Faculty, Staff and Student Publications

Publication Date

6-1-2023

Journal

Investigational New Drugs

DOI

10.1007/s10637-023-01357-4

PMID

37043123

PMCID

PMC12247185

PubMedCentral® Posted Date

7-11-2025

PubMedCentral® Full Text Version

Author MSS

Abstract

Background:: Metaplastic histology and mesenchymal differentiation have been associated with chemotherapy resistance in triple-negative breast cancer (TNBC). In the neoadjuvant setting, suboptimal on-treatment clinical response to chemotherapy is associated with low rates of pathological complete response (pCR). Given the previously demonstrated activity of pegylated liposomal doxorubicin, bevacizumab, and mTOR inhibition with temsirolimus (DAT) or everolimus (DAE) in metastatic, metaplastic TNBC, we conducted a phase II study of DAT/DAE as the second phase of neoadjuvant therapy in patients with metaplastic and/or mesenchymal TNBC experiencing suboptimal clinical response to neoadjuvant doxorubicin and cyclophosphamide (AC) (NCT02456857).

Patients and Methods:: Patients received liposomal doxorubicin (30mg/m2 intravenously [IV], every 21 days, x 4 cycles), bevacizumab (10-15mg/kg IV, every 21 days x 3 cycles), and temsirolimus (25mg IV, every 7 days, x 12 weeks) or everolimus (7.5mg orally, once daily). A two-stage Gehan-type design was employed to detect an improvement in pCR/residual cancer burden index I (RCB-I) from 5% to 20%.

Results:: From 2/11/2016 through 12/4/2019, 17 patients were enrolled. None of the study participants experienced a pCR. Among all 17 patients, 6%, 76%, and 18%, were found to have RCB-I, RCB-II, and RCB-III disease, respectively. No grade 4/5 treatment-related adverse events (TRAE) were observed. The most common grade 3 TRAEs were neutropenia (18%) and oral mucositis (18%).

Conclusion:: Neoadjuvant DAT/DAE failed to demonstrate meaningful clinical activity in patients with mesenchymal and/or metaplastic TNBC following suboptimal response to neoadjuvant AC. Further studies are needed to elucidate mechanisms of primary anthracycline resistance in metaplastic and/or mesenchymal TNBC.

Keywords

Humans, Female, Triple Negative Breast Neoplasms, Neoadjuvant Therapy, Breast Neoplasms, TOR Serine-Threonine Kinases, Antineoplastic Combined Chemotherapy Protocols

Published Open-Access

yes

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