At the 2024 CCA Summit, Laura Goff, MD, MSCI, MMHC, and Jingquan Jia, MD, PhD, debated the pros and cons of circulating tumor DNA (ctDNA) monitoring in biliary tract cancer (BTC). Dr Goff first debated on using ctDNA monitoring in patients with BTC. Her argument included that, for patients with cholangiocarcinoma (CCA), there is evidence that ctDNA testing can be used to confirm diagnosis, predict recurrence, identify actionable alterations, and deconstruct mechanisms of resistance.1
She gave an example of how ctDNA testing can confirm diagnosis. A study of 69 patients with CCA used a ctDNA 4-gene panel of differently methylated regions (HOXA1, PRKCB, CYP26C1, and PTGDR) and found that this gene panel showed specificity of 93% and sensitivity of 83% for diagnosis of CCA. Mutations were detectable by ctDNA monitoring, even in stage I disease.1,2
Patients with CCA have a very high recurrence rate after both transplant and resection. After surgery and transplant, positive ctDNA can be used as a prognostic factor. A tumor-informed ctDNA assay in patients with resected CCA showed that positive ctDNA before adjuvant chemotherapy resulted in poor recurrence-free survival.1
ctDNA testing can also be used to identify actionable alterations, which is critical to assess patients’ molecular profiles and personalize treatment. In one study, patients with BTC at the Mayo Clinic Comprehensive Cancer Center underwent ctDNA testing, which identified treatment-relevant alterations in 40% to 55% of patients with BTC.3 Dr Goff argued that ctDNA testing is a good method for gene profiling; tissue biopsies are often inadequate for profiling and have a failure rate of 26.8%.1
ctDNA testing cannot only identify actionable alterations; it can also characterize the development of resistance mechanisms. Tracking serial alterations can offer new therapy options or demonstrate the need to switch treatment. For example, in one patient, ctDNA monitoring when on FGFR inhibitor therapy identified point mutations as a mechanism of resistance.1
In summary, Dr Goff explained that ctDNA monitoring should be utilized in the management of patients with BTC, as it can aid in the diagnosis of CCA, can predict recurrence, identify actionable alterations, and characterize the development of resistance mechanisms.1
Conversely, Dr Jia explained the limitations of ctDNA assays, as well as the pitfalls of ctDNA detection in patients with BTC.4 She explained that it is difficult to isolate ctDNA from cell-free DNA (cfDNA) as it exists at low concentrations with only a small fraction derived from the tumor. Concentration of cfDNA varies depending on cancer type, and levels of cfDNA are influenced by trauma, infection, pregnancy, and/or transplant. In addition, levels of ctDNA correlate with tumor burden, which makes it difficult to detect in patients with early-stage cancer or with minimal disease burden.4
Dr Jia also argued that ctDNA testing cannot be used to rule out genomic alterations, as some targetable driver mutations can be missed by ctDNA testing. A retrospective cohort study of >2000 patients with advanced non–small cell lung cancer investigated ctDNA testing prior to starting first-line systemic treatment. Results showed that 63.0% of all patients tested negative for alterations; however, some of those patients underwent reflux tissue testing, and of those who had additional testing, 37% tested positive for alterations.4 In addition, in CCA there is a lower detection rate of FGFR2 fusions in blood. Results from 2 large studies in CCA both independently showed that the rate of FGFR2 fusion detected in blood is significantly lower than FGFR2 fusion detected in tissue.
In addition, low tumor shedding limits ctDNA detection rates in patients with BTC. One study found that the median ctDNA tumor fraction in CCA was low at 1.7%. In patients with advanced BTC, ctDNA was not detected in 16% to 24% of cases.4
Lastly, Dr Jia argued that ctDNA findings, either in a minimal residual disease (MRD) setting or advanced-disease setting, have limited impact on clinical practice. ctDNA MRD positivity has no impact on the type of adjuvant chemotherapy regimen used in patients with BTC, and ctDNA findings do not impact the choice of first-line systemic therapy regimens for patients with advanced BTC.4
In summary, Dr Jia advised that there are many limitations to the use of ctDNA in patients with BTC. Many factors can lead to false-positive and false-negative ctDNA results, and a negative ctDNA result does not ensure that the tumor is negative for alterations. In BTC, low tumor shedding limits ctDNA detection rates, and sensitivity for FGFR2 fusion in ctDNA is low. Currently, ctDNA findings have limited impact on clinical practice.4
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