Pharmacogenetic testing in oncology: a Brazilian perspective

Abstract

Pharmacogenetics, a major component of individualized or precision medicine, relies on human genetic diversity. The remarkable developments in sequencing technologies have revealed that the number of genetic variants modulating drug action is much higher than previously thought and that a true personalized prediction of drug response requires attention to rare mutations (minor allele frequency, MAF<1%) in addition to polymorphisms (MAF>1%) in pharmacogenes. This has major implications for the conceptual development and clinical implementation of pharmacogenetics. Drugs used in cancer treatment have been major targets of pharmacogenetics studies, encompassing both germline polymorphisms and somatic variants in the tumor genome. The present overview, however, has a narrower scope and is focused on germline cancer pharmacogenetics, more specifically, on drug/gene pairs for which pharmacogenetics-informed prescription guidelines have been published by the Clinical Pharmacogenetics Implementation Consortium and/or the Dutch Pharmacogenetic Working Group, namely, thiopurines/TPMT, fluoropyrimidines/UGT1A1, irinotecan/UGT1A1 and tamoxifen/CYP2D6. I begin by reviewing the general principles of pharmacogenetics-informed prescription, pharmacogenetics testing and the perceived barriers to the adoption of routine pharmacogenetics testing in clinical practice. Then, I highlight aspects of the pharmacogenetics testing of the selected drug-gene pairs and finally present pharmacogenetics data from Brazilian studies pertinent to these drug-gene pairs. I conclude with the notion that pharmacogenetics testing has the potential to greatly benefit patients by enabling precision medicine applied to drug therapy, ensuring better efficacy and reducing the risk of adverse effects.

Pharmacogenomic biomarker information differences between drug labels in the United States and Hungary: implementation from medical practitioner view

“…This is in line with the EMA statement that PGx information are preferentially present in drug labels having antineoplastic properties [10]. In the field of oncology, pharmacogenetic biomarkers represent a complex combination of germline and somatic variants [11]. Importantly, somatic mutations in tumor cell are increasingly implicated biomarkers in targeted therapy, applied in treatment selection, and are also often associated with treatment efficacy [12].…”

Comparison of dose-dense vs. 3-weekly paclitaxel and carboplatin in the first-line treatment of ovarian cancer in a propensity score-matched cohort

“…There are ethnic differences in polymorphisms of genes involved in the metabolism of paclitaxel, especially in CYP2C8 and CYP3A4/5 enzymes [ 23 ]. There are few data about distribution of pharmacogenetics polymorphisms among Brazilians, besides the fact that the Brazilian population is highly heterogeneous and admixed, which may cause high heterogeneity of drug responses [ 29 ]. A small study showed that the frequency of CYP2C8*2, for example, is similar to other registries, being more common in Brazilian black population (13% of the sample) and rare for white and Asian Brazilians (1 and 0%, respectively) [ 30 ].…”

The c.415C>T polymorphism in NUDT15 is more frequent than the polymorphisms in TPMT in Chilean patients who use thiopurine drugs

“…Furthermore, a study of Native populations living in reservations areas in Brazil disclosed the highest range of rs116855232 MAF (19.4–31.7% in Kaingang and Guarani) reported so far for any population worldwide [8]; In other Native American populations from Brazil, the MAF of rs116955232 was reported as ranging from 5.2% in Xavante (Center-West region; [8]) to 9.4% in Amazonian groups [9]. For comparison, in admixed cohorts from the Southeast region of Brazil, with average Native ancestry <10% [7], the MAF of rs116855232 is < 1.3% [6,10].…”