IDH1 and IDH2 Driven Intrahepatic Cholangiocarcinoma (IHCC): A comprehensive genomic and immune profiling study.

4009 Background: IDH1/2 genetic aberrations (GA) occur in 20% of IHCC cases and may be specifically targeted by IDH inhibitors. The genomic and immunologic profile of IHCC with IDH1/2 GA remains undefined. IDH1 mutations impair DNA damage repair (DDR), loss of heterozygosity (LOH) and may represent a biomarker for DDR in these patients. Methods: Comprehensive genomic profiling (CGP) was performed in 3,067 cases of advanced stage IHCC using a hybrid capture-based FDA-approved assay. Tumor mutational burden (TMB) was determined on 0.8 Mbp of sequenced DNA and microsatellite instability (MSI) was determined on 95 loci. PD-L1 expression in tumor cells (Dako 22C3) was measured by immunohistochemistry (IHC). Genomic LOH (gLOH) was assessed for samples meeting quality criteria. Densities of tumor associated immune cells and immune-checkpoint markers expressed in epithelial malignant cells and in the tumor microenvironment of 100 surgical samples from 96 patients were evaluated by IHC using digital image analysis of 14 markers (CD3, CD4, CD8, CD68, PD1,PD-L1, B7-H4, B7-H3, IDO1, ICOS, VISTA, OX40, TIM3, LAG3). Tissue microarrays were generated for multiplex immune panel analysis. A p value < 0.05 was considered statistically significant. Results: 426 (14%) of IHCC were IDH1+ and 125 (4%) were IDH2+ (Table) and were mutually exclusive. All IDH1 GA occurred at the R132 locus and included R132C (69%) and R132L/G/S/H/F (16%/7%/4%/3%/ < 1%) and 119Q ( < 1%) and IDH2 GA at R172 (94.4%) and R140 (6.6%). IDH1+ and IDH2+ IHCC had fewer co-occurring targetable GA than IDH1/2 wildtype (WT, IDHwt) cases including FGFR2 rearrangements (RE) (P <.0001), ERBB2 (P =.0009) and BRAF (P =.04). Median gLOH were not significantly different between IDH1+ IDH2+ IHCC vs. IDHwt IHCC (p = 0.37). Potential biomarkers of immune checkpoint inhibition (ICI) response including MSI High, TMB > 10 mut/Mb, and PD-L1 positivity were more frequent in IDHwt IHCC than IDH1+ IHCC. 29/96 (30%) surgical patients were positive for IDH1/2 mutation though mutational status did not confer a statistically significant difference in the 14 immune biomarker panel expression. Conclusions: CGP reveals significant differences in GA between IDH1+, IDH2+ and IDHwt IHCC consistent with IDH1 and IDH2 being driver oncogenes for IHCC. Immune biomarker expression and gLOH did not differ significantly between IDH mutated and WT cases.[Table: see text]