Using ctDNA as a Predictive Biomarker in Patients With CCA Before and During Chemotherapy: Subanalysis of the Phase 2 STAMP Trial

In a subanalysis of the STAMP trial, circulating tumor DNA was assessed for its clinical effectiveness in detecting molecular residual disease in patients with cholangiocarcinoma.

Prompt identification of molecular residual disease (MRD) through detection of circulating tumor DNA (ctDNA) can affect the management of patients with cancer¹; however, there is insufficient knowledge on the utility of identifying MRD using ctDNA in patients with resected cholangiocarcinoma (CCA).²

STAMP was a randomized, phase 2 study that examined the effect of adjuvant gemcitabine/cisplatin (GemCis) treatment in patients with resected, lymph node–positive, extrahepatic CCA and found no differences between the 2 arms in terms of recurrence-free survival and overall survival.³ Changhoon Yoo, MD, PhD, presented a subanalysis of the STAMP trial at the 2023 ASCO annual conference. The subanalysis examined the feasibility of monitoring ctDNA to assess the risk of recurrence in patients with resected CCA.²

Plasma samples were collected at 3 different time points post-surgery: 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 CCA, 40 had stage III, and 12 had stage IV.² Of the 89 patients, 49% received capecitabine and 51% received GemCis. At the MRD time point (baseline, preadjuvant chemotherapy, 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

ctDNA positivity was linked to a substantially lower DFS compared with ctDNA negativity, despite inadequate plasma volumes and a modified blood collection protocol. 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 and suggests that ctDNA monitoring may benefit patients with resected CCA in terms of decision-making. Further prospective studies are required, however, to confirm 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, 2023; 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. . 2023;77(5):1540-1549.