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

Clinton Yam, Nour Abuhadra, Ryan Sun, Beatriz E. Adrada, Qing Qing Ding, Jason B. White, Elizabeth E. Ravenberg, Alyson R. Clayborn, Vicente Valero, Debu Tripathy, Senthilkumar Damodaran, Banu K. Arun, Jennifer K. Litton, Naoto T Ueno, Rashmi K. Murthy, Bora Lim, Luis Baez, Xiaoxian Li, Aman U. Buzdar, Gabriel N. HortobagyiAlistair M. Thompson, Elizabeth Ann Mittendorf, Gaiane M. Rauch, Rosalind P. Candelaria, Lei Huo, Stacy Moulder, Jeffrey T. Chang

Research output: Contribution to journalArticlepeer-review

11 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)2878-2889
Number of pages12
JournalClinical Cancer Research
Volume28
Issue number13
DOIs
StatePublished - Jul 1 2022

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

MD Anderson CCSG core facilities

  • Biostatistics Resource Group

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