title: Inhibition of the phosphoinositide 3-kinase pathway for the treatment of patients with metastatic metaplastic breast cancer.
abstract: BACKGROUND
  Mesenchymal/metaplastic breast cancers (MpBCs) are often triple-negative (TNBC), and chemo-refractory, and can harbor phosphoinositide 3-kinase (PI3kinase) alterations; thus, therapy with mTor inhibitors may demonstrate activity.
  
  
  METHODS
  Patients with mesenchymal/MpBC treated with temsirolimus-based regimens were evaluated. Mutational analyses [polymerase chain reaction (PCR)-based DNA sequencing method, mass spectrometric detection (Sequenom MassARRAY), or next-generation sequencing] as well as loss of phosphatase and tensin homolog (PTEN) (immunohistochemistry) were performed (archived tissue when available).
  
  
  RESULTS
  Twenty-three patients (one of whom was on two separate trials) were treated using temsirolimus-containing regimens: temsirolimus alone (n = 1 patient) or combined with the following: liposomal doxorubicin and bevacizumab (DAT, n = 18); liposomal doxorubicin (DT, n = 1); paclitaxel and bevacizumab (TAT, n = 2); paclitaxel (TT, n = 1); carboplatin and bevacizumab (CAT, n = 1). Response rate [complete response (CR) + partial response (PR)] was 25% across all regimens; 32% in the anthracycline-based regimens [DAT and DT (CR = 2, PR = 4; N = 19)]. An additional two patients achieved stable disease (SD) ≥6 months [total SD ≥6 months/CR/PR = 8 (33%)]. Molecular aberrations in the PI3K pathway were common: PIK3CA mutation = 6/15 (40%), PTEN mutation = 3/11 (27%), and PTEN loss = 2/11 (18%). A point mutation in the NF2 gene (K159fs*16; NF2 alterations can activate mTor) was found in one patient who attained CR (3+ years). Of the eight patients who achieved SD ≥6 months/CR/PR, all 4 patients with available tissue had a molecular aberration that activate the PIK3CA/Akt/mTOR axis: PIK3CA mutation = 2; PTEN loss = 1; NF2 aberration = 1.
  
  
  CONCLUSIONS
  DAT has activity in MpBCs including complete CRs. Molecular aberrations that can activate the PI3 K/Akt/mTOR axis are common in MpBC.
authors: Department of Investigational Cancer Therapeutics (Phase I), The University of Texas, M.D. Anderson Cancer Center, Houston Department of Breast Medical Oncology, The University of Texas, M.D. Anderson Cancer Center, Houston smoulder@mdanderson.org.
authors: S
authors: S
authors: Moulder
authors: Department of Investigational Cancer Therapeutics (Phase I), The University of Texas, M.D. Anderson Cancer Center, Houston.
authors: T
authors: T
authors: Helgason
authors: Department of Investigational Cancer Therapeutics (Phase I), The University of Texas, M.D. Anderson Cancer Center, Houston.
authors: F
authors: F
authors: Janku
authors: Department of Investigational Cancer Therapeutics (Phase I), The University of Texas, M.D. Anderson Cancer Center, Houston.
authors: J
authors: J
authors: Wheler
authors: Department of Investigational Cancer Therapeutics (Phase I), The University of Texas, M.D. Anderson Cancer Center, Houston.
authors: J
authors: J
authors: Moroney
authors: Department of Breast Medical Oncology, The University of Texas, M.D. Anderson Cancer Center, Houston.
authors: D
authors: D
authors: Booser
authors: Department of Pathology, The University of Texas, M.D. Anderson Cancer Center, Houston.
authors: C
authors: C
authors: Albarracin
authors: Department of Breast Medical Oncology, The University of Texas, M.D. Anderson Cancer Center, Houston.
authors: P K
authors: PK
authors: Morrow
authors: Department of Investigational Cancer Therapeutics (Phase I), The University of Texas, M.D. Anderson Cancer Center, Houston.
authors: J
authors: J
authors: Atkins
authors: Department of Breast Medical Oncology, The University of Texas, M.D. Anderson Cancer Center, Houston.
authors: K
authors: K
authors: Koenig
authors: Department of Pathology, The University of Texas, M.D. Anderson Cancer Center, Houston.
authors: M
authors: M
authors: Gilcrease
authors: Department of Hematology and Oncology, UCSD Moores Cancer Center, San Diego, USA.
authors: R
authors: R
authors: Kurzrock
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D000068258:Bevacizumab / Q000008:administration & dosage; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D016190:Carboplatin / Q000008:administration & dosage; D058534:Class I Phosphatidylinositol 3-Kinases; D004317:Doxorubicin / Q000008:administration & dosage / Q000031:analogs & derivatives; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008648:Mesoderm / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D008679:Metaplasia / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009367:Neoplasm Staging; D051059:PTEN Phosphohydrolase / Q000037:antagonists & inhibitors* / Q000235:genetics; D017239:Paclitaxel / Q000008:administration & dosage; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011092:Polyethylene Glycols / Q000008:administration & dosage; D016133:Polymerase Chain Reaction; D011379:Prognosis; D020123:Sirolimus / Q000008:administration & dosage / Q000031:analogs & derivatives; D015996:Survival Rate; D055815:Young Adult
chemical_list: D000068258:Bevacizumab; D016190:Carboplatin; D058534:Class I Phosphatidylinositol 3-Kinases; D004317:Doxorubicin; D051059:PTEN Phosphohydrolase; D017239:Paclitaxel; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011092:Polyethylene Glycols; D020123:Sirolimus; C506643:liposomal doxorubicin; C401859:temsirolimus; C484760:PIK3CA protein, human; C494929:PTEN protein, human
keywords: bevacizumab; liposomal doxorubicin; metaplastic breast cancer; temsirolimus