Cholangiocarcinoma (CCA) is the second most common liver cancer and a leading cause of cancer-related death. Mutations in IDH1/2 (IDH1/2 mut) are found in approximately 15% of intrahepatic CCA, constituting a unique molecular entity. This study aims to provide a detailed clinical and molecular characterisation of IDH1/2 mut CCA.
We retrospectively reviewed genomically profiled CCA patients treated at a single institution from 2011-2021. The FoundationOne CDx panel or an in-house exome-targeted panel was used for genomic profiling. Overall survival (OS) was the primary endpoint and progression-free survival (PFS) was the secondary endpoint. Samples from advanced CCA patients were used to generate patient-derived xenografts (PDXs) models. H&E staining, immunohistochemistry, targeted exome sequencing and genome-wide RNA-sequencing (RNAseq) analyses were performed to molecularly profile PDXs and compare the expression of wild type IDH1 (IDH1 wt) and IDH1 mut.
Of the 357 CCA patients identified, 77 were IDH1/2 mut (21.5%). Patients with IDH1/2 mut were younger (median 59 vs 62 years, p<0.001), had a higher prevalence of female patients (64.9 vs 44.5%, p=0.002), more advanced at the time of diagnosis (stage IV 71.4 vs 56.7%, p=0.02), less likely to have undergone resection of the primary tumour (22.1 vs 44.5%, p<0.001) or received adjuvant treatment (7.8 vs 25.6%, p=0.001). We found no significant difference in OS between IDH1/2 mut and IDH1/2 wt CCA (19.5 vs 15.1mo, HR 0.87, 95% CI 0.65-1.14, p=0.34). CCA patients with IDH1/2 mut who received second-line targeted therapy (n=25) showed similar PFS and OS to those treated with second-line chemotherapy (n=34) (median PFS 2.83 vs 2.71mo, HR 0.78, 95% CI 0.45-1.38, p=0.4; median OS 11.9 vs 7.5mo, HR 0.89, 95% CI 0.51-1.56, p=0.7). The advanced CCA PDX collection accurately recapitulated the histopathological and molecular features of the original CCA tumours. RNAseq of PDX revealed significant downregulation of immune-related genes in IDH1 mut CCA PDXs.
Compared to second-line chemotherapy, current targeted therapy show comparable clinical benefit in CCA patients with IDH1/2mut. Molecular profiling of CCA PDXs suggests that IDH1 mut is potentially associated with CCA immune alterations.
Clinical trial identification
Legal entity responsible for the study
Vall d'Hebron Institute of Oncology (VHIO).
H. Verdaguer: Financial Interests, Institutional, Funding, Outside the submitted work: Eisai, Merck, AstraZeneca. T. Macarulla: Financial Interests, Personal, Other, Outside the submitted work: Swedish Orphan Biovitrum (SOBI) AB, Ability Pharmaceuticals SL, Advance Medical HCMS, Aptitude Health, Basilea Pharma, Baxter, BioLineRX Ltd, Celgene, Eisai, Genzyme, Got It Consulting SL, IATTGI, Imedex, Ipsen Bioscience, Laboratorios Menarini, Lilly, Marketing Farmacéutico & Investigación Clínica SL, MDS, Medscape, Monte Verde SA, Novocure, Paraxel, PPD Development, QED Therapeutics, Roche Farma, TRANSWORLD EDITORS SL, Zymeworks; Financial Interests, Personal, Other: AstraZeneca, Servier, Sanofi-Aventis, Incyte. All other authors have declared no conflicts of interest.