title: EGFR mutations detected in plasma are associated with patient outcomes in erlotinib plus docetaxel-treated non-small cell lung cancer.
abstract: OBJECTIVE
  Activating mutations in the epidermal growth factor receptor (EGFR) are associated with enhanced response to EGFR tyrosine kinase inhibitors in non-small cell lung cancer (NSCLC), whereas KRAS mutations translate into poor patient outcomes. We hypothesized that analysis of plasma for EGFR and KRAS mutations from shed tumor DNA would have clinical utility.
  
  
  METHODS
  An allele-specific polymerase chain reaction assay using Scorpion-amplification refractory mutation system (DxS, Ltd) was used to detect mutations in plasma DNA from patients with advanced stage NSCLC treated as second- or third-line therapy on a phase I/II trial of docetaxel plus intercalated erlotinib.
  
  
  RESULTS
  EGFR mutations were detected in 10 of 49 patients (20%). Six (12%) had single activating mutations in EGFR, associated with improved progression-free survival (median, 18.3 months), compared with all other patients (median, 3.9 months; p = 0.008), or those with wild-type EGFR (median, 4.0 months; p = 0.012). Four of 49 patients harbored a de novo T790M resistance mutation (median progression-free survival, 3.9 months). EGFR mutational status was associated with clinical response (45 assessable, p = 0.0001); in the six patients with activating mutations, all achieved complete (33%) or partial (67%) response. All CR patients had E19del detectable in both tumor and plasma. KRAS mutations were detected in two of 49 (4%) patients, both of whom had rapid progressive disease.
  
  
  CONCLUSIONS
  Activating EGFR mutations detected in shed DNA in plasma are significantly associated with favorable outcomes in patients with advanced NSCLC receiving docetaxel plus intercalated erlotinib. The addition of docetaxel in this schedule did not diminish the efficacy of erlotinib against patients with EGFR activating mutations.
authors.affiliation: Division of Hematology and Oncology, University of California, Davis Cancer Center, Sacramento, California 95817, USA. pcmack@ucdavis.edu
authors.forename: Philip C
authors.initials: PC
authors.lastname: Mack
authors.forename: William S
authors.initials: WS
authors.lastname: Holland
authors.forename: Rebekah A
authors.initials: RA
authors.lastname: Burich
authors.forename: Randeep
authors.initials: R
authors.lastname: Sangha
authors.forename: Leslie J
authors.initials: LJ
authors.lastname: Solis
authors.forename: Yueju
authors.initials: Y
authors.lastname: Li
authors.forename: Laurel A
authors.initials: LA
authors.lastname: Beckett
authors.forename: Primo N
authors.initials: PN
authors.lastname: Lara
authors.forename: Angela M
authors.initials: AM
authors.lastname: Davies
authors.forename: David R
authors.initials: DR
authors.lastname: Gandara
mesh_terms: D000230:Adenocarcinoma / Q000097:blood / Q000188:drug therapy / Q000235:genetics; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000235:genetics; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000235:genetics; D002294:Carcinoma, Squamous Cell / Q000097:blood / Q000188:drug therapy / Q000235:genetics; D004273:DNA, Neoplasm / Q000097:blood*; D000077143:Docetaxel; D066246:ErbB Receptors / Q000097:blood / Q000235:genetics*; D000069347:Erlotinib Hydrochloride; D005260:Female; D005838:Genotype; D006801:Humans; D008175:Lung Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D009367:Neoplasm Staging; D016133:Polymerase Chain Reaction; D011379:Prognosis; D011518:Proto-Oncogene Proteins / Q000097:blood / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras); D011799:Quinazolines / Q000008:administration & dosage; D043823:Taxoids / Q000008:administration & dosage; D016896:Treatment Outcome; D018631:ras Proteins / Q000097:blood / Q000235:genetics
chemical_list: D014408:Biomarkers, Tumor; D004273:DNA, Neoplasm; C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; D011799:Quinazolines; D043823:Taxoids; D000077143:Docetaxel; D000069347:Erlotinib Hydrochloride; C512478:EGFR protein, human; D066246:ErbB Receptors; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins