Genotyping of circulating tumor DNA in cholangiocarcinoma reveals diagnostic and prognostic information

Abstract

Diagnosis of Cholangiocarcinoma (CCA) is difficult, thus a noninvasive approach towards (i) assessing and (ii) monitoring the tumor-specific mutational profile is desirable to improve diagnosis and tailor treatment. Tumor tissue and corresponding ctDNA samples were collected from patients with CCA prior to and during chemotherapy and were subjected to deep sequencing of 15 genes frequently mutated in CCA. A set of ctDNA samples was also submitted for 710 gene oncopanel sequencing to identify progression signatures. The blood/tissue concordance was 74% overall and 92% for intrahepatic tumors only. Variant allele frequency (VAF) in ctDNA correlated with tumor load and in the group of intrahepatic CCA with PFS. 63% of therapy naive patients had their mutational profile changed during chemotherapy. A set of 76 potential progression driver genes was identified among 710 candidates. The molecular landscape of CCA is accessible via ctDNA. This could be helpful to facilitate diagnosis and personalize and adapt therapeutic strategies.

Molecular targeted therapies: Ready for “prime time” in biliary tract cancer

“…185 In addition, it has been reported that the mutational profile changes during therapy in 63% of patients, which highlights the importance of not relying solely on tissue acquired at time of initial diagnosis when "Precision Medicine" strategies are being explored. 184 The benefit of IDH1 inhibition in IDH1-mutant CCA has now been demonstrated in a phase III clinical trial, 125 which is encouraging in many ways. First, it confirms the feasibility of running randomised clinical trials targeting only a subpopulation of a rare disease, with adequate international collaboration.…”

“…Circulating tumour (ct)DNA in blood showed a concordance of 74% with tissue DNA (92% for patients with iCCA) when a cohort of patients with biliary tract cancer was analysed. 184 Even though this would support access to targeted therapies based on ctDNA findings, this is rarely considered an option in current clinical trials, and some patients may not be able to access a potentially promising therapy due to the lack of "biopsiable" disease. Similarly, sequencing in fine-needle aspiration specimens needs to be improved to allow as many patients as possible to access molecular profiling and "Precision Medicine".…”

Targeted Therapies in Advanced Biliary Tract Cancer: An Evolving Paradigm

“…In this study, 80 patients received molecularly matched therapy and had a significantly longer progression-free survival (HR, 0.60; 95% CI, 0.37-0.99; p = 0.047) than patients who received unmatched treatment. The study reported by Ettrich et al showed that the mutational profile of the 23 available blood-tumor pairs was concordant in 74% of patients, with a higher concordance rate in iCCA (92%) versus eCCA (55%) [36]. These studies suggest that ctDNA-based molecular profiling is feasible and can be clinically useful in patients with BTC.…”

“…However, a tumor tissue sample for genomic profiling is not available in a large number of patients, which underscores the importance of exploring ctDNA-based genomic profiling. As discussed earlier, ctDNA-based profiling has a high concordance rate with tissue-based profiling [35,36]. As ctDNA-based genomic profiling becomes standardized and readily available, patient enrollment in clinical trials based on ctDNA profiling will help further advancement in this field.…”

Translating Biomarkers of Cholangiocarcinoma for Theranosis: A Systematic Review

“…To improve these poor outcomes, discovery of new diagnostic markers, development of targeted therapies to improve the translation of new strategies such as nanomedicine-based technology, and predictive markers to determine response to therapy should be explored. There has been a recent push towards the identification of genetic drivers of CCA progression and this may reveal specific markers which could expedite the development of more effective and individualized therapies [ 10 , 11 ].…”