Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, Netherlands
Gerardus Hussaarts , Daan Hurkmans , Esther Oomen De Hoop , Leonie J. van Harten , Stan Berghuis , Robbert J. van Alphen , Leontine E.A. Spierings , Quirine C. van Rossum , Mijntje B. Vastbinder , Ron H.N. van Schaik , Teun van Gelder , A. Jager , Roelof W.F. van Leeuwen , Ron H.J. Mathijssen
Background: Tamoxifen is extensively used as endocrine therapy for breast cancer. It is a prodrug that is primarily metabolized by CYP2D6 and CYP3A4, particular into endoxifen. In daily practice, the herb curcumin is widely used among patients (pts) because of its presumed anti-tumor effects. Preclinical studies show effects of curcumin on phase I and II drug metabolism, leading to altered plasma levels. We hypothesized that curcumin increases endoxifen exposure by affecting phase II metabolism. Therefore, we performed a randomized, 3-phase, cross-over study to compare tamoxifen exposure in breast cancer pts +/- curcumin, and with the addition of the bioenhancer piperine. Methods: Pharmacokinetic sampling (PK) was performed in 15 pts at the 28th, 56th and 84th day of the trial. In the 28 days prior to PK, tamoxifen (20 mg qd) was either given alone, or combined with curcumin (1,200 mg TID), or with curcumin + piperine (10mg TID) in this order or vice versa. Genotyping was performed to determine CYP2D6 and CYP3A4 phenotypes. Primary endpoint was difference in geometric means for AUC0-24h. A linear mixed model was used to analyze log-transformed area under the curve (AUC). For multiple testing a Bonferroni correction was applied. Results: Tamoxifen AUC0-24h decreased with 7.3 % (95% CI: -0.5,-13.6%; p = .04) with curcumin and 13.0% (95% CI: -5.6,-19.9%; p = .002) with curcumin and piperine, compared to tamoxifen alone. Endoxifen AUC0-24h decreased with 8.9% (95% CI: -0.9,-16.3%; p = .029) and 13.5% (95% CI: -2.8,-23.0%; p = .015), respectively. CYP2D6-screening resulted in 6 intermediate metabolizers (IM), and 6 extensive metabolizers (EM). Interestingly, for pts with a EM phenotype, effects of curcumin with piperine on drug exposure (AUC0-24h) seem to be higher than for IM phenotype pts (a decrease of 21.8% vs 4.8% for tamoxifen, and 22.6% vs 10.2% for endoxifen, respectively). No severe toxicity resulting from co-treatment was observed. Conclusions: In contrast to our hypothesis, the exposure of tamoxifen and endoxifen significantly decreased by concomitant use of curcumin +/- piperine. Although limited effects in most pts, co-treatment with these herbs could drop endoxifen levels below the threshold for efficacy, especially for EM phenotype pts. Clinical trial information: NTR6149.
Disclaimer
This material on this page is ©2024 American Society of Clinical Oncology, all rights reserved. Licensing available upon request. For more information, please contact licensing@asco.org
Abstract Disclosures
2016 ASCO Annual Meeting
First Author: Clara Inkyung Lee
2016 ASCO Annual Meeting
First Author: John Gordon Lenehan
2018 ASCO Annual Meeting
First Author: Anabel Beatriz Sanchez-Spitman
2012 ASCO Annual Meeting
First Author: Bavanthi Balakrishnar