title: Clinical usefulness of PI3K/Akt/mTOR genotyping in companion with other clinical variables in metastatic renal cell carcinoma patients treated with everolimus in the second and subsequent lines.
abstract: BACKGROUND
  The aim of this study was to search for predictive and prognostic factors in patients with metastatic renal cell carcinoma (mRCC) treated with everolimus among the components of PI3K/AKT/mTOR pathway.
  
  
  METHODS
  In a prospective, one-arm, phase II study, patients with mRCC received everolimus (10 mg/day) using a 30-day cycle. A prospectively planned evaluation of potential biomarkers of PI3K/AKT/mTOR pathway.
  
  
  RESULTS
  The median age of the 58 patients enrolled into the study was 60 years (range 41-78 years). In multivariate analysis, it was found that the adverse independent predictors for everolimus therapy were histological grade G1/2 {hazard ratio (HR): 2.68 [95% confidence interval (CI) 1.29-5.58, P = 0.0082]}, increased lactate dehydrogenase (LDH) level before treatment [HR: 2.55 (95% CI 1.30-4.99, P = 0.0064)] and the PIK3CA gene variant rs6443624 (HR: AC + AA versus CC = 2.08, 95% CI 1 11-3.89, P = 0.0254). In multivariate analysis, it was observed that the adverse independent prognostic factors were: elevated corrected calcium level [HR: 4.17 (95% CI 1.66-10.51; P = 0.0024)] and the PIK3CA gene variant rs6443624 [HR: AC + AA versus CC = 1.97 (95% CI 1.02-3.79; P = 0.0421)].
  
  
  CONCLUSIONS
  The PI3KCA gene polymorphism, LDH, and histologic grade can predict the effects of everolimus treatment. The corrected calcium level and the PIK3CA gene variant rs6443624 may be independent prognostic factors. Further investigation is needed to confirm and validate these findings prospectively in other RCC trials.
authors.affiliation: Department of Oncology, Military Institute of Medicine, Warsaw, Poland lubo@esculap.pl.
authors.forename: L
authors.initials: L
authors.lastname: Bodnar
authors.affiliation: Department of Oncology, Military Institute of Medicine, Warsaw, Poland.
authors.forename: R
authors.initials: R
authors.lastname: Stec
authors.affiliation: Department of Pathology, Military Institute of Medicine, Warsaw, Poland.
authors.forename: S
authors.initials: S
authors.lastname: Cierniak
authors.affiliation: Department of Oncology, Military Institute of Medicine, Warsaw, Poland.
authors.forename: A
authors.initials: A
authors.lastname: Synowiec
authors.affiliation: Department of Oncology, Military Institute of Medicine, Warsaw, Poland.
authors.forename: G
authors.initials: G
authors.lastname: Wcisło
authors.affiliation: Department of Pathology, Military Institute of Medicine, Warsaw, Poland.
authors.forename: M
authors.initials: M
authors.lastname: Jesiotr
authors.affiliation: Department of Pathology, Military Institute of Medicine, Warsaw, Poland.
authors.forename: R
authors.initials: R
authors.lastname: Koktysz
authors.affiliation: Department of Pathology, Military Institute of Medicine, Warsaw, Poland.
authors.forename: W
authors.initials: W
authors.lastname: Kozłowski
authors.affiliation: Department of Oncology, Military Institute of Medicine, Warsaw, Poland.
authors.forename: C
authors.initials: C
authors.lastname: Szczylik
mesh_terms: D000328:Adult; D000368:Aged; D002291:Carcinoma, Papillary / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality / Q000556:secondary; D002292:Carcinoma, Renal Cell / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality / Q000556:secondary; D058534:Class I Phosphatidylinositol 3-Kinases; D000068338:Everolimus / Q000627:therapeutic use*; D005260:Female; D005500:Follow-Up Studies; D005838:Genotype; D006801:Humans; D007680:Kidney Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D060787:Neoplasm Grading; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D016133:Polymerase Chain Reaction; D011379:Prognosis; D011446:Prospective Studies; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use; D015996:Survival Rate; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics*
chemical_list: D058534:Class I Phosphatidylinositol 3-Kinases; D000068338:Everolimus; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D058570:TOR Serine-Threonine Kinases; C546842:MTOR protein, human; C484760:PIK3CA protein, human
keywords: AKT; PI3KCA; everolimus; mTOR; renal cell carcinoma