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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

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posted on 2019-02-15, 13:41 authored by M Peeters, T Price, M Boedigheimer, TW Kim, P Ruff, P Gibbs, A Thomas, G Demonty, K Hool, A Ang
Background: Mutations in EGFR 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.Methods: 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 RAS 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 EGFR pathway genes was also examined.Results: Overall, 261 patients in the panitumumab arm had evaluable plasma samples. Patients with a higher RAS mutant allele frequency at baseline had worse clinical outcomes than those with a lower frequency (P < 0.001, Cox PH model); however, RAS mutations did not necessarily preclude patients from deriving benefits. The objective response rate (complete or partial response) was 10.8% for patients with baseline RAS mutations and 21.7% for those with BRAF mutations. The 63-gene panel analysis revealed an increase in tumor mutational burden from baseline to SFU (P < 0.001, Wilcoxon signed rank test). Baseline mutations in EGFR pathway genes, when analyzed both categorically and continuously, were associated with shorter survival.Conclusions: When mutations in EGFR pathway genes were analyzed continuously, higher mutant allele frequency correlated with poorer outcomes. However, extended RAS mutation, by itself, did not preclude clinical responses to panitumumab in a monotherapy setting.

Funding

This work was supported by Amgen Inc.

History

Citation

Clin Cancer Res, 2019, 25 (4)

Author affiliation

/Organisation/COLLEGE OF LIFE SCIENCES/School of Medicine/Cancer Research Centre

Version

  • AM (Accepted Manuscript)

Published in

Clin Cancer Res

Publisher

American Association for Cancer Research

issn

1078-0432

eissn

1557-3265

Acceptance date

2018-11-19

Copyright date

2019

Publisher version

http://clincancerres.aacrjournals.org/content/25/4/1216

Notes

The file associated with this record is under embargo until 12 months after publication, in accordance with the publisher's self-archiving policy. The full text may be available through the publisher links provided above.

Language

en

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