Abstract
IntroductionIn this study (PRECISE), we assess the clinical utility of a germline DNA sequencing‐based test (ToxNav) for mutations in DPYD and ENOSF1 genes to alter clinician‐prescribed fluoropyrimidine doses and the use of a digital application (PROMinet) to record patient‐reported chemotherapy toxicity.Materials and methodsAdult patients with a histological diagnosis of colorectal cancer (CRC) who consented to fluoropyrimidine‐based chemotherapy were recruited prospectively and given a digital application to monitor and record associated toxicities. Patient samples were analyzed for 18 germline coding variants in DPYD and 1 ENOSF1 variant.ResultsGenetic testing was performed for 60 patients and identified one patient at increased risk of fluoropyrimidine‐based toxicities. Uptake of genetic testing was high and results were available on average 17 days from initial clinical encounter. Patient‐reported chemotherapy toxicity identified differences in 5‐fluorouracil vs capecitabine regime profiles and identified profiles associated with subsequent need for chemotherapy dose reduction and hospital admission.DiscussionThe PRECISE clinical trial demonstrated that a germline DNA sequencing‐based test can provide clinically relevant information to alter clinicians' fluoropyrimidine prescription. The study also obtained high volume, high granularity patient‐reported toxicity data that might allow the improvement and personalization of chemotherapy management.
Highlights
In this study (PRECISE), we assess the clinical utility of a germline DNA sequencing‐based test (ToxNav) for mutations in Dihydropyrimidine dehydrogenase (DPYD) and ENOSF1 genes to alter clinician‐prescribed fluoropyrimidine doses and the use of a digital application (PROMinet) to record patient‐reported chemotherapy toxicity
To assess 5‐FU and capecitabine toxicity‐associated alleles, a 19 single nucleotide polymorphism (SNP) panel consisting of germline polymorphisms in DPYD and ENOSF1 was determined and diagnostic accuracy was evaluated in 888 patients from the QUASAR 2 clinical trial.[16]
This study built on genome‐wide association studies and meta‐analyses performed using data available from a number of studies, including QUASAR 2, where genetic markers of toxicity resulting from fluoropyrimidine‐based therapies in the DPYD and ENOSF1 genes were identified and assessed for their clinical utility.[15,17]
Summary
5‐fluorouracil (5‐FU) and its oral prodrug capecitabine are the most commonly prescribed chemotherapeutic agents for treating colorectal cancer (CRC) and feature prominently in many chemotherapy regimens. Toxicity‐ associated alleles are rare and seen in between 1.7% and 3.1% of the population.[13,15] To assess 5‐FU and capecitabine toxicity‐associated alleles, a 19 single nucleotide polymorphism (SNP) panel consisting of germline polymorphisms in DPYD and ENOSF1 was determined and diagnostic accuracy was evaluated in 888 patients from the QUASAR 2 clinical trial.[16] In brief, this study built on genome‐wide association studies and meta‐analyses performed using data available from a number of studies, including QUASAR 2, where genetic markers of toxicity resulting from fluoropyrimidine‐based therapies in the DPYD and ENOSF1 genes were identified and assessed for their clinical utility.[15,17]. It is hypothesized that this data will improve the breadth and depth of chemotherapy toxicity recording, identify patients at risk of severe side effects, and increase clinical awareness of needing formal dose reductions
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