5-fluorouracil (5-FU) and its oral analog capecitabine are fluoropyrimidine chemotherapy agents used in several solid tumors. Approximately 5% of patients inherit diminished or null activity genetic variants in DPYD, which encodes the enzyme that metabolizes fluoropyrimidine, leading to higher systemic drug exposure and increased risk of severe and fatal toxicity. Many European countries recommend DPD/DPYD screening prior to fluoropyrimidine treatment and there are guidelines from Clinical Pharmacogenetics Implementation Consortium (CPIC) that recommend safe fluoropyrimidine starting doses in known DPYD carriers. However, DPYD testing is not recommended by the FDA or clinical oncology practice guidelines, which has led to minimal testing in the United States. One of the main reasons for the lack of clinical uptake is the cost of testing large numbers of patients to find the relatively uncommon (~5%) DPYD carriers. A potential solution that has not been explored, to our knowledge, is to use existing research-only genetic data to identify suspected carriers of actionable genotypes who should undergo confirmatory testing prior to treatment. This talk will summarize the evidence of the clinical benefit of pre-treatment DPYD testing and the reasons that testing is rarely conducted in the US. I will then describe ongoing work to use an institutional genetic data repository for ultra-efficient DPYD implementation at the University of Michigan Rogel Cancer Center. Finally, I will describe our efforts to get oncology clinical guidelines and the FDA to recommend pre-treatment DPYD testing and give the audience a simple way to support our effort.
1. Identify the five actionable DPYD variants that increase risk of fluoropyrimidine toxicity
2. Describe the main reasons that pre-treatment DPYD testing is not conducted in the United States
3. Recognize the benefits of using existing institutional genetic data for efficient pharmacogenetic implementation