Circulating tumor DNA status and dynamics predict recurrence in patients with resected extrahepatic cholangiocarcinoma

Background & Aims

Surgery is the only curative therapeutic option for resectable extrahepatic cholangiocarcinoma (eCCA), but recurrence is common, and prognosis is poor. There is an unmet clinical need for improved decision-making regarding adjuvant chemotherapy (ACT). Here we evaluated the usefulness of monitoring longitudinal circulating tumor DNA (ctDNA) for minimal residual disease (MRD) in patients of the STAMP trial, which compares the efficacy of adjuvant capecitabine (CAP) versus gemcitabine plus cisplatin (GemCis).

Methods

Between July 2017 and November 2020, 101 patients were randomized 1:1 to receive GemCis (n=50) or CAP (n=51). Efficacy outcomes were analyzed with an extended follow-up of 19 months from the previous report. From a biomarker cohort of 89 patients, longitudinal plasma samples (n=254) were prospectively collected post-surgery before adjuvant chemotherapy (ACT), and on-ACT at 12 and 24 weeks from cycle 1 day 1 (C1D1). ctDNA was evaluated using a personalized, tumor-informed, 16-plex PCR-NGS assay and was correlated with clinical outcomes.

Results

In the extended follow-up analysis, median disease-free survival (DFS) and overall survival (OS) did not significantly differ between the CAP and GemCis groups. Significantly inferior DFS was associated with ctDNA-positivity before ACT (HR, 1.8; p=0.029), on-ACT at 12 weeks from C1D1 (HR, 7.72; p<0.001), on-ACT at 24 weeks from C1D1 (HR, 5.24; p<0.001), and anytime post-surgery (HR, 3.81; p<0.001). Analysis of pre-treatment to on-treatment ctDNA dynamics revealed that serially ctDNA-negative patients exhibited a significantly longer DFS compared to those with sustained ctDNA-positivity (HR, 6.7; p<0.001) or who turned ctDNA-positive (HR, 5.8; p<0.001).

Conclusion

In patients with resected eCCA, ctDNA status and dynamics predicted recurrence during adjuvant therapy, and may help optimize clinical decision-making.

Impact and implications

The findings from this study highlight the critical role of ctDNA as a prognostic biomarker and monitoring tool for patients with resected extrahepatic cholangiocarcinoma (eCCA). By demonstrating the superiority of ctDNA to predict disease recurrence compared to conventional biomarkers such as CA 19-9 and CEA, this study underscores its potential in guiding decision-making during adjuvant chemotherapy. These results may be crucial to refine post-surgical treatment strategies and improve patient outcomes. The practical application of ctDNA monitoring could lead to more personalized treatment approaches, enabling timely interventions based on minimal residual disease (MRD) status.

Clinical Trial Registration number

NCT03079427