title: Cell-free DNA in healthy individuals, noncancerous disease and strong prognostic value in colorectal cancer.
abstract: The purpose was to investigate total cell-free DNA (cfDNA) in colorectal cancer (CRC) patients during treatment with second-line chemotherapy and in healthy controls and patients with different comorbidities. Patient treated with second-line irinotecan for metastatic CRC (n = 100), a cohort of healthy controls with and without comorbidity (n = 70 and 100, respectively) were included. cfDNA was quantified by an in-house developed quantitative polymerase chain reaction from plasma samples drawn prior to the first cycle of chemotherapy and at time of progression. cfDNA levels were significantly higher in CRC compared to controls, with a clear capability for discriminating between the groups (receiver operation curve analysis; area under the curve 0.82, p < 0.0001). Patients with high levels had a shorter survival from irinotecan compared to those with lover levels. The cohort independent upper normal limit divided patients into high and low risk groups. The progression-free survival (PFS) was 2.1 months [95% confidence interval (CI) 2.0-3.4] and 6.5 (95% CI 4.2-7.2) months [hazard ratio (HR) 2.53; 95% CI 1.57-4.06, p < 0.0001] and overall survival (OS) 7.4 months (95% CI 4.3-8.7) and 13.8 months (95% CI 11.9-18.9; HR 2.52; 95% CI 1.54-4.13, p < 0.0000), respectively. Cox regression multivariate analysis showed a PFS HR of 1.4 (95% CI 1.1-1.7) for each increase in cfDNA quartile, p = 0.03 and 1.6 (1.3-2.0) for OS, p < 0.0001, respectively. A combined marker analysis with plasma KRAS mutations added further prognostic impact, which was consistent when performed on the samples drawn at time of progression. In conclusion, cfDNA measurement holds important clinical information and could become a useful tool for prediction of outcome from chemotherapy in mCRC.
authors.affiliation: Department of Oncology, Vejle Hospital, Vejle, Denmark; Department of Oncology, Aarhus University Hospital, Aarhus, Denmark.
authors.forename: Karen-Lise Garm
authors.initials: KL
authors.lastname: Spindler
authors.forename: Ane L
authors.initials: AL
authors.lastname: Appelt
authors.forename: Niels
authors.initials: N
authors.lastname: Pallisgaard
authors.forename: Rikke F
authors.initials: RF
authors.lastname: Andersen
authors.forename: Ivan
authors.initials: I
authors.lastname: Brandslund
authors.forename: Anders
authors.initials: A
authors.lastname: Jakobsen
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D016022:Case-Control Studies; D015179:Colorectal Neoplasms / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology; D004247:DNA / Q000032:analysis*; D018450:Disease Progression; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D009154:Mutation; D009362:Neoplasm Metastasis; D011379:Prognosis; D016016:Proportional Hazards Models; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D012307:Risk Factors; D018631:ras Proteins / Q000235:genetics
chemical_list: D004247:DNA; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D018631:ras Proteins
keywords: cfDNA; irinotecan; metastatic colorectal cancer; plasma; prognosis