Impact of Metabolizing Enzymes on Drug Response of Endocrine Therapy in Breast Cancer

Pilar H Saladores; Jana C Precht; Werner Schroth; Hiltrud Brauch; Matthias Schwab

Disclosures

Expert Rev Mol Diagn. 2013;13(4):349-65. 

In This Article

Other Enzymes Involved in Tamoxifen Metabolism

Plasma metabolite analytics in patients receiving tamoxifen showed that despite a CYP2D6 PM status, patients can have high levels of endoxifen,[19] with 24% of PM patients even reaching therapeutic levels.[44] It follows that other DMEs are likely to influence endoxifen formation and therefore the formation of endoxifen cannot be predicted solely by CYP2D6 genotype.

Phase I

Reduced CYP2C9 enzyme function variants are encoded by the *2 and *3 alleles.[67] They are frequent in populations of European descent (35%) but are less common in Asians and Africans.[68,69] German individuals genotyped as carriers of CYP2C9 reduced-activity alleles had lower plasma levels of endoxifen compared with those who were homozygous for the normal function alleles.[19] No such association was observed in Asian patients, most likely due to the lower frequency of these variants in that population.[43] Given that CYP2C9 contributes significantly to the formation of 4-OH-Tam, it can be concluded that a proportion of endoxifen derives from demethylation of (Z)-4-OH-Tam.[70]

The major variants of CYP2C19 include the *2 and *3 alleles, both considered null, and the promoter variant *17 resulting in increased expression.[25] Studies in The Netherlands linked the *2 allele with increased survival rates in women undergoing tamoxifen treatment;[71,72] however, this was not confirmed in a German study.[73] Rather, the UM allele *17,[74] which is frequent in Europeans and North Africans but not in Asians, has been linked to improved benefit with respect to breast cancer recurrences and relapse-free survival.[73]

The most common CYP2B6 variant allele is *6, which is present in various populations with frequencies ranging from 15 to 60%.[75] The role of the *6 allele was investigated specifically with regard to the hydroxylation of tamoxifen to (Z)-4-OH-Tam, with no correlation being observed between the CYP2B6 variant and the metabolite.[19]

The CYP3A isoforms CYP3A4 and CYP3A5 contribute to tamoxifen metabolism, particularly during the conversion of the parent drug to both NDM-Tam and (Z)-4-OH-Tam. CYP3A4 shows remarkable interindividual variability attributed to environmental factors including medication and food, but its variability is also influenced by gender and age. For instance, CYP3A4 expression was found to be twofold higher in liver samples from females compared with males, and was also considerably increased after treatment with carbamazepine or St John's wort.[76] CYP3A4 activity, like other CYPs, was shown to increase with age.[77] The influence of grapefruit juice on CYP3A4 was discovered by chance and has since been extensively investigated.[78,79] Notably, potent CYP3A4-inducing compounds (e.g., rifampin, aminoglutethimide, tamoxifen and 4-OH-Tam)[80–82] may cause drug–drug interactions modulating the levels of parent drug tamoxifen and its metabolites. Known variants of CYP3A4 include the *1B allele, a promoter variant linked with altered enzyme activity; however, this finding has been controversially debated.[83]CYP3A4*22 has a frequency of 5–7% in Europeans and this intron 6 polymorphism results in a reduced mRNA expression and decreased enzyme activity in human liver.[84] While cis-acting genetic variants may play a minor role in CYP3A4 variability, it is of note that a recently identified SNP (rs4253728) in the gene coding for PPAR-α, a transcription factor that binds to the CYP3A4 promoter, was shown to be associated with the CYP3A4 phenotype.[85,86] Such trans-acting regulatory factors could be of potential interest for genetic testing; however, their contribution to the variability in tamoxifen response awaits further clarification.

The common variant CYP3A5*3 leads to reduced enzyme function. The frequency is higher in populations of European descent (73–93%) compared with those of Asian (74–77%) and African descent (27–50%).[87,88] A slight increase in endoxifen levels in individuals carrying at least one copy of the normal function allele has been reported,[47] but subsequent studies did not confirm this.[19,43] It is likely, however, that the CYP3A5*3 deficiency allele contributes to variation in the levels of the primary metabolite NDM-Tam.

Phase II

Tamoxifen metabolites are inactivated prior to elimination through conjugation with a glucuronide or sulfate group by UGTs and SULTs, respectively. Some of the major enzymes include, but are not limited to, UGT1A4, UGT2B7, UGT2B15 and SULT1A1 (Figure 1). It is known that these enzymes, similar to CYPs, have functionally relevant genetic variants potentially influencing the efficacy of tamoxifen. For instance, in vitro studies showed that the UGT1A4*3 (rs2011425, 142T>G, L48V)[204] polymorphism increases glucuronidation of tamoxifen and 4-OH-Tam.[89] Plasma metabolite studies showed a significant decrease in the metabolic ratio of tamoxifen/tamoxifen-N-glucuronide in patients homozygous for the *3 allele; however, an association with 4-OH-Tam and its glucuronidation reaction was not apparent in vivo.[19] Currently, the clinical relevance of the UGT1A4*3 variant is unknown.

The UGT2B7 gene has a common polymorphism referred to as UGT2B7*2[90] with a frequency of approximately 50% in individuals of European descent.[91]In vitro studies indicated that the variant displayed significantly reduced glucuronidation activities against the trans isomers of 4-OH-Tam and endoxifen compared with the wild-type UGT2B7 allele.[92] However, no association between UGT2B7*2 and tamoxifen and its metabolites was observed.[19] Regarding tamoxifen outcome, no correlation with UGT2B7*2 was reported.[56,93]

The UGT2B15 gene harbors a nonsynonymous polymorphism which is designated the *2 allele, resulting in twofold increased activity.[94] A trend of increased breast cancer recurrence for carriers of UGT2B15*2 alleles was observed for patients treated with tamoxifen;[95] however, no association with either metabolite levels or outcome has been confirmed in other studies.[19,93,96]

SULT1A1 is the most abundant hepatic SULT enzyme and is mainly present in breast cancer cells. Moreover, it is predominantly involved in the sulfation of 4-OH-Tam. Because the SULT1A1*2 allele has been linked with reduced enzyme activity,[97] several studies addressed the possible influence of SULT1A1*2 on tamoxifen metabolism and outcome. Results of these studies were inconsistent, showing either a lack of association with regard to metabolite levels[47] or nonfavorable outcome,[98] but most showed a lack of association with clinical outcome of tamoxifen therapy.[96,99,100]SULT1A1 copy number variations seem to best explain variable activity in vitro, questioning the relevance of other polymorphisms.[101] No correlation between SULT1A1 copy number and disease-free survival in patients receiving tamoxifen has been observed.[102]

The genetic polymorphisms of other DMEs involved in tamoxifen metabolism may be important but their value in predicting treatment response is presently unknown due to the lack of evidence.

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