Profiling of 3,634 cholangiocarcinomas (CCA) to identify genomic alterations (GA), tumor mutational burden (TMB), and genomic loss of heterozygosity (gLOH).

Abstract

4087 Background: The management of CCA has evolved as targeted and immune checkpoint inhibitor (ICPI) therapies have emerged. We used comprehensive genomic profiling (CGP) to characterize the genomic alterations (GA) that have potential to personalize therapy for CCA. Methods: 3634 CCA underwent hybrid capture based CGP on 0.8-1.1 Mb of the coding genome to identify GAs in exons and select introns in up to 404 genes, TMB, microsatellite status (MSI) and % monoallelic genome (gLOH). PD-L1 expression was determined by IHC (Dako 22C3). Results: 52% of CCA were female with a median age of 62 years (range 16 - > 89). The most common biopsy sites were liver (74%), lymph node (4%), bile duct (3.3%), and lung (2%). MSI-high was rare (1%), 118 and 47 cases had TMB > 10 and > 20 mut/mb respectively. Of the latter, 51% (24/47) were MSI-H. PD-L1 amplification (AMP) was present in 0.27%. Of 490 CCA tested, 43 (9%) were positive for PD-L1 expression. 11% of cases had gLOH > 16%, only 2 cases had both TMB > 20 and gLOH > 16%. GA were most common in TP53 (31%), CDKN2A (29%), KRAS (20%) and ARID1A (17%). Potentially targetable GAs included FGFR2 (11%, 85% fusions), BRAF (5%, 50% V600E), ERBB2 (5%, 72% AMP), MET (2%, 90% AMP), EGFR (0.52%) and rarer ( < 0.5%) FGFR3, RET, FGFR1, ALK, and ROS1 fusions. The FGFR2 fusions had 128 unique 3’ partner genes including BICC1 (26%), CCDC6 (3.2%), AHCYL1 (2.6%) and KIAA1217 (2.6%). FGFR2 fusions occurred in a mutually exclusive fashion from high gLOH (p < 0.002), but not high TMB. GA in IDH1 (15%) were mutually exclusive of FGFR2 fusions (p < 1e-13), but co-occurred with PBRM1 GA (23%, p < 1e-21), ARID1A (26% p < 1e-10). IDH1 GA had gLOH similar to the overall CCA population but were enriched for low TMB (p < 1e-3). Conclusions: Nearly 20% of CCA cases harbor targetable kinase GA, half of which were FGFR2 fusions. Independently, an additional 10% (gLOH) and 1% (high TMB, MSI and/or PD-L1 AMP) may benefit from PARP inhibitors and ICPI respectively. Independently, co-mutation of IDH1 and PBRM1/ARID1A defines a class of CCA that warrants further investigation for sensitivity to PARP inhibitors and may serve as a paradigm for other tumors (ie. gliomas) with a similar co-occurrence landscape.

Molecular targeted therapies: Ready for “prime time” in biliary tract cancer

“…93 Such findings have been confirmed by others, including a trend toward mutual exclusion of FGFR2 fusions and IDH1 mutations. 94 In addition, molecular findings seem to vary depending on aetiology, especially for iCCA. Non-Opistorchis viverrini (OV)-related iCCA demonstrated statistically significant increased prevalence of BAP1, IDH1/IDH2 83 and FGFR alterations, 83,95 while OV-related iCCA showed more TP53 mutations, 95 KRAS and SMAD4 mutations 82 and HER2 amplifications.…”

“…93 IDH1 mutations frequently appear together with lower expression of ARID1A 90 and rarely together with FGFR2 fusions. 94 IDH1 and IDH2 mutations seem to be point mutations located in the arginine 132 (R132) and 172 (R172) residue, respectively. 89,104,109,[114][115][116] Another genetic footprint of IDH mutations is its link with a hypermethylated phenotype.…”

“…136 Even though BICC1 is one of the most frequent fusion companions for FGFR2, multiple other partners have been identified. 84,92,94,132,137,138 It seems clear that FGFR2 fusions are more relevant than mutations when it comes to the treatment of iCCA. 139 Whether specific partners have any relevance in terms of carcinogenesis or response to therapy is still to be elucidated.…”

Personalized Medicine in Advanced Cholangiocarcinoma

“…Immunotherapy with programmed cell death-1 (PD-1), PD-L1, and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitors has emerged as a promising therapeutic option in various cancers such as melanoma, non-small cell carcinoma, and renal cell carcinoma, to name a few. In a comprehensive genomic analysis of 3,364 cholangiocarcinoma tumor specimens, 3.5% of the tumors showed >10 mutations/megabase (Mb), whereas 1.4% showed >20 mutations/Mb 54. In this analysis, PD-L1 expression was seen in 9% of the samples analyzed, substantiating the possible role of checkpoint inhibitors.…”

FGFR inhibitors in cholangiocarcinoma: what’s now and what’s next?

“…Of note, they are found nearly exclusively in intrahepatic, but not in perihilar or extrahepatic CCA, or hepatocellular carcinoma. 9 , 10 , 12 Fusions that involve other members of the FGFR family are rare in biliary tract cancers, with an incidence below 0.5%. 13 Although there is initial evidence that FGFR2 genetic alterations occur more frequently in younger patients and are associated with a more indolent disease progression, 13 it remains enigmatic whether FGFR2 fusion positive patients represent a distinct prognostic subgroup.…”