RAS and BRAF mutations in cell‐free DNA are predictive for outcome of cetuximab monotherapy in patients with tissue‐tested RAS wild‐type advanced colorectal cancer

摘要

In metastatic colorectal cancer, RAS and BRAF mutations cause resistance toanti-EGFR therapies, such as cetuximab. Heterogeneity in RAS and BRAFmutations might explain nonresponse in a subset of patients receiving cetuximab.Analyzing mutations in plasma-derived circulating tumor DNA (ctDNA)could provide a more comprehensive overview of the mutational landscape ascompared to analyses of primary and/or metastatic tumor tissue. Therefore,this prospective multicenter study followed 34 patients with metastatic colorectalcancer who were tissue-tested as RAS wild-type (exons 2–4) during routinework-up and received third-line cetuximab monotherapy. BRAF mutation statuswas also tested but did not exclude patients from therapy. At baseline andupon disease progression, cell-free DNA (cfDNA) was isolated for targetednext-generation sequencing (NGS). At 8 weeks, we determined that patientshad benefited from treatment. NGS of cfDNA identified three patients withRAS mutations not detected in tumor tissue during routine work-up. Anothersix patients had a BRAF or rare RAS mutation in ctDNA and/or tumor tissue.Relative to patients without mutations in RAS/BRAF, patients with mutationsat baseline had shorter progression-free survival [1.8 versus 4.9 months(P 0.001)] and overall survival [3.1 versus 9.4 months (P = 0.001)]. Inpatients with clinical benefit (progressive disease after 8 weeks), ctDNA testingrevealed previously undetected mutations in RAS/BRAF (71%) and EGFR(47%), which often emerged polyclonally. Our results indicate that baselineNGS of ctDNA can identify additional RAS mutation carriers, which couldimprove patient selection for anti-EGFR therapies. Acquired resistance, inpatients with initial treatment benefit, is mainly explained by polyclonal emergenceof RAS, BRAF, and EGFR mutations in ctDNA.