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A Comprehensive Genomic and Immune Profiling Study of IDH1- and IDH2-Driven Intrahepatic CCA

2021 Year in Review: Cholangiocarcinoma — December 17, 2021

A comprehensive genomic and immune characterization of IDH-mutated and wild-type intrahepatic CCA revealed significant differences in genetic alterations.

To define the genomic and immunologic profile of intrahepatic cholangiocarcinoma (iCCA) with IDH1/2 genetic alterations, biomarker analysis with comprehensive genomic profiling was performed in a large sample set; results of this study were reported at the 2021 American Society of Clinical Oncology Annual Meeting.

In this study, comprehensive genomic profiling was performed in 3067 patients with advanced-stage iCCA. Given the relationship between IDH mutations and homologous recombination defects, genomic loss of heterozygosity in IDH1/2-mutated cases, IDH wild-type, and BRCA-mutated iCCA were examined. The status of tumor mutational burden (TMB), microsatellite instability (MSI), and PD-L1 expression in IDH-mutated and IDH wild-type iCCA was evaluated to identify potential biomarkers of immune checkpoint inhibition response. In 100 surgical samples from 96 patients, immunohistochemistry analysis was performed to assess densities of tumor-associated immune cells and immune checkpoint markers expressed in epithelial malignant cells and in the tumor microenvironment, to examine potential biomarkers for immunotherapy and to characterize the immune microenvironment of IDH1/2-altered iCCA.

Of the 3067 samples tested, 426 (14%) samples were IDH1-positive, 125 (4%) were IDH2-positive, and 2516 (82%) were IDH wild-type. The incidence of IDH1 and IDH2 alterations was found to be mutually exclusive. Furthermore, compared with IDH1/2 wild-type iCCA, there were significantly fewer co-occurring targetable genetic alterations in IDH1-positive and IDH2-positive iCCA, including FGFR2 rearrangements (P <.0001), ERBB2 amplifications/variants (P = .0009), TP53 (P <.0001), CDKN2A/CDKN2B (P <.0001), MTAP (P <.0001), and BRAF (P = .04). No significant difference in median genomic loss of heterozygosity was seen between IDH1-positive/IDH2-positive iCCA and IDH wild-type iCCA (P = .37).

Tumor samples with IDH wild-type iCCA showed a higher frequency of biomarkers of immune checkpoint inhibition response, including MSI-high, TMB >10 mut/Mb, and PD-L1 positivity, compared with IDH1-positive iCCA. In the samples from 96 surgical patients, 30% were positive for IDH1/2 mutation; however, no significant difference was observed between IDH1/2-mutated and IDH wild-type cohorts in the 14 immune biomarker panel expression.

These biomarker analyses reveal significant differences in genetic alterations between IDH-mutated and IDH wild-type iCCA, with no significant differences observed in immune biomarker expression and genomic loss of heterozygosity.

Source: Makawita S, Borad MJ, Carapeto F, et al. IDH1 and IDH2 driven intrahepatic cholangiocarcinoma (IHCC): a comprehensive genomic and immune profiling study. J Clin Oncol. 2021;39(suppl_15):4009-4009.

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