The use of tests that assess genomic variants in circulating tumor DNA (ctDNA) is on the rise. A new joint review from the American Society of Clinical Oncology (ASCO) and the College of American Pathologists (CAP) has provided an assessment of current evidence about the use of such ctDNA tests in oncology. The review also lays out a framework for future research and clinical practice guidelines to help better inform clinical practice.1

Jason D. Merker, MD, PhD, FCAP, College of American Pathologists.

Jason D. Merker, MD, PhD, FCAP, College of American Pathologists.

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

Analysis of ctDNA enables clinicians to assess the characteristics of a patient’s tumor through a simple blood test, often referred to as a ‘liquid biopsy.’ The term ‘liquid biopsy’ may refer to assays that analyze proteins, DNA, or cancer cells that circulate in the blood. Recently, it has been used in reference to mutations found in ctDNA. Compared to traditional biopsies, which involve removing a piece of tumor tissue from the body, a liquid biopsy is less invasive and is associated with fewer potential complications.

Despite growing excitement over the use of liquid biopsies in oncology—with possible applications including cancer screening, informing treatment decisions, and monitoring response to treatment—the strategy raises a number of questions.

  • Preanalytical considerations. How should the samples for liquid biopsies be collected and handled—and how do these techniques differ among different types of tests?
  • Analytical validity. How well does the test perform? Can the test detect and measure the presence of a biomarker accurately, reproducibly, and reliably?
  • Clinical validity. Do the results of the test accurately divide one population of patients into two or more separate groups? Can the test accurately detect a pathologic state or predict outcomes for groups of patients whose test results differ?
  • Clinical utility. Is it proven that using the results of the test to make clinical decisions actually benefits the patient and does not pose a risk?
Daniel F. Hayes, MD, FACP, FASCO, American Society of Clinical Oncology.

Daniel F. Hayes, MD, FACP, FASCO, American Society of Clinical Oncology.

“Like all new things in medicine, the use of ctDNA assays in routine cancer care requires evidence of clinical utility,” says Daniel F. Hayes, MD, FACP, FASCO, and an ASCO member of the expert panel that developed the review. “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.”

To conduct the review, a multidisciplinary panel of experts appointed by ASCO and CAP examined evidence from 77 relevant articles published from January 2007 to March 2017. The review was limited to the analysis of literature focused on sequence and gene copy number variants in ctDNA from solid tumors. Key findings from the review include the following:

  • At this time, there is not enough evidence to know whether use of the majority of ctDNA tests is justified for patients with advanced cancer, outside of screening for participation in, or during, a clinical trial.
  • Evidence supports the use of ctDNA tests to screen potential candidates for participation in a clinical trial, or to carry out testing during a clinical trial. But there is not enough evidence at this time to support the routine use of ctDNA tests for cancer screening, early-stage cancer, making treatment decisions, monitoring how well a treatment is working, or finding remaining cancer cells after treatment.
  • There are inconsistent findings when testing with liquid biopsies versus testing with tumor tissue, so negative liquid biopsy results should be confirmed with tumor tissue genotyping.

To date, only a single liquid biopsy test has shown sufficient clinical utility to earn FDA approval—the Roche Cobas assay for mutations in the EGFR gene, to be used in non-small-cell lung cancer. Nevertheless, a variety of liquid biopsy tests have been made available for use in clinical practice.

“There is very significant potential for many different applications of ctDNA tests in the future,” says Merker. “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.”

When used for the purpose of informing treatment decisions, Merker stresses, ctDNA test results will have to be integrated with other pieces of information to come up with the best possible option for the patient.

According to the associations, increasing use of liquid biopsy tests in clinical care highlights the clear need for data to inform clinical decisionmaking, which will require more robust research in the field. As more evidence is published, ASCO and CAP will be poised to provide clinical practice recommendations either in the form of provisional clinical opinions or a formal clinical practice guideline.

“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,” says Hayes.


  1. Merker JD, Oxnard GR, Compton C, et al. Circulating tumor DNA analysis in patients with cancer: American Society of Clinical Oncology and College of American Pathologists joint review. J Clin Oncol. Advanced online publication, March 5, 2018; doi: 10.1200/JCO.2017.76.8671.