title: Molecular determinants of outcome with mammalian target of rapamycin inhibition in endometrial cancer.
abstract: BACKGROUND
  Targeting the phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathway is of increasing interest as a therapeutic strategy in many tumors. The aim of this study was to identify molecular markers associated with mTOR inhibitor activity in women with metastatic endometrial cancer.
  
  
  METHODS
  Archival tumor samples were collected from 94 women with recurrent or metastatic endometrial cancer who participated in 3 National Cancer Insitute of Canada Clinical Trials Group phase 2 trials investigating single-agent mTOR inhibitors: IND160A and IND160B (temsirolimus) and IND192 (ridaforolimus). Analyses included mutational profiling using the OncoCarta Panel version 1.0 and immunohistochemical expression of the tumor suppressor gene PTEN (phosphatase and tensin homologue) and stathmin, a marker of PI3K activation. Associations between biomarker results and clinical outcomes were assessed.
  
  
  RESULTS
  Mutations were found in 32 of 73 analyzed tumors, PIK3CA (21 patients) was the most common mutated gene. Co-mutations were seen in 8 tumors, most frequently KRAS and PIK3CA (4 cases). PTEN loss was observed in 46 of 85 samples analyzed and increased stathmin expression was observed in 15 of 65 analyzed samples. No correlation was observed between biomarkers and response or progression. In patients taking concurrent metformin, there was a trend toward lower progression, of 11.8% versus 32.5% (P = .14).
  
  
  CONCLUSIONS
  No predictive biomarker or combination of biomarkers for mTOR inhibitor activity were identified in this study. Restriction and enrichment of study entry, especially based on archival tumor tissue, should be undertaken with caution in trials using these agents.
authors.affiliation: Princess Margaret Hospital, Toronto, Ontario, Canada.
authors.forename: Helen J
authors.initials: HJ
authors.lastname: Mackay
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Eisenhauer
authors.forename: Suzanne
authors.initials: S
authors.lastname: Kamel-Reid
authors.forename: Ming
authors.initials: M
authors.lastname: Tsao
authors.forename: Blaise
authors.initials: B
authors.lastname: Clarke
authors.forename: Katherine
authors.initials: K
authors.lastname: Karakasis
authors.forename: Henrica M J
authors.initials: HM
authors.lastname: Werner
authors.forename: Jone
authors.initials: J
authors.lastname: Trovik
authors.forename: Lars A
authors.initials: LA
authors.lastname: Akslen
authors.forename: Helga B
authors.initials: HB
authors.lastname: Salvesen
authors.forename: Dongsheng
authors.initials: D
authors.lastname: Tu
authors.forename: Amit M
authors.initials: AM
authors.lastname: Oza
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D058534:Class I Phosphatidylinositol 3-Kinases; D016889:Endometrial Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D005260:Female; D006801:Humans; D008875:Middle Aged; D009154:Mutation; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics* / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D020123:Sirolimus / Q000008:administration & dosage / Q000031:analogs & derivatives; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics*
chemical_list: D058534:Class I Phosphatidylinositol 3-Kinases; D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D020123:Sirolimus; D058570:TOR Serine-Threonine Kinases; C515074:ridaforolimus; C401859:temsirolimus; C546842:MTOR protein, human; C484760:PIK3CA protein, human; C494929:PTEN protein, human
keywords: endometrial cancer; metformin; predictive biomarkers; rapalogs; stathmin