ASCO/CAP Panel Says Evidence Does Not Yet Support ctDNA Testing Outside of Clinical Trials

After reviewing data from a decade of clinical research, a joint panel from ASCO and the College of American Pathologists concluded that circulating tumor DNA testing should be used only to screen for participation in, or during, a clinical trial.

Daniel F. Hayes, MD

After reviewing data from a decade of clinical research, a joint panel from ASCO and the College of American Pathologists (CAP) concluded that at this time, circulating tumor DNA (ctDNA) testing should be used only to screen for participation in, or during, a clinical trial. The panel noted that this could change as more robust research becomes available.

Based on current evidence, the panel found that it is not possible to know whether the use of most liquid biopsies in advanced cancer is justified outside the context of a clinical trial. Furthermore, the panel concluded that there is not enough evidence to support the routine use of ctDNA tests for early-stage cancer, making treatment decisions, monitoring how well a treatment is working, finding remaining cancer cells, or for cancer screening, except in the context of a clinical trial.

The panel also concluded that liquid biopsy results are inconsistent compared with testing with tumor tissue, so negative liquid biopsy results should be confirmed with tumor tissue genotyping.

“Like all new things in medicine, the use of ctDNA assays in routine cancer care requires evidence of clinical utility,” panel member Daniel F. Hayes, MD, said in a press release. Hayes serves as the clinical director of the Breast Oncology Program at the University of Michigan Comprehensive Cancer Center. “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 panel reviewed 77 articles analyzing sequencing and gene copy number variants in ctDNA from solid tumors published from January 2007 to March 2017. Panel members wanted to determine if liquid biopsies provided analytical validity, clinical validity, and clinical utility, as well as to identify differences in pre-clinical considerations between the different tests.

The panel found that establishing the clinical utility of ctDNA assays is challenging, especially compared with a standard biopsy for tumor genotyping, because there is little prospective trial data available. At present, only the Cobas assay forEGFRmutations in non—small cell lung cancer (NSCLC) has demonstrated sufficient clinical utility to win FDA approval. Polymerase chain reaction–based ctDNA assays forEGFRin NSCLC andKRASin colorectal cancer are available for commercial use in Europe, but clinical utility of the assays approved in the United States and Europe was established using only retrospective analysis.

There is limited evidence of clinical validity of ctDNA analysis in other tumor types and for variants that were not analyzed as part of the ctDNA studies forEGFRin lung cancer andKRASin colorectal cancer. A wide range of ctDNA assays have been developed and clinically studied for detection of potentially targetable variants, such asBRAFvariants in melanoma andPIK3CAandESR1variants in breast cancer. However, although several liquid biopsy tests are commercially available, the clinical utility of these assays has not been established.

“There is very significant potential for many different applications of ctDNA tests in the future,” Jason D. Merker, MD, PhD, said in a statement. Merker is an assistant professor of pathology at the Stanford University Medical Center and co-chair of the panel. “However, we need to make sure that we develop the body of evidence as part of clinical trials to support these applications in various tumor types. This is critical to ensure that we are providing the best care for our patients.”

Because liquid biopsy can identify ctDNA in early-stage disease, there is great interest in the potential for using ctDNA to detect cancer in asymptomatic individuals and populations. However, the panel concluded that there are no data on clinical validity in this setting and no evidence of clinical utility. Further, the risk for false-positive results, both technical and biologic, has not been established.

As more liquid biopsy tests are introduced and their use in clinical care grows more common, the panel said more and more robust research will be necessary to inform clinical decision-making. However, because tumor genotyping is a rapidly evolving area of research, the panel believes that researchers will eventually produce stronger evidence allowing for better assessment of the clinical validity and utility of ctDNA assays.

“What is promising is that this area of research is rapidly evolving, so there should be enough evidence soon to formulate evidence-based guidance for a variety of clinical scenarios,” Hayes said.


Merker JD, Oxnard GO, Compton C, et al. Circulating tumor DNA analysis in patients with cancer: American Society of Clinical Oncology and College of American Pathologists Joint Review [published online March 5, 2018].J Clin Oncol. doi: 10.1200/JCO.2017.76.8671.