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


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

In This Article


The steroidal AI exemestane undergoes Phase I metabolism to the active metabolite 17-dihydroexemestane[139] by CYP1A1/2 and possibly CYP4A11. The oxidation to 6-hydroxymethylexemestane is mediated by CYP3A4, CYP3A5 and CYP2B6.[140] 17-dihydroexemestane is subsequently glucuronidated to exemestane-17-O-glucuronide, predominantly by UGT2B17, but also by UGT1A4 as shown in vitro.[141] Although CYP3A4, CYP1A1 and CYP4A11 are polymorphic, there are currently no data on a potential impact of genetic variants on exemestane metabolism.[142] The oxidative CYP3A4-mediated pathway is of minor importance as concomitant medication with strong CYP3A4 inhibitors did not alter exemestane pharmacokinetics.[206] UGT2B17 pharmacogenetics have been described to impact Phase II metabolism of exemestane.[141]

The UGT2 locus is located on chromosome 4 at position 4q13.[143] The UGT2B17 gene shares 95% sequence homology with UGT2B15[144] and is expressed in the liver, intestine and antigen-presenting cells. Spielman et al. reported a remarkable variability in UGT2B17 gene expression with a 22-fold higher expression level in lymphoblastoid cell lines of individuals of European descent compared with those of Asians.[145] A frequent variation of UGT2B17 is a gene deletion (*2) with a prevalence of approximately 30% in Europeans.[144] As a consequence, approximately 11% of Europeans are UGT2B17 deficient. An enzyme-selective probe drug is currently not available for UGT2B17 phenotyping.[143] Because of the predominant role of UGT2B17 in exemestane metabolism, the impact of the UGT2B17 gene deletion has been investigated and a 14-fold decrease of exemestane-17-O-glucuronide formation in human liver microsomes homozygous for *2 compared with wild-type has been observed.[141] No information on the clinical consequences of this polymorphism is available. There was no influence of the UGT1A4 alleles *2 and *3 on exemestane glucuronidation activity in vitro.

Finally, a recent genome-wide association study (GWAS) provided initial evidence for the possible role of variants in target genes other than DMEs for AI-related adverse side effects. This case–control GWAS (551,395 SNPs investigated in 878 women) identified four SNPs in close proximity to the TCL1A gene that were associated with musculoskeletal adverse events during AI therapy of early breast cancer.[146] Additionally, Ingle et al. identified a relationship between TCL1A expression and IL-17, a cytokine involved in inflammatory processes.[146] Indeed, an estradiol-induced TCL1A expression and subsequently altered cytokine expression (including IL-17) has been observed in in vitro studies.[147]