Isocitrate dehydrogenase 1 mutations in biliary tract cancer patients in Spanish RETUD registry.

Abstract

500 Background: Isocitrate dehydrogenase 1 mutations (IDH1mut) define a distinct molecular subtype of biliary tract cancer (BTC). We characterized the epidemiology of a cohort of BTC patients (pt) harboring pathogenic IDH1mut, treatment patterns and efficacy outcomes (EO). Methods: We evaluated a real-world pt cohort from the Spanish RETUD registry, diagnosed with BTC between January 1st, 2017, and May 30th, 2025. IDH1 status was assessed by next-generation sequencing (NGS), polymerase chain reaction (PCR), immunohistochemistry (IHQ), or pyrosequencing (PSQ). Data included demographic and clinical characteristics, molecular profile, therapeutic procedures, and EO (objective response rate [ORR], overall survival [OS] and progression-free survival [PFS]). PFS and OS were estimated using the Kaplan-Meier method. Results: IDH1 status was determined in 445 pt from 31 centers. Among them, 73 (16.4%) presented pathogenic IDH1mut, with R132C mutation present in 53.4%. For IDH1mut pt, median (m) age at diagnosis (dx) was 64.5 years (y), 65.7% were women and the most frequent tumor location at dx was intrahepatic (91.8%). Among all pt with intrahepatic tumors, 24.2% harbored an IDH1mut. Metastatic disease occurred in 77.8% of all patients (78.1% in IDH1mut). Surgery was performed in 33.0% (21.9% IDH1mut) and locoregional therapy in 11.2% (9.6% IDH1mut). Systemic treatment was administered to 98.7% (100.0% IDH1mut), and 20.0% received immunotherapy. Among IDH1mut pt, 27.4% received anti-IDH1 therapy. Most frequent schemes for first and second line were CISGEM (71.6%) and FOLFOX (41.2%) respectively. With a m (min, max) follow-up time of 16.7 (0.9, 81.2) months (mo), mOS in IDH1mut vs IDH1 wild type (wt) were 20.2 mo (95% CI 17.8-28.6) and 18.4 mo (95% CI 16.5–20.4) (p=0.270). mOS in IDH1mut pt not treated with anti-IDH1 therapies was 20.0 mo (95% CI 17.1-28.6) compared to 18.4 mo (95% CI 16.5-20.4) in IDH1wt pt (p=0.450) and 26.1 mo (95% CI 17.8-54.0) in IDH1mut treated pt (p=0.530). First line mPFS and ORR were 8.3 mo (95% CI 7.7-9.5) and 22.4% in IDH1mut vs 6.1 mo (95% CI 5.4-7.3) and 28.9% in IDH1wt, respectively. A total of 49 (67.1%) IDH1mut patients presented co-expression with other biomarkers, 8 of them ESCAT-I. The most frequent co-mutations were CDKN2A (20.4%), CDKN2B (16.3%) and ARID1A (16.3%). Mutations of genes involved in RAS/MAPK signaling pathway like KRAS, BRAF and ERBB2 were less frequent in IDH1mut pt than in IDH1wt pt (10.2% vs 23.8%, 6.1% vs 6.7% and 4.1% vs 9.2% respectively). Regarding TP53/RB pathway, frequency was lower in IDH1mut pt for TP53 (10.2% vs 36.5%) and MDM2 (4.1% vs 4.4%) but not for CDKN2A/B (36.7% vs 34.2%). Conclusions: This analysis provides insights into the characterization of real-world IDH1 BTC pt. Patients receiving anti-IDH1 therapies showed a trend towards improved survival.