Clinical Utility of Comprehensive Cell-free DNA Analysis to Identify Genomic Biomarkers in Patients with Newly Diagnosed Metastatic Non–small Cell Lung Cancer

Abstract

Purpose: Complete and timely tissue genotyping is challenging, leading to significant numbers of patients with newly diagnosed metastatic non-small cell lung cancer (mNSCLC) being undergenotyped for all eight genomic biomarkers recommended by professional guidelines. We aimed to demonstrate noninferiority of comprehensive cell-free DNA (cfDNA) relative to physician discretion standard-of-care (SOC) tissue genotyping to identify guideline-recommended biomarkers in patients with mNSCLC. Patients and Methods: Prospectively enrolled patients with previously untreated mNSCLC undergoing physician discretion SOC tissue genotyping submitted a pretreatment blood sample for comprehensive cfDNA analysis (Guardant360). Results: Among 282 patients, physician discretion SOC tissue genotyping identified a guideline-recommended biomarker in 60 patients versus 77 cfDNA identified patients (21.3% vs. 27.3%; P < 0.0001 for noninferiority). In tissue-positive patients, the biomarker was identified alone (12/60) or concordant with cfDNA (48/60), an 80% cfDNA clinical sensitivity for any guidelinerecommended biomarker. For FDA-approved targets (EGFR, ALK, ROS1, BRAF) concordance was >98.2% with 100% positive predictive value for cfDNA versus tissue (34/34 EGFR-, ALK-, or BRAF-positive patients). Utilizing cfDNA, in addition to tissue, increased detection by 48%, from 60 to 89 patients, including those with negative, not assessed, or insufficient tissue results. cfDNA median turnaround time was significantly faster than tissue (9 vs. 15 days; P < 0.0001). Guideline-complete genotyping was significantly more likely (268 vs. 51; P < 0.0001). Conclusions: In the largest cfDNA study in previously untreated mNSCLC, a validated comprehensive cfDNA test identifies guideline-recommended biomarkers at a rate at least as high as SOC tissue genotyping, with high tissue concordance, more rapidly and completely than tissue-based genotyping. See related commentary by Meador and Oxnard, p. 4583

Liquid Biopsy in Non-Small Cell Lung Cancer: Highlights and Challenges

“…In particular, 60 (21.3%) and 77 (27.3%) patients tested positive for tissue and cfDNA genotyping, respectively. Among the 60 patients with a tissue positivity for at least one of the eight markers, 48 (80%) were concordant with the cfDNA results, and this concordance reached a percentage greater than 98% if considering the FDA-approved targets (i.e., EGFR, ALK, ROS1, BRAF) only [49].…”

Liquid biopsy as a follow‐up tool: Comment on longitudinal monitoring of somatic genetic alterations in circulating cell‐free DNA during treatment with epidermal growth factor receptor–tyrosine kinase inhibitors

“…In the new paradigm, the development of more sensitive detection methods, such as next‐generation sequencing (NGS), allows simultaneous evaluation of multiple somatic mutations; furthermore, the addition of other techniques, such as hybrid capture, makes it possible to determine the presence of other genetic alterations, such as fusions. This approach demonstrated a marked increase in the detection of therapeutically targetable mutations and improved delivery of molecularly guided therapy compared with tissue genotyping, with a shorter turnaround time . These results support a hypothetical change in the upfront management of NSCLC patients from “tissue first” to “blood first.”…”

“…This approach demonstrated a marked increase in the detection of therapeutically targetable mutations and improved delivery of molecularly guided therapy compared with tissue genotyping, 5,6 with a shorter turnaround time. 6 These results support a hypothetical change in the upfront management of NSCLC patients from "tissue first" to "blood first. "Recently, the therapeutic landscape of EGFR-mutated NSCLCs has been revolutionized by the advent of the third-generation EGFR-TKI osimertinib in a first-line setting, 7 replacing first-and second-generation inhibitors and changing the scenario of mechanisms of acquired resistance, including druggable alterations such as MET amplification, EGFR C797S mutation, PIK3CA mutation, BRAF mutation, and HER2 amplification/mutation, among others.…”

“…This approach demonstrated a marked increase in the detection of therapeutically targetable mutations and improved delivery of molecularly guided therapy compared with tissue genotyping, 5,6 with a shorter turnaround time. 6 These results support a hypothetical change in the upfront management of NSCLC patients from "tissue first" to "blood first. "…”

Prognostic value of TP53 concurrent mutations for EGFR- TKIs and ALK-TKIs based targeted therapy in advanced non-small cell lung cancer: a meta-analysis

“…Nowadays, the development of liquid biopsy allows a real-time biomolecular profiling of the tumor through the analysis of human body fluids, such as plasma, pleural effusions and urine, etc [64]. Cell free DNA (cfDNA), which refers to the free DNA fragments in circulation (plasma or serum) derived from tumor cells, is the most widely adopted source for tumor genotyping in advanced NSCLC [65,66].…”