Evaluation of Emergent Mutations in Circulating Cell-Free DNA and Clinical Outcomes in Patients with Metastatic Colorectal Cancer Treated with Panitumumab in the ASPECCT Study.

Abstract

Mutations in <i>EGFR</i> pathway genes are poor prognostic indicators in patients with metastatic colorectal cancer. Plasma analysis of cell-free DNA is a minimally invasive and highly sensitive method to detect somatic mutations in tumors. Plasma samples collected from panitumumab-treated patients in the ASPECCT study at baseline and safety follow-up (SFU) were analyzed by a next-generation sequencing-based approach for extended <i>RAS</i> mutant allele frequency as a continuous variable and their association with clinical outcomes and the mutational prevalence of 63 cancer-related genes. The correlation between patient outcome and baseline mutational status of <i>EGFR</i> pathway genes was also examined. Overall, 261 patients in the panitumumab arm had evaluable plasma samples. Patients with a higher <i>RAS</i> mutant allele frequency at baseline had worse clinical outcomes than those with a lower frequency (<i>P</i> < 0.001, Cox PH model); however, <i>RAS</i> mutations did not necessarily preclude patients from deriving benefits. The objective response rate (complete or partial response) was 10.8% for patients with baseline <i>RAS</i> mutations and 21.7% for those with <i>BRAF</i> mutations. The 63-gene panel analysis revealed an increase in tumor mutational burden from baseline to SFU (<i>P</i> < 0.001, Wilcoxon signed rank test). Baseline mutations in <i>EGFR</i> pathway genes, when analyzed both categorically and continuously, were associated with shorter survival. When mutations in <i>EGFR</i> pathway genes were analyzed continuously, higher mutant allele frequency correlated with poorer outcomes. However, extended <i>RAS</i> mutation, by itself, did not preclude clinical responses to panitumumab in a monotherapy setting.