Abstract
Background: Predictive biomarker development is a key challenge for novel cancer therapeutics. We explored the feasibility of next-generation sequencing (NGS) to validate exploratory genomic biomarkers that impact phase I trial selection. Methods: We prospectively enrolled 158 patients with advanced solid tumours referred for phase I clinical trials at the Royal Marsden Hospital (October 2012 to March 2013). After fresh and/or archived tumour tissue were obtained, 93 patients remained candidates for phase I trials. Results from tumour sequencing on the Illumina MiSeq were cross-validated in 27 out of 93 patients on the Ion Torrent Personal Genome Machine (IT-PGM) blinded to results. MiSeq validation with Sequenom MassARRAY OncoCarta 1.0 (Sequenom Inc., San Diego, CA, USA) was performed in a separate cohort. Results: We found 97% concordance of mutation calls by MiSeq and IT-PGM at a variant allele frequency ≥13% and ≥500 × depth coverage, and 91% concordance between MiSeq and Sequenom. Common 'actionable' mutations involved deoxyribonucleic acid (DNA) repair (51%), RAS-RAF-MEK (35%), Wnt (26%), and PI3K-AKT-mTOR (24%) signalling. Out of 53, 29 (55%) patients participating in phase I trials were recommended based on identified actionable mutations. Conclusions: Targeted high-coverage NGS panels are a highly feasible single-centre technology well-suited to cross-platform validation, enrichment of trials with molecularly defined populations and hypothesis testing early in drug development.
Original language | English (US) |
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Pages (from-to) | 828-836 |
Number of pages | 9 |
Journal | British Journal of Cancer |
Volume | 111 |
Issue number | 5 |
DOIs | |
State | Published - Jan 1 2014 |
Externally published | Yes |
Keywords
- biomarkers
- drug development
- next-generation sequencing
- pharmacological audit trail
- phase I trials
- phase II trials
ASJC Scopus subject areas
- Oncology
- Cancer Research