INTRODUCTION
In this issue of Brazilian Journal of Oncology (BJO), Suarez-Kurtz discusses the pharmacogenetics/
genomics (PGx) anticancer drug-testing program developed by his group at the Brazilian
National Cancer Institute (INCA).([1]) Drug -gene pairs were selected for PGx testing based on the presence of clinically
validated PGx associations and the availability of international guidelines with PGx-informed
dosing recommendations. Fluoropyrimidines-DPYD, irinotecan-UGT1A1, and thiopurines-TPMT/NUDT15
were initially included in the evaluation. Tamoxifen PGx testing was also briefly
mentioned.
The goal of this type of study is to identify genome variants that influence drug
effects, usually through alterations in drug pharmacokinetics (i.e., absorption, distribution,
metabolism or elimination) or pharmacodynamics, meaning changes in drug targets or
in biological pathways that alter sensitivity to its pharmacological effects. In cancer
patients, genome variations, as well as somatically acquired genome variants, can
influence the antitumor and/ or toxic effect of therapeutic agents.([1])
Most human disorders, including cancer, may be influenced by different genes and genetic
variants. Likewise, pharmacokinetics and pharmacological effects of therapeutic agents
can be determined by genes encoding drug-metabolizing enzymes, transporters, targets,
and disease-modifying genes. The genetic polymorphism in thiopurine methyltransferase
(TPMT) and its effects on the risk of bone marrow toxicity from therapeutic agents,
such as mercaptopurine or azathioprine illustrates this situation. As an example,
adjustments are recommended on the dosage of mercaptopurine, based on TPMT genetic
test results.([2])
However, when clinicians decide to prescribe the agents mentioned above, polymorphisms
in other relevant genes seem as important, such as ITPA, and polymorphisms in other
genes along the same pathway may be also relevant, as shown for inherited variants
of NUDT15 for the occurrence of thiopurine toxicity. NUDT15 variants appear to be
rare in Caucasian patients and individuals of African ancestry, but more common among
those of Asian origin.([3])
The higher frequency of thiopurine intolerance - due to distinct causes - can explain
differences in drug tolerability between these two patient populations, revealing
that TPMT variants are the major determinant of tolerated dose in European and African
patients, whereas NUDT15 is the major genetic determinant in Asian and Native Americans.
As metabolism and effects of thiopurines can be affected by both germline and somatic
genome variation, this can add to the complexity of interpreting cancer pharmacogenomics
in this context.([4])
5-fluorouracil (5-FU) is widely used in the treatment of solid malignancies and is
the backbone cytotoxic agent in anticancer drug regimens against gastrointestinal
neoplasms. Despite advances in its management, up to a third of patients treated with
fluoropyrimidines as monotherapy develops significant treatment-related toxicity,
with 0.5 to 1% deaths. The most well-known reason for 5-FU intolerance is the deficiency
of dihydropyrimidine dehydrogenase (DPD) activity, the key enzyme for its metabolism.
Complete DPD deficiency is observed in 0.1 to 0.5% of the population, whereas partial
DPD deficiency occurs in up to 15% of the population. Furthermore, DPD deficiency
is observed in about half of patients exhibiting severe toxicity.([5])
Polymorphisms in the gene encoding DPD (DPYD), as a predictor of fluoropyrimidine-related
toxicity is receiving more attention. Several sequence variations in the DPYD gene
have been identified, DPYD*2A being the most prevalent. The Clinical Pharmacogenetics
Implementation Consortium established that 5-FU and analogs should undergo dose reductions
based on clinical DPYD genotype tests. An initial dose reduction of at least 50% is
proposed for individuals who are heterozygous for DPYD*2A, DPYD*13, and c.2846 A>T,
who appear to show intermediate or partial DPD enzyme activity. The use of alternative
drugs, however, is strongly recommended for patients with complete DPD deficiency.([6])
It is important to consider that DPD activity is regulated not only at the level of
DPYD gene, but at the transcriptional and at the post-transcriptional levels as well.
DPYD genotyping fails to identify severe DPD deficiency in a significant percentage
of cases. In our laboratory, we have focused on functional studies, such as the measurements
of UH2/U metabolic ratios in plasma or saliva. These tests showed enough sensitivity
and specificity to deserve further evaluation. Other strategies for assessing DPD
activity, such as DPD phenotyping, are therefore critical to be pursued.([7])
DPD converts uracil, its endogenous substrate, into dihydrouracil, and the pretreatment
dihydrouracil (UH2)/uracil (U) ratio or uracil concentrations (U) alone have the potential
to identify patients at fluoropyrimidine-associated severe toxicity risk. The UH2/U
ratio correlates with 5-FU clearance and risk of toxicity. However, despite strong
evidence on its clinical validity, the use of the UH2/U ratio in daily clinical practice
has not been routinely applied. Further studies are needed to validate the strategies
mentioned above of DPD function measurements in a larger patient population.([8])
Irinotecan (IRI) is a prodrug converted in the liver by carboxylesterases (CES) to
7-ethyl-10hydroxycamptothecin (SN-38), which is much more active and cytotoxic than
its parent drug. Treatment with irinotecan is usually associated with doselimiting
toxicities, mainly diarrhea and neutropenia/ leukopenia. The wide interindividual
variability intolerability with the occurrence of severe toxicity is partially related
to interindividual pharmacokinetic and pharmacogenetic differences, especially in
the glucuronidation of the active metabolite through the action of UGT.([9])
Carriers of the UGT1A1*28 allele have consistently shown lower glucuronidation ratio,
with decreased SN-38G to SN-38 ratio. Due to the higher systemic exposure to SN-38
metabolite, patients with impaired UGT metabolism are at a higher risk of developing
drug-induced toxicity. Several studies have found a significant association between
the UGT1A1*28 polymorphism and severe neutropenia and/or diarrhea. Similar results
were found for the exon encoding UGT1A1*6 polymorphism in Asians, indicating a central
role of the variant allele in this ethnic population.([10])
Since SN-38 is much more cytotoxic than irinotecan, plasma levels of SN-38, clearance
of SN-38, and/or polymorphism of UGT1A1 have clinical relevance. The clearance ability
of SN-38 can be predicted by determining SN-38G/SN-38 plasma concentration ratios.
It was suggested a one-point plasma SN38G/SN-38 concentration ratio to define IRI
induced neutropenia and to guide IRI dose adjustments. We have recently reviewed the
pharmacokinetic and pharmacogenetic markers of irinotecan toxicity, pointing out that
the most straightforward approach for IRI dose individualization should be UGT1A1
genotyping.([11])
However, this strategy is still sub-optimal due to several other genetic and environmental
contributions to the variable pharmacokinetics of IRI and its active metabolites.
The quantification of IRI and its active metabolite SN-38 in dried blood spots may
be an alternative to individualize the drug dose through a minimally invasive collection
method. Our research group and others are researching such alternative sampling strategy
that eventually could allow larger studies to evaluate the relationship between exposure
to IRI and its metabolites to toxicity and clinical responses, also supporting the
establishment of exposure targets.([12])
As briefly mentioned by Suarez-Kurtz, the metabolism of tamoxifen (TAM) is also important
to be considered when prescribing this drug. Cytochrome P450 plays an essential role
on TAM metabolic activation. The major metabolite N-desmethyltamoxifen (NDT) is produced
by CYP3A4/5, with minor contributions by CYPs 2D6, 1A, 1A2, 2C19, and 2B6. NDT undergoes
further 4-hydroxylation by CYP2D6 being converted to 4-hydroxy-N-desmethyltamoxifen
or (Z)-endoxifen (EDF).([13]) Using plasma samples obtained from breast cancer patients who attended our clinic,
we have also reported that CYP3A4 contributes to the bioactivation of TAM and becomes
increasingly important in case of reduced or absent CYP2D6 activity.([14])
The PGx anticancer drug-testing program developed by Suarez-Kurtz and his group at
the Brazilian National Cancer Institute is extremely welcome and must be discussed
and implemented in other institutions of the region. This may lead to more multi-institutional
partnerships and should bring a broader discussion on the use of pharmacogenomics
and pharmacokinetics in routine oncology practice. Although we have great perspectives
for the introduction of new immunotherapies and targeted agents, chemotherapy will
continue to be administered in cancer patients in the years to come.
We should bear in mind that pharmacodynamic effects of new classes of anticancer agents
would probably be influenced by different genes and genetic variants as well. In short,
the current estimation of anticancer therapy doses usually does not reflect the complexities
of metabolism. Therefore, efforts should be made in order to refine the ways we prescribe
these drugs, being conventional cytotoxic or newer ones. Maximizing benefits, while
minimizing side effects, should be our therapeutic goals.
