Circulating tumor DNA analysis guiding adjuvant treatment in resected stage III cholangiocarcinoma: a case report

Abstract

Background: Cholangiocarcinoma (CCA) is a rare and aggressive gastrointestinal cancer. Unfortunately, 60% to 70% of early-stage CCA patients experience disease recurrence after curative resection and standard adjuvant therapy. Currently, there is no reliable tool to identify CCA recurrence before radiographic detection. Longitudinal monitoring of circulating tumor DNA (ctDNA) has shown promising value in molecular identification of relapse prior to conventional surveillance in other solid tumors. However, there is a scarcity of data on ctDNA in CCA after curative surgery.

Case description: An 81-year-old male with stage 3A intrahepatic CCA achieved radiographic remission after curative resection and was started on standard adjuvant capecitabine on post-operative day (POD) 50. Tumor-informed ctDNA tested positive on two consecutive occasions, with the titer increasing from 0.16 mean tumor molecule (MTM)/mL on POD 92 to 0.80 MTM/mL on POD 183, despite being on capecitabine. carbohydrate antigen 19-9 (CA19-9) also continued to increase from 175.6 U/mL on POD 92 to 7,594.9 U/mL on POD 217. Notably, surveillance computed tomography (CT) scans showed no evidence of disease (NED) on POD 126, 186, and 211. Molecular profiling and next-generation sequencing (NGS) panels from CCA tissue revealed microsatellite instability-high (MSI-H). After extensive discussions with the patient regarding the rising ctDNA titer despite being on capecitabine for nearly 6 months, we initiated pembrolizumab on POD 224 prior to radiographic recurrence. Given the tumor is MSI-H, and the preferred toxicity profile compared to the front-line chemotherapy option for CCA, we started pembrolizumab. ctDNA became undetectable, and CA19-9 returned to the reference range with pembrolizumab. As of the last follow-up on POD 876, the patient has continued pembrolizumab without noticeable side effects, and imaging continues to show NED, with persistent negative ctDNA and normal CA19-9 levels.

Conclusions: This case demonstrates the potential utility of tumor-informed ctDNA in CCA as (I) an early detection tool before radiographic recurrence; (II) a response monitoring tool as a surrogate biomarker that can guide therapy optimization; and (III) shows that early intervention with immunotherapy or potentially targeted agents based on ctDNA may lead to improved survival outcomes.

Keywords: Cholangiocarcinoma (CCA); case report; circulating tumor DNA (ctDNA); ctDNA-guided therapy.

Figure 1

Patient longitudinal plot based on tumor-informed multiplex PCR-NGS ctDNA assays. (I) ctDNA positive on POD 92, which implies MRD or relapse. This illustrates the early detection of recurrence by longitudinal ctDNA monitoring prior to radiographic surveillance. (II) ctDNA titer increased despite capecitabine, which implies the tumor is refractory to the treatment. (III) ctDNA was cleared by pembrolizumab, which reflects that the disease responded well to the agent. This illustrates well that the dynamics of ctDNA enables optimization of the treatment ahead of radiographic response. (IV) Long-term radiographic and molecular remission with almost 2 years with pembrolizumab. This long-term survival outcome could be due to the early initiation of pembrolizumab based on ctDNA positivity. ctDNA, circulating tumor DNA; CA19-9, carbohydrate antigen 19-9; NED, no evidence of disease; PCR, polymerase chain reaction; NGS, next-generation sequencing; POD, post-operative day; MRD, molecular residual disease.