center; Alistair AM Thompson, Baylor College of Medicine; Elizabeth A. Mittendori, Brigham and Women’s Hospital; Gaiane M Rauch, The University of Texas MD Anderson Cancer Center; Rosalind P Candelaria, The University of Texas MD Anderson Cancer Center; Lei Huo, The University of Texas MD Anderson Cancer Center; Stacy L Moulder, The University of Texas MD Anderson Cancer Center; Jeffrey T Chang, The University of Texas MD Anderson Cancer Center
• Language: English
• Date: 2022-07-01
• Publisher: AMER ASSOC CANCER RESEARCH
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2022, American Association for Cancer Research
• Final Published Version (URL): http://dx.doi.org/10.1158/1078-0432.CCR-21-3100
• Title of Journal or Parent Work: CLINICAL CANCER RESEARCH
• Volume: 28
• Issue: 13
• Start Page: 2878
• End Page: 2889
• Keywords: OVEREXPRESSION; IDENTIFICATION; SIGNATURES; CARCINOMA; Science & Technology; SELECTION; REVEALS FREQUENT; TO-MESENCHYMAL TRANSITION; STEM-CELL; METASTASIS; Life Sciences & Biomedicine; MUTATIONS; Oncology

Abstract

Purpose: Metaplastic breast cancer (MpBC) is a rare subtype of breast cancer that is commonly triple-negative and poorly responsive to neoadjuvant therapy in retrospective studies. Experimental Design: To better define clinical outcomes and correlates of response, we analyzed the rate of pathologic complete response (pCR) to neoadjuvant therapy, survival outcomes, and genomic and transcriptomic profiles of the pretreatment tumors in a prospective clinical trial (NCT02276443). A total of 211 patients with triple-negative breast cancer (TNBC), including 39 with MpBC, received doxorubicin-cyclophosphamide–based neoadjuvant therapy. Results: Although not meeting the threshold for statistical significance, patients with MpBCs were less likely to experience a pCR (23% vs. 40%; P ¼ 0.07), had shorter event-free survival (29.4 vs. 32.2 months, P ¼ 0.15), metastasis-free survival (30.3 vs. 32.4 months, P ¼ 0.22); and overall survival (32.6 vs. 34.3 months, P ¼ 0.21). This heterogeneity is mirrored in the molecular profiling. Mutations in PI3KCA (23% vs. 9%, P ¼ 0.07) and its pathway (41% vs. 18%, P ¼ 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 nonmetaplastic (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 histone deacetylase (HDAC) and RTK/MAPK pathways in MpBC, which may serve as new targetable vulnerabilities.