In 2005, Goetz et al. reported the first study in which a positive association was found between the cytochrome P450 2D6 isoenzyme (CYP2D6) genotype and tamoxifen efficacy in early breast cancer patients [
1]. Previously, it was demonstrated that genetic variants of CYP2D6, leading to an enzyme with impaired or absent activity, resulted in lower blood concentrations of the most important active tamoxifen metabolite, endoxifen [
2,
3]. At present, the discussion whether CYP2D6 activity is a relevant predictor of tamoxifen response is still timely, although conflicting data have created much controversy [
1,
4‐
12]. The variance of endoxifen blood concentrations among the separate CYP2D6 phenotypes (poor (PM), intermediate (IM), extensive (EM), and ultrarapid metabolizers (UM)) is large and may have contributed to these conflicting data. The CYP2D6 genotype only partially predicts endoxifen blood levels (
r
2 = 23–43 %); therefore, endoxifen concentration itself may be a better predictor of tamoxifen response [
3,
13]. Many studies have investigated the in vitro effects of endoxifen leading to the general belief that endoxifen is the most important active tamoxifen metabolite [
2,
3,
14‐
16]. However, no prospective study to date has directly addressed the possible association between endoxifen blood levels in patients and efficacy. In the Women’s Healthy Eating and Living (WHEL) study, the first retrospective correlation between endoxifen concentration and breast cancer survival was made [
17]. Patients with endoxifen levels in the range of the lowest quintile had a 35 % higher rate of breast cancer events suggesting a threshold effect with a reported endoxifen threshold of 5.97 ng/ml (=16.0 nM). In this study, 76 % of the CYP2D6 poor metabolizers had endoxifen levels within the range of the lowest quintile. This study, however, was not designed for this purpose and the borderline significant difference in outcome between the patients with the lowest endoxifen levels (lowest quintile) and the patients with higher endoxifen levels (HR = 0.74; 95 % CI 0.55–1.00) should be interpreted with caution. Patients with low endoxifen blood concentrations may experience less tamoxifen efficacy and may require a tamoxifen dose higher than the standard 20 mg once daily dose. In contrast, increasing the tamoxifen dosage to 90 mg daily did not affect tamoxifen response in metastatic breast cancer patients compared to a standard dose of 30 mg daily with equal response rate and duration. The investigators of this small study however did not account for CYP2D6 genotype or endoxifen level [
18]. CYP2D6 intermediate and poor metabolizers with low endoxifen levels may still benefit from higher tamoxifen doses.
In a recent study, the feasibility of increasing endoxifen concentration in intermediate (IMs) and poor metabolizers (PMs) was demonstrated [
19]. By increasing the 20 mg tamoxifen dose in IMs and PMs to 40 mg once daily, endoxifen levels were significantly increased. The increased endoxifen levels in IMs using 40 mg tamoxifen did not significantly differ with the endoxifen concentration found in extensive metabolizers (EMs) using the standard dosage, while the increased endoxifen levels in the dose escalated PMs were still significantly lower. Therefore, PMs and some IMs may need more than a double tamoxifen dose in order to reach the mean endoxifen level found in EMs. How to calculate the necessary tamoxifen dose and whether higher doses of tamoxifen can be safely used to reach this goal is unknown. In metastatic breast cancer and other advanced tumor types, a tamoxifen dose up to 120 mg daily seems tolerable with limited side effects during a short period of time [
18,
20‐
24].
In The Netherlands and Belgium, a prospective study (CYPTAM study: NTR1509) has included 650 early breast cancer patients using tamoxifen to relate predicted CYP2D6 phenotype and endoxifen serum concentration to disease-free survival [
25]. Patients with a CYP2D6 poor or intermediate metabolizer phenotype who were still treated with tamoxifen could be included in a pharmacokinetic study. The aim of the current pharmacokinetic study is to investigate the effect of a temporary one-step tamoxifen dose escalation on endoxifen serum concentration and toxicity in poor and intermediate metabolizers.