The diagnostic accuracy of next-generation sequencing in advanced NSCLC

Comprehensive genomic profiling is crucial for guiding treatment in advanced non-small cell lung cancer (NSCLC). However, tumor tissue-based targeted panel next-generation sequencing (TP-NGS) faces challenges, such as inadequate tissue sampling. Circulating tumor DNA (ctDNA) from peripheral blood has emerged as an alternative.

Participants with advanced NSCLC were enrolled in a Precision Oncology Program to enhance personalized treatments. TP-NGS was conducted using FoundationOne®CDx and FoundationOne®Liquid CDx. The study included an unpaired cohort and a paired cohort. We evaluated the impact of ctDNA tumor fraction (TF) on TP-NGS diagnostic accuracy, focusing on sensitivity as a key metric of efficacy.

We prospectively analyzed data from 561 patients, of whom 62·4 % (n = 340) were in the unpaired cohort and 39·4 % (n = 221) were in the paired cohort. Specifically, in the paired cohort, actionable mutations were found in 50·2 % (n = 111) of patients, predominantly common EGFR mutations in 65·8 % (n = 73). The ctDNA TF high (TF>1 %, range 1 %-72 %) group had a 100 % positive percent agreement (PPA), while the ctDNA TF low group had a PPA of 47·5 % for actionable mutations. The correlation between bTMB and tTMB was 0·13 for ctDNA TF low versus 0·71 for ctDNA TF high. The PPA for bTMB was 31·3 % for ctDNA TF low and 92·3 % for ctDNA TF high, with negative percent agreement (NPA) at 100 % and 85·6 %, respectively.

In the context of high ctDNA TF, blood-based TP-NGS can detect clinically actionable mutations and may effectively replace tissue biopsies when obtaining tumor tissue is impractical.