Evaluating the prognostic impact of IDH mutations in intrahepatic cholangiocarcinoma.

598 Background: Mutations in isocitrate dehydrogenase 1 and 2 ( IDH1 , IDH2 ) are common in intrahepatic cholangiocarcinoma (ICC), but their prognostic value is unclear. Using a large, clinically annotated dataset, we assessed their impact in resected and non-resected ICC. Methods: This was a retrospective study of ICC patients who underwent next-generation sequencing from 2008-2022. Adults treated with curative intent resection (resected) or managed nonoperatively (unresectable) were analyzed. Results: Of 795 patients, 25% had IDH1/2 mutations (80% IDH1 , 20% IDH2 ) ( IDH mut) and 43% underwent resection. High-risk genetic alterations ( TP53 mut, KRAS mut, CDKN2A del) were more frequent in IDH wild-type ( IDH wt) ( IDH mut, OR 2.26; q <0.001) (Table 1). In the entire cohort, median overall survival (OS) was 32 months in IDH mut and 28 months for IDH wt (p=0.2); by contrast, OS was 19 months in patients with high-risk alterations compared to 40 months without (p<0.001). In resected patients, recurrence free survival (RFS) in IDH mut was 20 months vs. 14 months for IDH wt (p=0.018), and OS was 69 months vs. 50 months, respectively (p=0.2); however, after controlling for high-risk genetic alterations, any benefit of IDH mut disappeared (RFS: HR 0.78; p=0.095; OS: HR 0.88; p=0.4). In unresectable patients, progression free survival (PFS) in IDH mut was 9.4 months compared to 9.1 months for IDH wt (p=0.7), and OS was 22 months vs. 18 months, respectively (p=0.13) There remained no significant differences after controlling for high-risk alterations (PFS: HR 1.03; p=0.8; OS: HR 0.94; p=0.6). IDH mutational status was not a significant survival predictor in multivariable models for both resected and non-resected patients. In 42 patients with unresectable IDH mut treated with IDH inhibitors, median OS was 12 months. Conclusions: In this large cohort of resected and non-resected ICC patients, IDH mutations were not an independent predictor of survival, after controlling for high-risk genetic alterations and clinical variables. Thus, IDH status should not be used in isolation to guide prognosis. Gene Mutation OverallN = 795 1 IDH mutN = 202 1 IDH wtN = 593 1 OR 95% CI q-value 2 TP53 151 (19%) 19 (9.4%) 132 (22%) 2.76 1.69, 4.73 <0.001 ARID1A 142 (18%) 51 (25%) 91 (15%) 0.54 0.37, 0.79 0.004 CDKN2A 136 (17%) 24 (12%) 112 (19%) 1.73 1.09, 2.83 0.043 BAP1 121 (15%) 39 (19%) 82 (14%) 0.67 0.44, 1.03 0.069 FGFR2 119 (15%) 6 (3.0%) 113 (19%) 7.69 3.62, 19.9 <0.001 CDKN2B 104 (13%) 20 (9.9%) 84 (14%) 1.50 0.91, 2.58 <jats:td colsp