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Page 64 Olivera et al. Cancer Drug Resist 2019;2:53-68 I http://dx.doi.org/10.20517/cdr.2018.25

UMPS rs1801019 GG, CG CC 2B: T Moderate risk of toxicity
Trastuzumab FCGR2A rs1801274 AA AG, GG 2B: E T Moderate risk of inefficacy
FCGR3A rs396991 CC AC, AA 2B: E Moderate risk of inefficacy
Vincristine CEP72 rs924607 CC, CT TT 2B: T I Moderate risk of toxicity

*As this line describes a group of drugs, no information from a single drug label can be provided. This table lists the SNPs with levels of
evidence 1 and 2 for the chemotherapeutic drugs and some others frequently employed in cancer patients (ondansetron and some pain
relief drugs), that still have not a published guideline with therapeutic recommendations. The information about the “reference” and
“risk” genotypes, with the proposed implications if the patient bears the risk one is provided. “CA” column describes the level of evidence
and the way in which the risk genotype affects the drug mechanism (D, dosage; E, efficacy; Pk, pharmacokinetics; T, toxicity) and what
does the drug label (FDA or EMA) state about performing genetic tests when prescribing that drug (T, testing required or recommended;
A, actionable; I, informative), not specifying genes or variants. SNPs related with a set of drugs have not been listed, this table only
includes the genes and SNPs directly linked with each individual drug. Date of PharmGKB access 15 January 2019. SNPs: single nucleotide
polymorphisms; CA: clinical annotation

as cardiovascular, such as obesity, diabetes, hypertension, coronary artery disease, lipid disorders and
[73]
peripheral vascular disease .
While Table 1 shows the drug-SNP pairs that are currently included in a guideline, Table 2 shows a
compilation of the current information according to the three main pillars explained at the initial section
of this work. It includes the majority of drugs used in chemotherapy treatments, and some antiemetic and
pain relief drugs that reach Clinical Annotations with Levels of Evidence 1 and 2, listed in PharmGKB,
but still do not have a therapeutic/dosing guideline published. Some SNPs may not be directly described
in PharmGKB Clinical Annotations under a drug name, but instead they can be found under the generic
name of that drug’s family. For instance, some relevant SNPs assigned to “cisplatin”, can only be reached
by searching “platinum compounds”. The possible genotypes for each SNP are divided into “Reference
Genotype” and “Risk Genotype”, having defined these groups in agreement with the biological or clinical
meaning of each genotype. Not necessarily the positive or negative effects of a given genotype are linked
to the most or least frequent variants, respectively. Variant frequencies can vary widely between different
ethnical human populations.

The “Implications” column provides an easy-to-use short interpretation of the content in the original
resource. The last column of the table shows the existence of a genetic test recommendation in the drug label,
according to FDA and/or EMA.

CONCLUSION
This work aims to summarize and make available to clinicians, in a practical way, the guidelines and
recommendations that exist so far with high level of evidence, of germline genetic variants associated with
drugs used in the treatment for both pediatric and adult oncology. In this way, our aim is to facilitate the
comprehension of the available information for decision making in clinical practice. The big consortia, as
well as relevant hospitals’ initiatives worldwide, are performing strong efforts to harmonize, to disseminate
[74]
and to integrate PGx as a real and useful tool for the clinicians’ routine .
PGx aims to improve patient’s life quality, reducing the adverse effects of drugs and improving the
effectiveness of these. Approximately 20% of pediatric oncology patients do not respond to standard
treatments, this percentage seems to be even higher in adults, where the available data on the risks and
benefits of treatment are scarce. Administered chemotherapeutic schemes include high doses and toxicity
risk, leading to a wide variety of side effects. This is often due to the low specificity of therapeutic target and
to the treatment intensification. Chemotherapy toxicity is a regular cause of morbidity and mortality in most
of these patients, with short- and long-term sequels. At present, there are PGx tests with sufficient evidence
to be implemented in clinical practice, regulated by different guides and drug regulatory agencies. So far,
most of them are aimed for treatment in adults and only well defined for its use in pediatric oncology in