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

SIMPLE SUMMARY: Germline pharmacogenomic variants impact the toxicity of many cancer treatment drugs. Though testing for pharmacogenomic variants prior to initiating systemic cancer treatment is not routine, the Clinical Pharmacogenetics Implementation Consortium recommends dosing modifications for six cancer treatment drugs based on variant genotypes: irinotecan and UGT1A1; 5-fluorouracil and capecitabine and DPYD; 6-mercaptopurine and thioguanine and TPMT; and tamoxifen and CYP2D6. The purpose of this study was to assess the frequency of cancer treatment-relevant germline pharmacogenomic variants in patients with cancer using residual germline whole-exome sequencing. We also evaluated the association of disease-relevant pharmacogenomic variants with treatment-associated toxicities. Approximately one-quarter of cancer patients carried a disease-relevant pharmacogenomic variant. Patients with toxicity-associated pharmacogenomic variant genotypes were more likely to experience drug-related toxicity than their wild-type counterparts. Universal pharmacogenomic screening is feasible using whole-exome sequencing originally obtained for quality control purposes and may be an effective germline pharmacogenomic screening strategy for patients who are candidates for irinotecan, 5-fluorouracil, capecitabine, or 6-mercaptopurine. 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.