Data from Circulating DNA Demonstrates Convergent Evolution and Common Resistance Mechanisms during Treatment of Colorectal Cancer

Abstract

<div>Abstract<p><b>Purpose:</b> Liquid biopsies allow the tracking of clonal dynamics and detection of mutations during treatment.</p><p><b>Experimental Design:</b> We evaluated under blinded conditions the ability of cell-free DNA (cfDNA) to detect <i>RAS</i>/<i>BRAF</i> mutations in the plasma of 42 metastatic colorectal cancer patients treated on a phase Ib/II trial of FOLFOX and dasatinib, with or without cetuximab.</p><p><b>Results:</b> Prior to treatment, sequencing of archival tissue detected mutations in 25 of 42 patients (60%), while the cfDNA assay detected mutations in 37 of 42 patients (88%). Our cfDNA assay detected mutations with allele frequencies as low as 0.01%. After exposure to treatment, 41 of 42 patients (98%) had a cfDNA-detected <i>RAS</i>/<i>BRAF</i> mutation. Of 21 patients followed with serial measurements who were <i>RAS/BRAF</i> mutant at baseline, 11 (52%) showed additional point mutation following treatment and 3 (14%) no longer had detectable levels of another mutant allele. Of <i>RAS</i>/<i>BRAF</i> wild-type tumors at baseline, 4 of 5 (80%) showed additional point mutations. cfDNA quantitative measurements from this study closely mirrored changes in CEA and CT scan results, highlighting the importance of obtaining quantitative data beyond the mere presence of a mutation.</p><p><b>Conclusions:</b> Our findings demonstrate the development of new <i>RAS</i>/<i>BRAF</i> mutations in patients regardless of whether they had preexisting mutations in the pathway, demonstrating a convergent evolutionary pattern. <i>Clin Cancer Res; 23(16); 4578–91. ©2017 AACR</i>.</p></div>

Genomic alterations and transcriptional phenotypes in circulating tumor DNA and matched metastatic tumor

“…The copyright holder for this preprint this version posted June 3, 2024. ; https://doi.org/10.1101/2024.06.02.597054 doi: bioRxiv preprint studies, mostly case reports or small cohorts querying single genes, or a panel of genes, suggested high concordance between ctDNA and tumor genomic alterations (13)(14)(15)(16)(17). A recent study used high-depth whole genome sequencing (WGS, median read depth 187X) to find concordant clonally expanded cancer driver alterations in both ctDNA and metastatic tumor, but ctDNA additionally harbored the genomes of multiple tumor subclones (18).…”