RAS/BRAF Circulating Tumor DNA Mutations as a Predictor of Response to First-Line Chemotherapy in Metastatic Colorectal Cancer Patients

Can J Gastroenterol Hepatol. 2018 Mar 7;2018:4248971. doi: 10.1155/2018/4248971. eCollection 2018.

Abstract

Background: Since circulating tumor DNA (ctDNA) offers clear advantages as a minimally invasive method for tumor monitoring compared with tumor tissue, we aimed to evaluate genotyping ctDNA using a next-generation sequencing- (NGS-) based panel to identify the prognostic value of mutation status in metastatic colorectal cancer (mCRC) patients with primary tumor resected and with subsequent lines of treatment in this study.

Methods: 76 mCRC patients treated in Beijing Chao-Yang Hospital from 2011 to 2017 were enrolled. Genotyping of RAS/BRAF in tumor tissue and ctDNA was determined by ARMS PCR and with a 40-gene panel using NGS, respectively. Patient clinicopathologic features and RAS/BRAF gene mutation status were evaluated by survival analysis for disease-free survival (DFS) and progression-free survival (PFS).

Results: Among 76 patients, KRAS distributions were not significantly correlated with any clinicopathologic features. The concordance between tumor tissue and ctDNA KRAS mutation was 81.25%. Mutations of RAS/BRAF had no significant impact on DFS after surgery (hazard ratio (HR), 1.205; 95% CI, 0.618 to 2.349; P = 0.5837) but prognosticated poorer PFS in subsequent first-line therapy (HR, 3.351; 95% CI, 1.172 to 9.576; P = 0.024).

Conclusion: ctDNA was comparable with tumor tissue for mutation detection. RAS/BRAF mutations detected in ctDNA predict a worse PFS in mCRC patients with first-line chemotherapy. Our results provide support for the prognostic value of RAS/BRAF ctDNA mutation detection in mCRC patients.

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
  • Biomarkers, Tumor / blood
  • Biomarkers, Tumor / genetics
  • China
  • Circulating Tumor DNA / genetics*
  • Cohort Studies
  • Colorectal Neoplasms / drug therapy*
  • Colorectal Neoplasms / genetics*
  • Colorectal Neoplasms / mortality
  • Colorectal Neoplasms / pathology
  • Disease-Free Survival
  • Female
  • Humans
  • Kaplan-Meier Estimate
  • Male
  • Middle Aged
  • Molecular Targeted Therapy / methods
  • Mutation
  • Neoplasm Invasiveness / pathology
  • Neoplasm Metastasis
  • Neoplasm Staging
  • Polymerase Chain Reaction / methods
  • Prognosis
  • Proto-Oncogene Proteins B-raf / genetics*
  • Proto-Oncogene Proteins p21(ras) / genetics*
  • Retrospective Studies
  • Risk Assessment
  • Statistics, Nonparametric
  • Survival Analysis
  • Treatment Outcome

Substances

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