title: The search continues: looking for predictive biomarkers for response to mammalian target of rapamycin inhibition in endometrial cancer.
abstract: OBJECTIVE
  PI3K/mammalian target of rapamycin (mTOR) pathway aberrations occur in 40% to 80% of endometrial cancer. Prior studies suggest KRAS mutations are associated with resistance to mTOR inhibitors in solid tumors. The objective of this study was to determine if biomarker expression in the PI3K/mTOR pathway or KRAS mutations would predict response to therapy with everolimus, an mTOR inhibitor.
  
  
  METHODS
  Specimens from a phase II study of everolimus in recurrent endometrioid endometrial cancer were utilized. The primary end point was clinical benefit rate (CBR: objective response and nonprogression at 20 weeks). Correlative studies evaluating PTEN expression and phospho-S6 ribosomal protein (pS6rp) status by immunohistochemistry and KRAS mutational analysis were performed.
  
  
  RESULTS
  Six of 28 evaluable patients achieved prolonged stable disease (SD) at 20 weeks (CBR, 21%). Loss of PTEN expression did not predict CBR (P = 0.62) with a positive predictive value (PPV) of 0.13. Five (83%) of 6 patients with SD maintained PTEN expression. Neither pS6rp expression (P = 0.65) nor KRAS mutation (P = 0.99) predicted CBR; the PPV was 0.14 for each. Eighty percent (4/5) of those with SD were KRAS wild type. Combined analysis of pS6rp expression and KRAS mutation provided 100% PPV (95% confidence interval, 39.6%-100%), suggesting no chance of CBR for these individuals with 100% specificity (95% confidence interval, 46.3%-100%).
  
  
  CONCLUSIONS
  S6rp phosphorylation, loss of PTEN expression, and presence of KRAS mutations alone did not correlate with CBR. However, positive pS6rp staining combined with KRAS mutation performed with 100% PPV and specificity to predict nonresponse. Identifying patients who will not benefit from mTOR inhibitors can direct therapy and reduce exposure to agents that add toxicity without clinical benefit.
authors.affiliation: Departments of *Gynecologic Oncology & Reproductive Medicine, †Pathology/Laboratory Medicine, ‡Biostatistics, and §Hematopathology, The University of Texas M. D. Anderson Cancer Center, Houston, TX.
authors.forename: Larissa A
authors.initials: LA
authors.lastname: Meyer
authors.forename: Brian M
authors.initials: BM
authors.lastname: Slomovitz
authors.forename: Bojana
authors.initials: B
authors.lastname: Djordjevic
authors.forename: Shannon N
authors.initials: SN
authors.lastname: Westin
authors.forename: David A
authors.initials: DA
authors.lastname: Iglesias
authors.forename: Mark F
authors.initials: MF
authors.lastname: Munsell
authors.forename: Yunyun
authors.initials: Y
authors.lastname: Jiang
authors.forename: Rosemarie
authors.initials: R
authors.lastname: Schmandt
authors.forename: Russell R
authors.initials: RR
authors.lastname: Broaddus
authors.forename: Robert L
authors.initials: RL
authors.lastname: Coleman
authors.forename: John M
authors.initials: JM
authors.lastname: Galbincea
authors.forename: Karen H
authors.initials: KH
authors.lastname: Lu
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D016889:Endometrial Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D000068338:Everolimus; D005260:Female; D006801:Humans; D007124:Immunoenzyme Techniques; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D009154:Mutation / Q000235:genetics; D060787:Neoplasm Grading; D051059:PTEN Phosphohydrolase / Q000378:metabolism*; D016133:Polymerase Chain Reaction; D011379:Prognosis; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D016283:Proto-Oncogene Proteins p21(ras); D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism*; D020123:Sirolimus / Q000031:analogs & derivatives* / Q000627:therapeutic use; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D018631:ras Proteins / Q000235:genetics*
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D007166:Immunosuppressive Agents; C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; D000068338:Everolimus; C546842:MTOR protein, human; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D058570:TOR Serine-Threonine Kinases; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins; D020123:Sirolimus