CYP2D6 genotype-guided tamoxifen dosing in hormone receptor-positive metastatic breast cancer (TARGET-1): A randomized, open-label, Phase II study

PURPOSE In patients taking tamoxifen, the CYP2D6 genotype causes different exposure of active metabolite endoxifen. The objective of this randomized, open-label, multicenter, phase II study was to prospectively evaluate whether CYP2D6 genotype-guided tamoxifen dosing in patients with hormone receptor-positive metastatic breast cancer could have an impact on the clinical outcome. METHODS Patients who needed first-line tamoxifen therapy were enrolled. Based on individual CYP2D6 genotype, patients heterozygous (wild type [wt]/variant [V]) or homozygous (V/V) for variant alleles of decreased or no function were randomly assigned to receive tamoxifen at an increased dose (ID arm; 40 mg daily) or regular dose (RD arm; 20 mg daily), and patients homozygous for wild-type alleles (wt/wt) received tamoxifen at 20 mg daily. The primary endpoint was the progression-free survival (PFS) rate at 6 months. The secondary endpoints included PFS and correlation of Z-endoxifen concentration with clinical outcomes. RESULTS Between December 2012 and July 2016, 186 patients were enrolled in Japan. Of 184 evaluable patients, 136 carried wt/V or V/V (ID arm, 70; RD arm, 66), and 48 carried wt/wt. PFS rates at 6 months were not significantly different between the ID and RD arms (67.6% v 66.7%). The serum trough concentrations of Z-endoxifen in the ID arm were significantly higher than those in the RD arm (median, 89.2 nM v 51.1 nM; P , .0001) and were also higher compared with wt/wt patients (72.0 nM; P = .045). No significant difference in Z-endoxifen concentrations was observed between patients with disease progression and those who were progression free at 6 months (P = .43). CONCLUSION In patients with CYP2D6-variant alleles, increasing tamoxifen dosing did not achieve a higher PFS rate at 6 months. The CYP2D6 genotype solely cannot explain individual variability in the efficacy of tamoxifen.