Background: Intrahepatic cholangiocarcinoma (ICC) is the second most prevalent hepatic cancer with 5-year survival rates below 10%. Tumors are often detected in advanced stages. Surgical resection is limited to non-advanced cases. Cytotoxic chemotherapy has only a moderate benefit. Most patients present recurrent ICC. Repeat treatment is life-prolonging but requires early diagnosis. Our preliminary data demonstrate that the proteome of primary ICC enables stratification of recurrence risk. Immune checkpoint blockade is an option but only for a subset of ICC patients.
Hypotheses: (a) after initial treatment blood profiling using genomics or proteomics will enable early diagnosis of recurrent ICC; (b) histomorphological, genomic, and (phospho-)proteomic profiling of primary ICC will yield markers for stratification of (early) recurrence risk; (c) single-cell profiling ICC undergoing immune therapy will uncover molecular markers for response and delayed recurrence.
Methods: We will assemble a multi-center ICC cohort (n > 550). Genomic, (phospho-)proteomic, and histo-morphological profiling will be performed. For ICC cases undergoing immuno-therapy (n > 50) we will perform single-cell RNA-seq and single-cell GET-seq to assess copy number variation, epigenetic landscapes, and chromatin dynamics. Liquid biopsies (blood) obtained from 60 ICC patients will be obtained at 3, 6, and 12 months post-treatment to probe cell-free DNA, circulating tumor cells, and serum proteome for markers of recurrent ICC. Data will be analyzed in an integrated manner by an expert in the field using statistical methods that are adequate for omics-type data.
Results and impact: Proteomic or genomic determinants in primary ICC that are prognostic for recurrence enable tailored follow-up schemes. Circulating markers that signal recurrent ICC enable timely intervention. Cellular profiles indicative of response to immuno-therapy enable tailored therapies even for advanced ICC to delay recurrence.