Prevalence of actionable pharmacogenomic variants in Brazilian patients with cancer

Jaqueline Bohrer Schuch^1*Mariana Botton²Angelica Baumont¹Giovana Curzel¹Nathan Araujo Cadore¹Claudia Bordignon¹Mahira Lopes Da Rosa¹Vitor Vasconcellos³Lilian Barros⁴Cristiano de Pádua Souza⁵Williams Barra⁶Daniela Louzeiro⁷Alessandra Notari⁸Juliana Menezes⁹Pedro Liedke²Gláucio Bertollo¹⁰Aline Gongora¹¹Henrique Ascenco¹²Eduardo Kowalski-Neto¹³Christina Oppermann¹⁴Gustavo Werutsky¹⁵Edilmar Santos¹⁶Flavio Brandão¹⁷Ruffo de Freitas Junior¹⁸ANGELICA NOGUEIRA-RODRIGUES¹⁹Andre Mancini²⁰Marina Bessel¹Gabriel Macedo¹Daniela Dornelles Rosa¹

• ¹Moinhos de Vento Hospital, Porto Alegre, Brazil
• ²Hospital de Clinicas de Porto Alegre, Porto Alegre, Brazil
• ³Hospital Universitario Cassiano Antonio Moraes, Vitoria, Brazil
• ⁴Instituto Brasileiro de Controle do Cancer, São Paulo, Brazil
• ⁵Hospital de Câncer de Barretos, Barretos, Brazil
• ⁶Universidade Federal do Para, Belém, Brazil
• ⁷Hospital de Oncologia Dr. Tarquinio Lopes Filho, São Luís, Brazil
• ⁸Hospital Escola da Universidade Federal de Pelotas, Pelotas, Brazil
• ⁹Hospital Nossa Senhora da Conceição, Porto Alegre, Brazil
• ¹⁰Hospital Santa Rita de Cássia, Vitória, Vitória, Brazil
• ¹¹Hospital do Câncer UOPECCAN, Cascavel, Brazil
• ¹²Hospital Universitário Maria Aparecida Pedrossian, Campo Grande, Brazil
• ¹³Hospital Calixto Midlej Filho, Itabuna, Brazil
• ¹⁴Hospital Femina, Porto Alegre, Brazil
• ¹⁵Hospital Sao Lucas da PUCRS, Porto Alegre, Brazil
• ¹⁶Liga Norte Riograndense Contra o Câncer, Natal, Brazil
• ¹⁷Santa Casa de Misericordia de Belo Horizonte, Belo Horizonte, Brazil
• ¹⁸Hospital do Câncer Araújo Jorge da Associação de Combate ao Câncer em Goiás, Goiânia, Brazil
• ¹⁹Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
• ²⁰Hospital Universitário Getúlio Vargas, Manaus, Brazil

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.