Diagnostic strategies towards clinical implementation of liquid biopsy RAS/BRAF circulating tumor DNA analyses in patients with metastatic colorectal cancer

Colorectal Cancer

J Mol Diagn. 2020 Sep 19:S1525-1578(20)30462-1. doi: 10.1016/j.jmoldx.2020.09.002. Online ahead of print.


Detection of KRAS, NRAS and BRAF mutations in tumor tissue is currently used to predict resistance to treatment with anti-EGFR antibodies of patients with metastatic colorectal cancer (mCRC). Liquid biopsies are minimally invasive and cell-free circulating tumor DNA (ctDNA) mutation analyses may better represent tumor heterogeneity. This study examined the incorporation of liquid biopsy RAS/BRAF ctDNA analyses into diagnostic strategies to determine mCRC patient eligibility for anti-EGFR

therapy. Tumor tissue and liquid biopsies were collected from 100 mCRC patients with liver-only metastases who participated in a multi-center prospective clinical trial. We compared three diagnostic strategies incorporating droplet digital PCR ctDNA analyses to routine tumor tissue RAS/BRAF mutation profiling using decision tree analyses. Tissue DNA mutations in KRAS, NRAS and BRAF were present in 54%, 0% and 3% of mCRC patients, respectively. A 93% concordance was observed between tissue DNA and liquid biopsy ctDNA mutations. The proportion of patients with RAS/BRAF alterations increased from 57% to 60% for diagnostic strategies that combined tissue and liquid biopsy mutation analyses. Consecutive RAS/BRAF ctDNA analysis followed by tissue DNA analysis in case of a liquid biopsy-negative result appeared to be the most optimal diagnostic strategy to comprehensively determine eligibility for anti-EGFR therapy in a cost-saving manner. These results highlight the potential clinical utility of liquid biopsies for detecting primary resistance to anti-EGFR targeted therapies.