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The standard-of-care for estrogen receptor (ER)-positive breast cancer patients who are functionally premenopausal is a 5-year treatment with the selective ER modulator tamoxifen1 as aromatase inhibitors are of limited use due to the strong hypothalamic–pituitary control of estrogen levels.2 Tamoxifen for 5 years substantially lowers the yearly relapse rates and mortality in primary breast cancer.3 Data from the Adjuvant Tamoxifen, Longer Against Shorter trial and the Adjuvant Tamoxifen Treatment offers more trial indicate further benefit by maintaining tamoxifen treatment for 10 years with 25% mortality reduction relative to 5 years.4, 5 Despite this success, about 50% of patients do not benefit from tamoxifen and frequent adverse drug reactions (ADR) including hot flashes, vasomotor and gynecologic symptoms as well as depression and diminished sexual functioning prevent particularly young women from staying on the drug.6, 7 Toward a personalized strategy of premenopausal breast cancer treatment, the possible association between serum concentration of the active tamoxifen metabolite endoxifen and the occurrence of side effects has been addressed;7, 8 yet, the potential of such an approach regarding treatment outcome in young women is unclear.
Tamoxifen, which acts at the ER, requires conversion into active metabolites (Z)-4-hydroxytamoxifen and (Z)-endoxifen that have up to 100-fold higher ER affinity than the parent drug.9, 10, 11 The cytochrome P450 enzyme CYP2D6 has a major role in the formation of endoxifen12 in postmenopausal women.13, 14, 15 CYP2D6 is highly polymorphic with more than 100 genetic variants (http://www.imm.ki.se/cypalleles/cyp2d6.htm) contributing to the high interindividual variability of enzyme activity. Impaired metabolism by CYP2D6 can be accurately predicted by loss- and reduced-function alleles resulting in the poor metabolizer (PM) and intermediate metabolizer (IM) phenotypes. Likewise, functional and duplicated CYP2D6 alleles correlate with extensive (EM) and ultra rapid (UM) metabolizer phenotypes, respectively.16 There are significant interethnic differences of CYP2D6 allele frequencies across geographic regions and populations leading to a shift of metabolizer phenotype prevalence with higher frequencies of IMs in Asians and UMs in Arabic/North African countries as compared with populations of European descent.17
Clinical outcome of adjuvant tamoxifen in postmenopausal patients is influenced by their CYP2D6 metabolizer phenotype which can be predicted by genetic testing18, 19, 20 using germline rather than tumor DNA.21, 22 However, the current debate on the validity of the postmenopausal data and the lack of CYP2D6 association with clinical outcome in some of these studies21, 22, 23, 24, 25, 26, 27, 28 point to the need of combined pharmacokinetic and pharmacogenetic analyses particularly in the case of testing the hypothesis in another patient group, i.e. premenopausal patients. Recently, lower endoxifen concentrations were shown to be associated with poor clinical outcome in a mixed cohort of pre- and postmenopausal patients.14 Notably, the in vitro pharmacological modeling of endoxifen concentrations for the treatment of ER positive breast cancer showed the essential requirement of endoxifen to block breast cancer cell growth in the presence of high estrogen concentrations equivalent to premenopausal patients.29, 30 Therefore, it is reasonable to hypothesize that variable endoxifen formation contributes to tamoxifen efficacy in premenopausal patients. Here, we present combined pharmacokinetic and pharmacogenetic analyses in purely premenopausal breast cancer patient cohorts of different ethnic origin to evaluate (i) the factors that influence active tamoxifen metabolite concentrations with a particular emphasis on CYP2D6 and (ii) whether tamoxifen metabolite concentrations and/or genetic variants of drug-metabolizing enzymes (DME) are suitable biomarkers for the prediction of clinical outcome.
Patients and methods
Patients and study design
Three ethnic groups of prospectively recruited hormone receptor-positive premenopausal breast cancer patients with adjuvant tamoxifen treatment were investigated (Figure 1). Of these, 164 Asian patients in part previously described31 (136 Chinese, 14 Malays and 14 Indians) have been provided by the Division of Medical Sciences, Humphrey Oei Institute of Cancer Research, Singapore. Another 78 consecutively recruited patients (2009–2011) in part previously described32 have been provided by the Hematology-Oncology Division, Internal Medicine, American University of Beirut, Lebanon (Leb). Furthermore, 345 patients were selected from the Prospective study of Outcomes in Sporadic versus Hereditary breast cancer (POSH) cohort, an observational cohort study comprised mainly of Caucasian patients (2956 patients recruited between 2001 and 2007) by the Cancer Sciences Academic Unit and University of Southampton Clinical Trials Unit, University of Southampton, UK.33, 34 Selection of patients for our current study was based on the availability of tamoxifen steady-state serum and germline DNA. Patients taking CYP2D6 inhibitors were excluded from the Singapore cohort and comprised only seven patients who received weak CYP2D6 inhibitors, venlafaxine, escitalopram or clomipramine in the Lebanon cohort. For the POSH cohort, data on co-medication was not available. In total, 587 premenopausal patients were investigated for the quantitation of tamoxifen metabolites and genotyping. Figure 1 shows the patient inclusion scheme to explain the underlying rationale for the survival analyses, which was performed in the POSH cohort but not in the Singapore and Lebanon cohorts due to incomplete follow-up and delayed study entry of their patients, respectively (Figure 1).
Figure 1.
Study flow diagram of premenopausal study. co-med, co-medication; HR, hormone receptor; Leb, Lebanon; POSH, Prospective study of Outcomes in Sporadic versus Hereditary breast cancer; Sing, Singapore; Tam, tamoxifen.Full figure and legend (100K)Download Power Point slide (1,008 KB)
Steady-state blood samples of patients treated with tamoxifen (20 mg per day) were collected on-site within the first year of treatment and immediately stored at −20 °C. Study approvals were obtained from the National Cancer Centre Ethics Review Committee (Singapore), American University of Beirut Institutional Review Board (Lebanon) and South and West MultiCentre Research Ethics Committee (MREC 00/6/69; POSH). All patients provided informed consent.
Measurement of tamoxifen and metabolites
Tamoxifen and its metabolites DM-Tam, (Z)-4-hydroxytamoxifen ((Z)-4-OH-Tam), (Z)-endoxifen, N-desmethyltamoxifen (DM-Tam), N,N-Didesmethyltamoxifen (DDM-Tam) and (Z)-norendoxifen ((Z)-4-OH-DDM-Tam; Supplementary Figure 1) were measured by liquid chromatography tandem mass spectrometry in the multiple reaction monitoring mode on a 6460 triple quadrupole mass spectrometer (Agilent Technologies, Waldbronn, Germany) as described previously.13 All analyses refer to the active (Z)-isomers of the tamoxifen metabolites which were separated from their respective inactive (E)-isomers.35
DNA isolation and genotyping
DNA samples were genotyped for CYP2D6 alleles associated with null (PM: *3, *4, *5 and *6) and reduced (IM: *9, *10 and *41) CYP2D6 function by matrix-assisted, laser desorption/ionization, mass spectrometry.18, 31 CYP2D6 gene duplication (UM) was determined via TaqMan Copy Number Assay (Applied Biosystems, Foster City, CA, USA). Absence of variant alleles or gene duplications was assigned to normal CYP2D6 function (EM). Individuals with ambiguous genotypes were verified by AmpliChip P450 assay (Roche Molecular Diagnostics, Mannheim, Germany), which revealed additional CYP2D6 alleles *14, *15 and *17. For genotype interpretation, we applied a CYP2D6 activity score36 to predict PM, IM, EM and UM phenotypes: PM/PM (0), PM/IM (0.5), IM/IM (0.75), PM/EM (1), IM/EM (1.5), EM/EM (2) and EM/UM (3). In survival analyses, CYP2D6 activity scores were classified into three phenotype classes: PM (0), hetEM/IM (0.5–1.5) and EM and UM (2 to 3). Genetic testing was also performed for CYP2C9 (*2, *3), CYP2C19 (*2,*3,*17) and CYP3A5*3, known to be involved in tamoxifen metabolism using TaqMan or Sequenom mass array genotyping.13
Study aims, power calculation and statistical analyses
Primary aim of this study was to determine factors that influence active tamoxifen metabolite concentrations with special emphasis on CYP2D6-catalyzed metabolite endoxifen. Thus, we performed a power calculation assuming a 50% decrease or increase of square root transformed endoxifen or log-transformed metabolic ratio (MR) DM-Tam/endoxifen per one unit of CYP2D6 activity score as a relevant gene-dose effect.13, 37 On the basis of the s.d. of the plasma concentrations in the three cohorts (excluding poorly/non-compliant patients), we computed that the sample size in the smallest cohort (n=77, Leb) would already provide 92.9% power in the analyses. Secondary aim was to test whether tamoxifen metabolite concentrations and/or genetic variants of DME can reliably predict clinical outcome in premenopausal patients. As there is no such data published in a purely premenopausal clinical setting, we consider this an exploratory investigation.
SPSS (version 20, Chicago, IL) and R-3.01 including libraries coin-1.0–22, MASS-7.3–27, mfp-1.4.9, party-1.0–8 and survival-2.37–4 (www.r.project.org) were used for statistical analyses. Clinical characteristics and DME genotypes were compared between study cohorts by Kruskal–Wallis and χ2-tests. Tamoxifen concentrations across all patients displayed two splits operationally used to define non-compliance (40 nM) and poor compliance (40–150 nM). Frequencies of CYP2D6 phenotypes between these groups were compared by χ2-tests. All following analyses excluded poorly/non-compliant patients.
Correlations of square root transformed endoxifen concentrations or log-transformed MR DM-Tam/endoxifen and CYP2D6 activity score were examined by linear models with stratification for ethnicity.
Survival analyses were strictly confined to the POSH cohort because of delayed study entry following breast cancer diagnosis and incomplete follow-up in the Lebanon and Singapore cohorts, respectively. The endpoint was distant relapse-free survival (DRFS) defined as the time from diagnosis to the earliest occurrence of distant metastasis or death from any cause. First, we tested which clinical characteristics, tamoxifen metabolites or CYP genotypes were associated with DRFS using univariate Cox regression and general asymptotic independence tests. Step-wise model selection (R-library mfp) revealed nodal status and chemotherapy use to be included as covariates in subsequent multivariate Cox regression. Conditional inference trees (P-value cutoff 0.15) and receiver operating characteristic analyses on DRFS were applied to identify cutoffs for MR DM-Tam/endoxifen and endoxifen concentration. For endoxifen, there was neither a split nor a significant association in multivariate Cox regression, hence we explored non-monotonic effects by dividing the POSH population into quarters. Associations between DRFS and classified endoxifen concentrations, MR DM-Tam/endoxifen or CYP2D6 phenotypes were investigated by Kaplan–Meier analyses and multivariate Cox regression adjusted for nodal status and chemotherapy use. All Cox models were stratified for ethnicity. All statistical tests were two-sided and statistical significance was defined as P<0.05.
Patient characteristics and cytochrome P450 genotypes
The median age of diagnosis was 39.1 years (range 22–59 years) (Table 1). Follow-up, age, body mass index (BMI), ethnicity, tumor size and proportion of patients treated with chemotherapy differed among cohorts. Genotypes were successfully obtained from 583 patients for CYP2D6 (99%) and in 97–99% for CYP3A5, CYP2C9 and CYP2C19. Genotypes met Hardy–Weinberg Equilibrium with few exceptions of minor deviations (Table 2). Notably, UM frequency in the POSH cohort was lower than expected38 likely due to sample size.
Tamoxifen metabolite profiling, compliance and CYP2D6 activity
There was a strong interindividual variability for tamoxifen and the five metabolites in each ethnic group (Figure 2). According to two tamoxifen concentration splits, we defined non-compliant (40 nM), poorly compliant (40–150 nM) and compliant (>150 nM) patients (Figure 2, dashed lines). Twenty-four POSH patients were non-compliant (7%) in their first-year serum sample, 10 patients were poorly compliant (2.9%). Of the other two cohorts, two patients were below 40 nM, whereas three patients were below 150 nM. There were no differences in CYP2D6 phenotype frequencies between poorly/non-compliant patients and the remaining patients, therefore subsequent genotype-phenotype correlations were not biased by excluding poorly/non-compliant patients (data not shown).
Figure 2.
Metabolic profiling for tamoxifen (Tam) and five measured metabolites, N-desmethyltamoxifen (DM-Tam), N,N-didesmethyltamoxifen (DDM-Tam), (Z)-endoxifen, 4-hydroxytamoxifen [(Z)-4-OH-DDM-Tam] and norendoxifen [(Z)-4-OH-DDMT-Tam] in study cohorts from Singapore (Sing, N=164), Lebanon (Leb, N=78) and Prospective study of Outcomes in Sporadic versus Hereditary breast cancer (POSH, N=345). Metabolite concentrations are presented as boxplots with whiskers defined by the 5th and 95th percentiles and extreme values outside the whiskers. The two dashed lines for Tam delineate putative non-compliant (40 nM) and poorly compliant (40–150 nM) patients as defined from Tam plasma concentrations. Patients with Tam concentrations <150 nM were excluded from further analyses.Full figure and legend (98K)Download Power Point slide (225 KB)
The compliant patients from each cohort are shown according to genotype-predicted CYP2D6 activity scores (Table 3). There was a strong gene-dose effect for an association between the CYP2D6 activity score and endoxifen concentrations (P<10−40) in all ethnic cohorts (Figure 3a). The contribution of CYP2D6 to the interindividual variability of endoxifen formation via DM-Tam, as deduced from MR DM-Tam/(Z)-endoxifen, was 46% (Singapore, P<10−17), 55% (Lebanon, P<10−9) and 55% (POSH, P<10−46), respectively (Figure 3b). Altogether, 53% of the interindividual variability of endoxifen formation from DM-Tam was attributed to CYP2D6 (Figure 3c; R2=0.53; P<10−77).
Figure 3.
Steady-state plasma concentrations of endoxifen and metabolic ratio DM-Tam/(Z)-endoxifen in premenopausal breast cancer patients according to genotype-based CYP2D6 activity score: (a) Endoxifen concentrations in Singapore (upper panel, N=160, R2=0.38; P<10−12), Lebanon (middle panel, N=77, R2=0.34; P<10−4) and POSH (lower panel, N=306, R2=0.33; P<10−21) cohorts. (b) Metabolic ratios of DMT/(Z)-endoxifen in Singapore (upper panel, R2=0.46; P<10−17), Lebanon (middle panel, R2=0.55; P<10−9) and POSH (lower panel, R2=0.55; P<10−46) cohorts. (c) Metabolic ratio DM-Tam/(Z)-endoxifen across all cohorts (N=548, R2=0.53; P<10−77). Data are presented as boxplots with whiskers defined by 5th and 95th percentiles and extreme values outside the whiskers. DM-Tam, N-desmethyltamoxifen. **P<10−3; ***P<10−5; ****P<10−10. POSH, Prospective study of Outcomes in Sporadic versus Hereditary breast cancer.Full figure and legend (107K)Download Power Point slide (278 KB)
Other factors influencing tamoxifen metabolism
The formation of norendoxifen from DDM-Tam precursor and (Z)-4-OH-Tam converted from tamoxifen was decreased in patient carriers of CYP2C19*2 and/or *3 (Figure 4a, P<0.001) and CYP2C9*2 and/or*3 alleles (Figure 4b), P<0.001, respectively. Lower levels of DM-Tam were observed in patients with a BMI higher than 30, both in Caucasians and non-Caucasians (Figure 4c, P<0.001). Notably, DM-Tam formation did not depend on the CYP3A5*3 reduced-function allele. Multivariate regression analyses across all cohorts showed that the combined genetic (CYP2C9, CYP2C19, CYP3A5) and non-genetic factors (age, BMI) contributed to only 2.8% of DM-Tam/endoxifen ratio as compared with 53% by CYP2D6.
Figure 4.
Impact of CYP2C19, CYP2C9 and body mass index on tamoxifen metabolite ratios: (a) Metabolic ratio (MR) DDM-Tam/norendoxifen according to the loss-of-function alleles CYP2C19*2/*3 predicting EM, hetEM (heterozygous *2 or *3) and PM (homozygous *2 or *3). (b) MR tamoxifen/(Z)-4-OH-TAM according to CYP2C9 *2/*3 reduced activity alleles defining hetEM (heterozygous *2 or *3) and PM (homozygous *2 or *3) versus EM with normal activity (absence of *2 or *3). (c) MR tamoxifen/DM-Tam stratified by BMI (30 or >30) in all patients, Caucasians and non-Caucasians. Data are presented as boxplots with whiskers defined by 5th and 95th percentiles and extreme values outside the whiskers. BMI, body mass index; DDM-Tam, DiDesmethyltamoxifen; DM-Tam, Desmethyltamoxifen; EM, extensive metabolizer; hetEM, heterozygous EM; PM, poor metabolizer; (Z)-4-OH-TAM, (Z)-4-hydroxytamoxifen.Full figure and legend (64K)Download Power Point slide (686 KB)
Tamoxifen metabolites and clinical outcome
POSH outcome analysis (N=306) was performed excluding hormone receptor-negative and poorly/non-compliant patients. There was no association between endoxifen concentrations and DRFS given the lack of a significant trend (Table 4, Figure 5a). However, following Madlensky et al.,14 when we classified patients into percentiles, we observed that patients with low endoxifen concentrations (<14.15 nM) had higher risk for distant relapse or death compared with those with high concentrations (>35 nM, P=0.03, Figure 5a), and showed a trend by multivariate Cox regression analysis of an increased hazard ratio (HR) of 1.94; 95% confidence interval (CI) 0.96–3.93; P=0.064 (Table 4). We next explored the MR DM-Tam/endoxifen and observed an increased HR with increasing MR (decreasing endoxifen formation rate) in multivariate Cox regression: HRper 1 unit=1.007; 95% CI 1.000–1.014; P=0.036 (Table 4). Because the per unit effect of this HR is rather small on a linear scale, we applied two cutoff values demonstrating worse (MR>115), moderate (MR 31–115) and better DRFS (MR<31) by Kaplan–Meier analysis (Log-rank P=0.001; Figure 5b). This was confirmed in multivariate Cox regression with an increased HR for patients with MR>115 (low endoxifen formation rate) compared with patients with MR<31 (high endoxifen formation rate): HR=3.82; 95% CI 1.47–9.89; P=0.006 (Table 4).
Figure 5.
Kaplan–Meier analyses for an association between (Z)-endoxifen concentrations, metabolic ratio (MR) Desmethyltamoxifen (DM-Tam)/(Z)-endoxifen or CYP2D6 phenotype score and distant relapse-free survival (DRFS) in the POSH cohort. Kaplan–Meier analyses for DRFS and the three predictor variables classified into groups. (a) Steady-state endoxifen concentrations split into four equally-sized patient groups (<14.1, 14.1–24.7, 24.7–35 and >35 nM), (b) MR DM-Tam/(Z)-endoxifen classified by conditional inference trees into three splits (<31, 31–115 and >115), (c) CYP2D6 phenotypes grouped into EM (plus UM), hetEM and PM. Corresponding Mantel–Cox log-rank tests are stratified for ethnicity. EM, extensive metabolizer; hetEM/IM, heterozygous EM/IM; IM, intermediate metabolizer; PM, poor metabolizer; POSH, Prospective study of Outcomes in Sporadic versus Hereditary breast cancer; UM, ultra rapid metabolizer.Full figure and legend (76K)Download Power Point slide (800 KB)
Table 4 - Cox proportional hazard models of DRFS for (Z)-endoxifen plasma levels, MR DM-Tam/(Z)-endoxifen or CYP2D6 activity score/phenotype.Full table
Importantly, none of the remaining metabolites including tamoxifen and DM-Tam showed an association between plasma concentrations and clinical outcome (Supplementary Figure 2).
CYP2D6 genotype and clinical outcome
Cox modeling revealed a significant linear association between CYP2D6 activity score and outcome (DRFS), both in univariate (P=0.008) and multivariate models (HRper 1 CYP2D6 score unit=0.62; 95% CI 0.43–0.91; P=0.013; Table 4). When grouping activity scores into the phenotype classes EM/UM, hetEM/IM and PM, Kaplan–Meier analysis indicated that PM patients have worse DRFS compared to EM subjects (Figure 5c; log-rank test P=0.042). When adjusted for nodal status and chemotherapy use, the association was no longer significant (HRPM vs EM=1.98; 95% CI 0.82–4.79; P=0.13; Table 4).
This is the first study that investigated a purely premenopausal breast cancer population for interindividual variability of tamoxifen metabolism and its influence on clinical outcome. In contrast to postmenopausal patients,13, 18, 19, 20, 37 little is known regarding the clinical relevance of variable tamoxifen metabolism for drug response in premenopausal patients. Although postmenopausal patients may receive aromatase inhibitor treatment as an alternative to tamoxifen, a personalized approach in the premenopausal setting must confront the lack of available alternatives and address the dilemma of young women stopping tamoxifen prematurely due to ADRs. Emerging data report a link between steady-state endoxifen concentrations and ADRs;7, 8 however, the two retrospective studies reporting an association between endoxifen blood concentrations and clinical outcome do not reflect the premenopausal setting. Notably, Madlensky et al.14 provided the first clinical outcome data for endoxifen; however, their study lacked premenopausal subgroup analysis. Similarly, a small exploratory study performed with 48 oophorectomized women is not reminiscent of the premenopausal setting.39
Our comprehensive approach with premenopausal women accounts for potential determinants of tamoxifen response, including tamoxifen metabolites, CYP2D6 phenotypes and drug compliance. Notably, compliance is a serious issue as non-compliance pertains to up to 50% of patients by year five of the recommended tamoxifen treatment and has been associated with poor survival.40, 41, 42, 43 In our study, tamoxifen compliance assessment via blood concentrations was limited to the first year of treatment and the poor/non-compliance rate of 10% (POSH) was lower than expected.41, 44 Although first-year compliance may not be predictive for compliance for the full 5-year treatment duration, this has been accounted for by excluding all poorly/non-compliant patients from subsequent analyses. Regardless of the true compliance rate known to us we suggest, that outcome stratification based on CYP2D6 metabolism would be perhaps even better in a fully compliant population. We observed a clear CYP2D6 gene-dose effect for plasma endoxifen and endoxifen formation from DM-Tam. This strong effect was independent of age, BMI or non-CYP2D6 DME polymorphisms, which together contributed less than 3% of the observed variability in endoxifen formation. The CYP2D6 effect is similar to that observed in postmenopausal patients and holds true across ethnic groups (Asians, Europeans and Middle Eastern Arabs) independent of the differences in CYP2D6 allele frequencies.45 Our data clearly show that endoxifen formation follows the same principle in pre- and postmenopausal women driven by CYP2D6. Yet, its contribution to formation is estimated at approximately 53% suggesting that other factors contribute to the bioavailability of endoxifen. Additional findings of a correlation between impaired CYP2C9 activity and decreased 4-OH-Tam formation, as well as CYP2C19 loss-of-function and decreased formation of the anti-estrogen norendoxifen, corroborate previous in vitro observations and point to additional relevant metabolic pathways involved in the formation of antiestrogens.46, 47 Moreover, a potential non-genetic influence on tamoxifen metabolism by adipose tissue acting as sequestering 'compartment' for lipophilic tamoxifen metabolites is supported by the observed association between BMI and decreased DM-Tam concentrations.
To understand the clinical relevance of tamoxifen metabolism in premenopausal patients, we conducted an outcome analysis (POSH) after excluding all patients with incomplete follow-up and/or delayed study entry (Singapore, Lebanon). The association of endoxifen concentrations with clinical outcome was inconclusive; yet, when we grouped endoxifen levels into distinct classes, patients with low concentrations (<14.1 nM) were at increased risk of distant relapse or death compared with patients with high endoxifen (>35 nM; Figure 5a). Importantly, the low endoxifen class contained 88% of all PMs (24 of 27 patients) thereby supporting the notion of a link between deficient CYP2D6 phenotype, reduced endoxifen concentration, and impaired clinical efficacy of tamoxifen. Our data are in line with those of Madlensky et al.14 who reported an distant recurrence rate for patients with low endoxifen concentrations (5.9 ng ml−1, 15.8 nM) in a patient cohort comprising pre- and postmenopausal patients. In contrast to endoxifen alone, using MR DM-Tam/endoxifen as a surrogate for CYP2D6 endoxifen formation demonstrated a strong association between high MR (low endoxifen concentrations) and an increased risk for recurrence or death, thereby substantiating the clinical relevance of the CYP2D6-mediated pathway for tamoxifen response. Together these data support the antagonistic potency of active metabolites at the ER, rather than the inhibition of ER by abundant tamoxifen and major metabolites through receptor saturation48, 49 in premenopausal patients. This is further substantiated by the lack of an outcome association with variable concentrations of tamoxifen and DM-Tam (Supplementary Figure 2). Notably, our in vivo data confirm the in vitro prediction by Maximov et al.29, 30 who demonstrated that endoxifen, rather than ER low-affinity tamoxifen metabolites, matters in blocking breast cancer cell replication in the presence of estrogen concentrations equivalent to premenopausal patients.
Our observation that CYP2D6 PM or low activity score patients had less favorable outcome compared with EM or high activity score patients supports the relevance of the CYP2D6 genotype for the prediction of tamoxifen outcome in premenopausal women, a hypothesis that has been originally postulated for the postmenopausal setting.18, 19, 20, 50 This association was considerably stronger when using activity scores as compared with classifying into three CYP2D6 phenotype groups (Table 4) supporting a gene-dose effect. Unlike in postmenopausal breast cancer where chemotherapy has been suggested to abrogate the CYP2D6 tamoxifen outcome effect,51 our data do not support this notion despite the large majority of POSH patients having received chemotherapy as it is the standard in the premenopausal setting. Combination chemotherapy produces chemical oophorectomy in the majority of premenopausal women over the age of 4052 resulting in lower circulating estradiol levels compared with premenopausal patients taking tamoxifen alone;53 however, the ovarian function of most POSH patients may have remained intact as inferred from their median age of 37.5 years. Another confounding factor in pharmacogenetic studies is the deviation from Hardy–Weinberg Equilibrium, which has been observed in the POSH cohort for CYP2D6*3 and *9, likely due to rare frequency or population admixture. Borderline deviation from Hardy–Weinberg Equilibrium was observed for CYP2D6*10 in the Singapore cohort, which could be attributed to the *36-*10 genotype (not analyzed)54 and/or population admixture (17% Malays/Indians vs 83% Chinese). Because genotyping was done from germline DNA, Hardy–Weinberg Equilibrium deviation is not considered a confounder in our outcome analysis.
A limitation of this study is its moderate sample size, given that more than 800 patients would be required to detect a CYP2D6-related clinical effect in postmenopausal women with sufficient power.22 This low power might explain the lack of significance with CYP2D6 phenotype in multivariate Cox analysis (P=0.13). However, breast cancer in young women is less frequent than in postmenopausal women, resulting in smaller available cohorts with simultaneous collection of serum, genomic DNA and detailed follow-up per patient. We therefore restricted our outcome analyses to the 306 compliant patients for whom, both pharmacogenetic and pharmacokinetic data were available. This design differs from a previous preliminary dataset with more patients but without control for compliance.55 It may be argued that this design may give rise to a selection bias; however, we believe that strict inclusion criteria including first-year compliance, serum availability for pharmacokinetic measurements and a reasonable follow-up time are integral to CYP2D6-related outcome analysis. Notwithstanding, our study presents the largest analyses of purely premenopausal patients for which pharmacokinetic and pharmacogenetic outcome associations have been described. No information on co-medication was available for the POSH cohort, a reason why we cannot comment on their possible influence on the results. In the Singapore and Lebanon cohorts, pharmacokinetic analyses were likely not influenced because no patient received moderate/strong CYP2D6 inhibitors. Collectively, our data for the association of tamoxifen outcome with endoxifen formation/concentrations in premenopausal patients must be considered exploratory therefore, its potential clinical relevance awaits confirmation by independent studies.
Our data support the notion that tamoxifen efficacy in premenopausal breast cancer patients is influenced by CYP2D6-mediated metabolism. If replicated, therapeutic drug level monitoring at steady-state could identify patients with high endoxifen levels or low DM-Tam/endoxifen ratio expected to have a lower risk of recurrence and who should therefore be encouraged to adhere to tamoxifen. On the basis of current research and developments toward improving therapeutic levels of endoxifen, patients with impaired/deficient CYP2D6 and suboptimal therapeutic endoxifen concentrations could be considered for the following: (i) increase of the standard tamoxifen dose as previously suggested for postmenopausal women,15, 56, 57 (ii) standard tamoxifen dose supplemented with endoxifen, a possibility currently explored by in silico modeling of CYP2D6 phenotype guided dosing schemes,58 (iii) treatment with (Z)-endoxifen hydrochloride of which first-in-man studies have already been published59 and further clinical trials are underway (www.clinicaltrials.gov: NCT01327781, NCT01273168) and (iv) aromatase inhibitor combined with ovarian suppression,60 as currently investigated in the Tamoxifen and EXemestane (TEXT) and Suppression of Ovarian Function Trial (SOFT) trials.61
Conflict of interest
HB and MS report scientific collaborations with Roche Molecular Diagnostics and Siemens Healthcare Diagnostics Products in the previous 3 years. The remaining authors declared no conflict of interest.
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- Maximov PY, McDaniel RE, Fernandes DJ, Korostyshevskiy VR, Bhatta P et al. Simulation with cells in vitro of tamoxifen treatment in premenopausal breast cancer patients with different CYP2D6 genotypes. Br J Pharmacol, (in press).
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- Awada Z, Haider S, Tfayli A, Bazarbachi A, Saghir NE, Salem Z et al. Pharmacogenomics variation in drug metabolizing enzymes and transporters in relation to docetaxel toxicity in Lebanese breast cancer patients: paving the way for OMICs in low and middle income countries. OMICS 2013; 17: 353–367. | Article | PubMed | ISI |
- Eccles D, Gerty S, Simmonds P, Hammond V, Ennis S, Altman D et al. Prospective study of Outcomes in Sporadic versus Hereditary breast cancer (POSH): study protocol. BMC Cancer 2007; 7: 160. | Article | PubMed |
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- McCague R, Leclercq G, Jordan VC. Nonisomerizable analogues of (Z)- and (E)-4-hydroxytamoxifen. Synthesis and endocrinological properties of substituted diphenylbenzocycloheptenes. J Med Chem 1988; 31: 1285–1290. | Article | PubMed | ISI |
- Zineh I, Beitelshees AL, Gaedigk A, Walker JR, Pauly DF, Eberst K et al. Pharmacokinetics and CYP2D6 genotypes do not predict metoprolol adverse events or efficacy in hypertension. Clin Pharmacol Ther 2004; 76: 536–544. | Article | PubMed | ISI | CAS |
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- Schroth W, Hamann U, Fasching PA, Dauser S, Winter S, Eichelbaum M et al. CYP2D6 polymorphisms as predictors of outcome in breast cancer patients treated with tamoxifen: expanded polymorphism coverage improves risk stratification. Clin Cancer Res 2010; 16: 4468–4477. | Article | PubMed | ISI |
- Love RR, Desta Z, Flockhart D, Skaar T, Ogburn ET, Ramamoorthy A et al. CYP2D6 genotypes, endoxifen levels, and disease recurrence in 224 Filipino and Vietnamese women receiving adjuvant tamoxifen for operable breast cancer. Springerplus 2013; 2: 52. | Article | PubMed |
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- Makubate B, Donnan PT, Dewar JA, Thompson AM, McCowan C. Cohort study of adherence to adjuvant endocrine therapy, breast cancer recurrence and mortality. Br J Cancer 2013; 108: 1515–1524. | Article | PubMed | ISI |
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- Coller JK, Krebsfaenger N, Klein K, Endrizzi K, Wolbold R, Lang T et al. The influence of CYP2B6, CYP2C9 and CYP2D6 genotypes on the formation of the potent antioestrogen Z-4-hydroxy-tamoxifen in human liver. Br J Clin Pharmacol 2002; 54: 157–167. | Article | PubMed | ISI | CAS |
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We thank the patients, physicians, nurses and data managers for their participation in this study. This work was supported by the Robert Bosch Foundation, Stuttgart, Germany, Deutsche Forschungsgemeinschaft (DFG, SCHR 1323/2-1 and MU 1727/2-1), Germany and IZEPHA (Grant 21-0-0), Germany, The German Cancer Consortium (DKTK), American University of Beirut Medical Practice Plan (AUBMPP), and National Medical Research Council Grant NMRC/1159/2008 and NMRCG13161. PS is a fellow of the FP7 EU Marie Curie Initial Training Network FightingDrugFailure (GA238132).
Author contributions
HB, TM, PS, WS and MS designed the research. BC, RD, BE, DE, BG, SG, MZH, JSLL, TM, RCHN, PS, ES, WS, AT, NSW, YSY and NKZ performed the research. HB, BC, BE, DE, ME, TM, PS, WS, MS, SW and NKZ analyzed the data. BC, DE and AT contributed study materials or patients. WS, MS and HB led the study. qDE established the POSH study cohort. BC established the Singapore study cohort. NZK and AT established the Lebanon study cohort as co-principle investigators. BC, RD, BE, DE, SG, MZH, JSLL, RCHN, AT, NSW, YSY and NKZ collected samples and data. PS and WS performed the genotyping. BG and TM performed the drug metabolite analytics. PS, WS, TM and SW performed the statistical analysis. HB, BC, DE, TM, PS, WS, MS, SW and NKZ wrote the manuscript. All other authors contributed primarily to the patient ascertainment and/or data, and sample collection and preparation. All authors reviewed the final manuscript.
Supplementary Information accompanies the paper on the The Pharmacogenomics Journal website
This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 3.0 Unported License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/3.0/.


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Search 321,000 hotels worldwide.
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The inn is a great central location for getting to wineries. The grounds are beautiful. Situated right across the street from vineyards. Enjoyed sitting in the hot tubs at the end of a day of wine tastings. Hotel staff was very knowledgeable and gave some great suggestions of places to try. Overall ...
Enjoyed quiet surroundings, pool and large bathroom in our suite.
Someone has to get the worst in in the house. We obviously must have picked the short straw at the Grape Leaf Inn when they put us in the Suavingnan Blanc room. Tiny, no seating except for a bench against the wall, other minor and stupid things wrong; things that individually one would ignore, but ...
Even though it is being expanded and renovated, I wish I could have stayed longer. The small touches, the beautiful rooms, the extraordinary food, the amazing gardens - everything was wonderful.
Lovely accommodations, great location, friendly staff
We enjoyed our stay at the Gaige House. It was a nice place... a cross between a Bed & Breakfast and an Inn. The features of the Bed & Breakfast we loved. The food was great, the staff was nice, the room was large and clean. Tile base of shower seemed to have come off and rooms are entered from the ...
High quality hotel with excellent rooms. The room is in classic European style and is really exceptional. The bathroom is very spacious with high quality facilities.
We were pleasantly surprised of how nice this hotel was. It's tucked away in a quiet location, yet it's right off a main road. The landscaping and hotel decor exudes a serene comfy feel. Sandy checked us in and welcomed us right away. She and Bob are very knowledgeable on things of Guerneville. If ...
The hotel staff was highly attentive. Turn down service made our stay special. The place is very clean and the gardens are perfectly manicured. The included breakfast is top notch. Many delicious options, fresh and healthy. We went here for our anniversary and had a lovely time.
The Lodge is in a lovely spot near the bay in Bodega Bay. We had just come from Mendocino which is gorgeous so the contrast was hard to overcome. The Lodge and grounds, pool etc very well maintained. Wine and cheese nice in evening and staff helpful. Rooms nice but not amazing. We felt the price ...
When you need to book a room with luxurious amazing amenities and the best rates, the 4 star hotels in Sonoma Valley, California are incredible options. Known for their extra perks, first-rate service, and fantastic locations, each of the Sonoma Valley 4 star hotels offers the ultimate experience for globe-trotting travelers. Relax in your expertly designed room. Kick back with around-the-clock room service.
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Legendary Motown performers of the 1960s, 1970s and 1980s reunite on stage to celebrate the silver anniversary of the greatest soul-pop sounds in music history. Thursday, May 25 at 8:30 PM
On Second Thought is a one-hour, daily news talk show that airs at 9 a.m. ET weekdays.
NOVA explores the unknowns of the world around us and even the worlds within us.
The GHSA state championships for football are right around the corner. There are 16 teams left on the road to the Georgia Dome and by late Saturday night all eight champions for 2016 will be... MORE
GPB Passport is the new member benefit that provides you with extended access to an on-demand library of quality local and national public television programming, including tens of thousands of hours of your favorite programs.
My heart goes out to all of the victims of the Boston Marathon bombing and their families and friends. Like many people who don't live in Boston, I feel helpless but want to do something to assist....


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Thursday, April 21, 2011
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Blogs Revolutionary Moments The Egyptian Revolution Goes NapoleonSep 3, 2013 8:36 pm
The Egyptian Revolution Goes Napoleon
The same disillusionment set in as the French Revolution progressed. In fact, in a superb article in the Chronicle of Higher Education published in 2006, Howard Brown of the University of Binghamton described how events of the Revolution presaged events of 2006. It seems to me that Brown's article actually does even better to foreshadow what has happened in Egypt the last month and especially this week. His article concentrates on the trajectory from constitutionalism to repression under Napoleon. The biggest difference is the incredible speed of the current transformation compared to two centuries ago. It took a month in Egypt for what transpired in France over a decade. This, of course, relates to the same acceleration in the revolutionary process that Alyssa Sepinwalldescribed elsewhere in this blog.
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We are excited to announce our summer Kindergarten RoundUp event on Thursday, June 15, 2017, from 9 a.m. to 4:30 p.m. for all children entering Kindergarten this coming fall.
Come join us for fun attractions including a large zoo and pony rides, 20-foot slide, CrayonLand, snow cones and cotton candy, and a fire truck! Call our office during business hours with questions or to learn more.
Because earaches don't understand office hours and sore throats don't observe holidays, Novant Health Forsyth Pediatrics offers after-hours care. If your child is sick on an evening or weekend, you can visit our after-hours care location where providers you know and trust will address those urgent pediatric needs.
After-hours care is available at our Kernersville after-hours location. Providers will be available to see children with acute medical concerns including sore throats, earaches, flu-like symptoms and minor injuries. Your child does not have to be an established patient at Novant Health Forsyth Pediatrics to get after-hours care.
After-hours care in Kernersville is available:
Our Kernersville, Oak Ridge and Walkertown offices offer early-morning sick clinics on weekdays for established patients of Novant Health Forsyth Pediatrics. From 8 a.m. until 9 a.m., established patients can stop by either of these offices for first-come, first-served care. No appointment is necessary and you do not need to call ahead. This is especially useful for parents wondering whether a child is too sick to attend school or daycare.
If your child is sick after hours or on a weekend, call 336-993-8333 to speak to a nurse. That nurse will advise you on whether to go to the after-hours or weekend clinic, to head to an emergency room or to schedule an appointment with our office during normal office hours.


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Summer Housing CP Towers (Knox) 1 BR/BA (1st Floor)
DescriptionAvailable for months of June/July this summer. 1 Bed and bath, and can comfortably fit two people for living. Close to college park nightlife (bars/food), grocery store, and convenience stores. Can come partly furnished if you would like (inquire for more info). Includes kitchen with gas stove, fridge, dishwasher, and microwave (if you want). Also has a patio. Willing to negotiate rent starting with a $600 discount for signing the sublet(original rent is $1500 a month). Also, utilities are included in rent (basically you don't have to pay them). Comes with a parking space. Please feel free to contact if you have any questions.
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text: >Pear Tree Greetings Winner Brett October 4, 2010 Tweet Stumble Share +1 Pin ShareShares 0>Enjoy your stickers, lucky winner!! Oh, wait! Was it you ?? Check here to see!! Tweet Stumble Share +1 Pin ShareShares 0 About the author: I'm a 30-something mom to three, brand ambassador. content creator, social media maven, blogger extraordinaire, earth lover, butcher, baker, candlestick maker (or something along those lines) – love word games, crafting, cake decorating or shooting pictures. 0 comments… add one Leave a Comment Cancel


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Pahar Ganj, Delhi, India- 110055.
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Parties Organized:
Bachelors Party
Graduation Party
Private Party
Birthday Party
Baby Shower Party
Kitty Party
Corporate Party
Engagement Party
Entertainment activities
Arranging & Booking the Venue
Average no. of people you cater to:
Above 100
Between 20 to 50
Between 50 to 100
Willing to travel:
25 Km
Different Wedding Types:
Muslim Wedding
North Indian Wedding
South Indian Wedding
Christian Wedding
Services Provided:
Make up & Hair Styling
Arranging Priests
House Decoration
Guest Management & Accomodation
Arranging & Booking the Venue
Photographer & Videographer
Gift Planner
Wedding Venue Decoration
Wedding Invites
Entertainment activities
Number of Guest:
Above 500
Willing to travel for:
25 Km
5No. D-270, Ground Floor, Nawada Housing Complex, Uttam Nagar, Near Kakraula Mor, New Delhi
Pahar Ganj, Delhi, India- 110055. .


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Relevant offers
Beauden Barrett returns to first five-eighth amid five changes to the Hurricanes starting lineup to face the Melbourne Rebels in Wellington on Saturday.
Coach Mark Hammett had toyed with shifting Barrett to fullback and his Taranaki team-mate Andre Taylor to the right wing to fill the gap created by Cory Jane's ankle injury, but instead restored Barrett to his familiar spot.
He swaps places with Tusi Pisi, who returns to the Hurricanes' bench after starting the 37-25 defeat to the Brumbies last Friday.
Alapati Leiua claims Jane's No 14 jersey, with the All Blacks winger expected to be sidelined for six weeks with a sprained ankle.
In the forwards, Jack Lam replaces injured openside flanker Karl Lowe (knee), Faifili Levave reclaims the No 6 jersey from All Blacks training squad callup Brad Shields, and prop Jeffery Toomaga-Allen returns for Reg Goodes.
The Hurricanes (6-6) are ninth on the Super Rugby ladder while the Rebels (4-7) are 10th, after their 32-31 win over the Force in Perth on Sunday.
HURRICANES: Andre Taylor, Alapati Leiua, Conrad Smith (c), Tim Bateman, Julian Savea, Beauden Barrett, TJ Perenara, Victor Vito, Jack Lam, Faifili Levave, Jason Eaton, Jeremy Thrush, Jeffery Toomaga-Allen, Dane Coles, Ben May. Reserves: Motu Matu'u, Reg Goodes, James Broadhurst, Brad Shields, Chris Eaton, Tusi Pisi, Jayden Hayward. Fairfax NZ
- Taranaki Daily News
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Sam Jones saves his longest drives until last at North Island champs
Hairdresser councillor let confidential information slip as he snipped
Surfers organise bodyboard competition in New Plymouth to support terminally-ill friend
Go golfing with a rugby player or dancing with a star to help your school
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Surfers organise bodyboard competition in New Plymouth to support terminally-ill friend
Dead French climber didn't have the experience to safely climb Mt Taranaki in winter
Hairdresser councillor let confidential information slip as he snipped
Tim Nanai-Williams ready for Super Rugby face-off with cousin SBW, when Chiefs meet Blues
Brad Markham: Immigration rule changes could leave NZ farms struggling
Go golfing with a rugby player or dancing with a star to help your school
Taranaki wedding bridge to remain closed as police say they are speaking to a company about the damage
Bullying Free Week part of the process but still a long way to go
Emergency streak for New Plymouth MP Jonathan Young
How will the Hurricanes do in 2015?Related story: Supporting players light up Hurricanes bright start to Super Rugby season
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5 items from 2008
18 November 2008 4:11 AM, PST | WENN | See recent WENN news »
Gwyneth Paltrow is out to prove she's more than a cooking show guide - she can actually serve up the treats too.
The Oscar-winner, who co-hosts Spanish travel and food show Spain... On The Road Again, is planning a Thanksgiving Day feast in her adopted London.
She tells HollyScoop.com, "I'm going to cook a big meal for all my ex-patriate American friends over there."
But the gathering won't include best pal Madonna: "She's on tour, so she'll be here (in America)." »
2 October 2008 6:28 PM, PDT | WENN | See recent WENN news »
Celebrity chef Mario Batali pulled a perfect prank on pal Gwyneth Paltrow when a hitchhiker he picked up on a remote Spanish road turned out to be R.E.M. star Michael Stipe.
Batali and Paltrow were shooting scenes for their new Spanish food and travel show Spain... On The Road Again when the masterchef pulled over to pick up a stranded tourist, under protest from his passenger.
Batali says, "Gwyneth was really nervous but it was just our friend Michael Stipe - I had invited him (along) to surprise her. We got her good." »
22 September 2008 11:10 PM, PDT | Digital Spy | See recent Digital Spy - Movie News news »
Gwyneth Paltrow has revealed that she refuses to hire a personal chef to help out in the kitchen. The actress, who appears in cookery series Spain... On The Road Again with Mario Batali, told People that she insists on cooking for husband Chris Martin and their children Apple and Moses. "I cook all the meals for my house," she said. "I really love to cook. Breads and pizzas is what I'm cooking and we all love it. "We have a wood burning pizza oven in our garden. Right now the (more) »
- By Simon Reynolds
18 September 2008 12:17 AM, PDT | WENN | See recent WENN news »
Gwyneth Paltrow and top chef Mario Batali had such fun filming cookery road trip Spain... On The Road Again the two pals are planning a second series.
The cookery and travel show has yet to air, but the two already have their sights set on a culinary trip through Italy.
Batali says, "We were going to go to Mexico but Gwyneth lives in Europe so I think we're gonna have to do Italy." »
5 June 2008 12:10 PM, PDT | WENN | See recent WENN news »
An Emmy Award-winning writer is suing the makers of Gwyneth Paltrow's new cookery show - claiming he was never paid for his work.
Paltrow stars in new TV series Spain... On The Road Again alongside celebrity chef Mario Batali which talks viewers through a variety of recipes and offers a gastronomic tour of the European country.
But the show - due to air this autumn - has been hit with legal action from Ben Karlin, a former head writer for Comedy Central's The Daily Show with Jon Stewart, who claims to have been approached to "conceptualise and oversee" a companion book to the programme in 2007.
Karlin has filed papers in New York accusing production company chief Charles Pinsky of approving his concept for the guide but then delaying giving him a written contract and eventually dismissing him without pay. He has also accused the show's stars - Batali and Paltrow - of refusing to co-operate with his work on the book.
Pinsky's attorney Leslie Ben-Zvi has hit back at the suit, insisting Karlin has misrepresented the facts.
He says, "We will vigorously defend this lawsuit, including the good names of Charles Pinsky and Mario Batali." »
5 items from 2008
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I'm fortunate that my place of work provides a week off for Spring Break, which gives us the perfect excuse to get away for a bit! This year, we chose to go somewhere I've wanted to go for awhile: Montreal, Quebec.
Two Nights in Miami
After working all day a few Fridays ago, we made the long drive down to Miami to visit the enrollment center for the Global Entry program. When you live in Florida, you are expected to have traveled to every major part of the state, but the truth is, neither of us have really spent time …
Bern's Steak House – Tampa, FL
It's set in a strip mall, but once you're inside you'll forget about that.
Miami's Wynwood District
As part of the application process for the US Customs and Border Protection's Global Entry Program, we had to attend an in-person interview at one of their Enrollment Centers. None of the airports near us had weekend hours, and the thought of sacrificing a vacation day to visit during the week didn't sit well, so …
Milktooth, Indianapolis, Indiana
My birthday was a few weeks ago, and since it was on a Sunday (and Easter Sunday at that) I wanted to take advantage of the occasion and get away for the weekend. We looked for flights that would fit the bill, and when it came time to decide between the final few cities, Michael said to pick a city that had a place I wanted to eat and so we booked.
Gifts for the Wayward Mother
Quick PSA: Sunday, May 14 is Mother's Day here in the USA. Okay, okay, stop freaking out – we've got your back, but you have to get on it. Below you'll find a few items that you can order for your mother-figure and likely receive in time (just make sure you order soon, and choose …
33 Hour Birthday Weekend in Indianapolis, Indiana
Back in March, we began looking for a cheap flight over my birthday weekend. We didn't have any particular place in mind, really, we just wanted to take off and go someplace else. As my birthday fell on Easter weekend this year, the flight costs were way higher than in the past, but we still had a few options. We decided on Indianapolis, Indiana because the price was right, I had Southwest points to use, we could get around without renting a car by using Uber/Lyft, and the times worked out well (leaving early-ish Saturday, arriving late Sunday night) for an overnight trip. Plus, I've wanted to visit Milktooth for awhile, which you'll hear about in a later post.
First Impressions of The Carry-On by Away
My last suitcase hasn't totally bitten the dust yet, but I'm starting to get more nervous about taking it on long trips as its zippers are starting to get wonky. I finally made the choice for a possible replacement when I read about Away's luggage features and their 100 day guarantee. After scoring my last suitcase (sold out) on clearance …
Why we use Airbnb
(we could probably end the post right here)
Oxford Exchange – Tampa, FL
A few weeks ago we visited Tampa, Florida to take Michael's sisters to Bern's Steakhouse (you'll hear about it another time!) as a belated Christmas gift. Before heading home the following day we decided to check out Oxford Exchange, a multi-use space near the University of Tampa that was once a stable. We've visited Tampa …


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Royal Orchid Metropole Hotel
Call us 1800-300-2400-1 (Toll Free) and Get additional Discount upto 50% for this Hotel.
You are getting lowest possible rate for this hotel
Room Description
Heritage Double Room
Room Amenities
- Air conditioning-Room
- Bottled water in room(complimentary)
- Bathrobes
- Internet access-wireless
- Internet access-high speed
- Complimentary toiletries
- Turndown service
- Desk
- Breakfast
- Complimentary Wi-Fi Internet
- Mandatory Supplementary Charges applicable during Christmas and New Year Payable at the Hotel by the guest.
- Compulsory Gala Dinner charge on 24th Dec of INR 2000 plus taxes per person INR 3000 plus taxes per person on 31st Dec to be paid directly at the hotel.
- Compulsory Gala Dinner charge on 24th Dec of INR 2500 plus taxes per person and INR 3000 plus taxes per person on 31st Dec to be paid directly at the hotel
Room Inclusions
- Breakfast
- Air conditioning
- Cable/satellite television channels,
- Coffee/tea
- maker
- Daily housekeeping
- Direct-dial phone
- Hair dryer
- Iron/ironing board
- LCD television
- Minibar,Shower/tub combination
- Wireless Internet access
About Royal Orchid Metropole Hotel
Royal Orchid Metropole is one of the hotels in Mysore. The hotel has Shikari, a restaurant which offers a variety of barbecue dishes, other cuisines and complimentary WIFI access. The hotel is situated at a distance of 17 km from Ranganthittu Bird Sanctuary. The rooms in the hotel are fully equipped with several modern conveniences which include comfortable beds, a television, a dvd player and a safe. The rooms feature a private balcony with tropical greenery views.
No of floors: 1 | No of rooms: 30
Checkin Time: 1300 pm
Checkout Time: 1200 pm
Hotel Amenities
4, 2008-08-21 09:19:10.537
Hotel is just fine
"The beds were not firm


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2 bus schedules from Madison, WI to Philadelphia, PA
Bus Madison x Philadelphia
HOW TO GET THE CHEAPEST bus TICKETS FROM Madison TO Philadelphia WITH Lamers Bus Lines, Greyhound?
There is a total of 2 bus companies operating this trip.
All Lamers Bus Lines, Greyhound have together a total of 2 bus schedules from Madison to Philadelphia.
Find that at the bus timetable these 2 transportation brands have different prices and service offers.
Compare all bus fare prices that vary according to comfort, ticket promotions, and availability.
Take a time and check customers 1787 bus reviews for Lamers Bus Lines, Greyhound services.
User reviews best describe Lamers Bus Lines, Greyhound bus trip experience.
Relating it services to bus quality, punctuality, cleanliness, and staff behavior.
This is useful information to search and compare bus prices.
bus booking in advance is the best way to find a cheap ticket to Philadelphia.
HOW MUCH IS A bus TICKET FROM Madison TO Philadelphia?
Any bus ticket to Philadelphia costs between USD 183 to USD 183 each seat.
You will find the cheapest ticket on Lamers Bus Lines for USD 183.
This bus leaves at 11:20 from MADISON.
On the contrary, the bus leaving at 11:20 have the most expensive ticket to Philadelphia for about USD 183.
HOW TO GET TO Philadelphia FROM Madison?
On average you find 2 daily schedules to Philadelphia from Madison.
Usually are 14 departures every week on this bus route.
On peak seasons bus companies may increase the number of available vehicles.
The company Greyhound has the largest fleet to Philadelphia.
It is an average of 1 bus schedules per day and 30 trips every month.
WHERE IS THE bus STATION ON Madison AND Philadelphia?
For this trip to Philadelphia, you can get on board at MADISON.
Moreover, get off the bus at PHILADELPHIA.
WHEN IS THE FIRST bus SCHEDULE FROM Madison TO Philadelphia?
The first bus time to Philadelphia is at 11:20.
The bus timetable may vary during weekdays.
WHEN IS THE LAST bus SCHEDULE TO Philadelphia?
The last departure time from Madison is at 18:10.
HOW FAR IS Philadelphia FROM Madison?
The bus traveling length from Madison to Philadelphia is around 23h 40m.
Lamers Bus Lines> advertise it has the fastest transportation from Madison.
Selecting this company, you probably arrive in about 1h in Philadelphia.
WHICH IS THE BEST WAY FOR bus BOOKING?
There are many different forms of acquiring a ticket.
You can get your bus ticket online on Lamers Bus Lines, Greyhound.
Alternatively, booking by phone or directly at the counter.
Find out more info on all about search and buy bus tickets in North America.
HOW TO GET TICKET REFUND ON Lamers Bus Lines, Greyhound?
Note that companies have different policies regarding fare types and changes.
Find out more information on bus carriers pages.
Bus Buster TRAVEL INFORMATION
Bus Buster has all information for you discover the best and cheapest bus ticket.
Explore all available tools and 1787 user reviews to best choose between Lamers Bus Lines, Greyhound.
Bus Buster does not sell tickets.
If you want to purchase bus tickets online, this site will redirect you to the official Lamers Bus Lines, Greyhound website.
Reserve your bus seat to Philadelphia in advance and have a nice trip.
Any tips about this journey? Help others. Join in!
Search related to "bus Madison x Philadelphia"
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- Bus Philadelphia x Atlantic City
- Bus Philadelphia x Richmond
- Bus Philadelphia x Newark


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Forum indexNikon 1 System TalkChange forum
Anyone miss the lack of AEB on the Nikon 1 System
Started Nov 21, 2012 | Discussions thread
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Bobby Handal • Veteran Member • Posts: 5,488
Re: Anyone miss the lack of AEB on the Nikon 1 System
In reply to vkyr2 • Nov 22, 2012
I think that it is a serious omission.
Some other "high speed" point and shoots like the Casio's have a variety of settings to take advantage of their "fastness" .
Fast EV bracketing, focus bracketing, WB bracketing are options that should be implemented.
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