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

Authors

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 Hortobagyi
Alistair M Thompson
Elizabeth A Mittendorf
Gaiane M Rauch
Rosalind P Candelaria
Lei Huo
Stacy L Moulder
Jeffrey T Chang

Publication Date

7-1-2022

Journal

Clinical Cancer Research

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 = 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 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.

Keywords

Antineoplastic Combined Chemotherapy Protocols, Breast Neoplasms, Female, Humans, Metaplasia, Neoadjuvant Therapy, Retrospective Studies, Triple Negative Breast Neoplasms

DOI

10.1158/1078-0432.CCR-21-3100

PMID

35507014

PMCID

PMC9250637

PubMedCentral® Posted Date

1-1-2023

PubMedCentral® Full Text Version

Author MSS

Published Open-Access

yes