Tamoxifen in liver disease: potential exacerbation of hepatic dysfunction

Tamoxifen, a non-steroidal anti-estrogen, has been used successfully for a decade as post-operative adjuvant therapy for breast cancer. Tamoxifen is generally well tolerated with few side effects, especially at the typical dose of 10 mg twice daily. However, hepatic effects have been reported after tamoxifen administration and are usually found to be cholestatic in nature. Although previous reports concentrate on tamoxifen as a probable cause of drug-induced hepatotoxicity, very little attention has been focused on the use of tamoxifen in patients with pre-existing liver dysfunction and the possible need for dose adjustment. We present the case of a 48-year-old woman with an acute exacerbation of her pre-existing liver dysfunction and subsequent elevations of tamoxifen blood levels after approximately one year of tamoxifen therapy for adjuvant treatment of breast cancer. Tamoxifen dosing was adjusted based on serum levels.     

A case of loco-regional recurrence of carcinoma of the male breast

The case of a 47-year-old man surgically treated with Halsted mastectomy for breast cancer and submitted to Tamoxifen therapy for more than four years is reported. A loco-regional recurrence following withdrawal of oestrogen antagonist therapy was observed and surgically treated by local excision. Normal karyotype analysis of peripheral leucocytes, normal male phenotype of the patient, his height and the lack of family history for breast cancer, as well as a possible dysfunction of the endocrine system were considered in the aetiopathogenesis of the disease.     

Trait anxiety, symptom perceptions, and illness-related responses among women with breast cancer in remission during a tamoxifen clinical trial.

Postmenopausal women with breast cancer in remission (N?=?140) who were participating in a randomized clinical trial of tamoxifen chemoprevention therapy completed measures of trait anxiety, symptoms, cancer worry, and breast self-examinations (BSEs) during the first 6 months of the trial. Trait anxiety was associated with heightened sensitivity to tamoxifen-induced symptoms (but not with tendencies to report increases in symptoms unrelated to tamoxifen use), greater tendencies to attribute symptoms to tamoxifen use, and greater cancer worry. Tamoxifen use increased BSE rates among high-anxiety participants. For low-anxiety participants, tamoxifen use increased cancer worry but not BSE rates. Trait anxiety appears to be associated with vigilant activation of illness-related representations that trigger attentiveness to sensations, worry, and protective coping in response to somatic cues. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Thrombosis of tibial arteries in a patient receiving tamoxifen therapy

BACKGROUND: Tamoxifen has been used extensively as adjuvant therapy in the treatment of pre- and post-menopausal patients with breast cancer. One of its known complications is venous thromboembolism. However, arterial thrombosis has been reported rarely. METHODS: A 49-year-old patient with breast cancer had had a total mastectomy 3 years earlier. She was receiving tamoxifen therapy when she developed a sudden onset of pain and numbness of the left foot and calf. An arteriogram showed thrombosis of her tibial arteries. RESULTS: This thrombosis was lysed successfully with urokinase therapy, and tamoxifen therapy was discontinued. At follow-up 4 months later, the patient had normal circulation to both legs. CONCLUSIONS: Patients receiving tamoxifen should be monitored closely for the development of venous or arterial thromboembolism.     

Coronary Artery Smoking Intervention Study (CASIS): 5-year follow-up

A case of an endometrial polyp which developed in a 74-year-old woman treated with tamoxifen for 15 years after breast cancer surgery was the stimulus for this brief and concise review of the endometrial changes caused by anti-estrogen treatment in post-menopausal women with breast cancer. Tamoxifen therapy has been associated with the development of endometrial polyps, hyperplasia and adenocarcinoma possibly mediated through its agonistic estrogenic properties. Hysteroscopy follow-up should be performed in this group of patients and hysteroscopy should be done before the beginning of therapy and repeated once a year during the treatment.     

Is there a basis for prevention of breast cancer with drugs?

The anti-oestrogen drug tamoxifen has led to one of the most important improvements in therapy for breast cancer patients achieved during the last decades. Tamoxifen reduces risk of relapse and improves survival in women with breast cancer. In addition, tamoxifen has favourable effects on the lipoprotein metabolism, reduces morbidity and death from myocardial infarction, and stabilizes bone density in women after menopause. Owing to the good therapeutic results in breast cancer patients and the additional favourable effects of tamoxifen, studies were started among healthy women with elevated risk of breast cancer. The intention was to examine whether tamoxifen could reduce the risk of breast cancer development in healthy women. Recent studies, however, have demonstrated higher risk of endometrium cancer in breast cancer patients treated with tamoxifen, and higher risk of histological abnormalities in the endometrium in healthy women. Prevention trials, when tamoxifen is given to healthy women, are disputed, owing to the apparent carcinogenic effect of tamoxifen.     

Tamoxifen restores the E-cadherin function in human breast cancer MCF-7/6 cells and suppresses their invasive phenotype

Tamoxifen is an antiestrogen used in adjuvant therapy of breast carcinoma and could potentially prevent the development of mammary cancer. While it is widely clinically used, its exact mechanisms of action are not yet fully elucidated. MCF-7/6 cells are estrogen receptor-positive invasive human breast cancer cells with a functionally inactive cell surface E-cadherin. In this study, we report that tamoxifen, and to a lesser extent its metabolites 4-OH-tamoxifen and N-desmethyltamoxifen, restore the function of E-cadherin in MCF-7/6 cells. In an aggregation assay, 10(-6) M tamoxifen significantly increases the aggregation of MCF-7/6 cells. This effect is abrogated by a monoclonal antibody against E-cadherin (HECD-1), is fast (within 30 min), and does not require de novo protein synthesis. Tamoxifen was also found to inhibit the invasion of MCF-7/6 cells in organ culture. Our data is the first demonstration that tamoxifen can activate the function of an invasion suppressor molecule and suggest that the restoration of E-cadherin function may contribute to the therapeutic benefit of tamoxifen in breast cancer patients.     

Binding characteristics of novel nonsteroidal antiestrogens to the rat uterine estrogen receptors

Tamoxifen (TAM), the only antiestrogen currently available for the endocrine therapy of breast cancer behaves as a mixed agonist/antagonist of estrogen action, thus limiting its therapeutic potential. We report the binding characteristics of a novel series of nonsteroidal antiestrogens to the rat uterine estrogen receptor. As measured by competition studies, the affinity of EM-652, the active metabolite of the prodrug EM-800, for the estrogen receptor is 7-11 times higher than that of 17beta-estradiol (E2), ICI 182780, and hydroxy-tamoxifen (OH-TAM), the active metabolite of Tamoxifen. EM-652 is 20x more potent than ICI 164384 and Droloxifene while it is 400 times more potent than Toremifene in displacing [3H]E2 from the rat uterine estrogen receptor. On the other hand, the prodrug EM-800 and Tamoxifen have respectively 150-fold and 410-fold less affinity for the estrogen receptor than the pure antiestrogen EM-652. No significant binding of EM-652, EM-800, TAM or OH-TAM was observed to the rat uterine progesterone receptor at concentrations up to 10,000 nM except for TAM that caused a 50% displacement of labeled R5020 at 4000 nM. No significant binding of EM-652 or EM-800 was observed on the rat ventral prostate androgen receptor or the rat uterine progesterone receptor. The present data demonstrate the high affinity and specificity of the new antiestrogen, EM-652, for the rat uterine estrogen receptor. The antiestrogen EM-652 thus becomes the compound having the highest known affinity for the estrogen receptor. Due to its unique potency and its pure antiestrogenic activity already demonstrated in many systems, this antiestrogen could well offer an important advance for the endocrine therapy of breast cancer, uterine cancer, and other estrogen-sensitive diseases in women.     

New muscle relaxants

Recurrent bleeding occurred in a premenopausal breast cancer woman during tamoxifen therapy. This bleeding required three curettages. Atypical hyperplasia and carcinoma were excluded, and the patient was prepared for endometrial ablation with two GnRH agonist injections. An endometrial ablation using the roller ball technique was carried out without complications. Tamoxifen therapy was continued postoperatively. During 24 months' follow-up the patient experienced no bleeding and no endometrium was seen by sonography.     

Tamoxifen (antiestrogen) therapy in advanced breast cancer

Fifty-nine postmenopausal women with advanced breast cancer were treated with tamoxifen (antiestrogen), 20 mg orally twice a day for at least 2 months. They had been previously treated with other types of hormonal therapy or intensive chemotherapies, or both. Nineteen of the 59 patients (32%) had either a complete response (seven patients) or partial response (12 patients). The median duration of response was 9+ months. Tumors containing estrogen receptors and those that responded to previous hormonal manipulation tended to respond to tamoxifen (60% and 69%, respectively). Patients with receptor-negative tumor or with a history of failure of previous hormonal treatments did not respond to tamoxifen therapy. Tamoxifen is effective against advanced breast cancer. Side effects of the treatment were mild.     

Current status of endocrine therapy for metastatic breast cancer

Hormonal manipulation is currently the mainstay of palliative care for metastatic breast cancer because it is well tolerated and produces significant responses in approximately one-third of unselected patients. Tamoxifen, a nonsteroidal antiestrogen, is currently considered first-line therapy. Second-line agents include progestins and aromatase inhibitors. New agents, such as the "pure" antiestrogens and the gonadotropin-releasing hormone (GnRH) agonists, are being tested. Other approaches for affecting the hormonal milieu are also under investigation, including combinations of hormonal agents, hormonal agents plus biologics, and hormonal agents plus antiproliferative agents. This review will address the basis for endocrine therapy and possible mechanisms of hormonal resistance, currently available agents and newer ones on the horizon, and areas of future interest.     

Tamoxifen increases the proliferation of human endometrial stromal cells in in vitro. A model for evaluation of endometrial hyperplasia

Tamoxifen given for breast cancer therapy, has a complex and an unclear action on the endometrium. A large number of literatures has attributed the proliferous changes in the endometrium caused by tamoxifen (Tam). No report has appeared on the endometrial cellular changes induced by Tam. The present study shows a significant (P < 0.001) increase in the proliferative activity due to Tam in endometrial stromal cells over control and estradiol (E2). This in vitro model is useful for the study of the hyperplasic effect of Tam at the cellular level.     

Gynecologic effects of tamoxifen and the association with endometrial carcinoma

Tamoxifen has been used as an adjuvant therapy for breast cancer for nearly two decades. The benefits of adjuvant tamoxifen therapy in prolonging disease-free and overall survival have been shown in randomized clinical trials. Despite this, some developing evidence suggests that tamoxifen causes a 2- to 3-fold increase in endometrial cancer. This paper reviews the reports of endometrial carcinoma in tamoxifen-treated patients. Two hundred fifty cases of endometrial carcinoma are reported, but only one case is identified in a premenopausal woman. When documented, 77% (n=127) of the cases are good-grade (grade 1 or 2) and 80% (n=125) are stage-I disease. Since the distribution of good grade (79%) and stage I (74%) from the Surveillance, Epidemiology and End Results (SEER) data are comparable, concerns about more aggressive or late-stage disease appear to be unwarranted. The modest increase in the incidence of early-stage, good-grade endometrial carcinoma described during tamoxifen therapy suggests that it would be unreasonable to institute an aggressive detection strategy of endometrial biopsies. This approach would only lead to further detection bias and would not be cost-effective. Physicians should ensure that patients do not have pre-existing endometrial cancer prior to adjuvant tamoxifen therapy for breast cancer and, furthermore, they should educate patients about signs and symptoms of early endometrial carcinoma and when reported these should be followed up with a gynecologic examination.     

The effects of tamoxifen treatment on the endometrium

OBJECTIVE: To investigate the association between tamoxifen and endometrial cancer. BACKGROUND: Tamoxifen is a nonsteroidal antiestrogenic drug that has been used successfully for 15 years in the treatment of all stages of breast carcinoma. In light of the positive results, several studies are now being conducted to test prolonged tamoxifen treatment as a prophylaxis against breast cancer in high-risk women. Although tamoxifen was thought to have only a few side effects, reports indicate that it is associated with an increased incidence of proliferative and neoplastic changes in the endometrium. As the current trend is to administer tamoxifen for prolonged periods and for more indications, the detrimental effects on the endometrium have vast implications. METHODS: Review of the current literature. RESULTS: Tamoxifen treatment is associated with an increased incidence of proliferative and neoplastic changes in the endometrium, with a 1.3 to 7.5 relative risk of developing endometrial carcinoma. CONCLUSIONS: The results of tamoxifen treatment in breast carcinoma override the risk of developing endometrial carcinoma. Any vaginal bleeding in women treated with tamoxifen should be investigated carefully and promptly. In the future it may be necessary to advise these women to undergo routine uterine cavity examination.     

Interim analysis of the incidence of breast cancer in the Royal Marsden Hospital tamoxifen randomised chemoprevention trial

BACKGROUND: Tamoxifen, a drug with antioestrogenic effects, is predicted to prevent the occurrence of breast cancer. We have undertaken a trial of tamoxifen in healthy women who are at increased risk of breast cancer because of family history. We report a planned interim analysis. METHODS: Between October, 1986, and April, 1996, we accrued 2494 healthy women aged between 30 and 70 with a family history of breast cancer. They have been randomised (double blind) to receive tamoxifen 20 mg per day orally or placebo for up to 8 years. Follow-up included clinical assessment, annual mammography, and assessment of toxicity and compliance. The primary endpoint was the occurrence of breast cancer, which was analysed on an intention-to-treat basis with a survival curve. FINDINGS: With a median follow-up of 70 months, 2471 women (tamoxifen 1238, placebo 1233) were suitable for analysis. The groups were evenly matched at baseline, and compliance was good. The overall frequency of breast cancer is the same for women on tamoxifen or placebo (tamoxifen 34, placebo 36, relative risk 1.06 [95% CI 0.7-1.7], p=0.8). Participants who were already on hormone-replacement therapy when they entered the study had an increased risk of breast cancer compared with non-users. Those participants who started such therapy while on trial had a significantly reduced risk. The safety profile of tamoxifen was as expected. INTERPRETATION: We have been unable to show any effect of tamoxifen on breast-cancer incidence in healthy women, contrary to the report from the NSABP-P1 study showing a 45% reduction in healthy women given tamoxifen versus placebo. Differences in the study populations for the two trials may underlie these conflicting findings: eligibility in our trial was based predominantly on a strong family history of breast cancer whereas in the NSABP trial was mostly based on non-genetic risk factors. The importance of oestrogen promotion may vary between such populations.     

Hormonal treatment of advanced breast cancer

Endocrine therapy for breast cancer has been used for almost a century, but because of the enormous success of tamoxifen there has been a resurgence of interest by the pharmaceutical industry to develop new and innovative endocrine therapies. Overall, the strategy is quite simple. Estrogen stimulates growth; therefore, the goal is to deny the breast tumor estrogens. Tamoxifen accomplishes this by blocking the estrogen receptor. The new antiestrogens, toremifene and droloxifene, however, appear to have no greater activity than tamoxifen in the treatment of advanced disease and therefore may ultimately offer no advantages over current therapy. In contrast, the pure antiestrogens hold additional promise as they may produce a more profound inhibitory effect on the tumor, and the response may be maintained longer. An orally active, pure antiestrogen, however, would be an important advance. The strategy of using GnRH agonists for premenopausal patients clearly has merit to produce a chemical oophorectomy. The strategy could be integrated into the general treatment plan for the young premenopausal patient taking tamoxifen who may not have had her menstrual cycles stopped by combination chemotherapy. The GnRH agonists would block the reflex rise in estradiol caused by tamoxifen therapy and ultimately produce a more efficient antihormonal therapy. Indeed, the different specific aromatase inhibitors can also be integrated into the treatment plan to produce a complete estrogen blockade. Whether the use will be found to be superior to pure antiestrogens, however, must await the completion of comparative clinical studies. If all the results of endocrine therapy are therapeutically similar, the final strategy may depend on the acceptability by the patient of an individual delivery method for each pharmaceutical approach.     

The anthocyanin responsible for purplish blue flower colour of Aconitum chinense

OBJECTIVE: The purpose of this article is to illustrate the regression of breast cancer as seen on mammograms of women treated with tamoxifen. SUBJECTS AND METHODS: Four elderly patients 72-88 years old were diagnosed with breast cancer on the basis of mammographic features. No surgery was performed because of multiple medical problems. Tamoxifen was initiated and the patients were closely monitored with physical examination and mammography for a minimum of 2 years. RESULTS: In all cases, the features of malignancy seen on mammograms regressed. These results were documented by a decrease in the number of calcifications and in the size of spiculated masses. CONCLUSION: These results suggest that tamoxifen, or one of its metabolites, may alter the biochemical nature of breast cancer.     

The Fanconi syndrome of cystinosis: insights into the pathophysiology

The evidence that alcohol consumption increases a woman's chances of getting breast cancer is now more persuasive. Higher blood concentrations of organochlorine compounds were not associated with increased risk of breast cancer in recent studies. The relationship of exogenous estrogen use to breast cancer risk is now clarified: current users of both oral contraceptives and hormone replacement therapy experience a slightly elevated risk that dissipates after cessation of use. Alcohol consumption and hormone replacement therapy are both associated with slightly increased breast cancer risk, but the overall health benefits of hormone replacement therapy and low levels of alcohol consumption appear to outweigh the risks in the general population. These circumstances underscore the complex decisions facing women and the need to consider individual risk factor profiles. For the genes BRCA1 and BRCA2, more data are needed to understand the risks associated with specific mutations, optimal implementation of genetic testing, and prevention and early detection strategies for women who have positive test results. Interesting leads in identifying women at increased risk for breast cancer have been generated via the study of genetic polymorphisms. The results of tamoxifen in the Breast Cancer Prevention Trial have made the possibility of chemoprevention for breast cancer a reality. Raloxifene, another antiestrogen, has emerged as a potential chemopreventive agent. Its efficacy in reducing breast cancer risk will be compared with that of tamoxifen in a randomized trial.     

Effects of an acute exposure to lindane (gamma-hexachlorocyclohexane) on brain and liver carbohydrate metabolism of rainbow trout

The ZR-75-1 ER positive breast cancer cell line, xenografted in female nude mice, has been used to determine the effect of tamoxifen on cell proliferation (as measured by mitosis) and cell death (as evidenced by apoptosis and necrosis). After 2 days treatment, there was a significant rise in apoptosis (p < 0.05), whereas a fall in mitosis was not apparent until 7 days (p < 0.05). Furthermore there was an increase in the apoptotic:mitotic ratio on day 7 (p < 0.05). These changes antedated tumour regression, which did not reach not significance until day 14. Tamoxifen did not increase necrosis (which significantly decreased in treated tumours once they had regressed (p < 0.01). In contrast tamoxifen treatment of xenografted MDA-MB-231 ER-negative breast cancer cells produced no significant effects on growth, apoptosis, or mitosis. This study presents clear evidence for tamoxifen inducing apoptosis in ZR-75-1 xenografts (but not MDA-MB-231 tumours). Since changes in apoptosis and mitosis antedate tumour regression, their assessment may provide the potential by which to predict tumour response to tamoxifen therapy.     

Study of the action of tamoxifen on the mammary gland epithelium of premenopausal patients by lysosome quantification

Tamoxifen is an antiestrogen drug widely utilized for the adjuvant hormonal treatment of breast carcinoma. Its use in the primary prophylaxis of this disease is currently being proposed. Although the drug has few side effects, its precise action on breast tissue that has not undergone neoplastic transformation has not been fully elucidated. This prospective, randomized study assessed the estrogen activity of tamoxifen on the mammary gland epithelium of premenopausal patients using a quantitative analysis of mammary epithelium lysosome identified by the cytochemical technique of GOMORI for acid phosphatase and by light microscopy. Tamoxifen significantly increased the number of lysosomes only during the secretory phase of the menstrual cycle. We concluded that the early effect of the drug on normal mammary tissue is synergistic with the effect of estrogen during the premenopausal period.