title: Phase II study of temsirolimus in women with recurrent or metastatic endometrial cancer: a trial of the NCIC Clinical Trials Group.
abstract: OBJECTIVE
  Phosphatase and tensin homolog (PTEN) is a tumor suppressor gene, and loss of function mutations are common and appear to be important in the pathogenesis of endometrial carcinomas. Loss of PTEN causes deregulated phosphatidylinositol-3 kinase/serine-threonine kinase/mammalian target of rapamycin (PI3K/Akt/mTOR) signaling which may provide neoplastic cells with a selective survival advantage by enhancing angiogenesis, protein translation, and cell cycle progression. Temsirolimus, an ester derivative of rapamycin that inhibits mTOR, was evaluated in this setting.
  
  
  METHODS
  Sequential phase II studies evaluated single-agent activity of temsirolimus in women with recurrent or metastatic chemotherapy-naive or chemotherapy-treated endometrial cancer. Temsirolimus 25 mg intravenously was administered weekly in 4-week cycles.
  
  
  RESULTS
  In the chemotherapy-naive group, 33 patients received a median of four cycles (range, one to 23 cycles). Of the 29 patients evaluable for response, four (14%) had an independently confirmed partial response and 20 (69%) had stable disease as best response, with a median duration of 5.1 months (range, 3.7 to 18.4 months) and 9.7 months (range, 2.1 to 14.6 months). Only five patients (18%) had progressive disease. In the chemotherapy-treated group, 27 patients received a median of three cycles (range, one to six cycles). Of the 25 patients evaluable for response, one (4%) had an independently confirmed partial response, and 12 patients (48%) had stable disease, with a median duration of 4.3 months (range, 3.6 to 4.9 months) and 3.7 months (range, 2.4 to 23.2 months). PTEN loss (immunohistochemistry and mutational analysis) and molecular markers of PI3K/Akt/mTOR pathway did not correlate with the clinical outcome.
  
  
  CONCLUSIONS
  mTOR inhibition with temsirolimus has encouraging single-agent activity in endometrial cancer which is higher in chemotherapy-naive patients than in chemotherapy-treated patients and is independent of PTEN status. The difference in activity according to prior therapy should be factored into future clinical trial designs.
authors.affiliation: Princess Margaret Hospital, University Health Network, University of Toronto, Toronto, Ontario, Canada. amit.oza@uhn.on.ca
authors.forename: Amit M
authors.initials: AM
authors.lastname: Oza
authors.forename: Laurie
authors.initials: L
authors.lastname: Elit
authors.forename: Ming-Sound
authors.initials: MS
authors.lastname: Tsao
authors.forename: Suzanne
authors.initials: S
authors.lastname: Kamel-Reid
authors.forename: Jim
authors.initials: J
authors.lastname: Biagi
authors.forename: Diane Michele
authors.initials: DM
authors.lastname: Provencher
authors.forename: Walter H
authors.initials: WH
authors.lastname: Gotlieb
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Hoskins
authors.forename: Prafull
authors.initials: P
authors.lastname: Ghatage
authors.forename: Katia S
authors.initials: KS
authors.lastname: Tonkin
authors.forename: Helen J
authors.initials: HJ
authors.lastname: Mackay
authors.forename: John
authors.initials: J
authors.lastname: Mazurka
authors.forename: Joana
authors.initials: J
authors.lastname: Sederias
authors.forename: Percy
authors.initials: P
authors.lastname: Ivy
authors.forename: Janet E
authors.initials: JE
authors.lastname: Dancey
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Eisenhauer
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000627:therapeutic use; D015331:Cohort Studies; D018450:Disease Progression; D016889:Endometrial Neoplasms / Q000188:drug therapy* / Q000235:genetics; D005260:Female; D006801:Humans; D008875:Middle Aged; D009154:Mutation; D009362:Neoplasm Metastasis; D012008:Recurrence; D020123:Sirolimus / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; C401859:temsirolimus; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus