Evaluating the Prognostic Impact of IDH Mutations in Intrahepatic Cholangiocarcinoma.

Abstract

Isocitrate dehydrogenase 1 and 2 (<i>IDH1</i> and <i>IDH2</i>) 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. 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. Of the 795 patients analyzed, 25% had <i>IDH1/2</i> mutations (<i>IDH</i>mut) and 43% underwent resection. Median overall survival (OS) of the cohort was 32 months in <i>IDH</i>mut and 28 months for <i>IDH</i>wt (<i>P</i> = .2). High-risk genetic alterations (<i>TP53</i>mut, <i>KRAS</i>mut, and <i>CDKN2A</i>del) were more frequent in <i>IDH</i> wild-type (<i>IDH</i>wt; odds ratio, 2.26; q < 0.001). OS was 19 months in patients with high-risk alterations versus 40 months in patients without (<i>P</i> < .001). In resected patients, recurrence-free survival (RFS) in <i>IDH</i>mut was 20 months versus 14 months for <i>IDH</i>wt (<i>P</i> = .018), and OS was 69 months versus 50 months, respectively (<i>P</i> = .2). However, after controlling for high-risk alterations, the potential benefit of <i>IDH</i>mut was no longer apparent (RFS: hazard ratio [HR], 0.78; <i>P</i> = .095; OS: HR, 0.88; <i>P</i> = .4). In unresectable <i>IDH</i>mut patients, progression-free survival was 9.4 months versus 9.1 months for <i>IDH</i>wt (<i>P</i> = .7), and OS was 22 months versus 18 months, respectively (<i>P</i> = .13). There remained no differences after controlling for high-risk alterations. <i>IDH</i> status was not a significant survival predictor in multivariable models. In this cohort of patients with ICC, <i>IDH</i>mut was not an independent predictor of survival, after controlling for high-risk alterations and clinical variables. <i>IDH</i> mutational status alone should, therefore, not be used to guide prognosis.