NCI Office of Data Sharing (ODS) Data Jamboree (Abstract Submissions): Submission #28

Submission information
Submission Number: 28
Submission ID: 145176
Submission UUID: 8ad44e60-f55b-4dff-8dee-744244f20de3

Created: Mon, 06/23/2025 - 16:40
Completed: Mon, 06/23/2025 - 16:40
Changed: Mon, 06/23/2025 - 16:40

Remote IP address: 10.208.24.253
Submitted by: Anonymous
Language: English

Is draft: No
First Name Rachel
Middle Initial D.
Last Name Harris
Degree(s) Ph.D.
Position/Title/Career Status Clinical Research Scientist
Organization St. Jude Children's Research Hospital
Organization Address Memphis, TN
Email Rachel.Harris2@StJude.org
Other (Please Specify)
Abstract Category Employment of statistical methods or existing computational, mathematical, or informatics tools
Abstract Keywords Rhabdomyosarcoma, Pharmacogenomics, Neuroblastoma, Toxicities, Precision Medicine
Abstract Title Investigating UGT1A1 Variants and Irinotecan Toxicities in Pediatric Cancer: Insights from CCDI and COG Trials
Abstract Summary In adults, pharmacogenomic prescribing guidelines for irinotecan are based on actionable UGT1A1 genotypes, with dosing and labeling informed by pharmacogenomic data. UGT1A1*28 and UGT1A1*6 are well-established markers affecting irinotecan metabolism with implications for pharmacokinetics and toxicity. Patients homozygous for the UGT1A1*28 allele likely require irinotecan dose reductions, as supported by strong evidence in adults and FDA guidelines. UGT1A1 and irinotecan are designated as a level A gene-drug pair by CPIC and have a Pharmacogenomics Knowledge Base (PharmGKB) 1A evidence level, indicating potential genotype-related toxicity. However, evidence for these associations in children is limited, with existing studies yielding mixed results. There is a critical need to better understand UGT1A1 genotypes in the pediatric population, particularly in the context of treating rare pediatric cancers such as rhabdomyosarcoma and neuroblastoma.

We propose leveraging data from Children’s Oncology Group (COG) clinical trials and the Childhood Cancer Data Initiative (CCDI) Molecular Characterization Initiative (MCI) to investigate irinotecan-related toxicities and pharmacogenomic markers in children with cancer. In the ARST1431 trial, diarrhea was a reportable adverse event, with grade 3+ toxicity occurring in 14% of participants (n=297) despite protocol-directed anti-diarrhea care. Notably, our recent analysis of the CCDI cohort revealed that 92% of participants carried at least one actionable phenotype. Our objective is to better understand treatment-related toxicities and identify actionable genotypes to improve therapy for children with cancer.

To meet this objective, analyses will include two major aims: (1) quantify the frequency of clinically relevant UGT1A1 pharmacogenomic genotypes; and (2) assess associations between UGT1A1 genotypes and irinotecan-related diarrhea. Variants will be identified from PharmGKB to include UGT1A1 exonic variants with a level 3 or higher clinical annotation with irinotecan. Computational tools we will leverage include Plink, PharmCAT, and R.

Our proposed team includes Brooke Bernhardt, Pharm.D., Rachel Harris, Ph.D., Wenjian Yang, Ph.D., and Philip Lupo, Ph.D.
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