Evaluating the Prognostic Impact of IDH Mutations in Intrahepatic Cholangiocarcinoma

PURPOSE Isocitrate dehydrogenase 1 and 2 ( IDH1 and IDH2 ) mutations are common in intrahepatic cholangiocarcinoma (ICC), but their prognostic value is unclear. Using a large data set, we assessed their impact in resected and nonresected ICC. METHODS Adults from two medical centers (MSKCC and Erasmus) with ICC treated with curative-intent resection (resected) or managed nonoperatively (unresectable) who underwent next-generation sequencing were analyzed retrospectively. Kaplan-Meier and Cox regressions assessed the impact of IDH status on outcomes. RESULTS Of the 795 patients analyzed, 25% had IDH1/2 mutations ( IDH mut) and 43% underwent resection. Median overall survival (OS) of the cohort was 32 months in IDH mut and 28 months for IDH wt ( P = .2). High-risk genetic alterations ( TP53 mut, KRAS mut, and CDKN2A del) were more frequent in IDH wild-type ( IDH wt; odds ratio, 2.26; q < 0.001). OS was 19 months in patients with high-risk alterations versus 40 months in patients without ( P < .001). In resected patients, recurrence-free survival (RFS) in IDH mut was 20 months versus 14 months for IDH wt ( P = .018), and OS was 69 months versus 50 months, respectively ( P = .2). However, after controlling for high-risk alterations, the potential benefit of IDH mut was no longer apparent (RFS: hazard ratio [HR], 0.78; P = .095; OS: HR, 0.88; P = .4). In unresectable IDH mut patients, progression-free survival was 9.4 months versus 9.1 months for IDH wt ( P = .7), and OS was 22 months versus 18 months, respectively ( P = .13). There remained no differences after controlling for high-risk alterations. IDH status was not a significant survival predictor in multivariable models. CONCLUSION In this cohort of patients with ICC, IDH mut was not an independent predictor of survival, after controlling for high-risk alterations and clinical variables. IDH mutational status alone should, therefore, not be used to guide prognosis.