Circulating Tumor DNA-Based Genomic Profiling Assays in Adult Solid Tumors for Precision Oncology: Recent Advancements and Future Challenges

Abstract

Genomic profiling using tumor biopsies remains the standard approach for the selection of approved molecular targeted therapies. However, this is often limited by its invasiveness, feasibility, and poor sample quality. Liquid biopsies provide a less invasive approach while capturing a contemporaneous and comprehensive tumor genomic profile. Recent advancements in the detection of circulating tumor DNA (ctDNA) from plasma samples at satisfactory sensitivity, specificity, and detection concordance to tumor tissues have facilitated the approval of ctDNA-based genomic profiling to be integrated into regular clinical practice. The recent approval of both single-gene and multigene assays to detect genetic biomarkers from plasma cell-free DNA (cfDNA) as companion diagnostic tools for molecular targeted therapies has transformed the therapeutic decision-making procedure for advanced solid tumors. Despite the increasing use of cfDNA-based molecular profiling, there is an ongoing debate about a ‘plasma first’ or ‘tissue first’ approach toward genomic testing for advanced solid malignancies. Both approaches present possible advantages and disadvantages, and these factors should be carefully considered to personalize and select the most appropriate genomic assay. This review focuses on the recent advancements of cfDNA-based genomic profiling assays in advanced solid tumors while highlighting the major challenges that should be tackled to formulate evidence-based guidelines in recommending the ‘right assay for the right patient at the right time’.

Network approach in liquidomics landscape

“…Despite the advantages of liquid biopsy, the majority of assays still lack evidence of clinical utility and validity [24], with only four tests [25] obtaining approval from the Food and Drug Administration (FDA). One reason for this is that liquid biopsy assays often lack reproducibility [26] due to the absence of standardization across workflows.…”

Tepotinib in patients with non-small cell lung cancer with high-level MET amplification detected by liquid biopsy: VISION Cohort B

“… 47 In particular, detection of gene amplification is dependent on a high ctDNA fraction in circulation. 48 , 49 Therefore, ctDNA-based analysis may select a poorer prognostic group of patients compared with tissue-based screening. This is supported by the associations of higher ctDNA burden with poorer outcomes and/or tumor load in our trial as well as studies in other oncogene-driven subtypes.…”

Circulating H3K27 Methylated Nucleosome Plasma Concentration: Synergistic Information with Circulating Tumor DNA Molecular Profiling

“…Despite the high clinical specificity of ctDNA, physicians often face a high non-contributive detection rate of preoperative mutated plasma ctDNA, around 24% to 85% in the overall population of lung cancers, associated with the stage, in routine settings [ 34 , 35 , 36 ]. Even though there have been recent improvements in the sensitivity of sequencing technologies, there are still some limitations to ctDNA-based molecular profiling: (1) technical limitations relating to the low ctDNA concentration, and rare mutation detection; and (2) biological limitations, including tumor shedding [ 37 ]. CtDNA was detected after treatment in 64.3% of patients who had obvious clinical recurrence [ 38 ].…”