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Cancer Genomics and Diagnostics / Lung Cancer Treatments and Mutations / Cancer Cells and Metastasis · Journal article
JAMA · August 10, 2026
Well-designed and adequately powered for the question it asks.
Circulating tumor DNA (ctDNA) analysis is strongly associated with disease-free and overall survival outcomes in cancer patients, with consistent hazard ratios across treatment settings. A prospective cohort demonstrates detection of molecular relapse approximately 8.7 months earlier than standard imaging. However, the text acknowledges that optimal timing of testing, management of ctDNA-positive patients without radiographic disease, and cost-effectiveness of serial monitoring remain unclear.
Meta-analysis and prospective cohort study. Meta-analysis: patients with urothelial carcinoma undergoing treatment. Prospective cohort: patients with colorectal cancer receiving standard-of-care surveillance.. Intervention: Circulating tumor DNA (ctDNA) sequencing and analysis to detect genetic variants, measure ctDNA levels, and identify minimal residual disease. Compared with: Standard-of-care imaging surveillance (in prospective cohort); prognostic association examined in meta-analysis.
In meta-analysis of 1725 urothelial carcinoma patients, higher ctDNA levels associated with hazard ratio for disease-free survival of 20.69 (95% CI 9.63–44.43; P <0.001) In adjuvant setting, higher ctDNA associated with hazard ratio for disease-free survival of 4.51 (95% CI 3.04–6.69; P <0.001) In metastatic disease setting, higher ctDNA associated with hazard ratio for overall survival of 2.0 (95% CI 1.25–3.38; P =0.004)
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ctDNA monitoring enables earlier detection of cancer recurrence and guides molecularly directed therapy selection, but clinicians should recognize that optimal testing frequency, interpretation of ctDNA-positive results without radiographic evidence, and cost-effectiveness remain undefined. Clinical adoption should be informed by institutional protocols and ongoing trial evidence.
A rigorous meta-analysis of 1725 patients demonstrates that ctDNA levels are strongly associated with disease-free and overall survival across multiple cancer settings, with consistent hazard ratios and statistical significance, though optimal clinical application remains incompletely defined.
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ctDNA monitoring enables earlier detection of cancer recurrence and guides molecularly directed therapy selection, but clinicians should recognize that optimal testing frequency, interpretation of ctDNA-positive results without radiographic evidence, and cost-effectiveness remain undefined. Clinical adoption should be informed by institutional protocols and ongoing trial evidence.
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Importance: Circulating tumor DNA (ctDNA) evaluation, in which fragments of tumor DNA circulating in a patient's bloodstream are extracted and analyzed, can be used to monitor cancer progression, detect residual cancer after treatment, and identify genetic changes within cancer cells that could affect treatment response. Observations: ctDNA sequencing identifies cancer cell gene variants that inform the selection of molecularly directed therapies in several types of cancer, including non-small cell lung cancer, colorectal cancer, and breast cancer. Increases or decreases in ctDNA levels can indicate treatment response (ctDNA decrease) or cancer cell resistance and recurrence (ctDNA increase). Detecting ctDNA after curative intent therapy correlates strongly with cancer recurrence and poorer survival. In a meta-analysis of 1725 patients undergoing treatment for urothelial carcinoma, higher ctDNA levels were associated with poorer survival outcomes (hazard ratio for disease-free survival, 20.69 [95% CI, 9.63-44.43]; P <.001). This association was also observed in adjuvant settings (hazard ratio for disease-free survival, 4.51 [95% CI, 3.04-6.69]; P <.001) and in patients undergoing systemic therapy for metastatic disease (hazard ratio for overall survival, 2.0 [95% CI, 1.25-3.38]; P =.004; absolute rates not available). ctDNA detection may indicate minimal residual disease, defined as cancer cells detectable only by highly sensitive testing (eg, detection of 1 cancer cell in a population of 1 million normal cells) before disease progression is identified with imaging. Detecting an early increase in ctDNA and/or a novel sequence variation that may confer resistance to standard treatment can guide therapeutic decisions, such as changing to a new treatment, before tumor progression is detectable with conventional imaging. In a prospective cohort study of 130 patients with colorectal cancer, molecular relapse of disease was detected approximately 8.7 months earlier compared with standard-of-care imaging surveillance (5.5 months vs 14.2 months; P <.001). Similarly, patients with undetectable ctDNA levels may be able to discontinue therapy and be monitored, preventing potentially unnecessary exposure to chemotherapy that may have substantial adverse effects. However, the optimal timing of ctDNA testing, management of positive results in the absence of radiographic disease, and the cost-effectiveness of serial monitoring remain unclear. Conclusions and Relevance: ctDNA, consisting of small DNA fragments from cancer cells that can be analyzed in human blood, can help clinicians monitor cancer progression, detect minimal residual cancer, and identify genetic variants that may help guide treatment decisions. Use of ctDNA may help select best treatment and timing of therapy for a patient with cancer, but optimal clinical applications remain unclear.
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