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Olivera et al. Cancer Drug Resist 2019;2:53-68 I http://dx.doi.org/10.20517/cdr.2018.25 Page 61

The recommendations depend, then, upon the group to which each patient belongs. Nowadays, only
those patients included within the UM (allelic combinations *1/*1xN, *1/*2xN, *2/*2xN) group have
recommendations. This guide recommends using an alternative drug not metabolized by CYP2D6. The
[21]
authors state that there is no reason to expect differences in pediatric oncology, except in newborns .
The recommendations are considered informative by FDA.

Tamoxifen and CYP2D6
Around 65%-75% of breast cancers express estrogen receptors (ER) or progesterone receptors. This type of
cancer can be treated with endocrine therapy such as tamoxifen since it is a selective modulator of estrogen
receptor.

Tamoxifen is the unique hormonal agent approved by FDA for pre-menopausal breast cancer prevention,
in situ ductal carcinoma treatment and as adjuvant treatment in invasive pre-menopausal metastatic breast
cancer.

The metabolization of tamoxifen takes place within the liver and is performed by cytochrome P450 enzymes.
The main metabolism mechanism contributes to up to 90% of the global tamoxifen metabolism and consists
[39]
in the demethylation of tamoxifen to N-demethyltamoxifen by CYP3A4 , followed by the oxidation to
4-hydroxi-N-demethylmetamoxifen (endoxifen) mediated by CYP2D6 .
[40]
[41]
The gene variants are described in https://cpicpgx.org/alleles/ .
Both CPIC and DPWG have guides for the use of tamoxifen. CPIC guide focuses on the CYP2D6 role in the
ER+ cancer breast adjuvant treatment. The recommendations for ultrarapid (*1/*1xN, *1/*2xN, *2/*2xN) and
normal (*1/*1, *1/*2, *1/*9, *1/*41, *2/*2) metabolizers are to avoid strong and moderate CYP2D6 inhibitors.
Treatment can initiate with the standard tamoxifen dose (20 mg/day).

In intermediate metabolizers (*4/*10, *4/*41, *5/*9, *1/*4, *1/*5, *41/*41, *10/*10, *10/*41), aromatase inhibitor
therapy should be considered in post-menopausal patients and aromatase inhibitor combined with ovary
function suppression in pre-menopausal women since these methods present better outcomes than
[42]
tamoxifen regardless CYP2D6 genotype . In those cases the aromatase inhibitors are contraindicated,
tamoxifen doses higher than those approved by the FDA (40 mg/day) should be considered. It must be taken
into account that highest dose of tamoxifen (40 mg/day) increases the concentration of endoxifen without
reaching normal levels and then it could be considered if aromatase inhibitors contraindications exist [43,44] .

Lastly, in poor metabolizer patients (*3/*4, *4/*4, *5/*5, *5/*6) it is recommended to use an alternative
hormonal therapy such as aromatase inhibitor in post-menopausal patients and an aromatase inhibitor
combined with ovary function suppression in pre-menopausal women because these strategies are more
efficient than tamoxifen regardless the CYP2D6 genotype especially if they are deficient for CYP2D6
metabolism. Changing tamoxifen by anastrozole does not present higher recurrence risk.

The DPWG also elaborated a guide of recommendation directed to poor metabolizer genotypes (*3-*8,
*11-*16, *19-*21, *38, *40, *42) and intermediate metabolizer genotypes [two reduced activity alleles (*9,
*10, *17, *29, *36, *41) or one active allele (*1, *2, *33, *35) and one inactive (*3-*8, *11-*16, *19-*21, *38, *40,
*42) or one inactive allele (*3-*8, *11-*16, *19-*21, *38, *40, *42) and one reduced activity allele (*9, *10, *17,
*29, *36, *41) and one inactive (*3-*8, *11-*16, *19-*21, *38, *40, *42) allele]. It is recommended the use of
aromatase inhibitors in post-menopausal women since higher risk of relapse in breast cancer exists. Also, the
[6]
concomitant use of CYP2D6 inhibitors must be avoided for intermediate metabolizers .