Liquid biopsy is a promising method of monitoring response to treatment, but prospective comparisons of the performance of this approach with single-lesion tissue biopsy in large patient cohorts are needed. Now, such a comparison in patients with gastrointestinal tumours indicates that liquid biopsy might be a more effective tool to monitor acquired resistance to targeted therapy.

Credit: Simon Bradbrook/Springer Nature Limited

A total of 42 patients with gastrointestinal tumours (of seven molecular subtypes across colorectal, gastroesophageal or biliary tract cancer) with stable disease or a partial response to targeted therapies were involved in this prospective study. Post-progression cell-free DNA (cfDNA) was obtained from peripheral blood samples from all patients. At least one alteration previously validated as being related to resistance was identified in 32 of 42 patients (76%), 17 of whom (40% of all patients) had >1 resistance alteration, with a median of 3 alterations per patient. “These data suggest that the emergence of multiple resistance mechanisms is more common than previously thought and might be the rule rather than the exception”, explains co-lead author Gad Getz.

“Liquid biopsy enabled the identification of clinically relevant resistance alterations not detected in the matched tumour biopsy samples in a large proportion of patients, suggesting key advantages over standard tissue biopsy in the setting of acquired resistance”, highlights co-lead author Ryan Corcoran. When matched post-progression samples were available, resistance alterations were identified in tissue samples in 11 of 23 patients (48%) and in cfDNA in 20 (87%). In contrast with the results of cfDNA analysis, multiple resistance alterations were identified in tissue samples in only 2 of 23 patients (9%). Only one resistance alteration (an EGFR mutation) was identified in tissue samples but not in the matched cfDNA sample by clinical next-generation sequencing. The alteration was subsequently detected with high-sensitivity droplet digital PCR in the cfDNA sample.

Phylogenetic analysis of pretreatment and post-progression cfDNA, and post-progression and autopsy-derived tissue samples from five patients revealed a high degree of intrapatient heterogeneity in the acquisition of resistance mutations. “Liquid biopsies capture the clonal complexity of most of the lesions in the body and can facilitate detection of multiple resistance mechanisms,” summarizes Getz.

… the emergence of multiple resistance mechanisms … might be the rule rather than the exception

“In the setting of targeted therapies, liquid biopsies should be incorporated more regularly into clinical practice”, concludes Corcoran, adding “the optimal use of liquid biopsies to guide therapy decisions warrants further study.” Studies addressing the biological processes underlying the release of cfDNA and other molecules from tumour cells into circulation will also enable the optimal use of liquid biopsies.