Circulating free DNA as biomarker and source for mutation detection in metastatic colorectal cancer

PLoS One. 2015 Apr 13;10(4):e0108247. doi: 10.1371/journal.pone.0108247. eCollection 2015.

Abstract

Background: Circulating cell-free DNA (cfDNA) in plasma has shown potential as biomarker in various cancers and could become an importance source for tumour mutation detection. The objectives of our study were to establish a normal range of cfDNA in a cohort of healthy individuals and to compare this with four cohorts of metastatic colorectal cancer (mCRC) patients. We also investigated the prognostic value of cfDNA and analysed the tumour-specific KRAS mutations in the plasma.

Methods: The study was a prospective biomarker evaluation in four consecutive Phase II trials, including 229 patients with chemotherapy refractory mCRC and 100 healthy individuals. Plasma was obtained from an EDTA blood-sample, and the total number of DNA alleles and KRAS mutated alleles were assessed using an in-house ARMS-qPCR as previously described.

Results: Median cfDNA levels were higher in mCRC compared to controls (p < 0.0001). ROC analysis revealed an AUC of 0.9486 (p<0.00001). Data showed impaired OS with increasing levels of baseline cfDNA both when categorising patients by quartiles of cfDNA and into low or high cfDNA groups based on the upper normal range of the control group (Median OS 10.2 (8.3-11.7) and 5.2 (4.6-5.9) months, respectively, HR 1.78, p = 0.0006). Multivariate analysis confirmed an independent prognostic value of cfDNA (HR 1.5 (95% CI 1.3-1.7) for each increase in the cfDNA quartile). The overall concordance of KRAS mutations in plasma and tissue was high (85%).

Conclusions: These data confirm the prognostic value of cfDNA measurement in plasma and utility for mutation detection with the method presented.

Publication types

  • Clinical Trial, Phase II
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use
  • Biomarkers, Tumor / blood
  • Biomarkers, Tumor / genetics
  • Colon / drug effects
  • Colon / pathology
  • Colorectal Neoplasms / blood
  • Colorectal Neoplasms / drug therapy
  • Colorectal Neoplasms / genetics*
  • Colorectal Neoplasms / pathology*
  • DNA / blood*
  • DNA / genetics*
  • Female
  • Humans
  • Male
  • Middle Aged
  • Mutation*
  • Neoplasm Metastasis / drug therapy
  • Neoplasm Metastasis / genetics*
  • Neoplasm Metastasis / pathology
  • Prognosis
  • Prospective Studies
  • Proto-Oncogene Proteins p21(ras) / genetics
  • Rectum / drug effects
  • Rectum / pathology

Substances

  • Biomarkers, Tumor
  • KRAS protein, human
  • DNA
  • Proto-Oncogene Proteins p21(ras)

Grant support

This study was funded by the Research Counsil Vejle Hospital and Tryg fonden. The funders had no role in study design, data Collection and analysis, desicion to publish, or preparation of the manuscript.