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

Megan L Hutchcraft; Nan Lin; Shulin Zhang; Catherine Sears; Kyle Zacholski; Elizabeth A Belcher; Eric B Durbin; John L Villano; Michael J Cavnar; Susanne M Arnold; Frederick R Ueland; Jill M Kolesar

doi:10.3390/cancers13184524

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

Cancers (Basel). 2021 Sep 8;13(18):4524. doi: 10.3390/cancers13184524.

Authors

Affiliations

¹ Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Kentucky Markey Cancer Center, Lexington, KY 40536, USA.
² Department of Pharmacy Practice and Science, University of Kentucky College of Pharmacy, Lexington, KY 40536, USA.
³ Department of Pathology and Laboratory Medicine, University of Kentucky Chandler Medical Center, Lexington, KY 40536, USA.
⁴ Department of Pharmacy, Virginia Commonwealth University Medical Center, Richmond, VA 23298, USA.
⁵ Department of Clinical Research, University of Kentucky Markey Cancer Center, Lexington, KY 40536, USA.
⁶ Division of Biomedical Informatics, Department of Internal Medicine, University of Kentucky College of Medicine, Lexington, KY 40536, USA.
⁷ Kentucky Cancer Registry, University of Kentucky Markey Cancer Center, Lexington, KY 40536, USA.
⁸ Division of Medical Oncology, Department of Internal Medicine, University of Kentucky Markey Cancer Center, Lexington, KY 40536, USA.
⁹ Division of Surgical Oncology, Department of Surgery, University of Kentucky Markey Cancer Center, Lexington, KY 40536, USA.

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.

Keywords: 5-fluorouracil; cancer; irinotecan; mercaptopurine; pharmacogenomics; real word.

Grants and funding

P30 CA177558/CA/NCI NIH HHS/United States