ASCO’s ctDNA guidelines support testing for genetic alterations in select scenarios but do not endorse it for residual disease or recurrence monitoring.
ASCO has published its first clinical practice guideline on circulating tumor DNA (ctDNA) testing in patients with solid tumors or lymphoma, establishing baseline recommendations on when the testing should and should not be used to guide care, according to guidance published in JCO Oncology Practice.¹
The multidisciplinary expert panel based its recommendations on a systematic review of literature published between January 2017 and February 2025, which identified 54 meta-analyses and 22 study reports, including reports of 7 randomized trials. The panel concluded that although the clinical validity of ctDNA testing has been demonstrated across many settings, prospective evidence of clinical utility, including data showing that acting on ctDNA results improves patient outcomes, remains sparse.
“The role of minimal residual disease [MRD] testing in solid tumors is unclear,” lead study authors Christina M. Lockwood, PhD, DABCC, DABMGG, and Stacy W. Gray, MD, AM, and coauthors wrote.
Lockwood is an adjunct associate professor in the Department of Genome Sciences, an associate professor in the Department of Laboratory Medicine and Pathology, and head of the Division of Genetics & Solid Tumors at the University of Washington School of Medicine in Seattle.
Gray is director of Clinical and Scientific Strategy, vice president of System Strategy, and a professor of medical oncology & therapeutics research, population sciences at City of Hope in Duarte, California.
Previously, in 2018, ASCO and CAP conducted a joint systemic review to investigate the value of ctDNA testing, including its clinical validity and utility.2 At that time, the authors determined that a clinical practice guideline on ctDNA was not feasible, and no formal recommendations were published. However, since 2018, the amount of published data on ctDNA testing has increased, and the panel behind the current guideline aimed to provide guidance on this topic amid remaining uncertainty in the field.1
ASCO ctDNA Guideline: Key Recommendations
Recommendation 2 states that ctDNA testing for tumor genetic alterations may be used as a first assessment, a replacement, or in addition to tissue-based testing in 3 scenarios (evidence quality: moderate; strength of recommendation: conditional):
The guidelines emphasized that when ctDNA results are negative, inconclusive, or inconsistent with the clinical scenario, tissue-based confirmation should be sought.
The panel reported that ctDNA testing has high specificity and moderate sensitivity for detecting specific genetic alterations and that its results are generally concordant with those of tissue-based testing. It cited ESR1 mutation testing in breast cancer, which is preferentially performed on ctDNA, as an example of a regulatory-approved indication. A separate good practice statement advised that, outside a clinical trial, ctDNA testing should be offered only if the results could be applied to clinical decision-making, noting that testing to determine clinical trial eligibility is reasonable and appropriate.
Recommendation 4 (evidence quality: low; strength of recommendation: strong) states that ctDNA testing is not recommended as a replacement for any other form of testing except as outlined in recommendations 2 and 3. Recommendation 3 (evidence quality: low; strength of recommendation: conditional) permits ctDNA testing alongside standard-of-care (SOC) testing when a specific, evidence-based action can be taken with the results or when it could resolve conflict or ambiguity in a SOC assessment.
Regarding MRD, the panel identified no studies showing that acting on ctDNA-based MRD results led to improved outcomes, with one potential exception in the phase 3 IMvigor011 trial (NCT04660344), which showed that patients with nonmetastatic muscle-invasive bladder cancer who were not considered candidates for adjuvant chemotherapy and had MRD-positive disease benefited from receiving atezolizumab (Tecentriq) over placebo. The panel also noted that ctDNA-based MRD has shown prognostic associations in solid tumors. For instance, updated data from the GALAXY trial (UMIN000039205) linked postsurgical MRD positivity with an overall survival benefit from adjuvant chemotherapy in patients with resected colorectal cancer liver metastases. Additionally, MRD testing has been evaluated as a prognostic tool in non–small cell lung cancer. However, the ASCO guidelines distinguished such correlations from demonstrated clinical utility. The panel likewise concluded that ctDNA testing cannot currently be recommended for recurrence monitoring and that testing solely for prognosis is not recommended. Recommendation 5 (evidence quality: low; strength of recommendation: strong) advises against using fractional, percentage, or concentration-based measures of ctDNA or total cell-free DNA as a surrogate for disease burden outside a clinical trial.
The guidelines emphasized that clonal hematopoiesis can produce false-positive findings suggesting actionable alterations. Mutations in PIK3CA are nearly always of tumor origin, the panel noted, whereas variants in BRCA1/BRCA2 may arise from clonal hematopoiesis, warranting caution in interpretation. Assays that do not account for clonal hematopoiesis should be selected and interpreted accordingly. The panel added that germline variants may surface on ctDNA assays and that pathogenic variants potentially of germline origin should trigger dedicated germline testing. Because ctDNA levels are frequently low in plasma, only assays specifically optimized for ctDNA analysis should be used, and sensitivity may vary across assays.
The panel described ctDNA testing as a rapidly evolving field and framed the guideline as a foundation for future ASCO panels. It anticipated that subsequent updates may incorporate tumor type–specific recommendations and additional data in the MRD setting as prospective evidence matures.
