Usefulness of Circulating Tumor DNA in Identifying Somatic Mutations and Tracking Tumor Evolution in Patients With Non-small Cell Lung Cancer

Abstract

BACKGROUND:The usefulness of circulating tumor DNA (ctDNA) in detecting mutations and monitoring treatment response has not been well studied beyond a few actionable biomarkers in non-small cell lung cancer (NSCLC).RESEARCH QUESTION: How does the usefulness of ctDNA analysis compare with that of solid tumor biopsy analysis in patients with NSCLC? METHODS: We retrospectively evaluated 370 adult patients with NSCLC treated at the City of Hope between November 2015 and August 2019 to assess the usefulness of ctDNA in mutation identification, survival, concordance with matched tissue samples in 32 genes, and tumor evolution.RESULTS: A total of 1,688 somatic mutations were detected in 473 ctDNA samples from 370 patients with NSCLC. Of the 473 samples, 177 showed at least one actionable mutation with currently available Food and Drug Administration-approved NSCLC therapies. MET and CDK6 amplifications co-occurred with BRAF amplifications (false discovery rate [FDR], < 0.01), and gene-level mutations were mutually exclusive in KRAS and EGFR (FDR, 0.0009). Low cumulative percent ctDNA levels were associated with longer progression-free survival (hazard ratio [HR], 0.56; 95% CI, 0.37-0.85; P ¼ .006). Overall survival was shorter in patients harboring BRAF mutations (HR, 2.35; 95% CI, 1.24-4.6; P ¼ .009), PIK3CA mutations (HR, 2.77; 95% CI, 1.56-4.9; P < .001) and KRAS mutations (HR, 2.32; 95% CI, 1.30-4.1; P ¼ .004). Gene-level concordance was 93.8%, whereas the positive concordance rate was 41.6%. More mutations in targetable genes were found in ctDNA than in tissue biopsy samples. Treatment response and tumor evolution over time were detected in repeated ctDNA samples.INTERPRETATION: Although ctDNA analysis exhibited similar usefulness to tissue biopsy analysis, more mutations in targetable genes were missed in tissue biopsy analyses. Therefore, the evaluation of ctDNA in conjunction with tissue biopsy samples may help to detect additional targetable mutations to improve clinical outcomes in advanced NSCLC.

Disease monitoring of epidermal growth factor receptor (EGFR)‐mutated non‐small‐cell lung cancer patients treated with tyrosine kinase inhibitors via EGFR status in circulating tumor DNA

“…Therefore, it is of great importance to seek an alternative method as a supplement to radiological imagination in precision oncology. Numerous studies have found that quantification of baseline ctDNA predicted prognosis of patients harboring EGFR mutations 17,18 . Recent studies have shown that ctDNA clearance was of prognostic significance, in which molecular responders with undetectable ctDNA after targeted therapy had significantly longer survival than non‐responders 19,20 .…”

“…Numerous studies have found that quantification of baseline ctDNA predicted prognosis of patients harboring EGFR mutations. 17,18 Recent studies have shown that ctDNA clearance was of prognostic significance, in which molecular responders with undetectable ctDNA after targeted therapy had significantly longer survival than non-responders. 19,20 Therefore, molecular evaluation of ctDNA clearance helps to identify a group of patients that would benefit from EGFR-targeted therapy.…”

Daily Practice Assessment of KRAS Status in NSCLC Patients: A New Challenge for the Thoracic Pathologist Is Right around the Corner

“…KRAS mutations, notably the KRAS G12C mutation, can be identified from tissue samples (bronchial biopsies, transthoracic biopsies, and more rarely biopsies from a metastatic site or a surgically resected sample), from different cytological and fluid samples (bronchial aspirates, fine needle aspiration, endobronchial ultrasound and transbronchial needle aspiration, bronchoalveolar lavage, pleural and cerebrospinal fluid) and from blood [ 15 , 105 , 185 , 186 , 187 , 188 , 189 ]. These mutations are currently being characterized using targeted sequencing (RT-PCR and droplet digital PCR) or next-generation sequencing (NGS) approaches [ 189 , 190 ]. Moreover, liquid biopsy is certainly a very promising tool to use at baseline but also at progression in patients treated with specific inhibitors of KRAS G12C mutations to track new KRAS mutations, notably the Y96D mutation, as well as other mutations such as the R86S and H95D mutations [ 141 ].…”

“…In case of an inconclusive result, and if possible, depending on the patient status and tumor site, a tissue re-biopsy should be done to track resistance mechanisms [ 206 ]. NGS approaches can routinely use a LB and thus provide access to the KRAS status and associated genomic alterations [ 15 , 190 , 214 , 215 , 216 , 217 ]. However, NGS with a LB is currently not often available in most laboratories, in Europe at least, and is set up for routine testing in only a few comprehensive cancer centers [ 191 , 215 , 218 ].…”

New biochemical, immune and molecular markers in lung cancer: Diagnostic and prognostic opportunities

“…[115][116][117][118] Accordingly, baseline and posttreatment ctDNA indicated worse clinical outcomes. [119][120][121][122] Circulating tumor DNA has also been investigated in the evaluation of tumor mutation burden (TMB), a novel predictive marker reflecting the total number of existing mutations, which is thought to be predictive of the response to PD-1 and PD-L1 inhibitors. It was hypothesized that patients with a higher burden of somatic mutations would benefit from immune checkpoint inhibitors due to a better recognition of neoantigens.…”