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Page 58 Olivera et al. Cancer Drug Resist 2019;2:53-68 I http://dx.doi.org/10.20517/cdr.2018.25

- - IM: see Increased risk for relapse of breast cancer. Avoid
description in concomitant use of CYP2D6 inhibitors. Consider
oxycodone aromatase inhibitor for postmenopausal women
Tramadol CYP2D6 DPWG [6]
PM: see Select alternative drug (not oxycodone or codeine) or be
description in alert to insufficient effect
oxycodone
IM: see description Be alert to decreased efficacy, consider dose increase. If
in oxycodone still inadequate, do as PM
UM: see Reduce dose by 30% and be alert to ADEs, or do as PM
description in
oxycodone
A summary of the published guidelines is shown in this table, translating the information to single SNPs when possible. The original
guidelines, especially from CPIC, are much more extensive, so this table is only a comprehensive approach, useful for the majority of
cases, but deeper details must be consulted in the original publications. #Applicable to pediatrics. Classical asterisks nomenclature: *1 is
always considered the reference genotype. TPMT: *2 equivalent to rs1800462; *3A equivalent to *3B+*3C; *3B equivalent to rs1800460;
*3C equivalent to rs1142345; *4 equivalent to rs1800584. NUDT15: *3 equivalent to rs116855232. UGT1A1: *28 equivalent to rs8175347
(this is not a real SNP, but a short tandem repeat polymorphism). DPYD at CPIC guideline: IM, one normal function + one no function,
or one decreased function, or two decreased function alleles; PM, two no function, or one no function + one decreased function. No
function: c.1905+1G>A equivalent to rs3918290 and DPYD*2A; c.1679 T>G equivalent to rs55886062 and DPYD*13; Decreased function:
c.2846 A>T equivalent to rs67376798; c.1129-5923 C>G equivalent to rs75017182. CYP2D6: Date of access to CPIC-DPWG-PharmGKB
for guidelines: 15 January 2019. ADE: Adverse Drug Event; UM: ultrarapid metabolizer; NM: normal metabolizer; IM: intermediate
metabolizer; PM: poor metabolizer; CPIC: Clinical Pharmacogenetics Implementation Consortium; DPWG: Royal Dutch Association for
the Advancement of Pharmacy - Pharmacogenetics Working Group; SNP: single nucleotide polymorphism

These drugs are administered as prodrugs that are converted to thioguanine nucleotides (TGN) by the
hypoxanthine guanine phosphoribosyltransferase enzyme. TGNs integrate within DNA and RNA leading
to cancer cell death, what is inactivated by cytosolic Thiopurine S-methyltransferase (TPMT) enzyme via
S-methylation. For this reason, TPMT gene polymorphisms can alter the enzyme activity and trigger the
apoptosis of healthy cells and lead to ADRs .
[2]
Alleles *2 (rs1800462, C>G), *3A [haplotype *3B (rs1800460, C>T) + *3C (rs1142345, T>C)], *3B, *3C and *4
(rs1800584) are the most common variants and they are estimated to foresee up to 90% of TPMT function
and variability. Other 34 TPMT alleles with low frequencies in different populations have been also
described.

Initial doses of treatment with thiopurines are high since they derive from clinical trials performed in
general population, where wild type allele has a frequency of 86%-97%. These standard doses must be
administered only in those patients homozygous for wild type TPMT gene (*1/*1).

CPIC recommendations indicate that those patients with heterozygous TPMT (one functional allele *1 and
one non-functional allele), should initiate the treatment with 30%-80% of the target dose and been evaluated
according to tolerance. Finally, in those patients homozygous for non-functional variants of TPMT it is
recommended to begin with 10% of the target dose and 3 doses a week instead of daily treatment or to
[15]
change the drug employed .
[6]
The DPWG provides another clinical guide for the use of thiopurines. They recommend in intermediate
metabolizers (IM) heterozygous for TPMT function (containing 1 functional allele as *1, *1S, *1A, and one non-
functional allele like *2, *3A-*3D, *4-*18) to select an alternative drug or reduce the dose to 50% and increase it
under efficacy and hematologic surveillance. In poor metabolizers (PM) patients carrying two inactive alleles (*2,
*3A-*3D, *4-*18) it is recommended to select an alternative drug or to reduce the doses by 90% and increase it
according to the efficacy and hematologic toxicity data obtained by monitoring the patient.

However, there are patients with TPMT wild type genotype that present toxicity when treated with
thiopurines. This is most probably due to the existence of other variants involved in thiopurines metabolism