Pharmacogenomic tests of oncology drugs at Instituto Nacional de Câncer (INCA)

ABSTRACT

The implementation, current status and future perspectives of the pharmacogenetics/genomics (PGx) testing program developed at Instituto Nacional de Cancer (INCA) are presented. Initial selection of drug-gene pairs for PGx testing was based on clinically-validated PGx associations and availability of international guidelines with PGx-informed dosing recommendations. The selected pairs were fluoropyrimidines- DPYD, irinotecan- UGT1A1, and thiopurines- TPMT/NUDT15. The aims and rationale for the implemented PGx tests, frequency of the interrogated genetic variants and assigned metabolic phenotypes, and the individual dosing recommendations are reviewed. Planned developments, such as collaboration with other cancer treatment centers, testing of additional drug-gene pairs (e.g., tamoxifen- CYP2D6 ), and inclusion of PGx testing in the routine workout of targeted patients at INCA were impacted by the outbreak of the COVID-19 pandemics. The Brazilian Society of Clinical Oncology is invited to play a leading role in the evaluation of the clinical utility of PGx tests of germline variants for oncology drugs in Brazil.

RESUMO

É apresentada a implementação, o estado atual e as perspectivas futuras do programa de testes farmacogenéticos/genômicos (PGx) desenvolvido no Instituto Nacional de Câncer (INCA). A seleção inicial de pares de genes-medicamentos para testes PGx foi baseada em associações PGx clinicamente validadas e disponibilidade de diretrizes internacionais com recomendações de dosagem segundo as características PGx individuais. Os pares selecionados foram fluoropirimidinas- DPYD, irinotecano- UGT1A1 e tiopurinas- TPMT/NUDT15. Os objetivos e a justificativa para os testes PGx implementados, a frequência das variantes genéticas interrogadas e dos fenótipos metabólicos atribuídos, e as recomendações de dosagem individuais são apresentados. Desenvolvimentos planejados, como colaboração com outros centros de tratamento de câncer, testes adicionais de pares de medicamentos-genes (por exemplo, tamoxifeno- CYP2D6 ) e inclusão de testes de PGx na rotina de pacientes-alvo no INCA foram impactados pela pandemia COVID-19. A Sociedade Brasileira de Oncologia Clínica é convidada a desempenhar um papel de liderança na avaliação da utilidade clínica dos testes PGx de variantes germinativas para medicamentos oncológicos no Brasil.

Keywords:

DPYD - Fluoropyrimidines - Irinotecan - NUDT15 - Pharmacogenomics - Thiopurines - TPMT - UGT1A1.

Descritores:

DPYD - Fluoropirimidinas - Irinotecan - NUDT15 - Farmacogenômica - Tiopurinas - TPMT - UGT1A1.

CONFLICTS OF INTEREST None to declare.

Financial support: none to declare.

Clinical trials : Not Applicable

Publikationsverlauf

Eingereicht: 09. Dezember 2020

Angenommen: 19. Dezember 2020

Artikel online veröffentlicht:
14. Mai 2021

• REFERENCES

• US Food and Drug Administration (FDA). Table of pharmacogenomic biomarkers in drug labeling. Washington. DC: FDA; 2019; November 4; 2020. Available from: https://www.fda.gov/drugs/science-and-researchdrugs/table-pharmacogenomic-biomarkers-drug-labeling
• Suarez-Kurtz G, Kovaleski G, Elias AB, Motta VLA, Wolch K, Emerenciano M. et al Implementation of a pharmacogenomic program in a Brazilian public institution. Pharmacogenomics 2020; Jun; 21 (08) 549-557
• Wellmann R, Borden BA, Danahey K, Nanda R, Polite BN, Stadler WM. et al Analyzing the clinical actionability of germline pharmacogenomic findings in oncology. Cancer 2018; Jul; 124 (14) 3052-3065
• Dunnenberger HM, Crews KR, Hoffman JM, Caudle KE, Broeckel U, Howard SC. et al Preemptive clinical pharmacogenetics implementation: current programs in five US medical centers. Ann Rev Pharmacol Toxicol 2015; 55: 89-106
• Relling MV, Evans WE.. Pharmacogenomics in the clinic. Nature 2015; Oct; 526 (7573) 343-350
• Clinical Pharmacogenetics Implementation Consortium (CPIC). Guidelines [Internet]. Stanford. CA: CPIC; 2020; November 4; 2020. Available from: https://cpicpgx.org/guidelines/
• Dutch Pharmacogenetics Working Group (DPWG). Page DPWG [Internet]. Stanford. CA: PharmGKB; 2020; November 4; 2020. Available from: https://www.pharmgkb.org/page/dpwg
• Amstutz U, Henricks LM, Offer SM, Barbarino J, Schellens JHM, Swen JJ. et al Clinical Pharmacogenetics Implementation Consortium (CPIC) guideline for dihydropyrimidine dehydrogenase genotype and fluoropyrimidine dosing: 2017 update. Clin Pharmacol Ther 2018; Feb; 103 (02) 210-216
• Lunenburg CATC, Van Der Wouden CH, Nijenhuis M, Crommentuijn-van Rhenen MH, Boer-Veger NJ, Buunk AM. et al Dutch Pharmacogenetics Working Group (DPWG) guideline for the gene-drug interaction of DPYD and fluoropyrimidines. Eur J Hum Genet 2020; Nov; 28 (04) 508-517
• PharmGKB (US). Dutch Pharmacogenetics Working Group (DPWG). Guidelines August 2019 [Internet]. Stanford, CA: PharmGKB;; 2019. accessed on November 4, 2020 Available from: https://www.pharmgkb.org/guidelineAnnotation/PA166104951
• Goetz MP, Sangkuhl K, Guchelaar HJ, Schwab M, Province M, Whirl-Carrillo M. et al Clinical Pharmacogenetics Implementation Consortium (CPIC) guideline for CYP2D6 and tamoxifen therapy. Clin Pharmacol Ther 2015; May; 103 (05) 770-777
• PharmGKB (US). Dutch Pharmacogenetics Working Group (DPWG). Guidelines August 2019 [Internet]. Stanford, CA: PharmGKB;; 2019. accessed on November 4, 2020 Available from: https://www.pharmgkb.org/guidelineAnnotation/PA166104966
• Relling MV, Schwab M, Whirl-Carrillo M, Suarez-Kurtz G, Pui CH, Stein CM. et al Clinical pharmacogenetics implementation consortium guideline for thiopurine dosing based on TPMT and NUDT15 genotypes: 2018 update. Clin Pharmacol Ther 2019; May; 105 (05) 1095-1105
• PharmGKB (US). Dutch Pharmacogenetics Working Group (DPWG). Guidelines August 2019 [Internet]. Stanford, CA: PharmGKB;; 2019. accessed on November 4, 2020 Available from: https://www.pharmgkb.org/guidelineAnnotation/PA166104960
• Suarez-Kurtz G.. Pharmacogenetic testing in oncology: a Brazilian perspective. Clinics 2018; Oct; 73 (Suppl 1): e565s
• Sai K, Saeki M, Saito Y, Ozawa S, Katori N, Jinno H. et al UGT1A1 haplotypes associated with reduced glucuronidation and increased serum bilirubin in irinotecan-administered Japanese patients with cancer. Clin Pharmacol Ther 2004; Jun; 75 (06) 501-515
• Brazilian Genomic Variants (ABraOM). Public files for download [Internet]. São Paulo. SP: ABraOm; 2019; November 4; 2020. Available from: http://abraom.ib.usp.br/download/
• Cunha-Junior GF, Marco L, Bastos-Rodrigues L, Bolina MB, Martins FL, Pianetti GA. et al (13)C-uracil breath test to predict 5-fluorouracil toxicity in gastrointestinal cancer patients. Cancer Chemother Pharmacol 2013; Dec; 72 (06) 1273-1282
• Galarza AF, Linden R, Antunes MV, Hahn RZ, Raymundo S, Silva AC. et al Endogenous plasma and salivary uracil to dihydrouracil ratios and DPYD genotyping as predictors of severe fluoropyrimidine toxicity in patients with gastrointestinal malignancies. Clin Biochem 2016; Nov; 49 (16–17); 1221-1226
• Reis M, Santoro A, Suarez-Kurtz G.. Thiopurine methyltransferase phenotypes and genotypes in Brazilians. Pharmacogenetics 2003; Jun; 13 (06) 371-373
• Tonk ECM, Gurwitz D, Maitland-Van Der Zee AH, Janssens ACJW.. Assessment of pharmacogenetic tests: presenting measures of clinical validity and potential population impact in association studies. Pharmacogenomics J 2017; Jul; 17 (04) 386-392
• Suarez-Kurtz G.. Population impact of pharmacogenetic tests in admixed populations across the Americas. . Pharmacogenomics J. 2020. Oct; 27; Epub ahead of print. https://doi.org/10.1038/s41397-020-00200-w
• Guellec CB, Lafay-Chebassier C, Ingrand I, Tournamille JF, Boudet A, Lanoue MC. et al Toxicities associated with chemotherapy regimens containing a fluoropyrimidine: a real-life evaluation in France. Eur J Cancer 2020; Jan; 124: 37-46
• PharmGKB (US). Drug label annotations [Internet]. Stanford. CA: PharmGKB;; 2020. access in November 4, 2020 Available from: https://www.pharmgkb.org/labelAnnotations