Novel NGS Strategy Offers Potential Personalization Benefits for Patients With NSCLC


A plasma-based next-generation sequencing (NGS) option allows for sensitive detection and monitoring of mutations in advanced non-small cell lung cancer (NSCLC).

Genomic analysis of plasma cell-free DNA is a cutting-edge practice in current lung cancer care. However, the available assays are limited by multiple factors, including cost, turnaround time, and imperfect accuracy.

Geoffrey R Oxnard, MD, Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute (Boston, MA), and colleagues conducted a study to compare the effects of amplicon-based plasma NGS with hybrid-capture-based NGS. A total of 168 plasma specimens were sampled from 46 patients with NSCLC and a known targetable genotype (eg, EGFR, ALK/ROS1, and other rare genotypes). Plasma NGS was performed using enhanced tagged amplicon sequencing of hotspots and coding regions from 36 genes, along with intronic coverage for detection of ALK/ROS1 fusions. Researchers compared diagnostic accuracy with plasma ddPCR and tumor genotype.

Results of the study were published in Annals of Oncology (online January 9, 2018; doi:10.1093/annonc/mdy005).

Plasma samples were collected from the patients while they were on therapy and analyzed, blinded to tumor genotype. Researchers reported that matched plasma NGS and ddPCR across 120 variants from 80 samples showed high concordance of allelic fraction (R2 = 0.95).

Before treatment, sensitivity of plasma NGS for the detection of EGFR driver mutations was revealed to be 100% (30/30), compared with 87% (26/30) for ddPCR. Additionally, a full spectrum of rare driver oncogenic mutations was detected, including sensitive detection of ALK/ROS1 fusions (8/9 detected; 89%).


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In a separate analysis of 25 patients who were positive for EGFR T790M that developed resistance to osimertinib, 15 resistance mechanisms were detectable, including tertiary EGFR mutations (eg, C797S, Q791P) and mutations or amplifications of non-EGFR genes. Many of these mutations could be detected pre-treatment or months before progression, researchers noted.

Dr Oxnard and colleagues concluded that their blinded analysis demonstrated the ability of amplicon-based plasma NGS to detect a wide range of targetable genotypes in NSCLC with full accuracy. “The ability of plasma NGS to detect a range of pre-existing and acquired resistance mechanisms highlights its potential value as an alternative to single mutation digital PCR-based plasma assays for personalizing treatment of tyrosine kinase inhibitor resistance in lung cancer,” they wrote.—Zachary Bessette