ctDNA Assay Shows High Specificity for Post-Transplant Liver Cancer Recurrence

A personalized, tumor-informed circulating tumor DNA (ctDNA) assay demonstrated 100% specificity and 75% sensitivity for detecting cancer recurrence after liver transplantation in patients with hepatocellular carcinoma (HCC) or cholangiocarcinoma (CCA), according to findings from a prospective, single-center study published in the Journal of Gastrointestinal Oncology.¹ The study evaluated 100 ctDNA assays performed on 38 patients who underwent liver transplantation for primary liver cancer at Houston Methodist Hospital.

What were the key findings on ctDNA test performance?

Among the 38 patients, investigators performed 100 ctDNA assays, yielding 6 positive results, 85 negative results, and 9 results deemed insufficient to process (ITP). Recurrence occurred in 6 patients (15.8%); of these, ctDNA was positive in 3 patients, negative in 1, and ITP in 2.

Excluding ITP results (n = 31), the ctDNA assay achieved a sensitivity of 75% (95% CI, 19%-99%), specificity of 100% (95% CI, 87%-100%), negative predictive value of 96.4% (95% CI, 82%-100%), and positive predictive value of 100% (95% CI, 29%-100%). Standard-of-care biomarkers (alpha-fetoprotein [AFP] for HCC or carbohydrate antigen 19-9 [CA19-9] for CCA) in the same population showed a sensitivity of 75% (95% CI, 19%-99%) and specificity of 93% (95% CI, 76%-99%), with no statistically significant difference between ctDNA and standard biomarkers in sensitivity (P > .99) or specificity (P = .16).

When ctDNA, AFP, and CA19-9 results were considered jointly, sensitivity rose to 100% (95% CI, 54%-100%), with a specificity of 94% (95% CI, 79%-99%). Only 1 patient had ctDNA positivity that preceded imaging-based recurrence diagnosis; in 5 of the 6 patients who recurred, imaging detected recurrence before ctDNA did.

The median recurrence-free survival for the cohort was 583 days (IQR, 368-931), and median overall survival was 728 days (IQR, 411-1087). The overall ITP rate was approximately 10% (n = 9/100), primarily attributable to insufficient tumor tissue (8 of 9 ITP results), and was significantly associated with receipt of pre-transplant locoregional therapy as well as lower tumor stage and poorer differentiation on explant pathology (P < .05 for each).

How was the ctDNA surveillance study designed?

Investigators prospectively identified 38 patients undergoing liver transplantation for primary liver cancer between April 2018 and February 2023 at a single center. Of the patients, 33 had HCC, 4 had CCA, and 1 had mixed HCC-CCA. A personalized ctDNA assay (Signatera) was developed for each patient using whole exome sequencing of explanted tumor tissue to select up to 16 somatic, clonal single nucleotide variants; peripheral blood samples with 2 or more of these variants detected were defined as ctDNA positive. Testing was intended to occur every 3 months for 2 years and then every 6 months for up to 5 years after transplant, alongside standard-of-care cross-sectional imaging and AFP/CA19-9 testing on the same schedule.

What did the study authors conclude about ctDNA’s clinical role?

In their discussion, the study authors noted that ctDNA’s specificity and positive predictive value exceeded its sensitivity and negative predictive value, and that its specificity was numerically, though not statistically significantly, greater than that of AFP or CA19-9. The authors wrote that given this pattern, ctDNA “may better serve as a confirmatory test” for situations of diagnostic uncertainty in standard-of-care surveillance, rather than as a standalone screening tool.¹

The authors also pointed to 2 retrospective abstracts presented at the 2022 American Society of Clinical Oncology (ASCO) Annual Meeting that explored peritransplant ctDNA testing in HCC, one evaluating pre- and post-transplant ctDNA in 74 patients and the other evaluating pre-transplant ctDNA alone in 45 patients. In both, ctDNA detection was associated with recurrence but not with overall survival.^2,3

In their conclusion, the study authors stated that the high specificity and low sensitivity observed in this study suggest a role for ctDNA as a confirmatory or diagnostic adjunct that could reduce the need for invasive tissue biopsy when other surveillance modalities are inconclusive, cautioning that additional prospective studies are needed to determine how best to incorporate these tests into surveillance protocols before clinical adoption.

References

1. Abdelrahim M, Connor AA, Esmail A, et al. Tumor-informed circulating tumor DNA assay for surveillance post-liver transplantation in patients with hepatocellular and cholangiocarcinoma. J Gastrointest Oncol. 2025;16(4):1573-1585. doi:10.21037/jgo-24-791
2. Huang A, Guo DZ, Zhang X, et al. Application of circulating tumor DNA for prediction and surveillance of tumor recurrence after liver transplantation: a pilot study. J Clin Oncol. 2022;40(16_suppl):e16149. doi:10.1200/JCO.2022.40.16_suppl.e16149
3. Jiang N, Zeng X, Tang J, et al. Circulating tumor DNA is a potential prognostic risk factor of recurrence in patients with hepatocellular carcinoma treated by liver transplantation. J Clin Oncol. 2022;40(16_suppl):e16196. doi:10.1200/JCO.2022.40.16_suppl.e16196