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.
abstract: OBJECTIVE
  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.
  
  
  OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  METHODS
  Liposomal doxorubicin, bevacizumab, and the mTOR inhibitors temsirolimus or everolimus using 21-day cycles.
  
  
  METHODS
  Safety and response. When available, archived tissue was evaluated for aberrations in the PI3K pathway.
  
  
  RESULTS
  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).
  
  
  CONCLUSIONS
  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.
authors.affiliation: Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston.
authors.forename: Reva K
authors.initials: RK
authors.lastname: Basho
authors.affiliation: Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston.
authors.forename: Michael
authors.initials: M
authors.lastname: Gilcrease
authors.affiliation: Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston.
authors.forename: Rashmi K
authors.initials: RK
authors.lastname: Murthy
authors.affiliation: Investigational Cancer Therapeutics (Phase I Trials Program), The University of Texas MD Anderson Cancer Center, Houston.
authors.forename: Thorunn
authors.initials: T
authors.lastname: Helgason
authors.affiliation: Investigational Cancer Therapeutics (Phase I Trials Program), The University of Texas MD Anderson Cancer Center, Houston.
authors.forename: Daniel D
authors.initials: DD
authors.lastname: Karp
authors.affiliation: Investigational Cancer Therapeutics (Phase I Trials Program), The University of Texas MD Anderson Cancer Center, Houston5Sheikh Khalifa Bin Zayed Al Nahyan Institute for Personalized Cancer Therapy, The University of Texas MD Anderson Cancer Center, Houston6Breast Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston.
authors.forename: Funda
authors.initials: F
authors.lastname: Meric-Bernstam
authors.affiliation: Biostatistics, The University of Texas MD Anderson Cancer Center, Houston.
authors.forename: Kenneth R
authors.initials: KR
authors.lastname: Hess
authors.affiliation: Pediatrics, The University of Texas MD Anderson Cancer Center, Houston.
authors.forename: Shelley M
authors.initials: SM
authors.lastname: Herbrich
authors.affiliation: Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston.
authors.forename: Vicente
authors.initials: V
authors.lastname: Valero
authors.affiliation: Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston.
authors.forename: Constance
authors.initials: C
authors.lastname: Albarracin
authors.affiliation: Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston.
authors.forename: Jennifer K
authors.initials: JK
authors.lastname: Litton
authors.affiliation: Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston9Health Services Research, The University of Texas MD Anderson Cancer Center, Houston.
authors.forename: Mariana
authors.initials: M
authors.lastname: Chavez-MacGregor
authors.affiliation: Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston.
authors.forename: Nuhad K
authors.initials: NK
authors.lastname: Ibrahim
authors.affiliation: Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston.
authors.forename: James L
authors.initials: JL
authors.lastname: Murray
authors.affiliation: Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston.
authors.forename: Kimberly B
authors.initials: KB
authors.lastname: Koenig
authors.affiliation: Investigational Cancer Therapeutics (Phase I Trials Program), The University of Texas MD Anderson Cancer Center, Houston.
authors.forename: David
authors.initials: D
authors.lastname: Hong
authors.affiliation: Investigational Cancer Therapeutics (Phase I Trials Program), The University of Texas MD Anderson Cancer Center, Houston.
authors.forename: Vivek
authors.initials: V
authors.lastname: Subbiah
authors.affiliation: Investigational Cancer Therapeutics (Phase I Trials Program), The University of Texas MD Anderson Cancer Center, Houston10Division of Hematology and Oncology, University of California San Diego Moores Cancer Center, La Jolla.
authors.forename: Razelle
authors.initials: R
authors.lastname: Kurzrock
authors.affiliation: Investigational Cancer Therapeutics (Phase I Trials Program), The University of Texas MD Anderson Cancer Center, Houston.
authors.forename: Filip
authors.initials: F
authors.lastname: Janku
authors.affiliation: Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston4Investigational Cancer Therapeutics (Phase I Trials Program), The University of Texas MD Anderson Cancer Center, Houston.
authors.forename: Stacy L
authors.initials: SL
authors.lastname: Moulder
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D000068258:Bevacizumab / Q000008:administration & dosage* / Q000009:adverse effects; D004317:Doxorubicin / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives*; D053492:Elafin / Q000378:metabolism; D000068338:Everolimus / Q000008:administration & dosage / Q000009:adverse effects; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D008875:Middle Aged; D011092:Polyethylene Glycols / Q000008:administration & dosage / Q000009:adverse effects; D016016:Proportional Hazards Models; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors; D015398:Signal Transduction / Q000187:drug effects; D020123:Sirolimus / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D064726:Triple Negative Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology
chemical_list: D053492:Elafin; C506806:PI3 protein, human; D047428:Protein Kinase Inhibitors; C506643:liposomal doxorubicin; D000068258:Bevacizumab; D011092:Polyethylene Glycols; C401859:temsirolimus; D004317:Doxorubicin; D000068338:Everolimus; C546842:MTOR protein, human; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus