Search

Bertha Alejandra Martinez-Cannon,1,2 Andrea Castro-Sanchez,2 Regina Barragan-Carrillo,2 Sylvia de la Rosa Pacheco,1 Alejandra Platas,2,3 Alan Fonseca,2,3 Yoatzin Vega,2 Karen Bojorquez-Velazquez,3 Juan Enrique Bargallo-Rocha,2,3 Alejandro Mohar,3,4 Cynthia Villarreal-Garza1,2 1Breast Cancer Center, Hospital Zambrano Hellion TecSalud, Tecnologico de Monterrey, San Pedro Garza Garcia, Mexico; 2Joven & Fuerte: Programa para la Atencion e Investigacion de Mujeres Jovenes con Cancer de Mama, Mexico City, Mexico; 3Departamento de Investigacion y de Tumores Mamarios, Instituto Nacional de Cancerologia, Mexico City, Mexico; 4Instituto de Investigaciones Biomédicas de la Universidad Nacional Autónoma de México, Mexico City, MexicoCorrespondence: Cynthia Villarreal-GarzaBreast Cancer Center, Hospital Zambrano Hellion TecSalud, Tecnologico de Monterrey, Av. Batallon de San Patricio 112, Real San Agustin, 66278, San Pedro Garza Garcia, Nuevo Leon, MexicoEmail cynthiavg@gmail.comBackground: Breast cancer (BC) in young women is characterized by an unfavorable prognosis in hormone receptor-positive/HER2-negative tumors, which may be explained by low rates of tamoxifen adherence. In Mexico, up to 14% of all BC diagnoses occur in young women and no data on tamoxifen adherence has been reported.Objective: To estimate the rate of adherence to adjuvant tamoxifen in Mexican young women with BC (YWBC).Methods: A cross-sectional survey was conducted at the National Cancer Institute in Mexico City, among YWBC (≤ 40 years at diagnosis) receiving adjuvant tamoxifen. Adherence was measured subjectively, through self-reported surveys, and objectively, through medication possession ratio (MPR). Descriptive statistics were used to analyze sociodemographic characteristics. To compare associations between patients’ characteristics and adherence, Chi-square test was used for categorical variables and Student’s t-test or Mann–Whitney U-test for quantitative variables.Results: A total of 141 YWBC receiving adjuvant tamoxifen were included. Regarding subjective adherence, 95% expressed taking tamoxifen regularly, 70% reported missing 0 doses in the past 30 days, and 71.6% reported having adverse effects. Regarding objective adherence, 74.8% of patients had an MPR ≥ 80%. The association between subjective and objective adherence was statistically significant (p = 0.004). Subjective adherence was associated with not skipping tamoxifen doses when feeling worse. Objective adherence was associated with having a stable job, not skipping tamoxifen doses when feeling worse, taking additional medications, and time on tamoxifen treatment. Fifty-six percent considered the information on tamoxifen to be insufficient and 37% not understandable.Conclusion: In our study, high subjective and objective adherence rates to adjuvant tamoxifen were reported, although an important proportion of women reported high rates of adverse effects and not fully understanding the benefits of tamoxifen. Strategies to increase tamoxifen adherence may be even more important now that longer durations of treatment or further ovarian function suppression have become the standard of care in YWBC.Keywords: young women, breast cancer, tamoxifen, adherence, Mexico

Aim: We conducted a retrospective analysis in 71 Mexican Mestizo patients to evaluate the breast cancer-free survival (BCFS) among the inferred genetic phenotypes (GP) of CYP2D6. Patients & methods: CYP2D6 was genotyped through Taqman-probe analysis; GP were inferred according to international guidelines. The BCFS was estimated through Kaplan–Meier method and analyzed with a log-rank test; hazard ratios were calculated with 95% CI and p < 0.05. Results: The BCFS did not differ among CYP2D6 GP (p = 0.45) and recurrence risk was similar between gNM + gUM and gPM + gIM groups (hazard ratio: 1.54, 95% CI: 0.37–6.38; p = 0.55). Conclusion: The findings do not support any impact of CYP2D6 on BCFS. Evaluation of other genetic/nongenetic biomarkers is needed in Mexican Mestizo patients under tamoxifen treatment.

Pancreatic adenocarcinoma remains a chemotherapy-resistant and refractory malignancy with high mortality, unaffected by recent progress in anticancer treatment. Expression of estrogen receptors was detected almost 50 years ago, in both benign and malignant pancreatic cells. However, early preclinical studies in pancreatic cancer led to contradictory findings, and most clinical studies failed to demonstrate an effect with tamoxifen treatment. The identification of a second form of estrogen receptor seems to provide some explanation for these discrepancies. Predominantly expressed in malignant cells and structurally different from what was considered the only estrogen receptor, estrogen receptor β was recognized as a negative prognostic factor and a possible therapeutic target in pancreatic ductal adenocarcinoma. Therefore, findings of research before the identification of estrogen receptor β should be reconsidered, and further studies should be designed to reassess the expression and effect of this specific estrogen receptor type in pancreatic cancer.

Tamoxifen-induced radioresistance, reported in vitro, might pose a problem for patients who receive neoadjuvant tamoxifen treatment and subsequently receive radiotherapy after surgery. Previous studies suggested that DNA damage repair or cell cycle genes are involved, and could therefore be targeted to preclude the occurrence of cross-resistance. We aimed to characterize the observed cross-resistance by investigating gene expression of DNA damage repair genes and cell cycle genes in estrogen receptor-positive MCF-7 breast cancer cells that were cultured to tamoxifen resistance. RNA sequencing was performed, and expression of genes characteristic for several DNA damage repair pathways was investigated, as well as expression of genes involved in different phases of the cell cycle. The association of differentially expressed genes with outcome after radiotherapy was assessed in silico in a large breast cancer cohort. None of the DNA damage repair pathways showed differential gene expression in tamoxifen-resistant cells compared to wild-type cells. Two DNA damage repair genes were more than two times upregulated (NEIL1 and EME2), and three DNA damage repair genes were more than two times downregulated (PCNA, BRIP1, and BARD1). However, these were not associated with outcome after radiotherapy in the TCGA breast cancer cohort. Genes involved in G1, G1/S, G2, and G2/M phases were lower expressed in tamoxifen-resistant cells compared to wild-type cells. Individual genes that were more than two times upregulated (MAPK13) or downregulated (E2F2, CKS2, GINS2, PCNA, MCM5, and EIF5A2) were not associated with response to radiotherapy in the patient cohort investigated. We assessed the expression of DNA damage repair genes and cell cycle genes in tamoxifen-resistant breast cancer cells. Though several genes in both pathways were differentially expressed, these could not explain the cross-resistance for irradiation in these cells, since no association to response to radiotherapy in the TCGA breast cancer cohort was found.

Aim: The aim of the present study was to investigate the efficacy of osthole (7-metoxy-8-isopenthenocoumarin) alone and combined with tamoxifen (TAM) in the elimination of human cervical cancer cells via programmed death. The involvement of heat shock proteins, i.e. well-known molecular chaperones, will be investigated. Material/Methods: Three human cervical cancer cell lines, infected with human papilloma virus (HPV), i.e. HeLa (HPV 18), SiHa (HPV 16), and CaSki (HPV 16 and 18), were used in the experiments. After osthole and TAM treatment, cells stained with fluorochromes were analyzed microscopically according to apoptotic, autophagic, and necrotic morphology. Hsp27, Hsp72, and Hsp90 levels were analyzed by immunoblotting. Transfection with specific siRNA was used for blocking of Hsp expression. Results: In the HeLa, CaSki, and SiHa cell lines, osthole and TAM applied alone had no significant effect on cell death induction. This was correlated with an overexpression of heat shock proteins 27, 72, and 90. In the case of a combination of both drugs, the level of apoptosis was elevated only in SiHa cells. Preincubation with osthole followed by TAM addition as well as simultaneous incubation with both drugs was the most effective. This was correlated with the inhibition of Hsp27, Hsp72, and Hsp90 expression. Blocking of Hsp expression with specific siRNA increased the sensitivity of the studied cell lines to the induction of apoptosis, but not to autophagy or necrosis. Conclusions: Our results indicated that the elimination of heat shock proteins from cervical cancer cells sensitized them to initiation of apoptosis after osthole and tamoxifen treatment.

Monitoring drug uptake, its metabolism, and response on the single-cell level is invaluable for sustaining drug discovery efforts. In this study, we show the possibility of accessing the information about the aforementioned processes at the single-cell level by monitoring the anticancer drug tamoxifen using live single-cell mass spectrometry (LSC-MS) and Raman spectroscopy. First, we explored whether Raman spectroscopy could be used as a label-free and nondestructive screening technique to identify and predict the drug response at the single-cell level. Then, a subset of the screened cells was isolated and analyzed by LSC-MS to measure tamoxifen and its metabolite, 4-Hydroxytamoxifen (4-OHT) in a highly selective, sensitive, and semiquantitative manner. Our results show the Raman spectral signature changed in response to tamoxifen treatment which allowed us to identify and predict the drug response. Tamoxifen and 4-OHT abundances quantified by LSC-MS suggested some heterogeneity among single-cells. A similar phenomenon was observed in the ratio of metabolized to unmetabolized tamoxifen across single-cells. Moreover, a correlation was found between tamoxifen and its metabolite, suggesting that the drug was up taken and metabolized by the cell. Finally, we found some potential correlations between Raman spectral intensities and tamoxifen abundance, or its metabolism, suggesting a possible relationship between the two signals. This study demonstrates for the first time the potential of using Raman spectroscopy and LSC-MS to investigate pharmacokinetics at the single-cell level.

Recent identification of the neonatal 2nd coronary vascular population (2nd CVP) suggests that a subset of these vessels form de novo and mature in the inner myocardial wall of the postnatal heart. However, the origin of smooth muscle cells (SMCs) in the postnatal 2nd CVP remains undetermined. Using a tamoxifen-inducible Wt1-CreER driver and a Rosa26-RFP reporter line, we traced the lineage of epicardial cells to determine if they contribute to SMCs of the 2nd CVP. Late embryonic and postnatal induction of Wt1-CreER activity demonstrated that at these stages Wt1-labeled epicardium does not significantly migrate into the myocardium to form SMCs. However, following tamoxifen treatment at an early embryonic stage (E10.5), we detected Wt1 descendants (epicardium-derived cells, or EPDCs) in the outer myocardial wall at E17.5. When the 2nd CVP forms and remodels at postnatal stage, these early labeled EDPCs re-migrate deep into the inner myocardial wall and contribute to 2nd CVP-SMCs in the adult heart. Our findings reveal that SMCs in the postnatal 2nd CVP are pre-specified as EPDCs from the earliest wave of epicardial cell migration. Rather than the re-activation and migration of epicardial cells at later stages, these resident EPDCs mobilize and contribute to smooth muscle of the 2nd CVP during postnatal development.

Purpose The association between tamoxifen (TMX) treatment and the risk of developing hyperlipidemia remains unclear. Methods The records of 41,726 patients with breast cancer (28,266 received TMX and 13,460 did not) were obtained from the Taiwan National Health Insurance Research Database for the period from January 2000 to December 2008. Three-fold women without breast cancer were the control group (N = 125, 178). The main end point was developing hyperlipidemia during the follow-up. Results During a mean follow-up of 9 years, the patients with breast cancer demonstrated a rate of developing hyperlipidemia that was 6% less (adjusted hazard ratio [HR], 0.94; 95% confidence interval [CI], 0.90-0.97) than that of the control participants without breast cancer. Stratification by age group indicated that only women aged ≥ 55 years who were diagnosed with breast cancer exhibited a significantly reduced risk of hyperlipidemia compared with the control group. With the use of 2 types of adjusted models, we observed that the TMX users (aged ≥ 55 years) consistently exhibited a significantly lower risk of hyperlipidemia than the non-TMX users and control participants (adjusted HRs, 0.79 and 0.82 from models 1 and 2, respectively). Within the 8-year follow-up period, patients with breast cancer and 366 to 1500 days of TMX therapy and > 1500 days of TMX therapy had significantly lower risks of hyperlipidemia compared with patients with ≤ 365 days of TMX therapy (adjusted HR, 0.54; 95% CI, 0.50-0.59; adjusted HR, 0.21; 95% CI, 0.18-0.24, respectively). Conclusions In Asian patients with breast cancer, TMX use was associated with reduced risks of hyperlipidemia.

44. Zhang X, Cook KK, Hilakivi-Clarke L. Lifetime genistein alters mammary tumors’ response to anti-estrogen tamoxifen treatment by affecting immune function in rats. Presented at: Annual Meeting of the American Association of Cancer Research (abstract 904). April 19, 2015. http://www. abstractsonline.com/Plan/ViewAbstract.aspx?mID1⁄43682& sKey1⁄45c372efb-ca04-41ea-8c64-852c1ea4d8bf&cKey1⁄4 4b9b4b58-c9eb-40eb-9ac8-8f6d479ab8a9&mKey1⁄4 19573a54-ae8f-4e00-9c23-bd6d62268424. Accessed June 5, 2015.

Background: Tamoxifen (TAM) and aromatase inhibitor (AI) therapies have been associated with increased risk of thromboembolic and cardiovascular events, respectively, in addition to other side effects. This study analysed the risk of these events and the overall survival (OS) benefit in breast cancer patients treated with AI, compared with TAM-treated patients, in a large population-based cohort. Methods: This observational cohort study included women diagnosed with breast cancer and treated with TAM or AI. Data were extracted from primary care records in a population database (SIDIAP, System for the Development of Research in Primary Care). Incidence rates of study outcomes are reported. Survival analyses included Kaplan–Meier estimation and Cox proportional hazards models. Sensitivity analysis was carried out, using Fine and Gray models to account for competing risk of death. Confounding was minimized using propensity score adjustment and inverse probability weighting (IPW) adjustment. Results: Data from 3082 postmenopausal women treated with TAM, and 18,455 treated with AI, were available. Adjusted hazard ratios (HRs) [95% confidence interval (CI)] for AI users, compared with TAM group, were 0.93 (95%CI 0.69–1.26) for thromboembolic events (TEEs); 1.13 (95%CI 0.79–1.63) for cardiovascular events, and 0.76 (95%CI 0.70–0.82) for mortality. Additional analyses using competing risk analysis had similar results, while IPW adjustment showed a potential risk of pulmonary embolism (PE) [2.26 (95%CI 1.02–4.97)] in AI-treated patients. Conclusions: AI users had >20% lower all-cause mortality compared with TAM users, without increasing risk to experience cardiovascular and TEEs. This would locate AI therapy on the first line in clinical practice. Thus, AI might be the most preferable option in adjuvant hormonal therapy choice.

We report a patient who became pregnant while on tamoxifen treatment for breast cancer and who elected to continue her pregnancy. The normal child was delivered except for a right renal pelvicaliceal dilatation. The use of tamoxifen in pregnancy is complex, but is not necessarily associated with fetal harm. The relatively high frequency of severe congenital abnormalities indicates that it is prudent to stop tamoxifen before pregnancy.

Endocrine resistance is a major obstacle to hormonal therapy for breast cancers. Although reduced expression of estrogen receptor-α (ER-α) is a known contributing factor to endocrine resistance, the mechanism of ER-α downregulation in endocrine resistance is still not fully understood. Here we report that CUE domain-containing protein-2 (CUEDC2), a ubiquitin-binding motif-containing protein, is a key factor in endocrine resistance in breast cancer. We show that CUEDC2 modulates ER-α protein stability through the ubiquitin-proteasome pathway. Through the study of specimens from a large cohort of subjects with breast cancer, we found a strong inverse correlation between CUEDC2 and ER-α protein expression. Notably, subjects with tumors that highly expressed CUEDC2 had poor responsiveness to tamoxifen treatment and high potential for relapse. We further show that ectopic CUEDC2 expression impaired the responsiveness of breast cancer cells to tamoxifen. Therefore, our findings suggest that CUEDC2 is a crucial determinant of resistance to endocrine therapies in breast cancer.

Tamoxifen remains a cornerstone of treatment for patients with oestrogen-receptor-positive breast cancer. Tamoxifen efficacy depends on the biotransformation, predominantly via the cytochrome P450 2D6 (CYP2D6) isoform, to the active metabolite endoxifen. Both genetic and environmental (drug-induced) factors may alter CYP2D6 enzyme activity directly affecting the concentrations of active tamoxifen metabolites. Several studies suggest that germline genetic variants in CYP2D6 influence the clinical outcomes of patients treated with adjuvant tamoxifen. Here, we review the existing data relating CYP2D6 genotypes to tamoxifen efficacy.

Tamoxifen (TAM) ist in der adjuvanten Therapie des Mammakarzinoms ebenso etabliert wie die Strahlentherapie; der optimale Zeitpunkt fur den Beginn der Therapie mit TAM – simultan zur oder sequentiell nach Strahlentherapie – wird kontrovers diskutiert. In dieser Arbeit wird ein Literaturuberblick gegeben. In-vitro-Daten unterstutzen die Vermutung einer antagonistischen Wirkung von TAM auf den Tumor; im Tierexperiment zeigte sich eine synergistische Wirkung. Berucksichtigt man zusatzlich die Modulation der Wirkung von TAM beispielsweise durch Ostrogene oder andere Wachstumsfaktorrezeptoren, erscheint die kombinierte Wirkung von TAM und Bestrahlung zu komplex, um in einem zweidimensionalen, zellularen In-vitro-System untersucht werden zu konnen. Aus klinischer Sicht gibt es zurzeit keinen ausreichenden Anhalt fur eine reduzierte Strahlenwirkung am Tumor durch die simultane im Gegensatz zur sequentiellen Gabe von TAM. Um eine Radioprotektion sicher auszuschliesen, sollten jedoch prospektive, randomisierte klinische Studien mit dieser Fragestellung durchgefuhrt werden. Die aktuelle Literatur zu Interaktionen von Strahlentherapie und TAM ist widerspruchlich, aber klinisch und damit fur die Therapieentscheidung wohl nur von untergeordneter Bedeutung.

Individual women differ with respect to their sensitivity to estrogen and serum levels of sex hormone-binding globulin (SHBG) may reflect the individual response. We found a significant correlation between estrogen receptor (ER) concentrations in breast cancer tissue and SHBG levels during tamoxifen treatment. Estrogen sensitivity may be a general characteristic common to various organs and different between individual women.

Hypoxia is common in many solid tumours, including breast cancer. Hypoxia triggers the expression of hypoxia inducible factor-1 alpha (HIF-1 alpha), and HIF-1 alpha has been associated with an impaired prognosis in breast cancer and down-regulation of the oestrogen receptor (ER), potentially affecting the treatment efficiency of antioestrogens. The role of HIF-1 alpha regarding prognostic and treatment predictive information in breast cancer has not been established and we therefore analyzed HIF-1 alpha using immunohistochemistry in a cohort of 377 premenopausal stage II breast cancers arranged in a tissue microarray. The patients were included in a randomized trial with either 2 years of tamoxifen or no adjuvant treatment. The tamoxifen treatment effect could be studied in subgroups of breast cancer and pure prognostic information could be scrutinized for untreated control patients. HIF-1 alpha was scored as positive in 24% of the tumours and correlated positively to tumour size, Nottingham histological grade (NHG), Ki-67, Her2 and cyclin E expression and negatively to lymph node status, cyclin D1, ER and PR (progesterone receptor) expression. Surprisingly, there was no difference in tamoxifen response for patients with high or low HIF-1 alpha expressing tumours. In lymph node-positive patients as well as NHG 1/2 tumours, high HIF-1 alpha protein expression was significantly associated with an impaired recurrence-free survival (p = 0.014, 0.0.18). When analyzing the subgroup of NHG 1/2 tumours, a high HIF-1 alpha expression was the only independent significant prognostic marker in multivariate analysis, including standard prognostic markers, suggesting that HIF-1a might be a useful prognostic marker in this subgroup of breast cancer, with a rather good but diverse prognosis. (c) 2005 Wiley-Liss, Inc.

Some individuals with estrogen receptor–α (ER-α)-positive breast cancer do not respond to tamoxifen treatment. Increased expression of the ubiquitin ligase CUEDC2 may contribute to this endocrine resistance by reducing theamounts of ER-α (pages 708–714).

ative Group (EBCTCG) overview 2 and represents about 3.5% of the worldwide randomized experience. The latter study identified four independent prognostic factors of recurrence: age, histological grade, surgical resection extent, and estrogen receptor status/tamoxifen treatment. Curiously, Wickberg et al provide results in terms of all recurrences adopting a similar definition of that used in the overview. However, in the worldwide studies this definition was related to the fact that several trials only registered the first recurrence and not the

To evaluate possible predicting factors for endometrial cancer in postmenopausal breast cancer patients with tamoxifen treatment, we compared various clinical features between 12 postmenopausal breast cancer tamoxifen-treated patients with endometrial cancer and a control group of 261 otherwise similar patients without this endometrial pathology. These comparisons were based on a long-term prospective follow-up. Several clinical factors such as longer duration of breast disease, older patient age, lower frequency of chemotherapy administration, and higher frequency of postmenopausal bleeding were found among the tamoxifen-treated patients with endometrial cancers, and were significantly different when compared to the control group. Only eight (66.7%) had postmenopausal bleeding, and a preoperative diagnosis of endometrial cancer was made in only six (50.0%). When considering postmenopausal bleeding as a marker for endometrial cancer in the study patients, sensitivity was 67% and specificity was 98%.

To evaluate whether breast cancer (BC) patients with CYP2D6 gene variation have different clinical tamoxifen (TAM) treatment outcomes to those with normal function of CYP2D6.Systematic searches of the PubMed up to February 21, 2013, were retrieved. The study end points were disease-free survival (DFS) and overall survival (OS). Fixed or random-effects meta-analytical models were used to calculate summary hazard ratio (HR) and corresponding 95 % confidence intervals (CIs). Meta-regression, Galbraith plots, subgroup analysis, and sensitivity analysis were also performed.A total of 11,701 BC patients from 20 trials were included. Compared with reduced CYP2D6 function, normal function was associated with a trend toward improved DFS (HR = 1.37, 95 % CI 1.12-1.69, P = 0.002) and OS (HR = 1.25, 95 % CI 1.03-1.50, P = 0.021). We found significant heterogeneity between studies. When the analysis was stratified into subgroups, significantly worse DFS was found in the groups of intermediate metabolizer versus extensive metabolizer (HR = 1.65, 95 % CI 1.04-2.64, P = 0.035), Asian population (HR = 3.29, 95 % CI 1.64-6.63, P = 0.001), 5 years TAM treatment duration (HR = 1.59; 95 % CI 1.14-2.22, P = 0.006), concomitant chemotherapy (HR = 1.35, 95 % CI 1.04-1.76, P = 0.025), and TAM alone (HR = 1.44, 95 % CI 1.44-2.06, P = 0.045). With respect to OS, no significant association was demonstrated in stratified analyses.We concluded that CYP2D6 polymorphisms may influence tamoxifen treatment outcomes of DFS in BC patients.

The aim of this study was to assess among a population of women who had taken adjuvant tamoxifen for 5 years, how many were prepared to enter a randomised trial looking at the duration of tamoxifen treatment and what was the preference of those who declined trial entry. There is uncertainty as to the optimum duration of adjuvant tamoxifen and this is the subject of the aTTom (adjuvant Tamoxifen Treatment offer more?) trial in which patients are randomised to continue or stop tamoxifen after 5 years. Patients have been recruited to the aTTom trial in Dundee since 1996 and a record has been kept of all the patients with whom the trial was discussed. Patients who declined trial entry were allowed to choose whether to electively stop or continue tamoxifen. 306 patients were eligible for trial entry of whom 171 (56%) consented to randomisation (82 to continue and 89 to stop). Amongst the 135 (44%) who declined randomisation, 28 (21%) elected to stop tamoxifen treatment, 90 (67%) elected to continue and in 17 (13%) their decision was unclear. These results illustrate that patients eligible for the aTTom trial share our clinical equipoise. A majority (56%) of patients were agreeable to randomisation, but among those who declined, some (67%) preferred to continue, some (21%) to stop tamoxifen. This trial is unusual in that the patients have already experienced the treatment options, so the patients' preferences reflect a truly informed choice.

Tamoxifen is one of the most commonly used anticancer medications. Hepatic damage secondary to tamoxifen treatment is rare. Tamoxifen-induced multifocal hepatic fatty infiltration has not been reported previously. This report describes one case of steatohepatitis caused by tamoxifen in an elderly woman with a history of breast cancer. The patient had multifocal hepatic fatty infiltration secondary to tamoxifen therapy. After tamoxifen was discontinued, the features of multifocal hepatic fatty infiltration on CT improved dramatically, and hepatic transaminases normalized.

British Journal of Hospital Medicine, July 2013, Vol 74, No 7 371 © 2 01 3 M A H ea lth ca re L td 0.84 during years 7–9 and 0.75 (25% reduction) from 10 years onwards. Longer treatment with tamoxifen also reduced breast cancer deaths, with the benefit again increasing over time to 24% reduction from 10 years. Non-breast-cancer mortality was not affected. Lead author Professor Richard Gray, Professor of Medical Statistics at the University of Oxford, said: ‘This study and its international counterpart ATLAS confirm that there is definitely a survival benefit from longer tamoxifen treatment and many doctors will likely recommend continuing tamoxifen for an extra 5 years.’ Susan Mayor ameriCan soCiety of CliniCal onCology ChiCago, may 30–June 4

The authors con-cluded that older women who are taking tamoxifen mayhave an increased risk of developing diabetes. However,we believe that the article has some shortcomings that canbemisleading.Lipscombeetalhaveproposedthattamox-ifen can result in weight gain, which was one of the sug-gested mechanisms for the increased risk of diabetes inthese patients. However, the article provides no informa-tion regarding the weight of the patients in either groupand the results have not been adjusted for weight that wasproposedasariskfactorfordiabetes,whichisamethodo-logicalweakpointof thestudy.In addition,thesuggestedmechanism does not appear to be true because severalstudieshaveshownthattamoxifenhasnosignificanteffecton weight gain

Purpose: Medical treatment of Peyronie’s disease with tamoxifen has been initially proposed as acting upon the early phase of the disease. As recent reports show no significant benefit of tamoxifen, we review the long term results of tamoxifen treatment of Peyronie’s disease. Materials and Methods: Time to progression during tamoxifen treatment of patients showing acute disease and chronic disease was compared. The acute phase was identified by pain during erection. Progression was defined as enlargement of plaque size or appearance of calcification. Results: The average treatment duration was 15.9±013.8 months (range: 3 to 48 months). The median time to progression was 7 months for acute patients and 20 months for chronic patients. Eighty percent of patients in the acute phase showed relief of pain; however, overall progression was 72.1% (78.0% for acute, 66.7% for chronic). Patient history, comorbidities, serum testosterone or initial plaque characteristics, and severity of curvature were not predictive of disease progression. Conclusions: Tamoxifen showed no significant benefit in slowing the progression of Peyronie’s disease in the acute phase over the chronic phase. Peyronie’s disease continued to progress, though at a dampened rate for patient’s in the chronic phase.

The effects of OK-432 (Picibanil) on estrogen receptor (ER) levels and subsequent tamoxifen (TAM) treatment were examined in 189 female Sprague-Dawley rats with 7,12-dimethylbenz[a]anthracene (DMBA)-induced mammary cancers. When OK-432 was administered (0.1 KE/kg i.p. once weekly) for 12 weeks to the rats after DMBA, the average ER level of the TAM-responsive tumors in the OK-432-treated group was significantly higher than that in the control group. The antitumor effect of TAM was significantly greater in the OK-432-treated group. When OK-432 was administered to rats with established DMBA tumors, the average ER levels did not change significantly after 2 or 4 weeks of treatment. ER levels in the control group (no treatment) fell significantly after 2 or 4 weeks. These results suggest that hormone dependence of DMBA-induced rat mammary cancers may be maintained or augmented by the administration of OK-432.

Treatment with the aromatase inhibitor letrozole after five years of tamoxifen treatment seems to improve disease-free survival in postmenopausal women with primary breast cancer. ![][1] Study participant Kathy Anderson (left) and second author of the research paper Dr James Ingle of the Mayo Clinic in Rochester, Minnesota (right) Credit: AP PHOTO/AARON HARRIS The study, designed to test five years of letrozole treatment after tamoxifen therapy, was discontinued after a median follow up of only 2.4 years because the researchers observed survival benefit in the letrozole group compared with the placebo group. The study is scheduled to … [1]: /embed/graphic-1.gif

To determine the type of endometrial abnormalities associated with prolonged tamoxifen treatment and to investigate the correlation between tamoxifen dose and any abnormalities detected.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.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.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.

Summary: The improvement of impaired spermatogenesis by tamoxifen is well documented. The antiestrogen seems to act via an enhancement of gonadotropin release from the hypophysis, but there is evidence for a direct testicular effect. Thus we studied the serum levels of gonadotropins and steroid hormones in 22 patients with idiopathic oligozoospermia. To study the direct testicular effect, we tested the response of 5 normal males to hCG prior to and after the application of tamoxifen. FSH levels showed a continuous increase in the patients during the three months of treatment, while the stimulation by LH-RH was not altered. In the case of LH the basal as well the stimulated levels increased. Mean levels of testosterone, 17-hydroxyprogesterone, androstenedione and estradiol increased significantly during treatment. Sperm counts of patients were found to be considerably higher after three months. In the normal males no differences in steroid levels as a response to hCG with and without tamoxifen treatment occurred. Our results give evidence, that the hormonal changes occurring under tamoxifen treatment are not due to a direct testicular effect. Zusammenfassung: Die Verbesserung der gestorten Spermatogenese durch Tamoxifen ist gut belegt. Offenbar wirkt dieses Antiostrogen uber eine Steigerung der Gonadotropin-Sekretion aus der Hypophyse, aber es gibt auch Anhaltspunkte fur einen direkten testikularen Effekt. Unter diesem Gesichtspunkt untersuchten wir die Serumspiegel der Gonado-tropine und Steroidhormone bei 22 Patienten mit idiopathischer Oligozoospermie vor und nach der Behandlung mit Tamoxifen. Um den direkten testikularen Effekt zu unter-suchen, bestimmten wir bei 5 gesunden Kontrollpersonen die Blutspiegel androgener Ste-roide in ihrer Reaktion auf hCG vor und nach der Applikation von Tamoxifen. Die FSH-Spiegel bei den Patienten zeigen einen kontinuierlichen Anstieg wahrend der Behandlung, aber die Stimulierbarkeit durch LH-RH ist unverandert. Bei LH werden sowohl basale wie auch stimulierte Werte hoher. Die Mittelwerte von Testosteron, 17–OH–Progesteron, An-drostendion und Ostradiol nehmen wahrend der Behandlung signifikant zu. Die Samen-zelldichte ist nach drei Monaten angestiegen. Bei den Kontrollpersonen sind keine Unter-schiede der Steroidhormonlevel in ihrer Reaktion auf hCG vor und nach der Behandlung zu sehen. Die beobachteten hormonellen Verschiebungen sprechen nicht fur einen direkten testikularen Effekt.