PROJECT SUMMARY/ABSTRACT Precision cancer medicine uses patient molecular test results to guide cancer therapy selection. An increasing number of cancer therapies are now targeted to specific molecular alterations, and tumor molecular testing is now standard of care. A significant obstacle in advancing precision cancer therapy is the rapid pace of change in this field—making it challenging for oncologists to stay up to date. The long-term goal of this project is to integrate clinical decision support (CDS) for precision cancer therapy selection directly into the electronic health record (EHR). Ultimately, we will create an integrated CDS solution within the EHR that includes best practice alerts to oncologists and integration of CDS into the molecular testing result report. The objective of this R21 is to develop a CDS algorithm to match molecular test results to targeted therapy assertions from a widely used precision oncology knowledgebase, deliver an open-source web service application programming interface (API) that can support vendor-agnostic integration with any EHR that uses the new genomic data standards, and provide proof-of-concept, point-of-care CDS in our local EHR environment. We will accomplish this through the following specific aims: Aim 1. Develop an open-source algorithm and API for computing and storing biomarker-driven CDS from the My Cancer Genome (MCG) knowledgebase. We will develop an algorithm that will compute targeted therapy options for a patient’s tumor histology and molecular profile from the data stored in the MCG knowledgebase. We will build a web service API that receives molecular testing data, calls the MCG knowledgebase, runs the CDS algorithm, and outputs the computed CDS in a format that can be stored for rapid retrieval and that is compatible with EHRs using the new genomic data standards. Aim 2. Develop methods for integration of biomarker-driven CDS into the EHR as human-readable statements. In this aim, we will build API functions to receive communications from the EHR when an oncologist views tumor test results, retrieve cached CDS, and send CDS to the EHR. Using non-small cell lung cancer as a proof-of-concept, our initial use cases will provide integration of CDS with the molecular results report and best practice alerts to oncologists. This project will provide tools to match patient molecular test results to appropriate targeted therapies. At the conclusion of this project, an oncologist will be able to view CDS when they access patient molecular results in the EHR. This point-of-care CDS will facilitate delivery of the right information to the right person at the right time to maximize impact on clinical care.