Oncologists are increasingly using circulating tumor DNA (ctDNA) testing in clinical practice despite limited endorsement from National Comprehensive Cancer Network (NCCN) guidelines, creating a gap between real-world application and formal recommendations that experts say requires urgent attention.
Eric Lander, MD, site research leader at Minnesota Oncology, highlighted this disconnect during a recent Institute for Value-Based Medicine meeting, noting that practice patterns vary widely even among experts. "NCCN guidelines currently do not endorse consistent ctDNA testing," Lander said. "Although if you actually look at practice patterns of experts, we can take the field of GI [gastrointestinal] oncology as a whole, because that's where most of the data [are] in oncology, at least. There, the practice patterns can vary widely, and experts actually are already implementing this in their clinical practice."
The disparity was evident at a recent ASCO session examining expert ctDNA ordering patterns, where clinicians reported using the technology to guide decision-making in stage 2 colon cancer despite the absence of formal guideline support.
Critical Limitations Hampering Widespread Adoption
Two major limitations continue to challenge ctDNA implementation in clinical practice. First, the field lacks predictive studies demonstrating that treatment modifications based on ctDNA results definitively improve patient outcomes. "We still don't have any great predictive studies that show that modulating your treatment based on ctDNA testing is definitely going to improve patient outcomes as a predictive biomarker," Lander explained.
Second, significant variability exists among ctDNA vendors and their methodologies. The landscape includes both tumor-informed assays, which use patient tumor tissue data, and tumor-uninformed assays that operate independently of tissue analysis. "In general, as a broad generalization, tumor-informed assays are probably better at detecting molecular residual disease," Lander noted. "Yet I've certainly seen providers use tumor-uninformed assays for that purpose."
The lack of standardization extends to study methodologies, with different research efforts employing various ctDNA assays, making cross-study comparisons challenging. Even among vendors offering tumor-informed assays, methodological approaches differ substantially.
Implementation Challenges Across Healthcare Settings
Yang Xia, MD, PhD, from the Department of Respiratory Medicine at the Second Affiliated Hospital Zhejiang University School of Medicine, identified four key logistical challenges facing routine serial ctDNA testing implementation. Speaking at the 2025 World Lung Cancer Conference about monitoring strategies for non-small cell lung cancer with MET mutations, Xia emphasized that standardization remains problematic due to "lack of consensus on optimal panel timing and interpretation."
Turnaround time presents another significant barrier, with substantial geographic variation. "In China, it usually takes 1 week, but in the United States, it may [take up to] 1 month," Xia reported. Cost and reimbursement issues compound these challenges, as "coverage for serous testing is not universal."
Workflow integration represents the final hurdle, requiring coordination of "blood draw processing and data analysis" within existing clinical operations.
Personalized Approach Recommended
Despite these challenges, experts advocate for personalized ctDNA monitoring strategies rather than standardized protocols. Xia recommended "starting with specific testing for early response assessments" and conducting "canonical or permutation panels to identify the resistant mechanism" when resistance is suspected. "Not all patients need broad testing; base [the testing] on clinical context and resource availability," he advised.
Call for Regulatory Reform and Guideline Updates
The current regulatory landscape for ctDNA assays differs markedly from drug approval processes, raising concerns about validation rigor. Lander drew comparisons to immunotherapy approvals, noting that drugs like pembrolizumab and nivolumab "had to go through the same approval process with the FDA by testing your drug and many hundreds of patients to get that approval in many cases. Yet, these assays don't necessarily go through that same amount of rigor."
To address these gaps, experts are calling for comprehensive reforms including updated NCCN guidelines, head-to-head assay comparisons in identical patient populations, and regular reassessment of evolving methodologies. "That comparison will have to be done every few years, because the assay methodologies are changing by the year in many cases," Lander emphasized.
The disconnect between clinical practice and formal guidelines underscores the urgent need for evidence-based recommendations that can guide oncologists in leveraging ctDNA technology while ensuring optimal patient outcomes.
