title: Biomarker analysis in a phase III study of pemetrexed-carboplatin versus etoposide-carboplatin in chemonaive patients with extensive-stage small-cell lung cancer.
abstract: BACKGROUND
  Clinical results of a randomized phase III trial comparing pemetrexed-carboplatin (PC) with etoposide-carboplatin (EC) in chemonaive patients with extensive-stage disease small-cell lung cancer (ED-SCLC) resulted in trial closure for futility; biomarker analyses using immunohistochemistry (IHC) and single-nucleotide polymorphisms (SNPs) are described herein.
  
  
  METHODS
  Thymidylate synthase (TS), excision repair cross complementing-1 (ERCC1), glycinamide ribonucleotide formyltransferase (GARFT), and folylpolyglutamate synthetase (FPGS) were investigated using IHC (n=395). SNPs were genotyped for TS, FPGS, γ-glutamyl hydrolase (GGH), methylenetetrahydrofolate reductase (MTHFR), folate receptor-α FR-α, and solute carrier 19A1 (SLC19A1; n=611).
  
  
  RESULTS
  None of the IHC biomarkers (folate pathway or ERCC1) were found to be predictive or prognostic in this setting. rs2838952 (adjacent to SLC19A1) had significant treatment-independent association with overall survival (OS; hazard ratio 0.590, P=0.01). Nine GGH-associated SNPs interacted with rs3788205 (SLC19A1) for OS on the PC arm. rs12379987 (FPGS) interacted with treatment for OS (interaction P=0.036).
  
  
  CONCLUSIONS
  Potential ERCC1 and folate pathway IHC biomarkers failed to predict outcome in either study arm in ED-SCLC. SNPs in regions including FPGS and SLC19A1 and interacting SNPs in GGH and SLC19A1 were associated with differences in OS; however, none of these SNPs predicted for greater survival with PC over EC.
authors.affiliation: Department of Pulmonary Diseases, Vrije University Medical Center, Amsterdam, The Netherlands. ef.smit@vumc.nl
authors.forename: E F
authors.initials: EF
authors.lastname: Smit
authors.forename: M A
authors.initials: MA
authors.lastname: Socinski
authors.forename: B P
authors.initials: BP
authors.lastname: Mullaney
authors.forename: S P
authors.initials: SP
authors.lastname: Myrand
authors.forename: G V
authors.initials: GV
authors.lastname: Scagliotti
authors.forename: P
authors.initials: P
authors.lastname: Lorigan
authors.forename: M
authors.initials: M
authors.lastname: Reck
authors.forename: T
authors.initials: T
authors.lastname: Ciuleanu
authors.forename: J
authors.initials: J
authors.lastname: von Pawel
authors.forename: N A
authors.initials: NA
authors.lastname: Karaseva
authors.forename: A
authors.initials: A
authors.lastname: Szczesna
authors.forename: D
authors.initials: D
authors.lastname: Ohannesian
authors.forename: E
authors.initials: E
authors.lastname: Powell
authors.forename: R R
authors.initials: RR
authors.lastname: Hozak
authors.forename: S
authors.initials: S
authors.lastname: Hong
authors.forename: S C
authors.initials: SC
authors.lastname: Guba
authors.forename: N
authors.initials: N
authors.lastname: Thatcher
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D016190:Carboplatin / Q000008:administration & dosage; D017326:Clinical Trials, Phase III as Topic; D043170:Collagen Type XVIII / Q000235:genetics; D004268:DNA-Binding Proteins / Q000378:metabolism; D018572:Disease-Free Survival; D004720:Endonucleases / Q000378:metabolism; D005047:Etoposide / Q000008:administration & dosage; D005971:Glutamates / Q000008:administration & dosage; D006147:Guanine / Q000008:administration & dosage / Q000031:analogs & derivatives; D006801:Humans; D053208:Kaplan-Meier Estimate; D016015:Logistic Models; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000401:mortality; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000235:genetics; D000068437:Pemetrexed; D010453:Peptide Synthases / Q000235:genetics / Q000378:metabolism; D051026:Phosphoribosylglycinamide Formyltransferase / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D016032:Randomized Controlled Trials as Topic; D058978:Reduced Folate Carrier Protein / Q000235:genetics; D055752:Small Cell Lung Carcinoma / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000401:mortality; D013940:Thymidylate Synthase / Q000378:metabolism
chemical_list: D014408:Biomarkers, Tumor; D043170:Collagen Type XVIII; D004268:DNA-Binding Proteins; D005971:Glutamates; D058978:Reduced Folate Carrier Protein; C548699:SLC19A1 protein, human; D000068437:Pemetrexed; D006147:Guanine; D005047:Etoposide; D016190:Carboplatin; C573423:MTHFR protein, human; D042965:Methylenetetrahydrofolate Reductase (NADPH2); D013940:Thymidylate Synthase; D051026:Phosphoribosylglycinamide Formyltransferase; C071447:ERCC1 protein, human; D004720:Endonucleases; D010453:Peptide Synthases; C023103:folylpolyglutamate synthetase