Less than 5% of iCCA are tumor mutational burden-high (TMB-H), defined as ≥10 mut/Mb. The TMB-low (TMB-L), defined as ≤10 mut/Mb, have not been contrasted. Ongoing interest in the development of combination immunotherapy strategies make characterizing the genomic landscape of TMB-H iCCAs clinically relevant.
3,317 cases of iCCA underwent comprehensive genomic profiling with the FoundationOne CDx assay. Prevalence of different genomic alterations in cases with TMB-H were compared against TMB-L using Fischer’s exact test.
127 (3.9%) of 3,190 cases were TMB-H and of these cases 32.6% were TMB ≥ 20 mut/Mb. Compared to TMB-L cases, microsatellite instability (MSI) was higher in TMB-H (35.5% v 0.1%, p<.0001), as was high (≥50%) PD-L1 IHC staining (8.9% v 2.9%, p=0.47) and mutations in potential immunotherapy biomarkers PBRM1 (17.5% v 10.7%, p=.028) and STK11 (10.3% v 2.8%, p=.0001). TMB-H cases have lower frequencies of previously identified iCCA drivers such as FGFR2 fusions (0.8% v 8.2%, p=.0006), IDH1 mutations (1.6% v 14.0%, p<.0001) and IDH2 mutations (0% v 4.3%, p=.01). ERBB2 non-amplification structural variants are also increased (5.6% v 1.1%, p=.0009) in TMB-H. Mutations in genes with roles in genomic stability were increased with TP53 (61.9% v 34.1%, p<.0001) and ARID1A (38.9% v 17.8%, p<.0001). TMB-H cases had higher mutations in BRCA2 (7.9% v 2.2%, p=.0008) and ATM (7.9% v 3.1%, p=.008), but not BRCA1 (2.4% v 0.8%, NS). In contrast, TMB-L cases have higher incidences of CDKN2B (22.3% v 9.5%, p=.0003) and MTAP mutations (15.4% v 7.1%, p=.008).
TMB-H is nearly mutually exclusive with previously identified iCCA drivers such as IDH1, IDH2 and FGFR2 fusions. Additionally, TMB-H cases have a nearly two-fold increase in mutations in TP53 and ARID1A. Mutations in homologous recombination genes such as BRCA2 and ATM are enriched, but their overall incidence is low. Finally, TMB-H cases are enriched in multiple independent biomarkers of response to immunotherapy such as MSI, PD-L1, evolving ones such as PBRM1 and STK11 and depleted in resistance biomarkers such as MTAP. These findings support the clinical development of immunotherapy approaches for the treatment of TMB-H iCCA.
Clinical trial identification
Legal entity responsible for the study
J.S. Ross: Financial Interests, Personal, Full or part-time Employment, Medical Director: Foundation Medicine; Financial Interests, Personal, Stocks/Shares: Roche Holdings, Tango Therapeutics, Celsius Therapeutics. J. Rodon: Financial Interests, Personal, Advisory Board: Peptomyc, Kelun Pharmaceuticals/Klus Pharma, Ellipses Pharma, Molecular Partners, IONCTURA SA; Financial Interests, Institutional, Other, Clinical Research: Bayer, Novartis, Spectrum Pharmaceuticals, Symphogen, BioAlta, Pfizer, GenMab, CytomX, Kelun-Biotech, Takeda-Millenium, GlaxoSmithKline; Financial Interests, Institutional, Other, Research Funding: Blueprint Medicines, Black Diamond, Merck Sharp & Dohme; Financial Interests, Institutional, Research Grant, Research Funding/Clinical Research: Hummingbird, Yingli; Financial Interests, Institutional, Research Grant, Research Funding: Vall d'Hebron Institute of Oncology/Cancer Core Europe; Financial Interests, Institutional, Research Grant, Clinical Research: Bicycle Therapeutics, Taiho, Roche Pharmaceuticals, Merus, Curis, AadiBioscience, Nuvation, ForeBio, BioMed Valley Discoveries, Loxo Oncology, Hutchinson MediPharma, Cellestia, Deciphera, Ideaya, Amgen, Tango Therapeutics, Mirati, Linnaeus Therapeutics; Other, , Other, Other: VHIO/Ministero De Empleo Y Seguridad Social, Chinese University of Hong Kong, Boxer Capital, LLC, Tang Advisors, LLC; Other, Other, Travel Reimbursement: European Society for Medical Oncology. M. Javle: Financial Interests, Personal, Advisory Board: QED, Taiho, Merck, Transthera, Incyte, Servier, AstraZeneca; Financial Interests, Personal, Invited Speaker: Oncosil, INCYTE; Non-Financial Interests, Principal Investigator: qed, Basilea. All other authors have declared no conflicts of interest.