Use of NGS for stratification of patients with advanced NSCLC within the NHS using FFPE-extracted DNA from diagnostic biopsies


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Sumi Subramaniam1
1Cancer Research UK

Abstract

Background

The Cancer Research UK Stratified Medicine Programme 2 (SMP2) screens NSCLC cancer patients by NGS for clinically-actionable gene aberrations. Eligible patients can be recruited to a targeted therapy or ‘Non Actionable (immunotherapy) arm, of the National Lung Matrix Trial (NLMT). SMP2 aims to establish genomic screening at a national level within existing NHS pathways and ensure equity of access to targeted therapies to eligible patients in the UK.

Method

SMP2 utilizes DNA from excess diagnostic biopsy tissue and regions of interest are enriched using a custom 28-gene Illumina Nextera Rapid Capture panel before sequencing on MiSeq using V3 chemistry. Validation of the assay evaluated mean target coverage, detection limits, concordance, tumour content cut-off, number of reads required to call a variant, and number of base pairs on either side of the region of interest to be analysed. CNVs and SVs have been validated against FISH. The analytical pipeline was developed in-house at West Midlands Regional Genetics Service to accommodate a busy diagnostic service, and includes a reporting algorithm for determining confidence in calling wildtype.

Results

Greater than 2000 patients have been successfully screened through SMP2 over the past two years. CNVs and SVs called by NGS showed good concordance with FISH, subject to quality and tumour content of samples. Preliminary analysis indicates prevalence of SNVs consistent with published reports, including 33.5% KRAS and 16.1% EGFR mutations. The SMP2 testing panel has enabled the recruitment of >170 patients to NLMT, with 31% of samples sent for screening eligible for one of 20 biomarker-specific NLMT cohorts.

Conclusion

Establishing and delivering a nationwide screening programme within the NHS has raised numerous challenges across the entire patient and sample pathway. Lessons learned will now enable informed improvements which will ultimately increase the numberof molecularly eligible patients that can subsequently benefit from novel targeted therapies.