Prevalence of actionable pharmacogenomic variants in Brazilian patients with cancer

Abstract

Introduction: Pharmacogenomic (PGx) variants can influence drug efficacy and safety, yet their prevalence in Latin American populations with cancer is underexplored. Our aim is to characterize the frequency and phenotypic distribution of actionable pharmacogenes in Brazilian patients with metastatic prostate cancer (MPC) and Human Epidermal Growth Factor Receptor 2 (HER2)-positive breast cancer (BC).Methods: This analysis included 452 patients (259 BC, 193 MPC) from a multicenter study across 19 Brazilian sites. Exome sequencing was performed, and PGx variants were analyzed using the Pharmacogenomics Clinical Annotation Tool (PharmCAT) following the Clinical Pharmacogenetics Implementation Consortium (CPIC®) guidelines. Genotypes, star alleles, and predicted phenotypes were reported for 15 clinically relevant pharmacogenes.Results: Actionable PGx phenotypes were detected in 99.33% of participants. The decreased-function ABCG2 rs2231142 T allele occurred at 8.96%, and the VKORC1 rs9923231 T allele at 32.63%. In SLCO1B1, normal function predominated (63.11%), with 21.11% exhibiting decreased function. Normal metabolizer phenotypes were most frequent in CYP2C19 (45.35%), CYP2C9 (70.51%), and CYP3A4 (94.62%), whereas CYP2B6 was dominated by intermediate metabolizers (43.02%) and CYP3A5 by poor/intermediate metabolizers (93.79%). Normal diplotypes predominated in thiopurine-related genes (NUDT15: 92.92%; TPMT: 88.72%), although nonfunctional alleles were observed. In UGT1A1, decreased-function alleles accounted for approximately 37% of participants. Clinically relevant DPYD and RYR1 variants were rare (<2.0%).Conclusion: Nearly all Brazilian patients with cancer carried at least one actionable PGx variant, highlighting the potential impact of PGx-guided therapy in oncology. These results underscore the value of integrating pharmacogenomic strategies into clinical practice in Brazil.