Schnettler, Erica

Introduction: Pharmacogenomics is about selecting the “right drug in the right amount for the right patient.” In metastatic colorectal cancer, germline pharmacogenomics testing presents a unique opportunity to improve outcomes, since the genes dihydropyrimidine dehydrogenase and UDP-glucuronosyltransferase metabolizing the chemotherapy drugs, 5-fluorouracil, and irinotecan are already well known. In a retrospective analysis of the landmark TRIBE clinical trial [(TRIBE - TRIplet plus BEvacizumab multicenter, phase III trial by the Italian Cooperative GONO (Gruppo Oncologico Nord Ovest) group (NCT00719797)], the proportion of patients with serious adverse events was higher in those with dihydropyrimidine dehydrogenase/UDP-glucuronosyltransferase aberrations and was dose dependent. We aimed to report on the feasibility and the results of incorporating pharmacogenomics testing into clinical practice. Methods: As a quality improvement initiative and a center of individualized medicine grant, we integrated the use of OneOme RightMed comprehensive test, which reports on 27 genes related to pharmacogenomics and over 300 medications of interest. We limited initial testing to patients with colorectal cancer. Pharmacists provided dosage recommendations based on test results in real-time. Results: At our cancer center, 155 patients underwent pharmacogenomics testing from November 2017 to January 2019. Results were available within 3 to 5 days of testing for most patients and were integrated into treatment decision-making. Of 155 sampled participants, a total of 89 (57.4%) participants had an UGT1A1 variant genotype, NM_000463.2: c.-53_-52[8] *1/*28, n = 74 (47.7%); *28/*28, n = 15 (9.7%). Additionally, 4 (2.6%) participants were heterozygous for dihydropyrimidine dehydrogenase. Two (1.3%) individuals were heterozygous for both UDP-glucuronosyltransferase and dihydropyrimidine dehydrogenase genes. All (100%) the patients had at least 1 actionable aberration related to supportive care medications ( CYP-family) of all the possible medications listed on their pharmacogenomics report. Conclusion: Preemptive comprehensive pharmacogenomics testing can be integrated into clinical practice in real-time for patients with cancer given faster turnaround and low cost. Pharmacist-driven, patient-specific medication management consults add further value given the number of genes/drugs. This sets the stage for a prospective randomized clinical trial to demonstrate the amount of benefit this can result in these patients.

703 Background: In metastatic colorectal cancer (CRC), pharmacogenomics (PGx) testing presents a unique opportunity to improve outcomes since the genes DPYD & UGT1A1 encoding the enzymes metabolizing the chemotherapy drugs, 5-fluorouracil and irinotecan, are already well known. In the TRIBE clinical trial, proportion of patients with serious adverse events (SAEs) was higher in those with DPYD/UGT1A1 aberrations and were dose dependent. Critical barrier has been integration into clinical practice. We aimed to report on the feasibility and results of incorporating PGx testing into clinical practice. Methods: As a quality improvement initiative, we integrated the use of OneOme RightMed comprehensive test through funding from our center of individualized medicine, which reports on 28 genes and over 350 medications of interest. Pharmacists provided dosage recommendations based on test results real-time. Results: 126 patients have had the PGx testing since November 2017. Results have been available within 3-5 days. The table outlines the analyzed results thus far of variants in UGT1A1 and the DPYD-genes alongside the CYP450 genes. Of these, 59% had a DPYD/UGT1A1 aberration and 100% had at least one actionable aberration related to supportive care medications from all possible medications listed on their PGx report. Conclusions: Preemptive comprehensive PGx testing can be integrated into clinical practice in real-time for cancer patients. This sets the stage for a prospective randomized clinical trial to demonstrate the amount of benefit this can result in these patients. [Table: see text]

Significance Tumor cells adapt to hypoxia by modulating energy production and utilization. Endocytosis is an energy-consuming process that is suppressed during hypoxia. Our studies show that Dynamin 2 (DNM2), a key component of endocytic machinery, is transcriptionally suppressed by HIF-1. Genetic and pharmacological inactivation of DNM2 stabilized HIF-1α and HIF-2α. Furthermore, miR-199a, which is encoded from the opposite strand of DNM2 , exerts reciprocal negative regulation upon HIF-1α and HIF-2α. Overexpression of miR-199a decreased HIF-1α and HIF-2α, cell migration, and metastasis. These findings establish a regulatory loop between endocytic pathway and hypoxic response in tumor cells.