Over 650,000 patients in the U.S. are treated with chemotherapy per year, with the vast majority (~87%) reporting side effects, more than half of which involve severe toxicities requiring urgent medical care. Pharmacogenomics (PGx), the study of how germline genetic variants affect individual response to medications, has promise to personalize drug dosing to maximize safety and efficacy in oncology where many therapeutics have well-known germline PGx associations. However, routine use of genotype-guided dosing for chemotherapy is essentially nonexistent in the U.S. This may be because of several potential reasons including the feasibility of preemptive genotyping as well as a lack of randomized data.
The Implementation of Pharmacogenomic Testing in Oncology Care (PhOCus) trial is a randomized, prospective study to evaluate the effects of preemptive pharmacogenomic (PGx) testing on chemotherapy dosing decisions and medication related adverse events in oncology patients. We will focus on two specific medications with actionable PGx evidence and common use as chemotherapies in adult malignancies which to date have not been prospectively studied with respect to clinical outcomes in a randomized fashion: fluoropyrimidines and irinotecan. These agents have activity in multiple tumor types and are critical to many oncology patients’ care, with hundreds of thousands of new exposures per year in the United States cancer population. Dihydropyrimidine dehydrogenase (DPD) is the rate-limiting enzyme in fluoropyrimidine catabolism. Polymorphisms in the DPYD gene can result in enzyme deficiency leading to an increased risk of severe, sometimes fatal toxicities in ~10% of patients. Likewise, the active form of irinotecan (SN-38) is metabolized by the polymorphic enzyme UGT1A1. Enzyme activity is reduced in individuals who inherit polymorphisms such as the UGT1A1*28 allele. Approximately 40% of the population carries at least one allele that indicates an increased risk of irinotecan related toxicities including diarrhea and neutropenia. For the 10% of the population that carries two such risk alleles, FDA label guidance recommends irinotecan dose reduction of at least one level.
We seek to address the important gap between evidence and practice through the PhOCus Trial. Adult oncology patients receiving oncology care at the University of Chicago Medical Center and for whom treatment with a fluoropyrimidine and/or irinotecan is planned are eligible. Providers will be given access to subject-specific information and genotypic dosing guidance in the form of the interactive software tool, Genomic Prescribing System (GPS), throughout the subjects’ treatment course. We hypothesize that if clinicians are provided preemptive PGx information, they will dose-modify treatments in an effort to mitigate and/or avoid toxicities, which may improve tolerability and outcomes for cancer patients.
The link to the clinicaltrials.gov website for this study can be found here: https://www.clinicaltrials.gov/ct2/show/NCT04541381?term=o%27donnell&cond=pharmacogenomics&draw=2&rank=1