Purpose: Intrahepatic cholangiocarcinoma (IHC) are heterogeneous tumors. The hidden-genome classifier, a supervised machine learning–based algorithm, was used to quantify tumor heterogeneity and improve classification. Experimental Design: A retrospective review of 1370 patients with IHC, extrahepatic cholangiocarcinoma (EHC), gallbladder cancer (GBC), hepatocellular carcinoma (HCC), or biphenotypic tumors was conducted. A hidden-genome model classified 527 IHCs based on genetic similarity to EHC/GBC or HCC. Genetic, histologic, and clinical data were correlated. Results: 410 IHC (78%) had >50% genetic homology with EHC/GBC; 122 (23%) had >90% homology (“biliary-class”), characterized by alterations of KRAS, SMAD4, and CDKN2A loss. 117 IHC (22%) had >50% genetic homology with HCC; 30 (5.7%) had >90% homology (“HCC-class”), characterized by TERT alterations. Patients with biliary- vs. non-biliary-class IHC had median overall survival (OS) of 1 year (95% CI: 0.77, 1.5) vs. 1.8 years (95% CI: 1.6, 2.0) for unresectable disease and 2.4 years (95% CI: 2.1, NR) vs. 5.1 years (95% CI: 4.8, 6.9) for resectable disease. Large-duct-IHC (n=28) was more common in the biliary-class (n=27); HCC-class was comprised mostly of small-duct-IHC (64%, p=0.02). The hidden-genomic classifier predicted OS independent of FGFR2 and IDH1 alterations. By contrast, the histology subtype did not predict OS. Conclusions: IHC genetics form a spectrum with worse OS for tumors genetically aligned with EHC/GBC. The classifier proved superior to histologic subtypes for predicting OS independent of FGFR2 and IDH1 alterations. These results may explain the differential treatment responses seen in IHC and may direct therapy by help stratifing patients in future clinical trials.

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