Charting co-mutation patterns associated with actionable drivers in intrahepatic cholangiocarcinoma

Intrahepatic cholangiocarcinoma (iCCA) is a fatal disease with an overall 5-year survival below 10%. In recent years, iCCA has evolved as a "role model" for precision oncology in gastrointestinal cancers. However, its rarity, paired with its genomic heterogeneity, challenges the development and evolution of targeted therapies. Interrogating large datasets drives better understanding of the characteristics of molecular subgroups of rare cancers and allows identification of genomic patterns that remain unrecognized in smaller cohorts.We performed a retrospective analysis of 6130 patients diagnosed with iCCA from the FoundationCORE database who received diagnostic panel sequencing on the FoundationOne platform. Short variants/fusion-rearrangements and copy number alterations in300 tumor associated genes were evaluated, and the tumor mutational burden (TMB) as well as the microsatellite instability (MSI) status was available for the majority of the cohort.We provide a highly representative cartography of the genomic landscape of iCCA and outline the co-mutational spectra of seven therapeutically relevant oncogenic driver genes: IDH1/2, FGFR2, ERBB2, BRAF, MDM2, BRCA1/2, MET and KRASA detailed knowledge of the most prevalent genomic constellations is fundamental to accelerate therapeutic developments in iCCA. Our study provides a valuable resource for feasibility assessment of clinical trials and subgroup analyses, spurs the development of translationally relevant preclinical models, and generates a knowledge ground to anticipate potential resistance mechanisms to targeted therapies in genomically defined subgroups of iCCA patients.Due to the high frequency of targetable alterations, molecular diagnostics is recommended in patients with biliary tract cancers, and especially in those with intrahepatic cholangiocarcinoma. The identification of an actionable lesion, however, does not guarantee for therapeutic success, and the co-mutational spectrum may act as a critical modifier of drug response. Using a large dataset of comprehensive panel sequencing results from 6130 intrahepatic cholangiocarcinoma patients, we provide a detailed analysis of the co-mutational spectrum of the most frequent druggable genetic alterations, that is meant to serve as a reference to establish genetically relevant preclinical models, develop hypothesis driven combination therapies and identify recurrent genetic profiles.