Next-generation Sequencing of ctDNA Could Identify Resistance Mutations in NSCLC

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Next-generation sequencing of circulating DNA could be used to identify emergent resistance mutations.
Next-generation sequencing of circulating DNA could be used to identify emergent resistance mutations.

Next-generation sequencing (NGS) of circulating DNA (ctDNA) could be used to identify emergent resistance mutations in patients with non-small cell lung cancer (NSCLC), and therefore to inform subsequent courses of therapy, according to results of a study presented at the International Association for the Study of Lung Cancer (IASLC) 17th Annual World Conference on Lung Cancer in Austria.1

The National Comprehensive Cancer Network (NCCN) requires the detection of actionable genomic alterations for guideline-compliant workup of NSCLC adenocarcinoma. If NGS of ctDNA is sufficiently sensitive and specific, it could provide a comprehensive genotyping platform for clinical decision-making in cases where tissue is insufficient or at the time of progression on targeted therapy.

Researchers used a deep-coverage ctDNA plasma NGS test that targeted 54-70 genes to genotype 5206 patients with advanced-stage NSCLC between June 2014 and April 2016. They compared the frequency and distribution of somatic alterations in “key genes” to those described in The Cancer Genome Atlas (TCGA).

They evaluated the clinical impact of ctDNA testing by identifying resistance mechanisms that were emergent at progression on targeted therapies and by analyzing additional driver mutations they detected with ctDNA at baseline in 362 patients with NSCLC.

The researchers found ctDNA alterations in 86% of cases, epidermal growth factor receptor (EGFR) mutations in 25%,MET amplification in 4%, BRAF mutations in 3%, and other potentially actionable alterations in 9%. Mutation patterns among driver oncogenes were “highly consistent” with those described in TCGA. The positive predictive value of ctDNA-detected variants was 100% for EGFR mutations, 100% for KRAS mutations, and 96% for ALK, RET, or ROS1 fusions.

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Genotypic patterns of truncal mutations were highly consistent with TCGA in terms of frequency and distribution. The series represents the largest NSCLC ctDNA study to date.

Reference

  1. Mack P, Banks KC, Riess  JW, et al. Clinical utility of circulating tumor DNA (ctDNA) analysis by digital next generation sequencing of over 5,000 advanced NSCLC patients. Paper presented at: International Association for the Study of Lung Cancer 17th World Conference on Lung Cancer; December 2016; Vienna, Austria. 

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