Kelly Butler, Dr. Reham Abdel-Wahab
A recent study in Precision Oncology examined the diverse genetic and molecular profiles of biliary tract cancers (BTCs). With an eye toward therapeutic value, the study aimed to identify characteristics of each BTC subtype that confer responsiveness to targeted therapies and immunotherapies.
The researchers examined a group of 454 BTC samples that included intrahepatic cholangiocarcinoma (IHC, 267), extrahepatic cholangiocarcinoma (EHC, 34), and gallbladder cancer (GBC, 153). Similar to prior studies, each BTC subtype was associated with distinct mutations: IHC was related to genetic alterations of the FGFR2, BAP1, IDH1, and PBRM1 genes, while TP53 and ERBB2 mutations were more common in EHC and GBC.
Understanding the genetic profiles of BTCs is clinically essential because many new therapies are specific to certain genetic alterations (e.g., IDH1 inhibitors like ivosidenib for IDH1-mutated tumors and FGFR2 inhibitors like prmigatnib for cancers with FGFR2 fusions or rearrangements). Considering targeted therapies that are already FDA-approved or in phase II/III clinical trials, the study detected therapeutically actionable mutations in 30.5% of all BTCs. These clinically relevant mutations were most common in IHC (39.1%), followed by EHC (29.6%) and GBC (15%).
The study also identified differences in biomarkers associated with immunotherapy response. First, the overall tumor mutation burden was higher in EHC (2.63 m/MB) and GBC (2.5m/MB) than in IHC (1.92 m/MB). A higher overall mutation load means more neoepitopes/neoantigens on the cell surface, activating the immune system and increasing responsiveness to immunotherapies. Overexpression of the cell surface protein PD-L1 is also associated with responsiveness to immune checkpoint inhibitors, and the study found greater PD-L1 expression in GBC than in IHC. A similar trend was noted for several immune activation scores, including CYT, NRS, and IMPRES. These numerical scores estimate prognosis based on the number of immune cells in the tumor and surrounding tissue.
Based on this study, immunotherapies and targeted therapies are promising treatment options for BTCs. Irrespective of the BTC subtype, clinicians and patients should consider tumor genetic profiling to identify any therapeutically actionable mutations. The proportion of patients eligible for targeted therapies will only increase as researchers continue to develop novel treatments.
Kelly Butler is an NIH Postbac Research Fellow and the Founding Director of SAFE
Reham Abdel-Wahab is the Cholangiocarcinoma Foundation's Director of Research and Chief Scientific Officer.