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.
Highlights
Cholangiocarcinoma including intrahepatic cholangiocarcinoma (IHCC), extrahepatic cholangiocarcinoma (EHCC) and gallbladder cancer, are rare types of cancer with an incidence of 0.45 to 3.5/100000 in the Western world[1,2,3]
We did not have access to archived tumor tissue material of 1 patient (#18). circulating tumor DNA (ctDNA) sampled during 1st line palliative treatment was available from 11 patients and used for tracking of tumor-specific mutations in ctDNA under therapy. ctDNA sampled during 2nd or 3rd line therapy was available from 5 of the 24 patients
The results obtained from next generation sequencing (NGS) based targeted genotyping of tumor tissue from therapy naive CCA patients are in line with previously published data[16,17,18,19,20]
Summary
Cholangiocarcinoma including intrahepatic cholangiocarcinoma (IHCC), extrahepatic cholangiocarcinoma (EHCC) and gallbladder cancer, are rare types of cancer with an incidence of 0.45 to 3.5/100000 in the Western world[1,2,3]. Pancreatic, biliary and liver cancer patients are frequently pooled in literature, which makes the study results unclear These tumors are different in carcinogenesis, incidence and clinical management and should be viewed as separate entities. Precision medicine could be substantially supported by tools that allow monitoring of the tumor’s molecular profile over the time course of chemotherapy These gaps could be filled by the analysis of ctDNA. The major aim of our study was to evaluate whether ctDNA targeted genotyping is suitable for (i) non-invasive assessment of the tumor-specific mutational profile and (ii) the monitoring of this profile in locally advanced and metastatic CCA undergoing 1st line palliative chemotherapy
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