Important Role of Screening for Genomic Alterations in Cholangiocarcinoma

Comprehensive molecular profiling has demonstrated a diverse landscape of oncogenic genomic alterations in cholangiocarcinoma (CCA), which are often the drivers of CCA. In a recent review article, Tanios S. Bekaii-Saab, MD, FACP, Vice Chair and Section Chief for Medical Oncology, Department of Internal Medicine, Mayo Clinic Cancer Center, Phoenix, AZ, and colleagues provided an overview of the molecular heterogeneity of CCA, discussing the role of molecular tests for the diagnosis of patients with intrahepatic CCA, and the implications of the genomic alterations in the treatment of patients with this aggressive disease.

Intrahepatic CCA has a unique molecular landscape, such as IDH1 mutation and FGFR2 fusion or other alterations, that is not often seen in other solid tumors, the authors noted. The most common genetic alterations include TP53 mutations, CDKN2A/B loss, and KRAS mutations.

Studies have identified important differences between the molecular landscapes of intrahepatic CCA and extrahepatic CCA. For example, IDH1 mutations are found in up to 29% of patients with intrahepatic CCA and FGFR2 rearrangements are found in approximately 10% of patients, but those are rare in patients with extrahepatic CCA.

FGFR2 fusion or rearrangements and IDH1 mutation are currently the only genetic alterations in CCA for which targeted therapies have been approved. Large-scale genomic profiling also identified many other alterations for which targeted therapies are approved in other indications.

“Given the paucity of current treatment options and the limited effectiveness of standard chemotherapy in CCA, ‘molecular diagnosis’ provides an important opportunity for improved personalized treatment plans in CCA,” Bekaii-Saab and colleagues suggested.

Advances in next-generation sequencing (NGS) have allowed large gene panels to be assayed with high sensitivity, specificity, accuracy, and speed. Thanks to the progress in sequencing technologies in the past decade, turnaround times for NGS-based assays can produce results within 1 to 3 weeks.

Available tests vary regarding acceptable source material, genetic source for library construction, target selection technology, gene panel size, and type of detectable genomic alterations. NGS-based assays include FDA-cleared or FDA-approved in vitro diagnostic tests or internally validated laboratory tests.

Currently, several tumor profiling assays have been cleared or approved by the FDA for use as an in vitro diagnostic test, with panels of up to several hundred genes.

“Most patients with iCCA [intrahepatic CCA] have only limited biopsy sample available for molecular profiling; NGS allows the detection of multiple biomarkers in a single analysis, thus reducing the amount of tissue needed for testing,” Bekaii-Saab and colleagues observed.

The current cost of the NGS-based molecular profiling tests varies considerably. The authors noted a paucity of real-world evidence for the cost-effectiveness of NGS in routine clinical practice. However, the coverage of policies and private and government payers are starting to include NGS-based testing, particularly with recent FDA approvals of NGS-based companion diagnostic tests.

Transcriptomics, proteomics, and metabolomics may also provide vital information to improve treatment stratification of patients with CCA.

“The recent successes and continuing efforts in the development of targeted therapies for patients with CCA suggest that genomic profiling will become an integral diagnostic tool to guide treatment decisions in CCA,” Bekaii-Saab and colleagues concluded. “However, future development of precision medicine in CCA will likely require the integration of information from multiple omics approaches.”

Source: Bekaii-Saab TS, Bridgewater J, Normanno N. Practical considerations in screening for genetic alterations in cholangiocarcinoma. Ann Oncol. 2021;32:1111-1126.