title: EGFR molecular profiling in advanced NSCLC: a prospective phase II study in molecularly/clinically selected patients pretreated with chemotherapy.
abstract: BACKGROUND
  The optimal use of epidermal growth factor receptor (EGFR)-related molecular markers to prospectively identify tyrosine kinase inhibitor (TKI)-sensitive patients, particularly after a previous chemotherapy treatment, is currently under debate.
  
  
  METHODS
  We designed a prospective phase II study to evaluate the activity of EGFR-TKI in four different patient groups, according to the combination of molecular (EGFR gene mutations, EGFR gene copy number and protein expression, and phosphorylated AKT expression, pAKT) and clinicopathological (histology and smoking habits) factors. Correlations between molecular alterations and clinical outcome were also explored retrospectively for first-line chemotherapy and EGFR-TKI treatment.
  
  
  RESULTS
  Patients who had progressed during or after first-line chemotherapy were prospectively assigned to EGFR-TKI treatment as follows: (G1) EGFR mutation (n = 12); (G2) highly polysomic/amplified EGFR (n = 18); (G3) EGFR and/or pAKT positive (n = 41); (G4) adenocarcinoma/bronchoalveolar carcinoma and no smoking history (n = 15). G1 and G4 had the best and second-best overall response rate (25% and 20%, respectively), whereas the worst outcome was observed in G2 (ORR, 6%; p = 0.05). Disease control was highest in G1 and G4 (>50%) and lowest in G3 (<20%) (p = 0.02). Patients selected by EGFR mutation or clinical parameters (G1 and G4) also had significantly better progression-free survival and overall survival (p = 0.02 and p = 0.01, respectively). Multivariate analysis confirmed the impact of sex, smoking history, EGFR/KRAS mutation, and pAKT on outcomes and allowed us to derive an efficient predictive model. Histology, EGFR mutations, and pAKT were independent predictors of response to first-line chemotherapy at retrospective analysis, whereas pAKT and human epidermal growth factor receptor 2 expression were the only independent predictors of progression-free survival and overall survival.
  
  
  CONCLUSIONS
  Selection of patients based on either EGFR mutation or clinical characteristics seems an effective approach to optimize EGFR-TKI treatment in chemotherapy-pretreated non-small-cell lung cancer patients.
authors.affiliation: Department of Medical Oncology, Regina Elena National Cancer Institute, Rome, Italy. michelemilella@hotmail.com
authors.forename: Michele
authors.initials: M
authors.lastname: Milella
authors.forename: Carmen
authors.initials: C
authors.lastname: Nuzzo
authors.forename: Emilio
authors.initials: E
authors.lastname: Bria
authors.forename: Isabella
authors.initials: I
authors.lastname: Sperduti
authors.forename: Paolo
authors.initials: P
authors.lastname: Visca
authors.forename: Fiamma
authors.initials: F
authors.lastname: Buttitta
authors.forename: Barbara
authors.initials: B
authors.lastname: Antoniani
authors.forename: Roberta
authors.initials: R
authors.lastname: Merola
authors.forename: Alain
authors.initials: A
authors.lastname: Gelibter
authors.forename: Federica
authors.initials: F
authors.lastname: Cuppone
authors.forename: Valerio
authors.initials: V
authors.lastname: D'Alicandro
authors.forename: Anna
authors.initials: A
authors.lastname: Ceribelli
authors.forename: Massimo
authors.initials: M
authors.lastname: Rinaldi
authors.forename: Anna
authors.initials: A
authors.lastname: Cianciulli
authors.forename: Lara
authors.initials: L
authors.lastname: Felicioni
authors.forename: Sara
authors.initials: S
authors.lastname: Malatesta
authors.forename: Antonio
authors.initials: A
authors.lastname: Marchetti
authors.forename: Marcella
authors.initials: M
authors.lastname: Mottolese
authors.forename: Francesco
authors.initials: F
authors.lastname: Cognetti
mesh_terms: D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality; D018572:Disease-Free Survival; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000235:genetics*; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality; D008297:Male; D015999:Multivariate Analysis; D009154:Mutation; D011446:Prospective Studies; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use; D011518:Proto-Oncogene Proteins / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins / Q000235:genetics
chemical_list: C117307:KRAS protein, human; D047428:Protein Kinase Inhibitors; D011518:Proto-Oncogene Proteins; D066246:ErbB Receptors; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins