Evidence for Liquid Biopsy Lacking, Expert Panel Finds

There is not enough evidence, currently, to support the routine adoption of liquid biopsy tests for any of its promising clinical uses, according to a joint review published March 1 in both the Archives of Pathology & Laboratory Medicine and the Journal of Clinical Oncology. The joint panel said it did not find evidence to support liquid biopsy testing for screening, diagnosing early-stage cancer, making treatment decisions, or patient monitoring, outside of clinical trials.

“Like all new things in medicine, the use of circulating tumor DNA [ctDNA] assays in routine cancer care requires evidence of clinical utility,” said Daniel Hayes, M.D., a member of the expert panel, in a statement. “At present, there is insufficient evidence of clinical validity and utility for the majority of ctDNA assays in advanced cancer, including those that interrogate a panel of genes.”

The authors acknowledge that despite that fact that the U.S. Food and Drug Administration has only approved a single liquid biopsy test—the COBAS assay for EGFR mutations in non-small-cell lung cancer—the tests are being used in clinical practice.

“This is an area of great interest to both pathologists and oncologists. It’s also an area where we see a lot of commercial advertisement, and a lot of enthusiasm from the public,” said Jason D. Merker, M.D., Ph.D., expert panel cochair, said in a statement. “We thought it was a good time to look at the literature and take an evidence-based approach to various uses for ctDNA assays.”

Given the interest in the technology, an expert panel, convened by American Society of Clinical Oncology and College of American Pathologists, conducted a literature review on the use of ctDNA assays for solid tumors, including assessment of preanalytical variables, analytical validity, interpretation and reporting, and clinical validity and utility. Ultimately 77 identified articles were included. The experts key findings, included:

Uses of Liquid Biopsy

• Assessment of disease risk

• Screen unaffected patients for the disease

• Differential diagnosis of a proven malignancy

• Prognosis

• Assessment of treatment effectiveness

• Monitoring disease activity (for recurrence or progression)

Advantages of Liquid Biopsy vs. Traditional Biopsy

• More convenient

• Noninvasive and less risky

• Less expensive collection

• Can be performed serially

• More comprehensive assessment of the tumor burden (no spatial sampling limitations)

Preanalytical findings

• Plasma is the optimal specimen type
• Collection should occur in cell stabilization or EDTA tubes, with processing within 6 hours of collection

Analytical validity

• Examination of analytical validity should include evaluation of both the wet laboratory and bioinformatics portions of an assay
• Evidence has not established optimal lower limits of detection for various types of somatic variants
• Future studies should focus on cross-assay comparisons, assay robustness, and the development of proficiency testing mechanisms

Interpretation and reporting

• Variant allele fractions from ctDNA assays need further study
• Reporting of somatic variant should conveys the potential for discordance with tumor tissue testing
• Discussion of potential actionability should be limited to general associations between a variant and therapy options that have established clinical utility in the same primary tumor site

Clinical validity and utility

• Most assays have insufficient evidence to demonstrate clinical validity, and most have no evidence of clinical utility
• Evidence shows discordance between ctDNA assay results and genotyping tumor specimens, suggesting tissue genotyping should confirm lack of detection from ctDNA tests

Takeaway: While the expert panel currently did not find sufficient evidence to support the clinical use of liquid biopsies, they suggest that the rapid pace of research requires reevaluation of the literature soon.