title: Open-label randomized clinical trial of standard neoadjuvant chemotherapy with paclitaxel followed by FEC versus the combination of paclitaxel and everolimus followed by FEC in women with triple receptor-negative breast cancer†.
abstract: BACKGROUND
  Everolimus synergistically enhances taxane-induced cytotoxicity in breast cancer cells in vitro and in vivo in addition to demonstrating a direct antiproliferative activity. We aim to determine pharmacodynamics changes and response of adding everolimus to standard neoadjuvant chemotherapy in triple-negative breast cancer (TNBC).
  
  
  METHODS
  Phase II study in patients with primary TNBC randomized to T-FEC (paclitaxel 80 mg/m(2) i.v. weekly for 12 weeks, followed by 5-fluorouracil 500 mg/m(2), epirubicin 100 mg/m(2), and cyclophosphamide 500 mg/m(2) every 3 weeks for four cycles) versus TR-FEC (paclitaxel 80 mg/m(2) i.v. and everolimus 30 mg PO weekly for 12 weeks, followed by FEC). Tumor samples were collected to assess molecular changes in the PI3K/AKT/mTOR pathway, at baseline, 48 h, 12 weeks, and at surgery by reverse phase protein arrays (RPPA). Clinical end points included 12-week clinical response rate (12-week RR), pathological complete response (pCR), and toxicity.
  
  
  RESULTS
  Sixty-two patients were registered, and 50 were randomized, 27 received T-FEC, and 23 received TR-FEC. Median age was 48 (range 31-75). There was downregulation of the mTOR pathway at 48 h in the TR-FEC arm. Twelve-week RR by ultrasound were 29.6% versus 47.8%, (P = 0.075), and pCR were 25.9% versus 30.4% (P = 0.76) for T-FEC and TR-FEC, respectively. mTOR downregulation at 48 h did not correlate with 12-week RR in the TR-FEC group (P = 0.58). Main NCI grade 3/4 toxicities included anemia, neutropenia, rash/desquamation, and vomiting in both arms. There was one case of grade 3 pneumonitis in the TR-FEC arm. No grade 3/4 stomatitis occurred.
  
  
  CONCLUSIONS
  The addition of everolimus to paclitaxel was well tolerated. Everolimus downregulated mTOR signaling but downregulation of mTOR at 48 h did not correlate with 12-week RR in the TR-FEC group.
  
  
  BACKGROUND
  NCT00499603.
authors.affiliation: Department of Breast Medical Oncology Department of Systems Biology agonzalez@mdanderson.org.
authors.forename: A M
authors.initials: AM
authors.lastname: Gonzalez-Angulo
authors.affiliation: Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston.
authors.forename: A
authors.initials: A
authors.lastname: Akcakanat
authors.affiliation: Department of Breast Medical Oncology.
authors.forename: S
authors.initials: S
authors.lastname: Liu
authors.affiliation: Genenetech, San Francisco.
authors.forename: M C
authors.initials: MC
authors.lastname: Green
authors.affiliation: Department of Breast Medical Oncology.
authors.forename: J L
authors.initials: JL
authors.lastname: Murray
authors.affiliation: Department of Breast Medical Oncology.
authors.forename: H
authors.initials: H
authors.lastname: Chen
authors.affiliation: Departments of Biostatistics.
authors.forename: S L
authors.initials: SL
authors.lastname: Palla
authors.affiliation: Department of Breast Medical Oncology.
authors.forename: K B
authors.initials: KB
authors.lastname: Koenig
authors.affiliation: Clinical Cancer Prevention.
authors.forename: A M
authors.initials: AM
authors.lastname: Brewster
authors.affiliation: Department of Breast Medical Oncology.
authors.forename: V
authors.initials: V
authors.lastname: Valero
authors.affiliation: Department of Breast Medical Oncology.
authors.forename: N K
authors.initials: NK
authors.lastname: Ibrahim
authors.affiliation: Department of Breast Medical Oncology.
authors.forename: S
authors.initials: S
authors.lastname: Moulder-Thompson
authors.affiliation: Department of Breast Medical Oncology.
authors.forename: J K
authors.initials: JK
authors.lastname: Litton
authors.affiliation: Department of Breast Medical Oncology.
authors.forename: E
authors.initials: E
authors.lastname: Tarco
authors.affiliation: Department of Breast Medical Oncology.
authors.forename: J
authors.initials: J
authors.lastname: Moore
authors.affiliation: Department of Breast Medical Oncology.
authors.forename: P
authors.initials: P
authors.lastname: Flores
authors.affiliation: Department of Breast Medical Oncology.
authors.forename: D
authors.initials: D
authors.lastname: Crawford
authors.affiliation: Radiology.
authors.forename: M J
authors.initials: MJ
authors.lastname: Dryden
authors.affiliation: Pathology, The University of Texas MD Anderson Cancer Center, Houston.
authors.forename: W F
authors.initials: WF
authors.lastname: Symmans
authors.affiliation: Pathology, The University of Texas MD Anderson Cancer Center, Houston.
authors.forename: A
authors.initials: A
authors.lastname: Sahin
authors.affiliation: Department of Breast Medical Oncology.
authors.forename: S H
authors.initials: SH
authors.lastname: Giordano
authors.affiliation: Division of Hematology-Oncology, Yale University, New Haven.
authors.forename: L
authors.initials: L
authors.lastname: Pusztai
authors.affiliation: Departments of Biostatistics.
authors.forename: K-A
authors.initials: KA
authors.lastname: Do
authors.affiliation: Department of Systems Biology.
authors.forename: G B
authors.initials: GB
authors.lastname: Mills
authors.affiliation: Department of Breast Medical Oncology.
authors.forename: G N
authors.initials: GN
authors.lastname: Hortobagyi
authors.affiliation: Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, USA.
authors.forename: F
authors.initials: F
authors.lastname: Meric-Bernstam
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D003520:Cyclophosphamide / Q000008:administration & dosage / Q000009:adverse effects; D015251:Epirubicin / Q000008:administration & dosage / Q000009:adverse effects; D000068338:Everolimus; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage / Q000009:adverse effects; D006801:Humans; D008875:Middle Aged; D020360:Neoadjuvant Therapy / Q000379:methods*; D017239:Paclitaxel / Q000008:administration & dosage / Q000009:adverse effects; D015398:Signal Transduction / Q000187:drug effects; D020123:Sirolimus / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives; D058570:TOR Serine-Threonine Kinases / Q000187:drug effects / Q000378:metabolism; D064726:Triple Negative Breast Neoplasms / Q000188:drug therapy*
chemical_list: D015251:Epirubicin; D003520:Cyclophosphamide; D000068338:Everolimus; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D017239:Paclitaxel; D005472:Fluorouracil; D020123:Sirolimus
keywords: PI3K pathway inhibition; neoadjuvant systemic therapy; triple negative breast cancer