Real-World Evaluation of Universal Germline Screening for Cancer Treatment-Relevant Pharmacogenes

Authors

Megan L. Hutchcraft, University of KentuckyFollow
Nan Lin, University of KentuckyFollow
Shulin Zhang, University of KentuckyFollow
Catherine Sears, University of KentuckyFollow
Kyle Zacholski, Virginia Commonwealth University
Elizabeth A. Belcher, University of KentuckyFollow
Eric B. Durbin, University of KentuckyFollow
John L. Villano, University of KentuckyFollow
Michael J. Cavnar, University of KentuckyFollow
Susanne M. Arnold, University of KentuckyFollow
Frederick R. Ueland, University of KentuckyFollow
Jill M. Kolesar, University of KentuckyFollow

Abstract

The purpose of this study was to determine the frequency of clinically actionable treatment-relevant germline pharmacogenomic variants in patients with cancer and assess the real-world clinical utility of universal screening using whole-exome sequencing in this population. Cancer patients underwent research-grade germline whole-exome sequencing as a component of sequencing for somatic variants. Analysis in a clinical bioinformatics pipeline identified clinically actionable pharmacogenomic variants. Clinical Pharmacogenetics Implementation Consortium guidelines defined clinical actionability. We assessed clinical utility by reviewing electronic health records to determine the frequency of patients receiving pharmacogenomically actionable anti-cancer agents and associated outcomes. This observational study evaluated 291 patients with cancer. More than 90% carried any clinically relevant pharmacogenetic variant. At least one disease-relevant variant impacting anti-cancer agents was identified in 26.5% (77/291). Nine patients with toxicity-associated pharmacogenomic variants were treated with a relevant medication: seven UGT1A1 intermediate metabolizers were treated with irinotecan, one intermediate DPYD metabolizer was treated with 5-fluorouracil, and one TPMT poor metabolizer was treated with mercaptopurine. These individuals were more likely to experience treatment-associated toxicities than their wild-type counterparts (p = 0.0567). One UGT1A1 heterozygote died after a single dose of irinotecan due to irinotecan-related adverse effects. Identifying germline pharmacogenomic variants was feasible using whole-exome sequencing. Actionable pharmacogenetic variants are common and relevant to patients undergoing cancer treatment. Universal pharmacogenomic screening can be performed using whole-exome sequencing data originally obtained for quality control purposes and could be considered for patients who are candidates for irinotecan, 5-fluorouracil, capecitabine, and mercaptopurine.

Document Type

Article

Publication Date

9-8-2021

Notes/Citation Information

Published in Cancers, v. 13, issue 18, 4524.

© 2021 by the authors. Licensee MDPI, Basel, Switzerland.

This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).

Digital Object Identifier (DOI)

https://doi.org/10.3390/cancers13184524

Funding Information

This research was funded by the Markey Cancer Research Informatics Shared Resource Facility National Cancer Institute Cancer Center Support Grant, grant number P30 CA177558.

Related Content

Any requests for data must be submitted to: Jacyln K. McDowell, Epidemiologist, Kentucky Cancer Registry 2365 Harrodsburg Rd, Suite A230 Lexington, KY 40504.

Repository Citation

Hutchcraft, Megan L.; Lin, Nan; Zhang, Shulin; Sears, Catherine; Zacholski, Kyle; Belcher, Elizabeth A.; Durbin, Eric B.; Villano, John L.; Cavnar, Michael J.; Arnold, Susanne M.; Ueland, Frederick R.; and Kolesar, Jill M., "Real-World Evaluation of Universal Germline Screening for Cancer Treatment-Relevant Pharmacogenes" (2021). Pathology and Laboratory Medicine Faculty Publications. 47.
https://uknowledge.uky.edu/pathology_facpub/47