Hybrid Capture–Based Genomic Profiling of Circulating Tumor DNA from Patients with Advanced Non–Small Cell Lung Cancer

Abstract

Introduction: Genomic profiling informs selection of matched targeted therapies as part of routine clinical care in NSCLC. Tissue biopsy is the criterion standard; however, genomic profiling of blood-derived circulating tumor DNA (ctDNA) has emerged as a minimally invasive alternative. Methods: Hybrid capture-based genomic profiling of 62 genes was performed on blood-based ctDNA from 1552 patients with NSCLC. Results: Evidence of ctDNA was detected in 80% of samples, and in 86% of these cases, at least one reportable genomic alteration (GA) was detected. Frequently altered genes were tumor protein p53 gene (TP53) (59%), EGFR (25%), and KRAS (17%). Comparative analysis with a tissue genomic database (N ¼ 21,500) showed similar frequencies of GAs per gene, although KRAS mutation and EGFR T790M were more frequent in tissue and ctDNA, respectively (both p < 0.0001), likely reflecting the use of liquid versus tissue biopsy after relapse during targeted therapy. In temporally matched ctDNA and tissue samples from 33 patients with evidence of ctDNA in their blood, 64% of GAs detected in tissue were also detected in ctDNA, including 78% of short variants (58 of 74) and 100% of rearrangements (four of four), but only 16% of amplifications (four of 25).

EGFR T790M relative mutation purity predicts osimertinib treatment efficacy in non‐small cell lung cancer patients

“…MSAF is a valid tool for quantifying the tumor fraction of cell free DNA [16–18]. Numerous studies have shown that the MSAF, or baseline ctDNA level, is a prognostic factor in patients receiving chemotherapy [25], targeted therapy [26,27], and immunotherapy [21, 28–30], although most of the prognostic value of MSAF is correlated with baseline tumor burdens in patients.…”

“…Circulating tumor DNA (ctDNA) is shed from tumor cells throughout the body. The maximum AF among all somatic mutations detected in plasma sample can provide an estimate of the ctDNA fraction in blood [16–18]. This may be based on the hypothesis that mutation with maximum AF in blood is shared by the most malignant cells and represents the largest clone in a given patient's tumors.…”

The Role of the Liquid Biopsy in Decision-Making for Patients with Non-Small Cell Lung Cancer

“…In a comprehensive assessment of ctDNA from 1552 NSCLC patients, using hybrid capture-based genomic profiling, MET exon 14 skipping mutations were detected in 1.9% of cases. Moreover, additional activating SNVs of MET (p. L1195V, p. D1228H, and p. Y1230C) could be detected in three cases [ 50 ].…”

Maximum Somatic Allele Frequency in Combination With Blood-Based Tumor Mutational Burden to Predict the Efficacy of Atezolizumab in Advanced Non-small Cell Lung Cancer: A Pooled Analysis of the Randomized POPLAR and OAK Studies

“…The maximum somatic allele frequency (MSAF) is a useful bioinformatics tool for estimating the amount of tumor fraction of cell-free DNA in peripheral blood samples (10). Previous studies have revealed that a lower MSAF level was associated with a higher risk of missing important genomic alterations in the plasma, such as EGFR exon 19 deletion and EGFR T790M that are predictive of response to EGFR tyrosine kinases in advanced NSCLC (10,11). However, there exist limited data regarding the association between MSAF and treatment outcomes from ICIs.…”