A blood test capable of detecting molecular signs of liver cancer recurrence months before they become visible on imaging is gaining broader access in the United States. But an important clinical question remains: can identifying recurrence earlier ultimately improve patient outcomes?
On November 3, 2026, Natera announced that Medicare has expanded coverage for its Signatera molecular residual disease (MRD) test in hepatocellular carcinoma (HCC), the most common form of primary liver cancer.
The decision, made through the Centers for Medicare & Medicaid Services (CMS) Molecular Diagnostics Services Program (MolDX), covers serial Signatera testing during post-treatment surveillance for patients with early-stage HCC who have no evidence of disease following surgery.
The expansion follows clinical findings suggesting that personalized circulating tumor DNA (ctDNA) monitoring may identify recurrence considerably earlier than conventional surveillance methods.
Why Earlier Detection Matters in Liver Cancer
Hepatocellular carcinoma remains a major clinical challenge, particularly because recurrence is common even after potentially curative treatment.
According to the American Cancer Society, more than 42,000 new cases of liver cancer are expected in the United States in 2026.
For patients undergoing surgical resection, the risk of recurrence remains substantial. The American Association for the Study of Liver Diseases (AASLD) reports recurrence rates approaching 50–70% within five years.
Current postoperative surveillance relies largely on cross-sectional imaging, including CT or MRI, alongside serum alpha-fetoprotein (AFP) measurements. However, AFP is not elevated in all patients with HCC, and radiological findings can sometimes be difficult to interpret, particularly following liver surgery or transplantation.
This creates an opportunity for molecular surveillance approaches capable of identifying evidence of recurrent disease before conventional methods detect it.
The Clinical Evidence Behind Medicare’s Decision
The Medicare coverage expansion was supported by a study published in JCO Precision Oncology in July 2025, led by Maen Abdelrahim and colleagues.
The retrospective real-world analysis included 125 patients with HCC and 721 plasma samples, evaluating the feasibility of personalized, tumor-informed ctDNA testing for early detection of recurrence and disease monitoring.
The study included patients undergoing surveillance following liver transplantation or surgical resection, as well as smaller groups receiving treatment for recurrent or inoperable disease.
Signatera Versus AFP: What Did the Study Find?
The findings demonstrated differences in recurrence detection performance between ctDNA testing and AFP.
- Sensitivity: 83% for Signatera versus 42% for AFP.
- Specificity: Signatera achieved 100% specificity in the evaluated study population.
- Median lead time: Signatera detected recurrence a median of 7.9 months before imaging-confirmed recurrence, compared with 2.2 months for AFP.
- Maximum lead time: Molecular recurrence was detected up to 16.5 months before imaging-confirmed recurrence.
These results suggest that ctDNA monitoring may provide substantially more time to recognize molecular evidence of relapse.
Importantly, the study also examined the prognostic significance of ctDNA detection following surgery.
Among 34 evaluable patients in the surgical resection cohort, 10 (29.4%) had detectable ctDNA within the postoperative MRD assessment window of 2–12 weeks, and all 10 subsequently experienced clinical recurrence.
Postoperative ctDNA positivity was associated with significantly higher recurrence risk (HR 7.2; 95% CI, 2.6–20; P<0.0001).
During longitudinal surveillance, ctDNA was detected in 10 of 31 evaluable patients (32.3%), all of whom experienced recurrence (HR 18.0; 95% CI, 3.9–85; P<0.0001).
These findings support the potential prognostic value of serial ctDNA monitoring, although the relatively small cohorts and retrospective study design warrant cautious interpretation.
What Clinicians Are Saying
Commenting on the findings supporting the coverage expansion, Maen A. Abdelrahim, Chief of GI Medical Oncology at Houston Methodist Cancer Center and an author of the study, highlighted the limitations of conventional surveillance and the additional information provided by molecular testing.
“Signatera gave us a signal months earlier, and in our study, it helped clarify ambiguous scans.”
Abdelrahim emphasized that AFP can miss recurrences and that interpreting imaging findings following liver surgery or transplantation can be challenging.
From the company’s perspective, Adham Jurdi, Senior Medical Director of GI and Innovations, Medical Affairs, Oncology at Natera, described the Medicare decision as an important step toward improving access to personalized recurrence monitoring for patients with HCC.
How Does Signatera Work?
Signatera is a personalized, tumor-informed ctDNA assay designed to identify molecular residual disease by detecting tumor-specific DNA fragments circulating in the bloodstream.
Unlike conventional serum tumor markers, the test is developed using genomic information from an individual patient’s tumor.
The process involves sequencing tumor tissue to identify patient-specific somatic mutations and designing a customized assay to monitor those mutations in blood samples over time.
In the HCC study, investigators used a personalized 16-plex PCR-based next-generation sequencing assay.
This approach makes it possible to monitor molecular evidence of disease longitudinally, including during periods when conventional imaging shows no detectable recurrence.
The broader development of ctDNA-based monitoring across gastrointestinal malignancies has been examined in OncoDaily’s review of the evidence for ctDNA in GI cancers, which highlights both its prognostic potential and the remaining challenges in demonstrating clinical utility.
Earlier Detection Does Not Yet Mean Better Survival
Although the findings supporting Medicare coverage are encouraging, an important distinction remains between detecting recurrence earlier and demonstrating that earlier detection improves clinical outcomes.
The study established an association between ctDNA positivity and subsequent recurrence, but it did not demonstrate that ctDNA-guided interventions improve overall survival.
Several clinical questions therefore remain:
- Should a positive ctDNA result prompt more frequent imaging when conventional scans remain negative?
- Can molecular recurrence identify patients who would benefit from earlier systemic or locoregional intervention?
- Does acting on ctDNA positivity improve recurrence-free or overall survival compared with conventional surveillance?
- How should clinicians interpret negative ctDNA findings in patients who remain at substantial clinical risk?
Prospective studies evaluating ctDNA-guided management strategies will be important in determining whether molecular surveillance can translate earlier detection into improved patient outcomes.
For now, the newly announced Medicare coverage applies to the specified early-stage postoperative surveillance setting and should not be interpreted as a replacement for established imaging-based follow-up.
A New Step Toward Molecular Surveillance in HCC
The Medicare expansion represents another development in the growing clinical use of tumor-informed ctDNA testing.
In hepatocellular carcinoma, where postoperative recurrence remains common and conventional biomarkers have important limitations, serial molecular surveillance offers an additional method for assessing recurrence risk.
The findings suggest that a personalized blood test can detect molecular evidence of relapse months before conventional imaging. The next challenge is determining how clinicians should act on that information.
The central question is no longer only how early cancer recurrence can be detected, but whether acting on molecular recurrence can change the course of the disease.
Read further on OncoDaily: Beyond ctDNA: Unlocking Tissue Insights in MRD
