title: KRAS-mutated plasma DNA as predictor of outcome from irinotecan monotherapy in metastatic colorectal cancer.
abstract: BACKGROUND
  We investigated the clinical implications of KRAS and BRAF mutations detected in both archival tumor tissue and plasma cell-free DNA in metastatic colorectal cancer patients treated with irinotecan monotherapy.
  
  
  METHODS
  Two hundred and eleven patients receiving second-line irinotecan (350 mg m(-2) q3w) were included in two independent cohorts. Plasma was obtained from pretreatment EDTA blood-samples. Mutations were detected in archival tumour and plasma with qPCR methods.
  
  
  RESULTS
  Mutation status in tumor did not correlate to efficacy in either cohort, whereas none of the patients with mutations detectable in plasma responded to therapy. Response rate and disease control rate in plasma KRAS wt patients were 19 and 66% compared with 0 and 37%, in patients with pKRAS mutations, (P=0.04 and 0.01). Tumor KRAS status was not associated with PFS but with OS in the validation cohort. Plasma BRAF and KRAS demonstrated a strong influence on both PFS and OS. The median OS was 13.0 mo in pKRAS wt patients and 7.8 in pKRAS-mutated, (HR=2.26, P<0.0001). PFS was 4.6 and 2.7 mo, respectively (HR=1,69, P=0.01). Multivariate analysis confirmed the independent prognostic value of pKRAS status but not KRAS tumor status.
  
  
  CONCLUSIONS
  Tumor KRAS has minor clinical impact, whereas plasma KRAS status seems to hold important predictive and prognostic information.
authors.affiliation: 1] Department of Oncology, Vejle Hospital, Vejle, Denmark [2] Danish Colorectal Cancer Group South, Vejle Hospital, Kabbeltoft 25, 7100, Vejle, Denmark.
authors.forename: K G
authors.initials: KG
authors.lastname: Spindler
authors.forename: A L
authors.initials: AL
authors.lastname: Appelt
authors.forename: N
authors.initials: N
authors.lastname: Pallisgaard
authors.forename: R F
authors.initials: RF
authors.lastname: Andersen
authors.forename: A
authors.initials: A
authors.lastname: Jakobsen
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000972:Antineoplastic Agents, Phytogenic / Q000627:therapeutic use*; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000627:therapeutic use; D015331:Cohort Studies; D015179:Colorectal Neoplasms / Q000097:blood* / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D004273:DNA, Neoplasm / Q000097:blood* / Q000235:genetics; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D000077146:Irinotecan; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009362:Neoplasm Metastasis; D011379:Prognosis; D011446:Prospective Studies; D011518:Proto-Oncogene Proteins / Q000097:blood* / Q000235:genetics*; D048493:Proto-Oncogene Proteins B-raf / Q000097:blood / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras); D012189:Retrospective Studies; D016896:Treatment Outcome; D018631:ras Proteins / Q000097:blood* / Q000235:genetics*
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D004273:DNA, Neoplasm; C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; D000077146:Irinotecan; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins; D002166:Camptothecin