Abstract 2940: Molecular tumor profiling identifies actionable targets in patients with cholangiocarcinoma
Authors: Avogadri-Connors Francesca , Wei Ge , Dambkowski Carl L. , Li Gary , Soifer Harris S. 
Published: September 2020

Background: Cholangiocarcinoma (CCA) is the most common biliary tract malignancy with up to 10,000 new cases annually in the US. The absence of approved molecular therapies restricts CCA patients to chemotherapy options with limited clinical benefit. Recognizing that actionable genomic alterations occur in biliary tumors, NCCN guidelines state that molecular testing should be considered before the initiation of primary therapy. In this study, the catalog of genetic abnormalities in CCA patients was analyzed to determine the prevalence of actionable genomic alterations in CCA tumors and quantify the proportion of patients that may be eligible for an investigational therapy. Barriers to molecular testing and novel designs for biomarker-driven clinical trials will also be discussed.

Method: Actionable genetic alterations were cataloged through a comprehensive literature review and analysis of multiplatform genomic data from publicly-available databases. For this study, actionable genomic alterations were defined as: 1) known/likely driver mutations; 2) all gene fusions; 3) select copy number alterations. Correlative analysis of genomic alterations and clinical trial options was performed using an in-silico cohort of CCA subjects with available clinic genomic data that was extracted from the cBioPortal database (cbioportal.org, v3.1.6).

Results: The in-silico cohort consists of 393 CCA patients (median age at diagnosis, 59y (29-86y); 55% male/45% female; Stage IV, 65%) from the cBioPortal database (cbioportal.org, v3.1.6). The most common genetic alterations for each variant type were IDH1/2 mutations (10-18%), FGFR2 fusions (10-20%), and CDKN2A deletion (9-20%). Potentially actionable genomic alterations, which were mostly mutually exclusive, were also identified in KRAS (8%), PIK3CA (5%), PTEN (4%), ERBB2 (2.5%), BRAF (1.8%), and NTRK (1.8%). A rare fraction of patients (3/190, 1.6%) were classified as MSI-High. Given the mutual exclusivity of the actionable alterations, ~50% of CCA patients may be amenable to precision therapies alone or in combination with chemotherapy. The range of actionable biomarkers provides a rationale for a randomized umbrella trial with multiple targeted treatment arms and a single shared control arm.

Conclusions: Despite the updated guidelines and demonstrated clinical efficacy of molecularly-targeted drugs in CCA trials, a minority of newly diagnosed patients currently undergo comprehensive genomic profiling. Next-generation sequencing (NGS)-based molecular diagnosis has proved to be successful in detecting a broad spectrum of actionable alterations across many gene targets, enabling personalized treatment decisions. Therefore, we propose an upfront NGS testing scheme in CCA patients to ensure full understanding of potential options in later lines of treatment.

Citation Format: Francesca Avogadri-Connors, Ge Wei, Carl L. Dambkowski, Gary Li, Harris S. Soifer. Molecular tumor profiling identifies actionable targets in patients with cholangiocarcinoma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2940.