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

CYP2D6 Genotype-Driven Dosing of Tamoxifen

In postmenopausal women, AI can be given as another valid treatment option, which is especially important for patients who are CYP2D6 PMs. Nevertheless, the idea arises that it should be considered whether at least in IM women a higher dosage of tamoxifen may be an appropriate adjustment. Important clues came from recent prospective studies of CYP2D6 genotype-guided dosing of tamoxifen (Table 3). An increase in the standard dose of tamoxifen from 20 to 40 mg/day in IM patients whose baseline endoxifen levels were 46% lower compared with EM patients resulted in an increase in endoxifen concentrations close to those of EM patients independent of menopausal status. However, PMs displayed no significant increase of endoxifen levels after dose increase, in line with the fact that null alleles for CYP2D6 result in nonexpression of CYP2D6 protein.[64] It follows that at least one functional or partially functional allele, in the case of IMs, is necessary to reach endoxifen levels that are not statistically different from EMs upon dose adjustment.[64] Supportive evidence came from another study that increased tamoxifen dose from 20 to 30 mg/day in patients with baseline endoxifen levels below 40 nmol/l.[65] An increase to clinically meaningful endoxifen concentrations was observed;[16] however, this was dependent on CYP2D6 genotype, with PMs having lower rates of increase.[65] Moreover, after tamoxifen dose adjustments to 30 or 40 mg/day based on CYP2D6 genotype, Japanese patients with one copy of reduced functional allele reached endoxifen levels comparable with the patients with two functional alleles.[66] Collectively, these studies suggest that CYP2D6 molecular diagnostics could play an important role in the case of planned tamoxifen dose adjustment in patients with moderately impaired metabolizer statuses such as IM or heterozygous EM patients.

processing....