TY - JOUR
T1 - Molecular Characterization and Prospective Evaluation of Pathologic Response and Outcomes with Neoadjuvant Therapy in Metaplastic Triple-Negative Breast Cancer
AU - Yam, Clinton
AU - Abuhadra, Nour
AU - Sun, Ryan
AU - Adrada, Beatriz E.
AU - Ding, Qing Qing
AU - White, Jason B.
AU - Ravenberg, Elizabeth E.
AU - Clayborn, Alyson R.
AU - Valero, Vicente
AU - Tripathy, Debu
AU - Damodaran, Senthilkumar
AU - Arun, Banu K.
AU - Litton, Jennifer K.
AU - Ueno, Naoto T
AU - Murthy, Rashmi K.
AU - Lim, Bora
AU - Baez, Luis
AU - Li, Xiaoxian
AU - Buzdar, Aman U.
AU - Hortobagyi, Gabriel N.
AU - Thompson, Alistair M.
AU - Mittendorf, Elizabeth Ann
AU - Rauch, Gaiane M.
AU - Candelaria, Rosalind P.
AU - Huo, Lei
AU - Moulder, Stacy
AU - Chang, Jeffrey T.
N1 - Publisher Copyright:
©2022 American Association for Cancer Research
PY - 2022/7/1
Y1 - 2022/7/1
N2 - 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.
AB - 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.
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U2 - 10.1158/1078-0432.CCR-21-3100
DO - 10.1158/1078-0432.CCR-21-3100
M3 - Article
C2 - 35507014
AN - SCOPUS:85133980510
SN - 1078-0432
VL - 28
SP - 2878
EP - 2889
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 13
ER -