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1.  A candidate molecular signature associated with tamoxifen failure in primary breast cancer 
Introduction
Few markers are available that can predict response to tamoxifen treatment in estrogen receptor (ER)-positive breast cancers. Identification of such markers would be clinically useful. We attempted to identify molecular markers associated with tamoxifen failure in breast cancer.
Methods
Eighteen initially ER-positive patients treated with tamoxifen requiring salvage surgery (tamoxifen failure [TF] patients) were compared with 17 patients who were disease free 5 years after surgery plus tamoxifen adjuvant therapy (control patients). cDNA microarray, real-time quantitative PCR, and immunohistochemistry on tissue microarrays were used to generate and confirm a gene signature associated with tamoxifen failure. An independent series of 33 breast tumor samples from patients who relapsed (n = 14) or did not relapse (n = 19) under tamoxifen treatment from a different geographic location was subsequently used to explore the gene expression signature identified.
Results
Using a screening set of 18 tumor samples (from eight control patients and 10 TF patients), a 47-gene signature discriminating between TF and control samples was identified using cDNA arrays. In addition to ESR1/ERα, the top-ranked genes selected by statistical cross-analyses were MET, FOS, SNCG, IGFBP4, and BCL2, which were subsequently validated in a larger set of tumor samples (from 17 control patients and 18 TF patients). Confirmation at the protein level by tissue microarray immunohistochemistry was observed for ER-α, γ-synuclein, and insulin-like growth factor binding protein 4 proteins in the 35 original samples. In an independent series of breast tumor samples (19 nonrelapsing and 14 relapsing), reduced expression of ESR1/ERα, IGFBP4, SNCG, BCL2, and FOS was observed in the relapsing group and was associated with a shorter overall survival. Low mRNA expression levels of ESR1/ERα, BCL2, and FOS were also associated with a shorter relapse-free survival (RFS). Using a Cox multivariate regression analysis, we identified BCL2 and FOS as independent prognostic markers associated with RFS. Finally, the BCL2/FOS signature was demonstrated to have more accurate prognostic value for RFS than ESR1/ERα alone (likelihood ratio test).
Conclusions
We identified molecular markers including a BCL2/FOS signature associated with tamoxifen failure; these markers may have clinical potential in the management of ER-positive breast cancer.
doi:10.1186/bcr2158
PMCID: PMC2614524  PMID: 18928543
2.  Identification of a Putative Protein Profile Associated with Tamoxifen Therapy Resistance in Breast Cancer*S⃞ 
Tamoxifen resistance is a major cause of death in patients with recurrent breast cancer. Current clinical factors can correctly predict therapy response in only half of the treated patients. Identification of proteins that are associated with tamoxifen resistance is a first step toward better response prediction and tailored treatment of patients. In the present study we intended to identify putative protein biomarkers indicative of tamoxifen therapy resistance in breast cancer using nano-LC coupled with FTICR MS. Comparative proteome analysis was performed on ∼5,500 pooled tumor cells (corresponding to ∼550 ng of protein lysate/analysis) obtained through laser capture microdissection (LCM) from two independently processed data sets (n = 24 and n = 27) containing both tamoxifen therapy-sensitive and therapy-resistant tumors. Peptides and proteins were identified by matching mass and elution time of newly acquired LC-MS features to information in previously generated accurate mass and time tag reference databases. A total of 17,263 unique peptides were identified that corresponded to 2,556 non-redundant proteins identified with ≥2 peptides. 1,713 overlapping proteins between the two data sets were used for further analysis. Comparative proteome analysis revealed 100 putatively differentially abundant proteins between tamoxifen-sensitive and tamoxifen-resistant tumors. The presence and relative abundance for 47 differentially abundant proteins were verified by targeted nano-LC-MS/MS in a selection of unpooled, non-microdissected discovery set tumor tissue extracts. ENPP1, EIF3E, and GNB4 were significantly associated with progression-free survival upon tamoxifen treatment for recurrent disease. Differential abundance of our top discriminating protein, extracellular matrix metalloproteinase inducer, was validated by tissue microarray in an independent patient cohort (n = 156). Extracellular matrix metalloproteinase inducer levels were higher in therapy-resistant tumors and significantly associated with an earlier tumor progression following first line tamoxifen treatment (hazard ratio, 1.87; 95% confidence interval, 1.25–2.80; p = 0.002). In summary, comparative proteomics performed on laser capture microdissection-derived breast tumor cells using nano-LC-FTICR MS technology revealed a set of putative biomarkers associated with tamoxifen therapy resistance in recurrent breast cancer.
doi:10.1074/mcp.M800493-MCP200
PMCID: PMC2690491  PMID: 19329653
3.  Tumorigenic Effects of Tamoxifen on the Female Genital Tract 
Tamoxifen is widely used for endocrine treatment and breast cancer prevention. It acts as both an estrogen antagonist in breast tissue and an estrogen agonist in the female lower genital tract. Tamoxifen causes severe gynecologic side effects, such as endometrial cancer. This review focuses on the effects of prolonged tamoxifen treatment on the human female genital tract and considers its tumorigenicity in the gynecologic organs through clinical data analysis. Tamoxifen is associated with an increased incidence of benign endometrial lesions such as polyps and hyperplasia and a two- to four-fold increased risk of endometrial cancer in postmenopausal patients. Moreover, the incidence of functional ovarian cysts is significantly high in premenopausal tamoxifen users. To prevent tamoxifen from having severe side effects in gynecologic organs, frequent gynecological examination should be performed for both premenopausal and postmenopausal patients with breast cancer who are treated with this drug.
PMCID: PMC3160006  PMID: 21876648
tamoxifen; tumorigenicity; ovary; uterus; estrogenicity; breast cancer
4.  Loss of Rho GDIα and Resistance to Tamoxifen via Effects on Estrogen Receptor α 
Background
Estrogen receptor (ER) α is a successful therapeutic target in breast cancer, but patients eventually develop resistance to antiestrogens such as tamoxifen.
Methods
To identify genes whose expression was associated with the development of tamoxifen resistance and metastasis, we used microarrays to compare gene expression in four primary tumors from tamoxifen-treated patients whose breast cancers did not recur vs five metastatic tumors from patients whose cancers progressed during adjuvant tamoxifen treatment. Because Rho guanine dissociation inhibitor (GDI) α was underexpressed in the tamoxifen-resistant group, we stably transfected ERα-positive MCF-7 breast cancer cells with a plasmid encoding a short hairpin (sh) RNA to silence Rho GDIα expression. We used immunoblots and transcription assays to examine the role of Rho GDIα in ER-related signaling and growth of cells in vitro and as xenografts in treated nude mice (n = 8–9 per group) to examine the effects of Rho GDIα blockade on hormone responsiveness and metastatic behavior. The time to tumor tripling as the time in weeks from randomization to a threefold increase in total tumor volume over baseline was examined in treated mice. The associations of Rho GDIα and MTA2 levels with tamoxifen resistance were examined in microarray data from patients. All statistical tests were two-sided.
Results
Rho GDIα was expressed at lower levels in ERα-positive tumors that recurred during tamoxifen treatment than in ERα-positive tamoxifen-sensitive primary tumors. MCF-7 breast cancer cells in which Rho GDIα expression had been silenced were tamoxifen-resistant, had increased Rho GTPase and p21-activated kinase 1 activity, increased phosphorylation of ERα at serine 305, and enhanced tamoxifen-induced ERα transcriptional activity compared with control cells. MCF-7 cells in which Rho GDIα expression was silenced metastasized with high frequency when grown as tumor xenografts. When mice were treated with estrogen or estrogen withdrawal, tripling times for xenografts from cells with Rho GDIα silencing were similar to those from vector-containing control cells; however, tripling times were statistically significantly faster than control when mice were treated with tamoxifen (median tripling time for tumors with Rho GDIα small interfering RNA = 2.34 weeks; for control tumors = not reached, hazard ratio = 4.13, 95% confidence interval = 1.07 to 15.96, P = .040 [adjusted for multiple comparisons, P = .119]). Levels of the metastasis-associated protein MTA2 were also increased upon Rho GDIα silencing, and combined Rho GDIα and MTA2 levels were associated with recurrence in 250 tamoxifen-treated patients.
Conclusion
Loss of Rho GDIα enhances metastasis and resistance to tamoxifen via effects on both ERα and MTA2 in models of ERα-positive breast cancer and in tumors of tamoxifen-treated patients.
doi:10.1093/jnci/djr058
PMCID: PMC3071355  PMID: 21447808
5.  Risk of Parkinson's disease after tamoxifen treatment 
BMC Neurology  2010;10:23.
Background
Women have a reduced risk of developing Parkinson's disease (PD) compared with age-matched men. Neuro-protective effects of estrogen potentially explain this difference. Tamoxifen, commonly used in breast cancer treatment, may interfere with the protective effects of estrogen and increase risk of PD. We compared the rate of PD in Danish breast cancer patients treated with tamoxifen to the rate among those not treated with tamoxifen.
Methods
A cohort of 15,419 breast cancer patients identified from the Danish Breast Cancer Collaborative Group database was linked to the National Registry of Patients to identify PD diagnoses. Overall risk and rate of PD following identification into the study was compared between patients treated with tamoxifen as adjuvant hormonal therapy and patients not receiving tamoxifen. Time-dependent effects of tamoxifen treatment on PD rate were examined to estimate the likely induction period for tamoxifen.
Results
In total, 35 cases of PD were identified among the 15,419 breast cancer patients. No overall effect of tamoxifen on rate of PD was observed (HR = 1.3, 95% CI: 0.64-2.5), but a PD hazard ratio of 5.1 (95% CI: 1.0-25) was seen four to six years following initiation of tamoxifen treatment.
Conclusions
These results provide evidence that the neuro-protective properties of estrogen against PD occurrence may be disrupted by tamoxifen therapy. Tamoxifen treatments may be associated with an increased rate of PD; however these effects act after four years, are of limited duration, and the adverse effect is overwhelmed by the protection against breast recurrence conferred by tamoxifen therapy.
doi:10.1186/1471-2377-10-23
PMCID: PMC2862029  PMID: 20385012
6.  Meta-analysis of Vascular and Neoplastic Events Associated with Tamoxifen 
OBJECTIVE
Tamoxifen reduces the risk of developing breast cancer but also affects the risks of certain vascular and neoplastic events. Our purpose was to estimate the effects of tamoxifen on potentially life-threatening vascular and neoplastic outcomes.
DESIGN
Random effects meta-analysis of published randomized controlled trials.
PATIENTS
Participants in all trials in which a treatment arm that included tamoxifen was compared to a similar control arm. Breast cancer risk reduction and treatment trials were included.
INTERVENTIONS
Tamoxifen at variable dose and duration.
MEASUREMENTS AND MAIN RESULTS
Thirty-two trials (52,929 patients) reported one or more outcomes of interest. Tamoxifen was associated with significantly increased risks of endometrial cancer (relative risk [RR] 2.70; 95% CI, 1.94 to 3.75), gastrointestinal cancers (RR 1.31; 95% CI, 1.01 to 1.69), strokes (RR 1.49; 95% CI, 1.16 to 1.90), and pulmonary emboli (RR 1.88; 95% CI, 1.77 to 3.01). Tamoxifen had no effect on secondary malignancies other than endometrial and gastrointestinal cancers (RR 0.96; 95% CI, 0.81 to 1.13). In contrast, tamoxifen significantly decreased myocardial infarction deaths (RR 0.62; 95% CI, 0.41 to 0.93) and was associated with a statistically insignificant decrease in myocardial infarction incidence (RR 0.90; 95% CI, 0.66 to 1.23). Postmenopausal women had greater risk increases for neoplastic outcomes.
CONCLUSIONS
This meta-analysis of randomized trials found tamoxifen use to be significantly associated with several neoplastic and vascular outcomes. Consideration of tamoxifen use requires balance of potential benefits and risks.
doi:10.1046/j.1525-1497.2003.20724.x
PMCID: PMC1494944  PMID: 14687281
tamoxifen; adverse events; selective estrogen receptor modulators; chemoprevention
7.  New insights into the metabolism of tamoxifen and its role in the treatment and prevention of breast cancer 
Steroids  2007;72(13):829-842.
The metabolism of tamoxifen is being redefined in the light of several important pharmacological observations. Recent studies have identified 4-hydroxy N-desmethyl tamoxifen (endoxifen) as an important metabolite of tamoxifen necessary for antitumor actions. The metabolite is formed through the enzymatic product of CYP2D6 which also interacts with specific selective serotonin reuptake inhibitors (SSRIs) used to prevent the hot flashes observed in up to 45% of patients taking tamoxifen. Additionally, the finding that enzyme variants of CYP2D6 do not promote the metabolism of tamoxifen to endoxifen means that significant numbers of women might not receive optimal benefit from tamoxifen treatment. Clearly these are particularly important issues not only for breast cancer treatment but also for selecting premenopausal women, at high risk for breast cancer, as candidates for chemoprevention using tamoxifen.
doi:10.1016/j.steroids.2007.07.009
PMCID: PMC2740485  PMID: 17765940
selective serotonin reuptake inhibitors; raloxifene; selective estrogen receptor modulators; ospemifene; arzoxifene
8.  Relationships between CYP2D6 phenotype, breast cancer and hot flushes in women at high risk of breast cancer receiving prophylactic tamoxifen: results from the IBIS-I trial 
British Journal of Cancer  2012;107(2):230-233.
Background:
Several studies have reported discordant results regarding the impact of the CYP2D6 phenotype on both the effectiveness and the degree of endocrine symptoms associated with tamoxifen. Other studies have suggested that menopausal symptoms may be a predictive factor to tamoxifen response.
Methods:
We investigated the relationship between the CYP2D6-predicted phenotype and tamoxifen response in a nested case–control study among women from the International Breast cancer Intervention Study (IBIS-I), which evaluated tamoxifen in the preventive setting.
Results:
In this retrospective analysis of the tamoxifen-treated women in the IBIS-I study, 9 women (16.6%) who developed oestrogen receptor-positive invasive breast cancer had a 2D6 poor or intermediate metaboliser phenotype compared with 45 (20.6%) controls. Adjusted matched logistic regression revealed no significant difference between cases and controls for extensive vs intermediate metaboliser phenotype (OR=0.81 (0.30–2.23), P=0.7) or extensive vs poor metaboliser phenotype (OR=1.02 (0.31–3.32), P=0.9). Controls in the tamoxifen group with a poor metaboliser phenotype developed nonsignificantly fewer hot flushes compared with those with an extensive metaboliser phenotype (OR=0.40 (0.12–1.31)), but those with the intermediate phenotype developed nonsignificantly more hot flushes (OR=1.38 (0.58–3.29)) in an unadjusted analysis.
Conclusion:
Data from the preventive IBIS-I study did not support an association between the CYP2D6 phenotype and breast cancer outcome or the development of endocrine symptoms in tamoxifen-treated women.
doi:10.1038/bjc.2012.278
PMCID: PMC3394993  PMID: 22735900
breast cancer; CYP2D6 polymorphism; tamoxifen; hot flushes
9.  Endometrial cancer survival after breast cancer in relation to tamoxifen treatment: Pooled results from three countries 
Introduction
Tamoxifen is an effective treatment for breast cancer but an undesirable side-effect is an increased risk of endometrial cancer, particularly rare tumor types associated with poor prognosis. We investigated whether tamoxifen therapy increases mortality among breast cancer patients subsequently diagnosed with endometrial cancer.
Methods
We pooled case-patient data from the three largest case-control studies of tamoxifen in relation to endometrial cancer after breast cancer (1,875 patients: Netherlands, 765; United Kingdom, 786; United States, 324) and collected follow-up information on vital status. Breast cancers were diagnosed in 1972 to 2005 with endometrial cancers diagnosed in 1978 to 2006. We used Cox proportional hazards survival analysis to estimate hazard ratios (HRs) and 95% confidence intervals (CI).
Results
A total of 1,104 deaths occurred during, on average, 5.8 years following endometrial cancer (32% attributed to breast cancer, 25% to endometrial cancer). Mortality from endometrial cancer increased significantly with unfavorable non-endometrioid morphologies (P < 0.0001), International Federation of Gynaecology and Obstetrics staging system for gynecological malignancy (FIGO) stage (P < 0.0001) and age (P < 0.0001). No overall association was observed between tamoxifen treatment and endometrial cancer mortality (HR = 1.17 (95% CI: (0.89 to 1.55)). Tamoxifen use for at least five years was associated with increased endometrial cancer mortality (HR = 1.59 (1.13 to 2.25)). This association appeared to be due primarily to the excess of unfavorable histologies and advanced stage in women using tamoxifen for five or more years since the association with mortality was no longer significant after adjustment for morphological type and FIGO stage (HR = 1.37 (0.97 to 1.93)). Those patients with endometrioid tumors, who stopped tamoxifen use at least five years before their endometrial cancer diagnosis, had a greater mortality risk from endometrial cancer than endometrioid patients with no tamoxifen exposure (HR = 2.11 (1.13 to 3.94)). The explanation for this latter observation is not apparent.
Conclusions
Patients with endometrial cancer after breast cancer who received tamoxifen treatment for five years for breast cancer have greater endometrial cancer mortality risk than those who did not receive tamoxifen. This can be attributed to non-endometrioid histological subtypes with poorer prognosis among long term tamoxifen users.
doi:10.1186/bcr3206
PMCID: PMC3446354  PMID: 22691381
10.  Predicting prognosis using molecular profiling in estrogen receptor-positive breast cancer treated with tamoxifen 
BMC Genomics  2008;9:239.
Background
Estrogen receptor positive (ER+) breast cancers (BC) are heterogeneous with regard to their clinical behavior and response to therapies. The ER is currently the best predictor of response to the anti-estrogen agent tamoxifen, yet up to 30–40% of ER+BC will relapse despite tamoxifen treatment. New prognostic biomarkers and further biological understanding of tamoxifen resistance are required. We used gene expression profiling to develop an outcome-based predictor using a training set of 255 ER+ BC samples from women treated with adjuvant tamoxifen monotherapy. We used clusters of highly correlated genes to develop our predictor to facilitate both signature stability and biological interpretation. Independent validation was performed using 362 tamoxifen-treated ER+ BC samples obtained from multiple institutions and treated with tamoxifen only in the adjuvant and metastatic settings.
Results
We developed a gene classifier consisting of 181 genes belonging to 13 biological clusters. In the independent set of adjuvantly-treated samples, it was able to define two distinct prognostic groups (HR 2.01 95%CI: 1.29–3.13; p = 0.002). Six of the 13 gene clusters represented pathways involved in cell cycle and proliferation. In 112 metastatic breast cancer patients treated with tamoxifen, one of the classifier components suggesting a cellular inflammatory mechanism was significantly predictive of response.
Conclusion
We have developed a gene classifier that can predict clinical outcome in tamoxifen-treated ER+ BC patients. Whilst our study emphasizes the important role of proliferation genes in prognosis, our approach proposes other genes and pathways that may elucidate further mechanisms that influence clinical outcome and prediction of response to tamoxifen.
doi:10.1186/1471-2164-9-239
PMCID: PMC2423197  PMID: 18498629
11.  The Effects of Tamoxifen on Immunity 
Current medicinal chemistry  2009;16(24):3076-3080.
Tamoxifen is a widely known anti-estrogen which has been employed in adjuvant treatment of early-stage, estrogen-sensitive breast cancer for over 20 years. Less well known are the effects of tamoxifen on immune function, which we discuss here. We review the growing body of evidence which demonstrates immunomodulatory effects of tamoxifen, including in vitro and in vivo studies as well as observations made in breast cancer patients treated with tamoxifen. Taken together these studies suggest that tamoxifen is capable of inducing a shift from cellular (T-helper 1) to humoral (T-helper 2) immunity. Interestingly, the immunomodulatory effects of tamoxifen appear to be independent of the estrogen-receptor and may be mediated through the multi-drug resistance gene product, Permeability-glycoprotein, for which a role in immunity has recently emerged. We furthermore discuss the clinical implications of the immunomodulatory effects of tamoxifen which are twofold. First, tamoxifen may be utilized in the treatment of immune-mediated disorders, particularly of those arising from aberrant T-helper 1 cell activity, including allograft rejection, Crohn’s disease, and Th1-mediated autoimmune conditions such as diabetes mellitus, scleroderma, and multiple sclerosis. Second, given that cellular T-helper 1 immunity is targeted against cancer cells, the tamoxifen-induced shift away from cellular immunity represents a significant step in fostering a cancerogenic environment. This may limit the anti-cancer effects of tamoxifen and thus explain why tamoxifen is inferior compared to other anti-estrogens in preventing disease recurrence in early-stage breast tumors.
PMCID: PMC2902982  PMID: 19689284
Tamoxifen; immunity; modulation; Permeability-glycoprotein; P-glycoprotein
12.  CYP2D6 testing to predict response to tamoxifen in women with breast cancer 
PLoS Currents  2010;2:RRN1176.
Tamoxifen, a selective estrogen receptor modulator, is the standard of care for premenopausal women with estrogen or progesterone receptor-positive breast cancer and a valid option for treating post-menopausal women. However, a substantial number of tamoxifen-treated patients relapse following surgical resection, while remain disease-free for many years. It appears that the primary effectors of tamoxifen activity are its active metabolites, rather than tamoxifen itself. Cytochrome P450 (CYP) enzymes, CYP2D6 in particular, play a major role in the metabolism of tamoxifen to active metabolites. More than 75 germline CYP2D6 variants have been identified.
A test predicting lack of response to tamoxifen could supplement information used by clinicians and patients in treatment decision-making. For example, physicians and patients may opt to switch to an alternative therapy upfront.
doi:10.1371/currents.RRN1176
PMCID: PMC2940141  PMID: 20877451
13.  CYP2D6 testing to predict response to tamoxifen in women with breast cancer 
PLoS Currents  2010;2:RRN1176.
Tamoxifen, a selective estrogen receptor modulator, is the standard of care for premenopausal women with estrogen or progesterone receptor-positive breast cancer and a valid option for treating post-menopausal women. However, a substantial number of tamoxifen-treated patients relapse following surgical resection, while others remain disease-free for many years. It appears that the primary effectors of tamoxifen activity are its active metabolites, rather than tamoxifen itself. Cytochrome P450 (CYP) enzymes, CYP2D6 in particular, play a major role in the metabolism of tamoxifen to active metabolites. More than 75 germline CYP2D6 variants have been identified.
A test predicting lack of response to tamoxifen could supplement information used by clinicians and patients in treatment decision-making. For example, physicians and patients may opt to switch to an alternative therapy upfront.
doi:10.1371/currents.RRN1176
PMCID: PMC2940141  PMID: 20877451
14.  CYP2D6 Genotyping and Tamoxifen: An Unfinished Story in the Quest for Personalized Medicine 
Seminars in oncology  2011;38(2):263-273.
The philosophy behind personalized medicine is that each patient has a unique biologic profile that should guide the choice of therapy, resulting in an improved treatment outcome, ideally with reduced toxicity. Thus, there has been increasing interest in identifying genetic variations that are predictive of a drug’s efficacy or toxicity. Although it is one of the most effective drugs for treating breast cancer, tamoxifen is not effective in all estrogen receptor (ER)-positive breast cancer patients, and it is frequently associated with side effects, such as hot flashes. Relative resistance to tamoxifen treatment may be a result, in part, from impaired drug activation by cytochrome P450 2D6 (CYP2D6). Indeed, recent studies have identified allelic variations in CYP2D6 to be an important determinant of tamoxifen’s activity (and toxicity). This article will summarize the current information regarding the influence of the major genotypes and CYP2D6 inhibitors on tamoxifen metabolism, with a focus on its clinical utility and the current level of evidence for CYP2D6 genotyping of patients who are candidates for tamoxifen treatment.
doi:10.1053/j.seminoncol.2011.01.002
PMCID: PMC3769162  PMID: 21421116
15.  Effects of tamoxifen on vaginal blood flow and epithelial morphology in the rat 
BMC Women's Health  2006;6:14.
Background
Tamoxifen, a selective estrogen receptor modulator with both estrogenic and anti-estrogenic activity, is widely used as adjuvant therapy in breast cancer patients. Treatment with tamoxifen is associated with sexual side effects, such as increased vaginal dryness and pain/discomfort during sexual activity. There have been limited investigations of the effect of tamoxifen on estrogen-dependent peripheral genital arousal responses. The objective of this study was to investigate the effects of tamoxifen on vaginal physiology in the rat.
Methods
Female Sprague-Dawley rats were subjected to sham surgery or bilateral ovariectomy. After 2 weeks, sham-operated rats were implanted with subcutaneous osmotic infusion pumps containing vehicle (control) or tamoxifen (150 μg/day). Ovariectomized rats were similarly infused with vehicle. After an additional 2 weeks, vaginal blood flow responses to pelvic nerve stimulation were measured by laser Doppler flowmetry and vaginal tissue was collected for histological and biochemical assay.
Results
Tamoxifen treatment did not change plasma estradiol concentrations relative to control animals, while ovariectomized rats exhibited a 60% decrease in plasma estradiol. Tamoxifen treatment caused a significant decrease in mean uterine weight, but did not alter mean vaginal weight. Vaginal blood flow was significantly decreased in tamoxifen-infused rats compared to controls. Similar to ovariectomized animals, estrogen receptor binding was increased and arginase enzyme activity was decreased in tamoxifen-infused rats. However, different from control and ovariectomized animals, the vaginal epithelium in tamoxifen-infused rats appeared highly mucified. Periodic acid-Schiff staining confirmed a greater production of carbohydrate-rich compounds (e.g. mucin, glycogen) by the vaginal epithelium of tamoxifen-infused rats.
Conclusion
The observations suggest that tamoxifen exerts both anti-estrogenic and pro-estrogenic effects in the vagina. These physiological alterations may eventually lead to vaginal atrophy and compromise sexual function.
doi:10.1186/1472-6874-6-14
PMCID: PMC1590006  PMID: 16970814
16.  CYP2D6 Genotype and Tamoxifen Response for Breast Cancer: A Systematic Review and Meta-Analysis 
PLoS ONE  2013;8(10):e76648.
Objective
To evaluate evidence on the association between CYP2D6 genotype and tamoxifen response through.
Design
Systematic review and meta-analysis of prospective, cross-sectional and case-control studies published to 2012. For each study, relative risks and 95% confidence intervals were extracted and pooled with a fixed and random effects model. Heterogeneity, publication bias, subgroup, and meta-regression analyses were performed.
Data Sources
PubMed (inception-2012) and EMBASE (inception-2012).
Eligibility Criteria for Selecting Studies
Criteria for inclusion were studies reporting breast cancer outcomes in patients treated with tamoxifen and genotyped for polymorphisms in the CYP2D6 gene.
Results
Twenty-five studies of 13,629 individuals were identified, of which 22 investigated the association of CYP2D6 genotype with outcomes in breast cancer women all receiving tamoxifen treatment (“treatment-only” design). Three randomized trials evaluated the effect of CYP2D6 genotype on tamoxifen response (“effect modification” design). In analysis of treatment-only studies, the relative risk (RR) of all-cause mortality (>307 events in 4,936 patients) for carriers of a CYP2D6 reduced function allele was 1.11 (95% confidence interval (CI): 0.94 to 1.31) compared to individuals with normal/increased function CYP2D6 alleles. When we investigated a composite outcome including all-cause mortality and surrogate endpoints for overall survival (>307 events in 6,721 patients), carriers of a CYP2D6 reduced function allele had a RR of 1.27 (95% CI: 1.11 to 1.45). From two randomized trials that permitted effect-modification analysis, one had only 154 patients and showed evidence of effect modification of tamoxifen by CYP2D6 genotype for distant recurrence but was directionally opposite to that predicted, whereas a larger trial of 2,537 patients failed to show evidence of effect modification for breast cancer-free interval (P values for interaction 0.02 and 0.44, respectively).
Conclusions
Based on these findings, there is insufficient evidence to recommend CYP2D6 genotyping to guide tamoxifen treatment.
doi:10.1371/journal.pone.0076648
PMCID: PMC3788742  PMID: 24098545
17.  Novel pathway analysis of genomic polymorphism-cancer risk interaction in the breast cancer prevention trial 
Purpose
Tamoxifen was approved for breast cancer risk reduction in high-risk women based on the National Surgical Adjuvant Breast and Bowel Project's Breast Cancer Prevention Trial (P-1:BCPT), which showed 50% fewer breast cancers with tamoxifen versus placebo, supporting tamoxifen's efficacy in preventing breast cancer. Poor metabolizing CYP2D6 variants are currently the subject of intensive scrutiny regarding their impact on clinical outcomes in the adjuvant setting. Our study extends to variants in a wider spectrum of tamoxifen-metabolizing genes and applies to the prevention setting.
Methods
Our case-only study, nested within P-1:BCPT, explored associations of polymorphisms in estrogen/tamoxifen-metabolizing genes with responsiveness to preventive tamoxifen. Thirty-nine candidate polymorphisms in 17 candidate genes were genotyped in 249 P-1:BCPT cases.
Results
CYP2D6_C1111T, individually and within a CYP2D6 haplotype, showed borderline significant association with treatment arm. Path analysis of the entire tamoxifen pathway gene network showed that the tamoxifen pathway model was consistent with the pattern of observed genotype variability within the placebo-arm dataset. However, correlation of variations in genes in the tamoxifen arm differed significantly from the predictions of the tamoxifen pathway model. Strong correlations between allelic variation in the tamoxifen pathway at CYP1A1-CYP3A4, CYP3A4-CYP2C9, and CYP2C9-SULT1A2, in addition to CYP2D6 and its adjacent genes, were seen in the placebo-arm but not the tamoxifen-arm. In conclusion, beyond reinforcing a role for CYP2D6 in tamoxifen response, our pathway analysis strongly suggests that specific combinations of allelic variants in other genes make major contributions to the tamoxifen-resistance phenotype.
PMCID: PMC2998292  PMID: 21152245
Breast cancer; tamoxifen resistance; chemoprevention; pathway analysis; breast cancer risk; genomic polymorphisms
18.  Novel pathway analysis of genomic polymorphism-cancer risk interaction in the Breast Cancer Prevention Trial 
Purpose: Tamoxifen was approved for breast cancer risk reduction in high-risk women based on the National Surgical Adjuvant Breast and Bowel Project's Breast Cancer Prevention Trial (P-1:BCPT), which showed 50% fewer breast cancers with tamoxifen versus placebo, supporting tamoxifen's efficacy in preventing breast cancer. Poor metabolizing CYP2D6 variants are currently the subject of intensive scrutiny regarding their impact on clinical outcomes in the adjuvant setting. Our study extends to variants in a wider spectrum of tamoxifen-metabolizing genes and applies to the prevention setting. Methods: Our case-only study, nested within P-1:BCPT, explored associations of polymorphisms in estrogen/tamoxifen-metabolizing genes with responsiveness to preventive tamoxifen. Thirty-nine candidate polymorphisms in 17 candidate genes were genotyped in 249 P-1:BCPT cases. Results: CVP2D6_C1111T, individually and within a CYP2D6 haplotype, showed borderline significant association with treatment arm. Path analysis of the entire tamoxifen pathway gene network showed that the tamoxifen pathway model was consistent with the pattern of observed genotype variability within the placebo-arm dataset. However, correlation of variations in genes in the tamoxifen arm differed significantly from the predictions of the tamoxifen pathway model. Strong correlations between allelic variation in the tamoxifen pathway at CYP1A1-CYP3A4, CYP3A4-CYP2C9, and CYP2C9-SULT1A2, in addition to CYP2D6 and its adjacent genes, were seen in the placebo-arm but not the tamoxifen-arm. In conclusion, beyond reinforcing a role for CYP2D6 in tamoxifen response, our pathway analysis strongly suggests that specific combinations of allelic variants in other genes make major contributions to the tamoxifen-resistance phenotype.
PMCID: PMC2998292  PMID: 21152245
Breast cancer; tamoxifen resistance; chemoprevention; pathway analysis; breast cancer risk; genomic
19.  Luteinizing hormone-releasing hormone analogues in early breast cancer: updated status of ongoing clinical trials. 
British Journal of Cancer  1998;78 (Suppl 4):9-11.
In the year 2000, the ongoing meta-analysis of the Early Breast Cancer Trialists' Collaborative Group will be updated to include additional data from over 4000 patients treated with luteinizing hormone-releasing hormone analogues, principally goserelin. Four major international trials are currently in progress to evaluate the safety and efficacy of goserelin in comparison with the current standard treatments in early breast cancer, which are chemotherapy or tamoxifen. This paper provides an outline of the protocols and main objectives of the Zoladex Early Breast Cancer Research Association (ZEBRA) trial (goserelin versus cyclophosphamide-methotrexate-5-fluorouracil [CMF]), the Cancer Research Campaign (CRC) trial (goserelin versus tamoxifen versus the combination of goserelin and tamoxifen versus no further treatment), the International Breast Cancer Study Group (IBCSG) VIII trial (goserelin versus CMF versus CMF followed by goserelin) and the Eastern Cooperative Oncology Group (ECOG)/South Western Oncology Group (SWOG) trial (cyclophosphamide-doxorubicin-5-fluorouracil [CAF] versus CAF followed by goserelin versus CAF followed by goserelin plus tamoxifen). Preliminary results are expected from the CRC trial in 1998 and from the ZEBRA and ECOG/SWOG trials in 1999. Results from the wide range of comparator regimens, treatment durations and patient subgroups investigated in these trials will greatly increase the clinical database and should help to define the optimum role for goserelin in the treatment of early breast cancer in premenopausal women.
PMCID: PMC2062754  PMID: 9741782
20.  Selective serotonin reuptake inhibitors and breast cancer mortality in women receiving tamoxifen: a population based cohort study 
Objective To characterise whether some selective serotonin reuptake inhibitor (SSRI) antidepressants reduce tamoxifen’s effectiveness by inhibiting its bioactivation by cytochrome P450 2D6 (CYP2D6).
Design Population based cohort study.
Participants Women living in Ontario aged 66 years or older treated with tamoxifen for breast cancer between 1993 and 2005 who had overlapping treatment with a single SSRI.
Main outcome measures Risk of death from breast cancer after completion of tamoxifen treatment, as a function of the proportion of time on tamoxifen during which each SSRI had been co-prescribed.
Results Of 2430 women treated with tamoxifen and a single SSRI, 374 (15.4%) died of breast cancer during follow-up (mean follow-up 2.38 years, SD 2.59). After adjustment for age, duration of tamoxifen treatment, and other potential confounders, absolute increases of 25%, 50%, and 75% in the proportion of time on tamoxifen with overlapping use of paroxetine (an irreversible inhibitor of CYP2D6) were associated with 24%, 54%, and 91% increases in the risk of death from breast cancer, respectively (P<0.05 for each comparison). By contrast, no such risk was seen with other antidepressants. We estimate that use of paroxetine for 41% of tamoxifen treatment (the median overlap in our sample) would result in one additional breast cancer death within five years of cessation of tamoxifen for every 19.7 (95% confidence interval 12.5 to 46.3) patients so treated; the risk with more extensive overlap would be greater.
Conclusion Paroxetine use during tamoxifen treatment is associated with an increased risk of death from breast cancer, supporting the hypothesis that paroxetine can reduce or abolish the benefit of tamoxifen in women with breast cancer.
doi:10.1136/bmj.c693
PMCID: PMC2817754  PMID: 20142325
21.  Prognostic Significance of ESR1 Amplification and ESR1 PvuII, CYP2C19*2, UGT2B15*2 Polymorphisms in Breast Cancer Patients 
PLoS ONE  2013;8(8):e72219.
Introduction
Amplification of the ESR1 gene, coding for estrogen receptor alpha, was shown to predict responsiveness to tamoxifen, however its prognostic impact in breast cancer patients has not been thoroughly investigated. Other factors that could contribute to responsiveness to tamoxifen treatment are polymorphisms in ESR1 gene and genes involved in tamoxifen metabolism.
The aim of this study was to assess the prognostic role of ESR1 gene dosage in a consecutive group of breast cancer patients and to correlate this feature with clinico-pathological factors. Additionally, ESR1 PvuII, CYP2C19*2 and UGT2B15*2 polymorphisms were analyzed in the tamoxifen-treated subgroup of patients.
Materials and Methods
Primary tumor samples from 281 stage I-III consecutive breast cancer patients were analyzed for ESR1 gene dosage using real-time PCR with locked nucleic acids hydrolysis probes. In the tamoxifen-treated subgroup of patients, ESR1 PvuII, CYP2C19*2 and UGT2B15*2 polymorphism in leukocytes genomic DNA were analyzed. Results were correlated with clinico-pathological factors and with disease-free survival (DFS) and overall survival (OS).
Results
ESR1 amplification (with a cut-off level of 2.0) was found in 12% of the entire group of breast cancer patients, and in 18% of the ER-negative subgroup. This feature was associated with decreased DFS both in the entire group (P=0.007) and in the ER-negative subgroup (P=0.03), but not in the tamoxifen-treated patients.
Patients with ESR1 PvuII wt/wt genotype and at least one UGT2B15 wt allele had a worse DFS (P=0.03) and showed a trend towards decreased Os (P=0.08) in comparison to patients with ESR1 PvuII wt/vt or vt/vt genotype and UGT2B15 *2/*2 genotype.
Conclusions
ESR1 amplification can occur in ER-negative tumors and may carry poor prognosis. In the tamoxifen-treated subgroup, poor prognosis was related to the combined presence of ESR1 PvuII wt/wt and UGT2B15wt/wt or wt/*2 genotype.
doi:10.1371/journal.pone.0072219
PMCID: PMC3738574  PMID: 23951298
22.  Association Between the 21-Gene Recurrence Score Assay and Risk of Locoregional Recurrence in Node-Negative, Estrogen Receptor–Positive Breast Cancer: Results From NSABP B-14 and NSABP B-20 
Journal of Clinical Oncology  2010;28(10):1677-1683.
Purpose
The 21-gene OncotypeDX recurrence score (RS) assay quantifies the risk of distant recurrence in tamoxifen-treated patients with node-negative, estrogen receptor (ER)–positive breast cancer. We investigated the association between RS and risk for locoregional recurrence (LRR) in patients with node-negative, ER-positive breast cancer from two National Surgical Adjuvant Breast and Bowel Project (NSABP) trials (NSABP B-14 and B-20).
Patients and Methods
RS was available for 895 tamoxifen-treated patients (from both trials), 355 placebo-treated patients (from B-14), and 424 chemotherapy plus tamoxifen-treated patients (from B-20). The primary end point was time to first LRR. Distant metastases, second primary cancers, and deaths before LRR were censored.
Results
In tamoxifen-treated patients, LRR was significantly associated with RS risk groups (P < .001). The 10-year Kaplan-Meier estimate of LRR was 4.% (95% CI, 2.3% to 6.3%) for patients with a low RS (< 18), 7.2% (95% CI, 3.4% to 11.0%) for those with intermediate RS (18-30), and 15.8% (95% CI, 10.4% to 21.2%) for those with a high RS (> 30). There were also significant associations between RS and LRR in placebo-treated patients from B-14 (P = .022) and in chemotherapy plus tamoxifen–treated patients from B-20 (P = .028). In multivariate analysis, RS was an independent significant predictor of LRR along with age and type of initial treatment.
Conclusion
Similar to the association between RS and risk for distant recurrence, a significant association exists between RS and risk for LRR. This information has biologic consequences and potential clinical implications relative to locoregional therapy decisions for patients with node-negative and ER-positive breast cancer.
doi:10.1200/JCO.2009.23.7610
PMCID: PMC2849763  PMID: 20065188
23.  Prognostic and Predictive Value of the 21-Gene Recurrence Score Assay in a Randomized Trial of Chemotherapy for Postmenopausal, Node-Positive, Estrogen Receptor-Positive Breast Cancer 
The lancet oncology  2009;11(1):55-65.
SUMMARY
Background
The 21-gene Recurrence Score assay (RS) is prognostic for women with node-negative, estrogen receptor (ER)-positive breast cancer (BC) treated with tamoxifen. A low RS predicts little benefit of chemotherapy. For node-positive BC, we investigated whether RS was prognostic in women treated with tamoxifen alone and whether it identified those who might not benefit from anthracycline-based chemotherapy, despite higher recurrence risks.
Methods
The phase III trial S8814 for postmenopausal women with node-positive, ER-positive BC showed that CAF chemotherapy prior to tamoxifen (CAF-T) added survival benefit to tamoxifen alone. Optional tumor banking yielded specimens for RS determination by RT-PCR. We evaluated the effect of RS on disease-free survival (DFS) by treatment group (tamoxifen versus CAF-T) using Cox regression adjusting for number of positive nodes.
Findings
There were 367 specimens (40% of parent trial) with sufficient RNA (tamoxifen, 148; CAF-T, 219). The RS was prognostic in the tamoxifen arm (p=0.006). There was no CAF benefit in the low RS group (logrank p=0.97; HR=1.02, 95% CI (0.54,1.93)), but major DFS improvement for the high RS subset (logrank p=.03; HR=0.59, 95% CI (0.35, 1.01)), adjusting for number of positive nodes. The RS-by-treatment interaction was significant in the first 5 years (p=0.029), with no additional prediction beyond 5 years (p=0.58), though the cumulative benefit remained at 10 years. Results were similar for overall survival and BC-specific survival.
Interpretation
In this retrospective analysis, the RS is prognostic for tamoxifen-treated patients with positive nodes and predicts significant CAF benefit in tumors with a high RS. A low RS identifies women who may not benefit from anthracycline-based chemotherapy despite positive nodes.
doi:10.1016/S1470-2045(09)70314-6
PMCID: PMC3058239  PMID: 20005174
24.  Pathology of endometrium treated with tamoxifen. 
Journal of Clinical Pathology  1994;47(9):827-833.
AIMS--To determine the type of endometrial abnormalities associated with prolonged tamoxifen treatment and to investigate the correlation between tamoxifen dose and any abnormalities detected. METHODS--Endometria from 19 prospectively collected breast cancer patients treated with tamoxifen were ascribed a pathological diagnosis and the findings compared with those in a control group matched for age and presentation. The abnormalities were related to cumulative tamoxifen dose. RESULTS--The two asymptomatic treated patients had generalised simple endometrial hyperplasia at necropsy. No endometrial abnormalities were seen at necropsy in the two control cases. Of the 17 patients treated with tamoxifen who underwent surgery for gynaecological symptoms, 11 had hyperplastic endometrial polyps characterised by epithelial metaplasias and patchy periglandular condensation of stroma. Two women had primary endometrial malignancies with myometrial invasion, and three women, one of whom had previously presented with a benign polyp, had an endometrial polyp-cancer on a background of hyperplasia. Endometrial malignancies were confined to women who had taken more than 35 g of tamoxifen. The control group included no endometrial polyp-cancers, only one patient with an endometrial polyp, four women with endometrial hyperplasia and four with primary endometrial malignancy. CONCLUSIONS--These findings support a link between prolonged tamoxifen treatment and endometrial malignancy and identify a subgroup of patients--that is, those who have taken more than 35 g of tamoxifen, who may be at increased risk of endometrial cancer. The spectrum of pathological findings in patients treated with tamoxifen suggests that the drug promotes endometrial growth and that endometrial polyps may be an important intermediate step in endometrial carcinogenesis.
Images
PMCID: PMC494940  PMID: 7962652
25.  CYP2C19*2 predicts substantial tamoxifen benefit in postmenopausal breast cancer patients randomized between adjuvant tamoxifen and no systemic treatment  
Estrogen catabolism is a major function of CYP2C19. The effect of CYP2C19 polymorphisms on tamoxifen sensitivity may therefore not only be mediated by a variation in tamoxifen metabolite levels but also by an effect on breast cancer risk and molecular subtype due to variation in lifelong exposure to estrogens. We determined the association between these polymorphisms and tamoxifen sensitivity in the context of a randomized trial, which allows for the discernment of prognosis from prediction. We isolated primary tumor DNA from 535 estrogen receptor-positive, stages I–III, postmenopausal breast cancer patients who had been randomized to tamoxifen (1–3 years) or no adjuvant therapy. Recurrence-free interval improvement with tamoxifen versus control was assessed according to the presence or absence of CYP2C19*2 and CYP2C19*17. Hazard ratios and interaction terms were calculated using multivariate Cox proportional hazard models, stratified for nodal status. Tamoxifen benefit was not significantly affected by CYP2C19*17. Patients with at least one CYP2C19*2 allele derived significantly more benefit from tamoxifen (HR 0.26; p = 0.001) than patients without a CYP2C19*2 allele (HR 0.68; p = 0.18) (p for interaction 0.04). In control patients, CYP2C19*2 was an adverse prognostic factor. In conclusion, breast cancer patients carrying at least one CYP2C19*2 allele have an adverse prognosis in the absence of adjuvant systemic treatment, which can be substantially improved by adjuvant tamoxifen treatment.
Electronic supplementary material
The online version of this article (doi:10.1007/s10549-013-2568-0) contains supplementary material, which is available to authorized users.
doi:10.1007/s10549-013-2568-0
PMCID: PMC3695326  PMID: 23736997
Breast cancer; CYP2C19; Estrogen catabolism; Tamoxifen metabolism; Endocrine resistance

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