title: Prospective molecular marker analyses of EGFR and KRAS from a randomized, placebo-controlled study of erlotinib maintenance therapy in advanced non-small-cell lung cancer.
abstract: OBJECTIVE
  The phase III, randomized, placebo-controlled Sequential Tarceva in Unresectable NSCLC (SATURN; BO18192) study found that erlotinib maintenance therapy extended progression-free survival (PFS) and overall survival in patients with advanced non-small-cell lung cancer (NSCLC) who had nonprogressive disease following first-line platinum-doublet chemotherapy. This study included prospective analysis of the prognostic and predictive value of several biomarkers.
  
  
  METHODS
  Mandatory diagnostic tumor specimens were collected before initiating first-line chemotherapy and were tested for epidermal growth factor receptor (EGFR) protein expression by using immunohistochemistry (IHC), EGFR gene copy number by using fluorescent in situ hybridization (FISH), and EGFR and KRAS mutations by using DNA sequencing. An EGFR CA simple sequence repeat in intron 1 (CA-SSR1) polymorphism was evaluated in blood.
  
  
  RESULTS
  All 889 randomly assigned patients provided tumor samples. EGFR IHC, EGFR FISH, KRAS mutation, and EGFR CA-SSR1 repeat length status were not predictive for erlotinib efficacy. A profound predictive effect on PFS of erlotinib relative to placebo was observed in the EGFR mutation-positive subgroup (hazard ratio [HR], 0.10; P < .001). Significant PFS benefits were also observed with erlotinib in the wild-type EGFR subgroup (HR, 0.78; P = .0185). KRAS mutation status was a significant negative prognostic factor for PFS.
  
  
  CONCLUSIONS
  This large prospective biomarker study found that patients with activating EGFR mutations derive the greatest PFS benefit from erlotinib maintenance therapy. No other biomarkers were predictive for outcomes with erlotinib, although the study was not powered for clinical outcomes in biomarker subgroups other than EGFR IHC-positive [corrected]. KRAS mutations were prognostic for reduced PFS. The study demonstrated the feasibility of prospective tissue collection for biomarker analyses in NSCLC.
authors.affiliation: Schwarzwald-Baar Klinikum, Academic Teaching Hospital, University of Freiburg, Voehrenbacher Str 23, Villingen-Schwenningen, Germany 78050. wolfram.brugger@sbk-vs.de
authors.forename: Wolfram
authors.initials: W
authors.lastname: Brugger
authors.forename: Nadja
authors.initials: N
authors.lastname: Triller
authors.forename: Maria
authors.initials: M
authors.lastname: Blasinska-Morawiec
authors.forename: Stefan
authors.initials: S
authors.lastname: Curescu
authors.forename: Raimundas
authors.initials: R
authors.lastname: Sakalauskas
authors.forename: Georgy Moiseevich
authors.initials: GM
authors.lastname: Manikhas
authors.forename: Julien
authors.initials: J
authors.lastname: Mazieres
authors.forename: Renaud
authors.initials: R
authors.lastname: Whittom
authors.forename: Carol
authors.initials: C
authors.lastname: Ward
authors.forename: Karen
authors.initials: K
authors.lastname: Mayne
authors.forename: Kerstin
authors.initials: K
authors.lastname: Trunzer
authors.forename: Federico
authors.initials: F
authors.lastname: Cappuzzo
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism*; D004273:DNA, Neoplasm / Q000032:analysis; D018572:Disease-Free Survival; D004334:Drug Administration Schedule; D066246:ErbB Receptors / Q000235:genetics* / Q000378:metabolism; D000069347:Erlotinib Hydrochloride; D005240:Feasibility Studies; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D053208:Kaplan-Meier Estimate; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D016017:Odds Ratio; D011110:Polymorphism, Genetic; D011237:Predictive Value of Tests; D011379:Prognosis; D011446:Prospective Studies; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D016283:Proto-Oncogene Proteins p21(ras); D011799:Quinazolines / Q000008:administration & dosage / Q000627:therapeutic use*; D017422:Sequence Analysis, DNA; D018631:ras Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D004273:DNA, Neoplasm; C117307:KRAS protein, human; D047428:Protein Kinase Inhibitors; D011518:Proto-Oncogene Proteins; D011799:Quinazolines; D000069347:Erlotinib Hydrochloride; D066246:ErbB Receptors; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins