title: Tumor mutational analysis of GOG248, a phase II study of temsirolimus or temsirolimus and alternating megestrol acetate and tamoxifen for advanced endometrial cancer (EC): An NRG Oncology/Gynecologic Oncology Group study.
abstract: OBJECTIVE
  Rapamycin analogs have reproducible but modest efficacy in endometrial cancer (EC). Identification of molecular biomarkers that predict benefit could guide clinical development.
  
  
  METHODS
  Fixed primary tissue and whole blood were collected prospectively from patients enrolled on GOG 248. DNA was isolated from macro-dissected tumors and blood; next-generation sequence analysis was performed on a panel of cancer related genes. Associations between clinical outcomes [response rate (RR) 20%; progression-free survival (PFS) median 4.9months] and mutations (PTEN, PIK3CA, PIK3R1, KRAS, CTNNB1, AKT1, TSC1, TSC2, NF1, FBXW7) were explored.
  
  
  RESULTS
  Sequencing data was obtained from tumors of 55 of the 73 enrolled pts. Mutation rates were consistent with published reports: mutations in PTEN (45%), PIK3CA (29%), PIK3R1 (24%), K-RAS (16%), CTNNB1 (18%) were common and mutations in AKT1 (4%), TSC1 (2%), TSC2 (2%), NF1 (9%) and FBXW7 (4%) were less common. Increased PFS (HR 0.16; 95% CI 0.01-0.78) and RR (response difference 0.83; 95% CI 0.03-0.99) were noted for AKT1 mutation. An increase in PFS (HR 0.46; 95% CI 0.20-0.97) but not RR (response difference 0.00, 95% CI -0.34-0.34) was identified for CTNNB1 mutation. Both patients with TSC mutations had an objective response. There were no statistically significant associations between mutations in PIK3CA, PTEN, PIK3R1, or KRAS and PFS or RR.
  
  
  CONCLUSIONS
  Mutations in AKT1, TSC1 and TSC2 are rare, but may predict clinical benefit from temsirolimus. CTNNB1 mutations were associated with longer PFS on temsirolimus.
authors.affiliation: Dana Farber Cancer Institute, Boston, MA, United States. Electronic address: andrea.myers@novartis.com.
authors.forename: Andrea P
authors.initials: AP
authors.lastname: Myers
authors.affiliation: NRG Oncology Statistics and Data Management Center, Buffalo, NY, United States.
authors.forename: Virginia L
authors.initials: VL
authors.lastname: Filiaci
authors.affiliation: University of Iowa Hospitals and Clinics, Iowa City, IA, United States.
authors.forename: Yuping
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Stony Brook Medicine, Stony Brook, NY, United States.
authors.forename: Michael
authors.initials: M
authors.lastname: Pearl
authors.affiliation: Rush University Medical Center, Chicago, IL, United States.
authors.forename: Kian
authors.initials: K
authors.lastname: Behbakht
authors.affiliation: Memorial Sloan Kettering Cancer Center, Weill Cornell Medical College, New York, NY, United States.
authors.forename: Vicky
authors.initials: V
authors.lastname: Makker
authors.affiliation: Abington Memorial Hospital, Gladwyne, PA, United States.
authors.forename: Parviz
authors.initials: P
authors.lastname: Hanjani
authors.affiliation: University of Massachusetts Memorial Health Care, Worcester, MA, United States.
authors.forename: Susan
authors.initials: S
authors.lastname: Zweizig
authors.affiliation: Mercer University School of Medicine, Savannah, GA, United States.
authors.forename: James J
authors.initials: JJ
authors.lastname: Burke
authors.affiliation: Gynecologic Oncology of West Michigan, Grand Rapids, MI, United States.
authors.forename: Gordon
authors.initials: G
authors.lastname: Downey
authors.affiliation: University of Iowa Hospitals and Clinics, Iowa City, IA, United States.
authors.forename: Kimberly K
authors.initials: KK
authors.lastname: Leslie
authors.affiliation: Dana Farber Cancer Institute, Boston, MA, United States.
authors.forename: Paul
authors.initials: P
authors.lastname: Van Hummelen
authors.affiliation: Massachusetts General Hospital/Dana Farber Cancer Center, Boston, MA, United States.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Birrer
authors.affiliation: The University of Chicago Medical Center, Chicago, IL, United States.
authors.forename: Gini F
authors.initials: GF
authors.lastname: Fleming
mesh_terms: D058534:Class I Phosphatidylinositol 3-Kinases; D016889:Endometrial Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality; D005260:Female; D006801:Humans; D019290:Megestrol Acetate / Q000008:administration & dosage*; D009154:Mutation; D051059:PTEN Phosphohydrolase / Q000235:genetics; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics; D011446:Prospective Studies; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics; D020123:Sirolimus / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000627:therapeutic use; D013629:Tamoxifen / Q000008:administration & dosage*; D000077004:Tuberous Sclerosis Complex 1 Protein; D025521:Tumor Suppressor Proteins / Q000235:genetics
chemical_list: C000624650:TSC1 protein, human; D000077004:Tuberous Sclerosis Complex 1 Protein; D025521:Tumor Suppressor Proteins; D013629:Tamoxifen; C401859:temsirolimus; D019869:Phosphatidylinositol 3-Kinases; D058534:Class I Phosphatidylinositol 3-Kinases; C484760:PIK3CA protein, human; C494918:AKT1 protein, human; D051057:Proto-Oncogene Proteins c-akt; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; D019290:Megestrol Acetate; D020123:Sirolimus