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

• Published in: Clinical cancer research 2019-02, Vol.25 (4), p.1216-1225
• Main Authors: Peeters, Marc, Price, Timothy, Boedigheimer, Michael, Kim, Tae Won, Ruff, Paul, Gibbs, Peter, Thomas, Anne, Demonty, Gaston, Hool, Kristina, Ang, Agnes
• Format: Article
• Language: English
• Subjects: Adult; Biomarkers, Tumor - blood; Cell-Free Nucleic Acids - blood; Colorectal Neoplasms - blood; Colorectal Neoplasms - drug therapy; Colorectal Neoplasms - genetics; Colorectal Neoplasms - pathology; Disease-Free Survival; ErbB Receptors - blood; ErbB Receptors - genetics; Female; Gene Frequency; Genetic Heterogeneity; High-Throughput Nucleotide Sequencing; Humans; Male; Middle Aged; Mutant Proteins - blood; Mutant Proteins - genetics; Mutation; Neoplasm Metastasis; Panitumumab - administration & dosage; Prognosis; Proto-Oncogene Proteins B-raf - genetics; Proto-Oncogene Proteins p21(ras) - genetics; Signal Transduction - drug effects; Treatment Outcome
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-18-2072

Mutations in 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 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 pathway genes was also examined. Overall, 261 patients in the panitumumab arm had evaluable plasma samples. Patients with a higher mutant allele frequency at baseline had worse clinical outcomes than those with a lower frequency ( < 0.001, Cox PH model); however, mutations did not necessarily preclude patients from deriving benefits. The objective response rate (complete or partial response) was 10.8% for patients with baseline mutations and 21.7% for those with mutations. The 63-gene panel analysis revealed an increase in tumor mutational burden from baseline to SFU ( < 0.001, Wilcoxon signed rank test). Baseline mutations in pathway genes, when analyzed both categorically and continuously, were associated with shorter survival. When mutations in pathway genes were analyzed continuously, higher mutant allele frequency correlated with poorer outcomes. However, extended mutation, by itself, did not preclude clinical responses to panitumumab in a monotherapy setting.