title: Pretreatment EGFR T790M mutation and BRCA1 mRNA expression in erlotinib-treated advanced non-small-cell lung cancer patients with EGFR mutations.
abstract: OBJECTIVE
  Advanced non-small-cell lung cancer (NSCLC) patients harboring epidermal growth factor receptor (EGFR) mutations (deletion in exon 19 or L858R) show an impressive progression-free survival of 14 months when treated with erlotinib. However, the presence of EGFR mutations can only imperfectly predict outcome. We hypothesized that progression-free survival could be influenced both by the pretreatment EGFR T790M mutation and by components of DNA repair pathways.
  
  
  METHODS
  We assessed the T790M mutation in pretreatment diagnostic specimens from 129 erlotinib-treated advanced NSCLC patients with EGFR mutations. The expression of eight genes and two proteins involved in DNA repair and four receptor tyrosine kinases was also examined.
  
  
  RESULTS
  The EGFR T790M mutation was observed in 45 of 129 patients (35%). Progression-free survival was 12 months in patients with and 18 months in patients without the T790M mutation (P = 0.05). Progression-free survival was 27 months in patients with low BRCA1 mRNA levels, 18 months in those with intermediate levels, and 10 months in those with high levels (P = 0.02). In the multivariate analysis, the presence of the T790M mutation (HR, 4.35; P = 0.001), intermediate BRCA1 levels (HR, 8.19; P < 0.0001), and high BRCA1 levels (HR, 8.46; P < 0.0001) emerged as markers of shorter progression-free survival.
  
  
  CONCLUSIONS
  Low BRCA1 levels neutralized the negative effect of the T790M mutation and were associated with longer progression-free survival to erlotinib. We advocate baseline assessment of the T790M mutation and BRCA1 expression to predict outcome and provide alternative individualized treatment to patients based on T790M mutations and BRCA1 expression.
authors.affiliation: Catalan Institute of Oncology, Hospital Germans Trias i Pujol, Badalona, Spain. rrosell@iconcologia.net
authors.forename: Rafael
authors.initials: R
authors.lastname: Rosell
authors.forename: Miguel Angel
authors.initials: MA
authors.lastname: Molina
authors.forename: Carlota
authors.initials: C
authors.lastname: Costa
authors.forename: Sara
authors.initials: S
authors.lastname: Simonetti
authors.forename: Ana
authors.initials: A
authors.lastname: Gimenez-Capitan
authors.forename: Jordi
authors.initials: J
authors.lastname: Bertran-Alamillo
authors.forename: Clara
authors.initials: C
authors.lastname: Mayo
authors.forename: Teresa
authors.initials: T
authors.lastname: Moran
authors.forename: Pedro
authors.initials: P
authors.lastname: Mendez
authors.forename: Felipe
authors.initials: F
authors.lastname: Cardenal
authors.forename: Dolores
authors.initials: D
authors.lastname: Isla
authors.forename: Mariano
authors.initials: M
authors.lastname: Provencio
authors.forename: Manuel
authors.initials: M
authors.lastname: Cobo
authors.forename: Amelia
authors.initials: A
authors.lastname: Insa
authors.forename: Rosario
authors.initials: R
authors.lastname: Garcia-Campelo
authors.forename: Noemi
authors.initials: N
authors.lastname: Reguart
authors.forename: Margarita
authors.initials: M
authors.lastname: Majem
authors.forename: Santiago
authors.initials: S
authors.lastname: Viteri
authors.forename: Enric
authors.initials: E
authors.lastname: Carcereny
authors.forename: Ruth
authors.initials: R
authors.lastname: Porta
authors.forename: Bartomeu
authors.initials: B
authors.lastname: Massuti
authors.forename: Cristina
authors.initials: C
authors.lastname: Queralt
authors.forename: Itziar
authors.initials: I
authors.lastname: de Aguirre
authors.forename: Jose Miguel
authors.initials: JM
authors.lastname: Sanchez
authors.forename: Maria
authors.initials: M
authors.lastname: Sanchez-Ronco
authors.forename: Jose Luis
authors.initials: JL
authors.lastname: Mate
authors.forename: Aurelio
authors.initials: A
authors.lastname: Ariza
authors.forename: Susana
authors.initials: S
authors.lastname: Benlloch
authors.forename: Jose Javier
authors.initials: JJ
authors.lastname: Sanchez
authors.forename: Trever G
authors.initials: TG
authors.lastname: Bivona
authors.forename: Charles L
authors.initials: CL
authors.lastname: Sawyers
authors.forename: Miquel
authors.initials: M
authors.lastname: Taron
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000627:therapeutic use; D019313:BRCA1 Protein / Q000235:genetics*; D014408:Biomarkers, Tumor; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000235:genetics*; D004260:DNA Repair / Q000235:genetics; D018572:Disease-Free Survival; D066246:ErbB Receptors / Q000235:genetics*; D000069347:Erlotinib Hydrochloride; D005260:Female; D015870:Gene Expression; D019398:Genes, BRCA1; D018773:Genes, erbB-1; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use; D011799:Quinazolines / Q000627:therapeutic use*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D014408:Biomarkers, Tumor; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D012333:RNA, Messenger; D000069347:Erlotinib Hydrochloride; D066246:ErbB Receptors; D020794:Receptor Protein-Tyrosine Kinases