Evolving precision: Updates in targeted therapy for cholangiocarcinoma.

The development of Next-Generation Sequencing (NGS) techniques for extended genomic profiling has led to the identification of actionable molecular alterations in approximately half of the patients with biliary tract cancer (BTC), with the highest incidences among those with intrahepatic cholangiocarcinoma. Targeted drugs have demonstrated the ability to confer clinical benefit while maintaining a manageable safety profile. As a result, despite the lack of a head-to-head comparison with standard second-line chemotherapy, they are now recommended for patients with advanced disease who are still fit after progression to first-line palliative systemic anti-cancer treatment. In this review, we will contextualize the results observed with targeted drugs in clinical trials within the framework of clinical practice. We will provide an overview of available single-gene analyses that should be considered in case of lack of access to NGS, defining testing priorities, differences in yields, and therapeutic implications. Lastly, we will discuss future perspectives in the field of precision medicine for BTC, focusing on new strategies to overcome treatment resistance, on the optimal collocation of targeted drugs in the treatment algorithm, and on newly identified actionable alterations for which compounds are currently under investigation.