Circulating Tumor DNA Analysis in Patients With Cancer: American Society of Clinical Oncology and College of American Pathologists Joint Review

Abstract

Purpose Clinical use of analytical tests to assess genomic variants in circulating tumor DNA (ctDNA) is increasing. This joint review from ASCO and the College of American Pathologists summarizes current information about clinical ctDNA assays and provides a framework for future research. Methods An Expert Panel conducted a literature review on the use of ctDNA assays for solid tumors, including pre-analytical variables, analytical validity, interpretation and reporting, and clinical validity and utility. Results The literature search identified 1,338 references. Of those, 390, plus 31 references supplied by the Expert Panel, were selected for full-text review. There were 77 articles selected for inclusion. Conclusion The evidence indicates that testing for ctDNA is optimally performed on plasma collected in cell stabilization or EDTA tubes, with EDTA tubes processed within 6 hours of collection. Some ctDNA assays have demonstrated clinical validity and utility with certain types of advanced cancer; however, there is insufficient evidence of clinical validity and utility for the majority of ctDNA assays in advanced cancer. Evidence shows discordance between the results of ctDNA assays and genotyping tumor specimens and supports tumor tissue genotyping to confirm undetected results from ctDNA tests. There is no evidence of clinical utility and little evidence of clinical validity of ctDNA assays in early-stage cancer, treatment monitoring, or residual disease detection. There is no evidence of clinical validity and clinical utility to suggest that ctDNA assays are useful for cancer screening, outside of a clinical trial. Given the rapid pace of research, re-evaluation of the literature will shortly be required, along with the development of tools and guidance for clinical practice.

Circulating tumor DNA quantity is related to tumor volume and both predict survival in metastatic pancreatic ductal adenocarcinoma

“…This wide range may be explained by the various methods used. In the current study as well as in literature, it has been shown that detection rates of ctDNA are dependent on many factors, related to both tumor characteristics and technical aspects (volume of plasma input, method of cfDNA isolation, sequencing techniques and number of interrogated hotspots/genes) . In our cohort, the full spectrum of metastatic disease was included, varying from patients with small metastases, undetectable on standard imaging, to those with only distant lymph node or extensive organ metastases.…”

“…As illustrated by the joint review of the American Society of Clinical Oncology and the College of American Pathologists, questions remain about the validity and reproducibility of ctDNA analysis, hampering clinical application . ctDNA detection rates vary widely depending on cancer type and analysis technique; for mPDAC, rates between 38.8% and 86.1% have been reported .…”

Assessment of circulating tumor DNA in pediatric solid tumors: The promise of liquid biopsies

“…The available data indicate that ctDNA is detectable in a range of pediatric solid tumors at diagnosis, during treatment, and at the time of relapse (Table ). Criteria for determining how ctDNA assays should be adopted into clinical practice were recently outlined in an American Society of Clinical Oncology and College of American Pathologists joint review . They concluded that ctDNA assays must demonstrate (1) analytical validity, meaning the assay is able to detect a targeted variant with accuracy, reproducibility, and reliability; (2) clinical validity, meaning that the assay can divide a clinical group into one or more cohorts with significantly different outcomes; and (3) clinical utility, that the knowledge gained from the assay significantly improves clinical care.…”

Molecular Diagnostics in Clinical Oncology

“…Therefore, it is hard to expect, that this indirect and potentially error-prone examination of single tumor cells or circulating tumor-specific molecules will indeed replace the direct tissue analysis in the near future. It is also essential to acknowledge, that the majority of actionable mutations demonstrate limited intratumoral heterogeneity; therefore, the analysis of a single tumor lump is usually sufficient for the choice of treatment and liquid biopsy is unlikely to have a high added value for the initial selection of optimal drugs (Jamal-Hanjani et al, 2017; Merker et al, 2018). …”

“…The potential promise of these complex platforms has already been demonstrated in the study of early-stage cancers (Cohen et al, 2018). Nevertheless, many modern varieties of liquid biopsy still require proper clinical validation (Merker et al, 2018). …”