Impact of metabolizing enzymes on drug response of endocrine therapy in breast cancer

Saladores, Pilar H.; Precht, Jana C.; Schroth, Werner; Brauch, Hiltrud; Schwab, Matthias

doi:10.1586/erm.13.26

Cited by 22 publications

(27 citation statements)

References 147 publications

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“…For estrogen-receptor positive tumors, anti-estrogen therapy has been considered standard of care (2, 3). The goal of endocrine treatment is to prevent access of the tumor to estrogen, either through blocking the interaction of the estrogen receptor with co-regulatory proteins in tumor cells (Tamoxifen), or through a reduction or elimination of endogenous estrogen production (aromatase inhibitors) (4). Aromatase inhibitors block the enzyme aromatase that catalyzes the conversion of androgens into estrogens, the primary source of endogenous estrogens in postmenopausal women.…”

Section: Introductionmentioning

confidence: 99%

A Pilot Study Comparing the Effect of Flaxseed, Aromatase Inhibitor, and the Combination on Breast Tumor Biomarkers

McCann

Edge

Hicks

et al. 2014

Nutrition and Cancer

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Use of complementary approaches is common among breast cancer survivors. Potential interactions between aromatase inhibitors (AI) and high phytoestrogen foods, such as flaxseed (FS) are not often described. We conducted a pilot 2×2 factorial, randomized intervention study between tumor biopsy and resection, in 24 postmenopausal women with estrogen receptor positive (ER+) breast cancer, to assess the effects of flaxseed and anastrozole, and possible interactions between them, on serum steroid hormone and tumor-related characteristics associated with long-term survival (Roswell Park Cancer Institute, 2007–2010). The effect of each treatment vs placebo on outcomes was determined by linear regression adjusting for pre-treatment measure, stage, and grade. Although not statistically significant, mean ERβ expression was approximately 40% lower from pre- to post-intervention in the FS+AI group only. We observed a statistically significant negative association (β±SE −0.3±0.1; p=0.03) for androstenedione in the FS+AI group vs placebo and for DHEA with AI treatment (β±SE −1.6±0.6; p=0.009). Enterolactone excretion was much lower in the FS+AI group compared to the FS group. Our results do not support strong effects of flaxseed on AI activity for selected breast tumor characteristics or serum steroid hormone levels, but suggest AI therapy might reduce the production of circulating mammalian lignans from flaxseed.

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Section: Introductionmentioning

confidence: 99%

A Pilot Study Comparing the Effect of Flaxseed, Aromatase Inhibitor, and the Combination on Breast Tumor Biomarkers

McCann

Edge

Hicks

et al. 2014

Nutrition and Cancer

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“…Thus, the time to endoxifen C tss is likely to be relevant for the full therapeutic benefit of tamoxifen. As it is well-described in literature that endoxifen formation out of tamoxifen depends on CYP2D6 activity, time to endoxifen C tss and the level itself depend to a great extent on the CYP2D6 genotype (Stearns et al, 2003; Borges et al, 2006; Antunes et al, 2012; Damodaran et al, 2012; Maximov et al, 2013; Saladores et al, 2013). …”

Section: Discussionmentioning

confidence: 96%

“…More than 100 alleles of CYP2D6 have already been reported (http://www.cypalleles.ki.se/cyp2d6.htm). Patients with the extensive metabolizer (EM) genotype show significantly higher endoxifen steady-state levels than patients with an intermediate metabolizer (IM) genotype than patients with a poor metabolizer (PM) genotype, each undergoing tamoxifen treatment with the standard dose of 20 mg daily (Schroth et al, 2007, 2009, 2010; Brauch et al, 2011, 2013a,b; Saladores et al, 2013; Schwab et al, 2013). In addition, the metabolic pattern in CYP2D6 EMs resulting out of standard tamoxifen is associated with better treatment outcome (Schroth et al, 2009, 2010).…”

Section: Introductionmentioning

confidence: 99%

Addressing Adherence Using Genotype-Specific PBPK Modeling—Impact of Drug Holidays on Tamoxifen and Endoxifen Plasma Levels

et al. 2017

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Introduction: Tamoxifen is one of the most common treatment opportunities for hormonal positive breast cancer. Despite its good tolerability, patients demonstrate decreasing adherence over years impacting on therapeutic success. PBPK modeling was applied to demonstrate the impact of drug holidays on plasma levels of tamoxifen and its active metabolite endoxifen for different CYP2D6 genotypes.Materials and Methods: A virtual study with 24,000 patients was conducted in order to investigate the development of tamoxifen steady-state kinetics in patient groups of different CYP2D6 genotypes. The impact of drug holidays on steady-state kinetics was investigated assuming changing drug holiday scenarios.Results: Drug holidays in CYP2D6 extensive and intermediate metabolizers (EMs, IMs) exceeding 1 month lead to a decrease of endoxifen steady-state trough levels below the 5th percentile of the control group. Assuming drug holidays of 1, 2, or 3 months and administering a fixed-dose combination of 20 mg tamoxifen and 3 mg endoxifen EMs demonstrated re-established endoxifen steady-state trough levels after 5, 8, and 9 days. IMs receiving the same fixed-dose combination demonstrated re-established endoxifen steady-state trough levels after 7, 10, and 11 days.Discussion: The PBPK model impressively demonstrates the impact of drug holidays in different CYP2D6 genotypes on PK. Population simulation results indicate that drug holidays of more than 2 weeks cause a tremendous decrease of plasma levels despite the long half-life of tamoxifen. To improve therapeutic success, PBPK modeling allows identifying genotype-specific differences in PK following drug holidays and adequate treatment with loading doses.

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“…Interindividual variability because of the effects of single-nucleotide polymorphisms in genes encoding cytochrome P450 (CYP450) enzymes involved in Phase I of the TAM metabolic pathway has been shown in many studies 2–5. The CYP450 enzymes (CYP2D6, CYP2C9, CYP2C19, CYP3A4 and CYP3A5) are essential for the transformation of TAM from a prodrug form to its active metabolites (endoxifen [END] and 4-hydroxytamoxifen [4OHT]) 1,6,7.…”

Section: Introductionmentioning

confidence: 99%

Effects of <em>CYP2D6 </em>and <em>CYP3A5 </em>polymorphisms on tamoxifen and its metabolites in Thai breast cancer patients

Charoenchokthavee¹,

Areepium²,

Panomvana³

et al. 2017

BCTT

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PurposeThis study aimed to determine the effects of CYP2D6 and CYP3A5 polymorphisms on the levels of tamoxifen (TAM) and its metabolites in the plasma of breast cancer patients. The protocol was designed to test the associations between CYP2D6, CYP3A5 genotypes and phenotypes (extensive metabolizer [EM], intermediate metabolizer [IM] and poor metabolizer [PM]) and TAM, N-desmethyl tamoxifen (NDMT), endoxifen (END) and 4-hydroxytamoxifen (4OHT) concentrations.Patients and methodsOne hundred and thirty-four Thai breast cancer patients from the Thai Tamoxifen Project undergoing TAM treatment who met the inclusion/exclusion criteria were recruited. Plasma samples were assessed for the concentrations of TAM and its metabolites using high-performance liquid chromatography. The data are presented as actual values and metabolic ratios (MR). The hypotheses were tested using Kruskal–Wallis or Mann–Whitney U test, including the simple main effects analysis.ResultsThe patients had stage 0–IV breast cancer. The mean age and body mass index were 51.6±11.6 years and 24.0±4.3, respectively. Also, 53.0% of them were premenopausal, 10.4% were perimenopausal and 36.6% were postmenopausal, while 23.1% were CYP2D6-EM/CYP3A5-EM and 20.9% carried only CYP2D6 and CYP3A5 incomplete alleles. The median concentrations of TAM, NDMT, END and 4OHT were 374.7 (interquartile range [IQR] 230.2) ng/mL, 1,064.9 (IQR 599.6) ng/mL, 54.5 (IQR 52.5) ng/mL and 5.0 (IQR 3.1) ng/mL, respectively. MR (TAM-NDMT) and MR (NDMT-END) were statistically different (p=0.013 and p=0.014, respectively), while MR (4OHT-END) was not statistically different within the CYP2D6 phenotype (p=0.594). MR (TAM-4OHT) was not statistically different within the CYP2D6 phenotype (p=0.079), but it was potentially different from CYP3A5-PM (p=0.056). None of the MR was statistically different within the CYP3A5 phenotype.ConclusionCYP2D6 polymorphisms appear to affect END concentration through an NDMT subpathway and potentially affect 4OHT concentrations through a 4OHT subpathway in CYP3A5-PM group.

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Impact of metabolizing enzymes on drug response of endocrine therapy in breast cancer

Cited by 22 publications

References 147 publications

A Pilot Study Comparing the Effect of Flaxseed, Aromatase Inhibitor, and the Combination on Breast Tumor Biomarkers

A Pilot Study Comparing the Effect of Flaxseed, Aromatase Inhibitor, and the Combination on Breast Tumor Biomarkers

Addressing Adherence Using Genotype-Specific PBPK Modeling—Impact of Drug Holidays on Tamoxifen and Endoxifen Plasma Levels

Effects of <em>CYP2D6 </em>and <em>CYP3A5 </em>polymorphisms on tamoxifen and its metabolites in Thai breast cancer patients

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