Advancing early detection and targeted therapy: A comprehensive review of cholangiocarcinoma biomarkers

Background: Cholangiocarcinoma (CCA) is a highly malignant tumor derived from the bile duct epithelium with increasing incidence worldwide. It divides into three subtypes: intrahepatic (iCCA), perihilar (pCCA), and extrahepatic (eCCA). Imaging techniques such as abdominal ultrasound, computed tomography (CT), and magnetic resonance imaging (MRI) can assist in diagnosing CCA. Gemcitabine combined with cisplatin is the first-line treatment for CCA. However, CCA often carries a poor prognosis due to advanced stage at time of diagnosis. Isocitrate dehydrogenase (IDH)1 mutations are the most common targetable alteration in CCA, occurring in 13 the FDA approved ivosidenib for the treatment of IDH1-mutated CCA. Our study aims to highlight the effect of IDH-1 alteration and its response to ivosedinib as compared to the presence of other genomic alterations. Methods: We used cBioPortal for Cancer Genomics server to retrospectively analyze and gather genomic data related to CCA from 2018 to 2024. Our search included five studies, from which we identified 699 cases of iCCA. The prevalence of genetic mutations such as IDH1, IDH2, FGFR2, ARID1A, BRAF, KRAS, and TP53 was obtained. Survival outcomes were extracted with a 95CI) in patients who received ivosedinib therapy. We ensured to include overlapping groups to detect survival outcome superiority or inferiority based on the co-existence of genomic alterations. The Kaplan-Meier curves were conducted for an illustrated presentation of median overall survival (mOS) outcomes. Results: Among the studied cohort, IDH1 mutations were the most frequent, present in 16 cases. Combinations of mutations were also observed, with ARID1A (n=1), BAP1 (n=4), BRAF (n=1), FGFR2 (n=2), KRAS (n=2), TP53 (n=2), and PIK3CA (n=1) alongside IDH1. Survival outcomes varied based on mutation combinations. TP53 and IDH1 co-mutations (n=2) were associated with a mOS of 14.26 months. Co-mutations of ARID1A and IDH1 (n=4) were associated with a mOS of 21.85 months (95 12.55 - NA). Patients with IDH1 mutations alone (n=16) had a mOS of 46.75 months (95 20.87 - NA). While BAP1 and IDH1 co-mutations (n=4) demonstrated a mOS of 63.60 months (95 11.34 - NA). Conclusion: Our study showed that patients with IDH1 mutations, whether isolated or associated with other mutations such as BAP1, in patients who received ivosidenib as part of the treatment regimen, had superior mOS compared with other mutation types. More studies are needed to further elaborate on the effect of genomic alterations, both individually and in combination, on tumor response to therapy.Citation Format: Bayan Khasawneh, Waseem Abdelrahim, Abdullah Esmail, Ebtesam Al-Najjar, Ala Abudayyeh. Advancing early detection and targeted therapy: A comprehensive review of cholangiocarcinoma biomarkers [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Functional and Genomic Precision Medicine in Cancer: Different Perspectives, Common Goals; 2025 Mar 11-13; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2025;85(5 Suppl):Abstract nr A042.