Role Of Tamoxifen Research Articles

Tamoxifen's role in chemoprevention of breast cancer: An update

Tamoxifen is an oral antiestrogen first used in metastatic breast cancer in the early 1970s. Large clinical trials were initiated in the late 1970s and early 1980s to test the drug's role as adjuvant therapy in early stage breast cancer. Observations of marked decreases in the development of contralateral breast cancer among tamoxifen recipients suggested potential for the drug in chemoprevention of breast cancer, and a large clinical trial to test the efficacy of tamoxifen in prevention of invasive breast cancer among women at increased risk was implemented in the United States in 1992. This paper reviews the rational for the clinical studies of tamoxifen as a chemopreventive agent for breast cancer and summarizes new information that has contributed to our understanding of tamoxifen's actions at the molecular and clinical levels. Current knowledge about the drug's mechanism of estrogenic and antiestrogenic action and its beneficial effects on blood lipids and bone metabolism will be presented. Recent research findings about DNA adduct formation and hepatic lesions, tamoxifen-associated gynecologic conditions, and the occurrence of second primary cancers in other organ systems will also be discussed.

Management of ductal carcinoma in situ.

Ductal carcinoma in situ (DCIS) is an early, localized stage of breast carcinoma that has an excellent prognosis when it is properly treated. The significant increase in the frequency of diagnosis of DCIS in recent years is the result of both better recognition of DCIS among pathologists and widespread use of screening mammography. Multicentricity, bilaterality and histologic subtype are important considerations in the management of this disease. The clinical presentation of DCIS is the presence of either a palpable mass or a mammographic abnormality, most frequently in the form of an area of microcalcifications. For several decades, total mastectomy was considered the appropriate treatment for DCIS, and it should still be considered the standard to which more conservative forms of treatment must be compared. Breast conservation surgery has been used with increasing frequency in the treatment of DCIS but the adequacy of this approach remains subject to controversy. Segmental mastectomy alone may be applied with caution in carefully selected patients, while the rest of the patients undergoing breast conservation surgery should be treated with breast irradiation. Axillary node dissection is generally considered unnecessary in the treatment of DCIS. There is no role for adjuvant chemotherapy in the management of this disease. The role of tamoxifen in the treatment of DCIS is not clearly defined and it should be given only to patients enrolled in clinical trials. Ongoing research should clarify the controversies surrounding DCIS and enable us to define the optimal management for this disease.

Tamoxifen as adjuvant therapy in breast cancer. Current status.

Tamoxifen retains its place as the most important drug in the management of human breast cancer. As time passes, it becomes clear that this drug is no longer to be regarded as a simple antiestrogen, since it modifies other cellular signalling mechanisms, giving scientific credence to the growth inhibitory effects observed in estrogen receptor-negative tumours. With the role of tamoxifen in breast cancer being well documented, recent interest has concentrated on its now proven efficacy in adjuvant treatment of patients with the disease in its early stages, and on its prophylactic role in women at high risk of developing the disease. For tamoxifen to have any role at all in the latter situation, it must be demonstrably safe, and here again the toxicity profile is now much better understood.

Tamoxifen and breast cancer???from palliation to prevention

Tamoxifen, a synthetic antiestrogen, has been used in the treatment of all stages of breast cancer. The National Surgical Adjuvant Breast and Bowel Project (NSABP) is now in the process of evaluating the role of tamoxifen in the prevention of breast cancer (NSABP P-1 trial). Beneficial effects of tamoxifen in reducing coronary artery disease and preventing bone fractures in postmenopausal women will also be examined. Adjuvant therapy trials conducted during the 1980s provided extensive data on the biologic and possibly toxic effects of tamoxifen. These trials laid the groundwork to support the benefits and risks of the present preventional trial. The NSABP P-1 trial population of 16,000 participants will consist of women > or = 60 years of age and women 35-39 years old who are at increased risk for developing breast cancer. Nursing will play an important role in educating the public and counseling possible trial participants. Nurses monitoring the progress of this trial may witness the use of tamoxifen therapy come full cycle--from a palliative agent used in advanced breast cancer to a therapeutic agent that prevents the development of breast cancer.

The role of tamoxifen (T) in association with chemotherapy in metastatic melanoma (MM)

Zampino, M. G.; Zilembo, N.; Nolé, F.; Belli, F.; Santinami, M.; Bajetta, E. Author Information

Assessing the cost effectiveness of adjuvant therapies in early breast cancer using a decision analysis model

We have developed a decision analysis model that uses the results of available randomized controlled trials to model the natural history of early breast cancer and assess the potential clinical and financial effects of using adjuvant therapies. The original model was used to assess the impact of chemotherapy in hypothetical groups of 45-year-old and 60-year-old node-negative, estrogen receptor-negative women. Using the 1992 Early Breast Cancer Trialists' Collaborative Group report, we have expanded and revised the model to assess: 1) the role of tamoxifen alone, chemotherapy alone, or combined therapy in pre-menopausal women, and 2) chemotherapy in elderly women with node-negative, estrogen receptor-negative cancer. For pre-menopausal women, we found that chemotherapy increases quality adjusted life expectancy and survival by a substantial amount at a cost less than most accepted medical interventions. Combined therapy is beneficial and cost-effective in estrogen receptor-positive cancer. For the elderly, chemotherapy prolongs survival but to a lesser extent compared to younger women. The cost of this benefit is high but within the range of commonly reimbursed procedures for women under age 75 without other co-existing conditions. For most patients some form of adjuvant therapy is beneficial and cost-effective. The model builds upon the data derived from collaborative efforts assessing the effectiveness of adjuvant therapies. The model highlights the need for an equal commitment to assessing the economic and quality of life impacts of breast cancer treatments.

Enhancement of radiosensitivity by tamoxifen in C6 glioma cells.

The antiestrogen drug tamoxifen, which is used extensively in the treatment of breast cancer, has also been reported to inhibit the proliferation of some estrogen receptor-negative cell lines, including malignant glioma in vitro. To explore the possible role of tamoxifen in the treatment of malignant glioma, we have investigated its effects on cell growth and radiosensitivity in C6 glioma cells using a colony-forming assay and a tetrazolium-formazan growth rate assay. Pretreatment of C6 cells with tamoxifen resulted in dose-dependent inhibition of cell growth and enhancement of the antitumor effects of ACNU and irradiation. The radiosensitivity of the treated cells was enhanced by the administration of 5 mumol/L of tamoxifen either before and during irradiation or continuously before, during, and after irradiation [37% survival dose (Do) = 2.68 +/- 0.19 and 2.64 +/- 0.04 Gy, respectively, P < 0.01)], as compared with controls (Do = 3.79 +/- 0.25 Gy). In addition, protein kinase C activity was also inhibited by tamoxifen at the concentration in which the radiosensitivity was augmented in C6 cells. Taken together, our results demonstrate a synergistic effect of tamoxifen with radiation on intracellular damage in C6 glioma cells, which may in part be due to the inhibition of protein kinase C, suggesting that tamoxifen serves as a useful agent in combination therapy of glioma.

The role of tamoxifen in the treatment and prevention of breast cancer

Tamoxifen is a nonsteroidal antiestrogen that has found successful applications for each stage of breast cancer in the treatment of selected patients. Tamoxifen was originally introduced for the treatment of advanced disease in postmenopausal women; however, the drug is now also available for the palliative treatment of premenopausal women with estrogen receptor (ER) positive disease. The proven efficacy of tamoxifen and the low incidence of side effects made the drug an ideal agent to test as an adjuvant therapy for women with node-positive breast cancer. Laboratory studies indicate that long-term treatment schedules may provide maximal benefit in preventing recurrence, and recent analysis of clinical trials demonstrates that between 2 and 5 years of adjuvant tamoxifen therapy provides a survival advantage for postmenopausal women with node-positive disease. Similarly, adjuvant studies in node-negative breast cancer have demonstrated an increase in the disease-free survival of both pre- and postmenopausal patients with ER-positive tumors. However, the extended use of tamoxifen has raised questions about the long-term safety of antiestrogen therapy. Of special concern is the impact of tamoxifen on ovarian function in premenopausal women and the potential risks to the fetus if pregnancy occurs. Fortunately, there are no reports about the teratogenicity of tamoxifen in the human, but it is important that physicians counsel women about the risk of pregnancy. Tamoxifen should not be used if a patient is pregnant. Initial concerns that the long-term administration of an antiestrogen would increase bone loss and increase the risks of coronary heart disease appear to be unwarranted. Tamoxifen has some estogen-like activities in postmenopausal women and causes a preservation of bone in the lumbar spine and decrease in circulating cholesterol. Indeed, a reduction in fatal myocardial infarction (MI) has been noted during 5 years of tamoxifen therapy, possibly the direct result of a prolonged reduction in circulating cholesterol. However, the estrogen-like qualities of tamoxifen that could be valuable as a hormone replacement therapy for all postmenopausal women following a diagnosis of breast cancer may also increase the risk for developing endometrial carcinoma. To date, there are only a few reports of endometrial carcinoma being diagnosed during adjuvant therapy with tamoxifen; however, any instances of uterine bleeding or spotting should be followed up with an endometrial biopsy. There are some concerns about large doses of tamoxifen promoting liver cancer in rats. These results are of particular concern if tamoxifen is to be used as a preventive in normal women. However, tamoxifen is acting as a weak estrogen in the rat model, and other estrogens (eg, conjugated estrogens and estrogens used in oral contraceptives) are much more potent promoters of liver cancer. There are no reports of an increased incidence of hepatocellular carcinoma during long-term tamoxifen therapy; in fact, there is a report of the use of tamoxifen to treat the disease successfully. The estrogen-like properties of tamoxifen may encourage clones of breast cancer cells to grow in response to the drug. This form of drug resistance has been described in the laboratory, and a new pure antiestrogen is being evaluated for use as a second-line agent following the failure of long-term adjuvant tamoxifen therapy. The extensive clinical experience with tamoxifen has encouraged its evaluation as a preventive in women at risk of developing breast cancer. Several clinical studies are being positioned in different countries to address this question. All the laboratory studies demonstrate that tamoxifen will prevent or suppress mammary cancer, and clinical experience has shown a 40% reduction in the incidence of second primary breast cancers. The completion of randomized prevention trials with tamoxifen will place a valuable medical option in the hands of the physician who treats women at risk for breast cancer.

Adjuvant systemic therapy for early breast cancer

Systemic therapy (chemotherapy or hormonal therapy) as an adjuvant to modalities of local control is now an integral part of the management of almost all patients with primary breast cancer metastatic to axillary lymph nodes. In addition, recent data suggest an expanding role for such treatments in patients without axillary involvement. Although some node-negative patients should probably not receive adjuvant therapy, the precise criteria to be used for selection are still under active discussion in the literature. Of the two types of systemic treatment, it is generally accepted that chemotherapy is indicated for premenopausal patients and that tamoxifen is useful for postmenopausal patients whose tumors contain estrogen or progesterone receptors. The recent analysis of several studies has suggested that chemotherapy may add to the benefits of tamoxifen in some postmenopausal patients as well. A possible role for tamoxifen in younger patients is being evaluated. For patients at relatively low risk of systemic relapse (i.e., those with zero to three involved axillary lymph nodes), no chemotherapy regimen has yet shown an advantage over 6 months of cyclophosphamide, methotrexate and 5-fluorouracil. For patients at high risk, however, doxorubicin-based regimens have demonstrated benefits. High-dose chemotherapies, some involving autologous bone marrow support, are being investigated for patients with ten or more involved nodes who are at very high risk of the eventual development of stage IV disease.

Tamoxifen in premenopausal patients with metastatic breast cancer: a review.

The antiestrogen tamoxifen is the most widely used hormonal therapy for breast cancer. The drug exerts its antiproliferative effects primarily through estrogen receptor (ER)-mediated mechanisms, although other cellular actions may augment tumor inhibition. Clinically, tamoxifen has been less well studied in premenopausal than in postmenopausal patients. The drug has complex endocrine effects that are dependent on the treatment duration and dose, menopausal status, and target organ. In postmenopausal women receiving tamoxifen, serum estrogen levels remain low, and the normally elevated gonadotropin levels decrease. In contrast, serum estrogen levels are strikingly elevated in many premenopausal women, and gonadotropin concentrations are either unchanged or slightly increased. Large systematic trials in metastatic breast cancer have established tamoxifen as the recommended hormonal therapy for postmenopausal women with ER-positive tumors. Tamoxifen is also an active agent for premenopausal metastatic disease, and response rates are comparable to those reported for oophorectomy. Clinical experience with tamoxifen in this younger age group, however, is more limited. Few premenopausal women (less than 400) have been included in phase II and phase III trials. Two randomized trials (total of 160 patients) comparing oophorectomy with tamoxifen do not definitively establish therapeutic equivalence, and a survival advantage for either treatment cannot be excluded. Many questions remain concerning the appropriate role for tamoxifen in premenopausal patients. Still, tamoxifen has an attractive toxicity profile, and it offers a favorable therapeutic alternative for premenopausal women with ER-positive metastatic breast cancer who wish to avoid surgical or radiation castration.

Breast cancer prevention with tamoxifen: The role of tamoxifen in the prevention of breast cancer

Breast cancer prevention with tamoxifen: The role of tamoxifen in the prevention of breast cancer

The Role of Tamoxifen in Breast Cancer, Vol. 23 in Series

The Role of Tamoxifen in Breast Cancer, Vol. 23 in Series

Tamoxifen inhibition of an in vitro oestradiol-induced surface coat change on mouse blastocysts.

1. Eighty-nine hour post-coitus mouse blastocysts cultured in the presence of oestradiol-17beta underwent a histochemically detectable surface coat change. 2. Tamoxifen was found to inhibit this in vitro-induced change. The role of Tamoxifen as an inhibitor of implantation is discussed.