Plasma Cell-Free DNA Genotyping: From an Emerging Concept to a Standard-of-Care Tool in Metastatic Non-Small Cell Lung Cancer

Abstract

Plasma cell-free DNA (cfDNA) genotyping is an alternative to tissue genotyping particularly when tissue specimens are insufficient or unavailable and provides critical information that can be used to guide treatment decisions in managing patients with non-small cell lung cancer (NSCLC). In this article, we review the evolution of plasma cfDNA genotyping from an emerging concept, through development of analytical methods, to its clinical applications as a standard-of-care tool in NSCLC.The number of driver or resistance mutations recommended for testing in NSCLC continues to increase. Due to the expanding list of therapeutically relevant variants, comprehensive testing to investigate larger regions of multiple genes in a single run is often preferable and saves on time and cost, compared with performing serial single-gene assays. Recent advances in nucleic acid next-generation sequencing have led to a rapid expansion in cfDNA genotyping technologies. Analytic assays that have received regulatory approval are now routinely used as diagnostic companions in the setting of metastatic NSCLC. As the demand for plasma-based technologies increases, more regulatory approvals for cfDNA genotyping assays are expected in the future.Plasma cfDNA genotyping is currently aiding oncologists in the delivery of personalized care by facilitating matching of patients with targeted therapy and monitoring emergence of resistance to therapy in NSCLC. Further advances currently underway to increase assay sensitivity and specificity will potentially expand the use of plasma cfDNA genotyping in early cancer detection, monitoring response to therapy, detection of minimal residual disease, and measurement of tumor mutational burden in NSCLC. The Oncologist ;9999:• • Implications for Practice: Plasma cell-free DNA (cfDNA) genotyping offers an alternative to tissue genotyping particularly when tissue specimens are insufficient or unavailable. Advances in cfDNA genotyping technologies have led to analytic assays that are now routinely used to aid oncologists in the delivery of personalized care by facilitating matching of patients with targeted therapy and monitoring emergence of resistance to therapy. Further advances underway to increase assay sensitivity and specificity will potentially expand the use of plasma cfDNA genotyping in early cancer detection, monitoring response to therapy, detection of minimal residual disease, and evaluation of tumor mutational burden in NSCLC. OVERVIEW OF MOLECULAR TESTING IN NON-SMALL CELL LUNG CANCER (NSCLC)The diagnostic journey for lung cancer begins with identification of the carcinoma through pathological evaluation to classify the histologic subtype, imaging (including computed tomography [CT] and magnetic resonance imaging [MRI]) to determine the extent of disease, and molecular diagnostic testing to inform therapeutic strategies [1]. Targeted therapies have transformed the treatment landscape of NSCLC. Current clinical guidelines [1-3] recommend broad

Advances in the management of non-small-cell lung cancer harbouring EGFR exon 20 insertion mutations

“… 31 Currently, US FDA-approved companion diagnostics are Guardant360 ® CDx (Guardant, California, CA) and FoundationOne ® Liquid CDx (Foundation Medicine, Cambridge, MA). 98 Other detection methods, such as Sanger sequencing, RNA sequencing, direct sequencing and mass spectroscopy, are alternative options that are less commonly used. 17 …”

Liquid Biopsy Analysis as a Tool for TKI-Based Treatment in Non-Small Cell Lung Cancer

“…Thus, current clinical guidelines recommend cfDNA testing for the detection of molecular alterations in NSCLC, either in treatment-naïve patients or in patients who progressed to EGFR TKIs [ 141 ]. EGFR- mutant NSCLC constitutes one of the major paradigms of integrating liquid biopsy testing in the clinical setting that is validated through the liquid biopsy tests already approved by the FDA [ 142 ].…”

Next Generation Sequencing Technology in Lung Cancer Diagnosis

“…Jin et al were able to identify miR-181-5p, miR-30a-3p, miR-30e-3p and miR-361-5p as being specific for adenocarcinoma, and miR-10b-5p, miR-15b-5p and miR-320b for SCLC (small cell lung cancer) [62]. In addition, taking advantage of the many benefits of NGS, oncology researchers have developed liquid biopsy testing for lung cancer diagnosis [63]. Leighl et al observed a very high concordance for NGS results from cfDNA and tissue DNA in untreated metastatic NSCLC [64].…”

“…NGS testing was successfully recommended in lung cancer diagnosis by different expert panels [66] and oncology organizations [67]. Gray et al performed a thorough survey of the relevant literature regarding liquid biopsy and observed that the advantages of NGS have helped to develop different assays using liquid biopsy samples for the early diagnosis, treatment selection, minimal disease detection, monitoring treatment efficacy and evaluation of tumor burden in lung cancer [63]. Sueoka-Aragane et al observed that the analysis of ctDNA by NGS could be a promising tool for the evaluation of the efficacy of osimertinib in NSCLC with EGFR T790M mutation [68].…”