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Page 22 Kaehler et al. Cancer Drug Resist 2019;2:18-30 I http://dx.doi.org/10.20517/cdr.2019.05

For further rare genetic variants with low frequencies, especially DPYD*3 (rs72549303) and DPYD*4
(rs1801158), analyses of effects and dose-adjustments is still ongoing. In an in vitro-expression system,
reduced enzyme activity was observed for D949V, while M166V, E828K, K861R and P1023T variants leading
to increased enzyme activity compared to the wild type [35,38] .

DPD activity scores are based on the functionally characterized variants c.190511G>A, c.1679T>G, c.2846A>T,
and. c.1129-5923C>G. Based on these estimated activity scores, the recent CPIC guidelines strongly suggest
[39]
for patients with complete DPD deficiency to avoid the use of fluoropyrimidines . This is also due for
patients having a very low activity score of 0.5. In cases were no alternative for 5-FU are considered, strong
dose reduction and therapeutic drug monitoring is recommended. Since also intermediate metabolizers have
an increased risk of adverse events, dose reductions of 25%-50% should be considered.

Moreover, combinational analysis of DPYD and UGT1A1 genotypes in Italian colorectal cancer patients
receiving fluoropyrimidines/irinotecan revealed that the incremental cost between DPYD variant and
UGT1A1*28/*28 carriers and non-carriers was €2,975, indicating the relevance of these pharmacogenetic
[40]
traits also from an economic perspective . In addition, a recent study stressed the relevance of DPYD
[41]
testing accompanied by genotype-dependent dose reduction for the use of fluoropyrimidines . Concluding,
patients not only of non-European descent could benefit from genetic testing for DPYD/UGT1A1 variants.

Tamoxifen and CYP2D6
The estrogen receptor antagonist tamoxifen has been successfully used in treatment of estrogen-receptor
positive breast cancer since more than 40 years. Tamoxifen is metabolized mainly by CYP2D6 resulting
in various metabolites of which endoxifen has the strongest affinity to the estrogen receptor. As a result,
CYP2D6 genotype tightly correlates to endoxifen plasma levels in patients. In several studies it was shown
that CYP2D6 genotype is a determinant marker of tamoxifen efficacy [Table 1] contributing to 34%-52% of
[42]
absolute endoxifen plasma level . Several variants have been described for CYP2D6 being associated with
normal (CYP2D6*1, CYP2D6*2), decreased (e.g., CYP2D6*10) or complete loss of function (e.g., CYP2D6*3,
CYP2D6*4). Furthermore, CYP2D6 copy number variants may lead to excessive metabolism and ultrarapid
[43]
CYP2D6 phenotype (reviewed in ). Indeed, several studies suggested an association of CYP2D6 genotype
and overall survival, relapse- or recurrence-free survival [43-46] . Accordingly, the CPIC guidelines for CYP2D6
and tamoxifen therapy recommend that CYP2D6 poor metabolizers should be treated alternatively with
aromatase inhibitors and in CYP2D6 intermediates dosage adjustments should be performed to prevent
therapy failure of tamoxifen. In addition, CYP2D6 inhibitors should be avoided regardless of the CYP2D6
genotype . Regarding the use of treatment alternatives, esp. aromatase inhibitors, their use in pre-
[43]
menopausal patient still is contraindicated due to occurrence of treatment-associated amenorrhea, unless
[47]
suppression of ovarian function is performed simultaneously . This has been shown in recent studies,
clearly showing superior overall and disease-free survival rates in combination of aromatase inhibitors or
[48]
tamoxifen plus ovarian suppression . In post-menopausal patients, the optimal treatment strategy is still
controversial, as treatment-duration and -switching between tamoxifen and aromatase inhibitors is still
under investigation [49,50] . This adds additional complexity to the relevance of CYP2D6 genotyping for the use
of tamoxifen. So far, due to a number of inconsistencies, pharmacogenetic analysis of CYP2D6 status has
not yet been considered in the drug label. As reviewed recently, some inconsistencies in the role of CYP2D6
can be explained by the proportion of DNA isolated from peripheral blood cells or tumor tissue. So far, any
association of treatment outcome to CYP2D6 genotype failed when using tumor tissue as DNA source .
[51]
However, in 960 women from the Quilt Study cohort, neither the CYP2D6 genotype nor the concomitant
use of CYP2D6 inhibitors had any influence on the clinical outcome . In addition, in a prospective study
[52]
including 667 pre- and postmenopausal patients, no association was found between endoxifen concentrations
and relapse-free survival time, and there was also lack of association between CYP2D6 genotype and relapse-
free survival time. As any selection bias or non-consideration of confounding factors was regarded as small,
the authors concluded, that the results of this study do not support CYP2D6 genotyping to guide tamoxifen
[53]
treatment in the adjuvant setting .