Using ctDNA as a Predictive Biomarker in Patients With CCA: Subanalysis of the STAMP Trial

Prompt identification of molecular residual disease (MRD) through detection of circulating tumor DNA (ctDNA) can affect the management of a patient with cancer1; however, information is limited regarding the utility of identifying MRD using ctDNA in patients with resected cholangiocarcinoma (CCA).²

STAMP was a randomized, phase 2 trial that investigated the role of adjuvant gemcitabine/cisplatin (GemCis) therapy in patients with resected, lymph node–positive, extrahepatic CCA and demonstrated no differences in recurrence-free survival and overall survival between the 2 arms.³ At the 2023 ASCO annual meeting, Changhoon Yoo, MD, PhD, presented a subanalysis of the STAMP trial, which aimed to evaluate the feasibility of monitoring ctDNA to predict the risk of recurrence in patients with resected CCA who were enrolled in the STAMP trial.²

Plasma samples were collected at 3 different time points postsurgery: preadjuvant chemotherapy (baseline n=89), during adjuvant chemotherapy after 5 cycles of treatment (n=88), and during adjuvant chemotherapy after 8 cycles of treatment (n=77); collected plasma samples were <2 mL in volume and deviated from the standard Clinical Laboratory Improvement Amendments standard operating procedures, which may have impacted ctDNA detection. A total of 254 plasma samples were collected from 89 patients; 37 had stage II, 40 had stage III, and 12 had stage IV CCA.² Of the 89 patients, 49% received capecitabine and 51% received GemCis. At the MRD time point (baseline, preadjuvant chemotheray, n=89), 22 (24.7%) patients were ctDNA positive. These patients had significantly shorter disease-free survival (DFS) compared with ctDNA-negative patients (hazard ratio [HR], 1.8; 95% confidence interval [CI], 1.06-3.07; P=.029).² In all, 17 patients were ctDNA positive during adjuvant chemotherapy at 5 cycles of treatment, and 15 patients were ctDNA positive during adjuvant chemotherapy at 8 cycles of treatment; both of these groups had a significantly shorter DFS compared with ctDNA-negative patients (HR, 7.72; 95% CI, 4.09-14.56; P<.001 and HR, 5.24; 95% CI, 2.75-9.97; P<.001, respectively).² Throughout the course of the study, 56 patients remained ctDNA negative, 12 patients converted to ctDNA negative, 11 patients converted to ctDNA positive, and 10 patients were persistently ctDNA positive. Patients who remained or turned ctDNA positive demonstrated significantly worse DFS compared with patients who were persistently ctDNA negative (HR, 6.7; 95% CI, 3.1-14.3; P<.⁰⁰¹ and HR, 5.8; 95% CI, 2.8-11.9; P<.001, respectively). The researchers also analyzed how well clinicopathological factors predicted DFS. Among these factors, only ctDNA positivity at the adjuvant-chemotherapy-after-5-cycles-of-treatment time point and a pathological grade of G3 were significantly associated with poor DFS (HR, 6.97; 95% CI, 3.56-13.6; P<.⁰⁰¹ and HR, 3.38; 95% CI, 1.27-9; P=.015, respectively), which demonstrated significant prognostic capabilities for DFS.²

Although there were suboptimal plasma volumes and an altered blood collection protocol, ctDNA positivity was still associated with significantly reduced DFS compared with ctDNA negativity. In addition, ctDNA outperformed the other factors in its ability to predict DFS. This analysis is a pioneer in showcasing the clinical impact of using ctDNA-based MRD detection and monitoring in patients with CCA in the adjuvant setting. This indicates that ctDNA monitoring could potentially enhance the decision-making process for patients with resected CCA; however, it is imperative to conduct more expansive prospective research to affirm the validity of these findings.²

References

1. Kasi PM, Fehringer G, Taniguchi H, et al. Impact of circulating tumor DNA-based detection of molecular residual disease on the conduct and design of clinical trials for solid tumors. JCO Precis Oncol. 2022;6:e2100181.
2. Yoo C, Laliotis G, Jeong H, et al. Utility of circulating tumor DNA (ctDNA) as a predictive biomarker for disease monitoring in patients with cholangiocarcinoma before and during adjuvant chemotherapy: sub-analysis of the randomized phase 2 STAMP trial. Poster presented at: ASCO 2023 Annual Meeting, June 2-6; Chicago, IL.
3. Jeong H, Kim KP, Jeong JH, et al. Adjuvant gemcitabine plus cisplatin versus capecitabine in node-positive extrahepatic cholangiocarcinoma: the STAMP randomized trial. Hepatology. 2023;77(5):1540-1549.