Reference Detail

Ref Type

Journal Article

PMID

(27893038)

Authors

Basho RK, Gilcrease M, Murthy RK, Helgason T, Karp DD, Meric-Bernstam F, Hess KR, Herbrich SM, Valero V, Albarracin C, Litton JK, Chavez-MacGregor M, Ibrahim NK, Murray JL, Koenig KB, Hong D, Subbiah V, Kurzrock R, Janku F, Moulder SL

Title

Targeting the PI3K/AKT/mTOR Pathway for the Treatment of Mesenchymal Triple-Negative Breast Cancer: Evidence From a Phase 1 Trial of mTOR Inhibition in Combination With Liposomal Doxorubicin and Bevacizumab.

Journal	Vol	Issue	Date	Pages	Journal Short Title
JAMA oncology	3	4	2017 Apr 01	509-515	JAMA Oncol

URL

Abstract Text

Triple-negative breast cancer (TNBC) classified by transcriptional profiling as the mesenchymal subtype frequently harbors aberrations in the phosphoinositide 3-kinase (PI3K) pathway, raising the possibility of targeting this pathway to enhance chemotherapy response. Up to 30% of mesenchymal TNBC can be classified histologically as metaplastic breast cancer, a chemorefractory group of tumors with a mixture of epithelial and mesenchymal components identifiable by light microscopy. While assays to identify mesenchymal TNBC are under development, metaplastic breast cancer serves as a clinically identifiable surrogate to evaluate potential regimens for mesenchymal TNBC.To assess safety and efficacy of mammalian target of rapamycin (mTOR) inhibition in combination with liposomal doxorubicin and bevacizumab in patients with advanced metaplastic TNBC.Phase 1 study with dose escalation and dose expansion at the University of Texas MD Anderson Cancer Center of patients with advanced metaplastic TNBC. Patients were enrolled from April 16, 2009, to November 4, 2014, and followed for outcomes with a cutoff date of November 1, 2015, for data analysis.Liposomal doxorubicin, bevacizumab, and the mTOR inhibitors temsirolimus or everolimus using 21-day cycles.Safety and response. When available, archived tissue was evaluated for aberrations in the PI3K pathway.Fifty-two women with metaplastic TNBC (median age, 58 years; range, 37-79 years) were treated with liposomal doxorubicin, bevacizumab, and temsirolimus (DAT) (N = 39) or liposomal doxorubicin, bevacizumab, and everolimus (DAE) (N = 13). The objective response rate was 21% (complete response = 4 [8%]; partial response = 7 [13%]) and 10 (19%) patients had stable disease for at least 6 months, for a clinical benefit rate of 40%. Tissue was available for testing in 43 patients, and 32 (74%) had a PI3K pathway aberration. Presence of PI3K pathway aberration was associated with a significant improvement in objective response rate (31% vs 0%; P = .04) but not clinical benefit rate (44% vs 45%; P > .99).Using metaplastic TNBC as a surrogate for mesenchymal TNBC, DAT and DAE had notable activity in mesenchymal TNBC. Objective response was limited to patients with PI3K pathway aberration. A randomized trial should be performed to test DAT and DAE for metaplastic TNBC, as well as nonmetaplastic, mesenchymal TNBC, especially when PI3K pathway aberrations are identified.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
PIK3CA act mut	triple-receptor negative breast cancer	predicted - sensitive	Bevacizumab + Doxorubicin + Temsirolimus	Phase I	Actionable	In a Phase I trial, triple-receptor negative breast cancer patients, including those with PIK3CA activating mutations, demonstrated an overall response rate of 21% (11/52) and clinical benefit rate of 40% (21/52) when treated with a combination of Avastin (bevacizumab), Adriamycin (doxorubicin), and either Afinitor (everolimus) or Torisel (temsirolimus) (PMID: 27893038).	27893038
PIK3CA act mut	triple-receptor negative breast cancer	predicted - sensitive	Bevacizumab + Doxorubicin + Everolimus	Phase I	Actionable	In a Phase I trial, triple-receptor negative breast cancer patients, including those with PIK3CA activating mutations, demonstrated an overall response rate of 21% (11/52) and clinical benefit rate of 40% (21/52) when treated with a combination of Avastin (bevacizumab), Adriamycin (doxorubicin), and either Afinitor (everolimus) or Torisel (temsirolimus) (PMID: 27893038).	27893038