Implementation of DPYD gene sequencing as an adaptation of pharmacogenetic screening to prevent severe toxicity during cancer treatment with fluoropyrimidine chemotherapy

Abstract/project summary The fluoropyrimidine chemotherapies 5-fluorouracil and capecitabine are essential agents for the treatment of colorectal, breast, and pancreatic cancer; however, these agents are also responsible for hundreds of fatal adverse drug events in the United States (US) each year. Dihydropyrimidine dehydrogenase (DPD) deficiency is a leading cause of severe and fatal toxicity from fluoropyrimidine chemotherapy. DPD deficiency is present in 3-8% of people and confers an estimated 25-times increased risk of fatal toxicity during fluoropyrimidine chemotherapy. Pre-treatment screening for DPD deficiency is feasible and has been widely implemented in Europe. Most US patients do not receive screening, however. As US health care providers decide whether to implement screening for DPD deficiency prior to fluoropyrimidine chemotherapy, there is a critical need to identify screening approaches with the greatest potential to effectively and equitably prevent severe and fatal adverse events in diverse patient populations. The overall objective of the proposed research is to evaluate and compare the clinical utility, equity, and implementation-readiness of genotypic and phenotypic approaches to DPD deficiency screening in the ancestrally diverse US population. The central hypothesis is that phenotypic and expanded genotypic approaches to DPD deficiency screening will show greater clinical utility and greater equity for preventing severe chemotherapy toxicity in the US than DPYD genotyping of only the four canonical DPYD gene variants. In Aim 1 of the proposed research, we will evaluate and characterize DPD deficiency in subjects from groups underrepresented in prior research, including subjects who identify as Black, Asian, and/or Hispanic, using both genotypic and phenotypic assays. In Aim 2 we will evaluate the clinical utility and equity of genotypic, phenotypic, and hybrid approaches to DPD deficiency screening in the ancestrally diverse US population, using model-based analysis. In Aim 3 we will evaluate barriers and facilitators to implementation of genotypic and/or phenotypic screening for DPD deficiency in diverse patient populations and practice settings, incorporating perspectives of patients, oncologists, and pharmacists. The proposed work will enhance knowledge about the diagnostic characteristics of DPD deficiency in Black, Asian, and Hispanic populations. Additionally, the research findings will provide quantitative and qualitative data to inform evidence- based policy and clinical decision making regarding effective, equitable, and scalable approaches to screening for DPD deficiency in the US cancer care delivery setting.