title: PI3K/AKT/mTOR inhibitors in patients with breast and gynecologic malignancies harboring PIK3CA mutations.
abstract: OBJECTIVE
  Mutations of the PIK3CA gene may predict response to phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) inhibitors. Concomitant mutations in the mitogen-activated protein kinase (MAPK) pathway may mediate resistance.
  
  
  METHODS
  Tumors from patients with breast, cervical, endometrial, and ovarian cancer referred to the Clinical Center for Targeted Therapy (Phase I Program) were analyzed for PIK3CA, KRAS, NRAS, and BRAF mutations. Patients with PIK3CA mutations were treated, whenever feasible, with agents targeting the PI3K/AKT/mTOR pathway.
  
  
  RESULTS
  Of 140 patients analyzed, 25 (18%) had PIK3CA mutations, including five of 14 patients with squamous cell cervical, seven of 29 patients with endometrial, six of 29 patients with breast, and seven of 60 patients with ovarian cancers. Of the 25 patients with PIK3CA mutations, 23 (median of two prior therapies) were treated on a protocol that included a PI3K/AKT/mTOR pathway inhibitor. Two (9%) of 23 patients had stable disease for more than 6 months, and seven patients (30%) had a partial response. In comparison, only seven (10%) of 70 patients with the same disease types but with wild-type PIK3CA treated on the same protocols responded (P = .04). Seven patients (30%) with PIK3CA mutations had coexisting MAPK pathway (KRAS, NRAS, BRAF) mutations (ovarian cancer, n = 5; endometrial cancer, n = 2), and two of these patients (ovarian cancer) achieved a response.
  
  
  CONCLUSIONS
  PIK3CA mutations were detected in 18% of tested patients. Patients with PIK3CA mutations treated with PI3K/AKT/mTOR inhibitors demonstrated a higher response rate than patients without mutations. A subset of patients with ovarian cancer with simultaneous PIK3CA and MAPK mutations responded to PI3K/AKT/mTOR inhibitors, suggesting that not all patients demonstrate resistance when the MAPK pathway is concomitantly activated.
authors.affiliation: The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Filip
authors.initials: F
authors.lastname: Janku
authors.forename: Jennifer J
authors.initials: JJ
authors.lastname: Wheler
authors.forename: Shannon N
authors.initials: SN
authors.lastname: Westin
authors.forename: Stacy L
authors.initials: SL
authors.lastname: Moulder
authors.forename: Aung
authors.initials: A
authors.lastname: Naing
authors.forename: Apostolia M
authors.initials: AM
authors.lastname: Tsimberidou
authors.forename: Siqing
authors.initials: S
authors.lastname: Fu
authors.forename: Gerald S
authors.initials: GS
authors.lastname: Falchook
authors.forename: David S
authors.initials: DS
authors.lastname: Hong
authors.forename: Ignacio
authors.initials: I
authors.lastname: Garrido-Laguna
authors.forename: Rajyalakshmi
authors.initials: R
authors.lastname: Luthra
authors.forename: J Jack
authors.initials: JJ
authors.lastname: Lee
authors.forename: Karen H
authors.initials: KH
authors.lastname: Lu
authors.forename: Razelle
authors.initials: R
authors.lastname: Kurzrock
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics*; D058534:Class I Phosphatidylinositol 3-Kinases; D016889:Endometrial Neoplasms / Q000188:drug therapy; D005260:Female; D005833:Genital Neoplasms, Female / Q000188:drug therapy* / Q000235:genetics*; D006801:Humans; D008875:Middle Aged; D009154:Mutation; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000235:genetics; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D002583:Uterine Cervical Neoplasms / Q000188:drug therapy / Q000235:genetics
chemical_list: D058534:Class I Phosphatidylinositol 3-Kinases; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; C484760:PIK3CA protein, human; C494918:AKT1 protein, human