Analysis of Circulating Tumor DNA Superior to Tumor Tissue for Detection of Actionable Mutations in Metastatic Colorectal Cancer

Mutation testing including RAS and BRAF mutations in metastatic colorectal cancer (mCRC) is mandatory for appropriate treatment selection. Currently mutation analysis is performed using tumor-tissue. However, data on the clinical utility of liquid biopsies (circulating tumor DNA; ctDNA) for mutation analysis are emerging.

According to a French multicenter, prospective, blinded study comparing ctDNA analysis to tumor tissue analysis in 140 patients with mCRC, ctDNA analysis was a faster and more sensitive method for detection of molecular alterations such as RAS and BRAF mutations. Using ctDNA analysis, the median turnaround time was reduced from 16 days to 2 days. Compared to tumor tissue analysis, ctDNA analysis was more sensitive and led to detection of a greater number of patients with KRAS (59% vs 44%), NRAS (11.8% vs 7.2%), and BRAF (14.4% vs 7.2%) mutations. The rates of concordance between ctDNA and tumor-tissue analysis were 72%, 74%, and 87% for KRAS exon 2, KRAS exon 3/4, and BRAFV600E respectively.

In addition, ctDNA analysis  detected a greater number of tumors with more than one mutation. Single RAS mutations were found in 45% of patients using tumor-tissue analysis, but only in 29% of patients using ctDNA analysis. Instead, 45% of ctDNA samples contained multiple mutations, compared with only 2% of tumor-tissue samples. KRAS and NRAS were the most common mutation combination.

In a post hoc analysis, the authors investigated potential factors that may have contributed to the discordance between results with ctDNA analysis versus tumor tissue analysis. They found that use of biopsy, absence of primary tumor in place at the time of blood draw, a long delay between tumor-tissue and blood collection, tumor site, or type of tissue analyzed seem to affect concordance.