Randomized trial of estrogen vs. tamoxifen therapy for advanced breast cancer

Forty-three postmenopausal females with advanced breast cancer were studied in a prospective comparative trial of estrogen vs. an anti-estrogen (tamoxifen) therapy with a crossover to the alternative hormone with progressive disease. Ten of 19 patients (53%) responded to primary tamoxifen therapy and six of 24 (25%) responded to primary estrogen therapy. Crossover responses were observed in seven of 19 (37%) on the secondary tamoxifen therapy and in two of 10 (20%) on secondary estrogen therapy, and were not related to the response to the primary hormonal maneuver. Responses were related to the presence of estrogen receptor protein (ERP), particularly for tamoxifen therapy, although responses were observed in three of six ERP negative patients receiving estrogen and in seven of 25 (28%) of patients with an unknown ERP status. Complications were observed in 35 instances with estrogen therapy and in only five instances with tamoxifen therapy. Initial hormonal therapy with tamoxifen in postmenopausal patients with advanced breast cancer and ERP status positive or unknown is superior to primary estrogen treatment. Secondary therapy and response to estrogen or tamoxifen is not necessarily predicted by the initial hormone response, and crossover to the alternative therapy is generally indicated.     

"Flare" Followed by Successful Tamoxifen Therapy in Two Cases of Advanced Breast Cancer

An antiestrogen, tamoxifen, is an effective drug in the treatmentof advanced breast cancer. The drug is generally very well toleratedand serious side effects such as the so-called "flare in thetumor" have rarely been observed. We have had two patients withadvanced breast cancer who showed the "flare" soon after theinitiation of tamoxifen therapy, and both patients finally achievedpartial response to tamoxifen. It is important not to misinterpretthe "flare" as progressive disease during tamoxifen therapy.     

To switch or not to switch: should the updated Intergroup Exemestane Study alter our decision?

Adjuvant therapy for breast cancer with aromatase inhibitors improves survival compared with tamoxifen; however, whether they should be given upfront or sequentially after 2-3 years of tamoxifen in estrogen receptor-positive early breast cancer affecting postmenopausal women is unclear. The Intergroup Exemestane Study looked at 4724 postmenopausal patients with estrogen receptor-positive or unknown breast cancer who had been disease free for 2-3 years on tamoxifen and were randomly assigned to switch to exemestane or to continue tamoxifen for the remainder of a 5-year endocrine treatment period. A significant disease-free survival advantage (p = 0.0001) was seen in favor of exemestane, with an absolute benefit of 3.3% by the end of treatment. This trial is the first to show an overall survival advantage for switching in estrogen receptor-positive breast cancer (p相似文献   

The impact of PTEN tumor suppressor gene on acquiring resistance to tamoxifen treatment in breast cancer patients

Tamoxifen is a standard therapeutical treatment in patients with estrogen receptor positive breast carcinoma. However, less than 50% of estrogen receptor positive breast cancers do not respond to tamoxifen treatment whereas 40% of tumors that initially respond to treatment develop resistance over time. The underlying mechanisms for tamoxifen resistance are probably multifactorial but remain largely unknown. The primary aim of this study was to investigate the impact of PTEN tumor suppressor gene on acquiring resistance to tamoxifen by analyzing loss of heterozygosity (LOH) and immunohystochemical expression of PTEN in 49 primary breast carcinomas of patients treated with tamoxifen as the only adjuvant therapy. The effect of PTEN inactivation on breast cancer progression and disease outcome was also analyzed. Reduced or completely lost PTEN expression was observed in 55.1% of samples, while 63.3% of samples displayed LOH of PTEN gene. Inactivation of PTEN immunoexpression significantly correlated with the PTEN loss of heterozygosity, suggesting LOH as the most important genetic mechanism for the reduction or complete loss of PTEN expression in primary breast carcinoma. Most importantly, LOH of PTEN and consequential reduction of its immunoexpression showed significant correlation with the recurrence of the disease. Besides, our study revealed that LOH of PTEN tumor suppressor was significantly associated with shorter disease free survival, breast cancer specific survival and overall survival. In summary, our results imply that LOH of PTEN could be used as a good prognostic characteristic for the outcome of breast cancer patients treated with tamoxifen.     

Long-term adjuvant tamoxifen therapy for breast cancer

Tamoxifen (ICI46,474) is a competitive inhibitor of estrogen action which has found ubiquitous application in the treatment of breast cancer. The drug is the front line endocrine therapy for breast cancer and is the proven treatment of choice for the adjuvant therapy of postmenopausal women with node-positive disease. Tamoxifen is available for the treatment of premenopausal patients with advanced disease, and is being evaluated in clinical trials as an adjuvant therapy for premenopausal patients with either node-positive or node-negative disease. Laboratory studies demonstrate that tamoxifen is a tumoristatic agent and long-term treatment strategies (chemosuppression) should be considered to apply the antiestrogen to its maximal therapeutic advantage. Optimal therapy with tamoxifen may also be achieved by treatment strategies to lower circulating estrogen levels in the premenopausal patient.Tamoxifen is a well tolerated drug, and long-term therapy does not appear to induce metabolic tolerance. Concerns about premature osteoporosis or cardiovascular disease appear to be unfounded because tamoxifen has an appropriate level of target site-directed estrogenic activity. Isolated reports about the growth or appearance of endometrial carcinoma during long-term adjuvant tamoxifen therapy must be balanced against the risks of withholding treatment to patients with a fatal disease.     

Treatment of advanced breast cancer with megestrol acetate after therapy with tamoxifen

The efficacy of megestrol acetate in the treatment of advanced (Stage IV) carcinoma of the breast was studied in 48 evaluable patients who had been initially treated with tamoxifen. Forty-five patients had previously responded to the tamoxifen therapy. Fifteen patients (31%) had partial remissions, sixteen patients (33%) had stable disease, and seventeen patients (36%) had progressively disease. The median response duration was seven months for responding patients and six months for disease-stable patients. These results suggest that megestrol acetate is an effective agent for the palliation of advanced breast cancer relapsing following response to tamoxifen therapy.     

“Studies on the estrogen receptor in breast cancer” — 20 years as a target for the treatment and prevention of cancer

Summary In 1973, McGuire and Chamness (In: O'Malley BW and Means AR (eds) Receptors for Reproductive Hormones, Plenum Press) summarized their work on the estrogen receptor in animal and human breast tumors, and in so doing described a target for therapeutic intervention. At that time there were no clinically useful antiestrogens, but the subsequent development of tamoxifen for breast cancer therapy has revolutionized the approach to treatment. Long-term adjuvant tamoxifen adjuvant therapy (i.e. greater than one year) has proven efficacy to enhance the survival of breast cancer patients. In addition, because there is an associated 40% decrease in contralateral breast cancer during adjuvant tamoxifen therapy and tamoxifen maintains bone density and reduces fatal myocardial infarction, clinical trials to test the worth of tamoxifen as a preventive for breast cancer in high risk women have started in the United States, United Kingdom, and Italy. Initial concerns that long-term tamoxifen causes endometrial cancer have been placed in perspective and analyzed by a review of the literature. Tamoxifen only doubles the normal risk of detecting endometrial cancer, (i.e. to 2 per 1,000 tamoxifen-treated women per year), and 80% of these cases are early stage, good prognosis disease. Annual gynecological examinations and education are essential to provide reassurance for patients.The success of tamoxifen has encouraged the development of new antiestrogens to exploit the estrogen receptor as a therapeutic target. Droloxifene and TAT-59 mimic the metabolite 4-hydroxytamoxifen in having a high affinity for the estrogen receptor (Jordan et al, J Endocrinol 75:305, 1977). These drugs appear to have a pharmacological profile similar to tamoxifen. In contrast, the new pure antiestrogens have a distinct mechanism of action and will be valuable either as a first line therapy for advanced breast cancer or as a second line endocrine therapy after the failure of long-term adjuvant tamoxifen therapy.Finally, a new strategy is being developed to exploit the target site specific action of antiestrogens. Raloxifene, an antiestrogen with high affinity for the estrogen receptor but only weak estrogenicity for the uterus, prevents rat mammary tumorigenesis and maintains bone density. The drug is to be evaluated as a treatment for osteoporosis, but may also prevent the development of breast and endometrial cancer in a broad group of treated subjects.The identification of the estrogen receptor as a target for therapeutic opportunities has proved to be extremely beneficial for the control of breast cancer and has the added potential to control osteoporosis and coronary heart disease in women.Presented at the 17th Annual San Antonio Breast Cancer Symposium. The William L. McGuire Memorial Lectures are sponsored by an educational grant from Wellcome Oncology.     

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 estrogen-like activities in postmenopausal women and causes a preservation of bone in the lumbar spine and a 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.(ABSTRACT TRUNCATED AT 400 WORDS)     

Current status of endocrine treatment of carcinoma of the breast

Sequential administration of endocrine therapies can result in objective remission in a significant fraction of patients with metastatic breast cancer. Combined hormonal therapies and combined hormonochemotherapies have not resulted in better results than the sequential administration of these same therapies. Tamoxifen (an antiestrogen) given as an initial therapy results in local control of the disease in a significant fraction of patients with locally advanced breast cancer who are not candidates for cytotoxic therapy. Tamoxifen as an adjuvant therapy for operable breast cancer prolongs disease-free survival and reduces mortality in patients greater than 50 yr of age with higher estrogen receptor concentrations. The role of tamoxifen as adjuvant therapy for patients less than 50 yr of age remains unclear. Also, adjuvant tamoxifen in combination with cytotoxic drugs has not produced superior results, and the duration of adjuvant tamoxifen therapy remains to be determined. Experimental data suggest prolonged administration of tamoxifen may be needed to control micrometastases.     

Role of anti-aromatase agents in postmenopausal advanced breast cancer

PURPOSE: Endocrine therapy is a well-recognized approach to the treatment of postmenopausal patients with advanced breast cancer, particularly those with estrogen receptor-positive tumors. The availability of anti-aromatase agents, both reversible (nonsteroidal) and irreversible (steroidal), provides clinicians with additional hormonal treatment options. METHODS: A MEDLINE search was conducted to identify studies that evaluated anti-aromatase therapy in the treatment of postmenopausal women with advanced breast cancer. In selecting studies, priority was given to randomized, controlled trials. RESULTS: Tamoxifen is the standard first-line therapy for advanced breast cancer. However, recent results have demonstrated the efficacy of newer anti-aromatase agents in this setting. Among patients who have progressed after tamoxifen therapy, anti-aromatase agents have emerged as first choice therapy based on their better tolerability and improved efficacy compared with megestrol acetate. Exemestane and anastrozole (irreversible and reversible anti-aromatase agents, respectively) have demonstrated survival benefits over megestrol acetate in second-line therapy. Anti-aromatase agents have also demonstrated efficacy in patients who have failed multiple hormonal therapies. Based on these data, an algorithm for the treatment of postmenopausal women with advanced breast cancer is proposed. CONCLUSIONS: The enhanced tolerability and superior efficacy of anti-aromatase inhibitors compared with megestrol acetate has resulted in these agents becoming the endocrine treatment of choice for women with advanced breast cancer who have progressed after tamoxifen treatment. The increased use of tamoxifen in the adjuvant setting and the demonstrated activity of aromatase inhibitors in first-line therapy will further increase the role of these agents.     

Optimizing the antihormonal treatment and prevention of breast cancer

The incidence of breast cancer is rising throughout the world. Breast cancer is slowly becoming more prevalent in countries which previously had low rates of cancer as well as becoming a leading cause of cancer death in some countries. Fortunately, a large number of these tumors are estrogen receptor (ER) positive and respond to anti-hormonal adjuvant therapy which until recently has been 5 years of tamoxifen treatment. Unfortunately, a significant number of patients develop recurrent cancers and the recurrent tumors are resistant to tamoxifen treatment. In addition, because of tamoxifen's selective estrogenic actions, there have been reports of venous thrombosis, endometrial cancer, and strokes in patients receiving tamoxifen therapy. Thus, there are other novel therapies such as aromatase inhibitors that block estrogen production in postmenopausal women or fulvestrant that destroys the estrogen receptor. This paper will summarize the therapeutic options for anti-hormonal therapy, the role of anti-hormonal agents in advanced breast cancer, and adjuvant therapy and the current status of chemoprevention with selective ER modulators.     

Drug resistance to tamoxifen during breast cancer therapy

Summary Breast cancer is the most common malignancy occurring in Western women, and is one of the leading causes of cancer mortality. The nonsteroidal antiestrogen tamoxifen has been shown to be an effective treatment for pre and postmenopausal women with all stages of the disease. Tamoxifen provides effective palliation when used to treat patients with advanced disease, and adjuvant tamoxifen therapy produces significant increases in both disease-free and overall survival (Early Breast Cancer Trialists Collaborative Group. Lancet 339:1-15, 71-85, 1992). Data from the laboratory have shown that the primary action of tamoxifen is tumoristatic rather than tumoricidal, and long-term therapy is therefore recommended. Unfortunately, many patients experience disease progression while taking tamoxifen. Some tamoxifen resistant tumors may remain sensitive to alternative endocrine therapies, while others may become refractory to any hormonal manipulation. Many models have been developedin vitro andin vivo to study the progression of breast cancer growth from tamoxifen sensitive to tamoxifen resistant. We and others have used long-term estrogen deprivation and long-term tamoxifen exposure to develop cell lines and tumors capable of growth in the presence of clinically relevant tamoxifen concentrations. Recently our laboratory has also shown that mutations in the estrogen receptor can cause an antiestrogen-occupied receptor to behave as though it were occupied by an estrogen. Breast cancer is a highly heterogeneous disease and it is likely that the mechanisms which cause tamoxifen resistant growth are equally heterogeneous. Several of the models from our laboratory and others which may contribute to an understanding of this complex phenomenon are discussed here.     

Current status of endocrine therapy for breast cancer

Endocrine therapy is usually indicated prior to chemotherapy as the first line therapy for metastatic breast cancer patients because of its milder toxicity. Patients who respond to a first-line endocrine therapy have a high chance of responding to a second-line endocrine therapy, and thus the responders to a first-line endocrine therapy would better be treated with second or third-line endocrine therapy. In the adjuvant setting, tamoxifen (antiestrogen) has been proven to improve the prognosis of both pre- and postmenopausal estrogen receptor positive breast cancer patients, and goserelin (LH-RH agonist) has been proven to improve prognosis in premenopausal women comparable to chemotherapy (CMF). Very recently, preliminary results have indicated that anastrozole (aromatase inhibitor) is superior to tamoxifen as adjuvant treatment for estrogen receptor positive postmenopausal breast cancer patients. In addition, the recent success of tamoxifen in a chemoprevention trial seems to have ushered in a new era wherein prevention of breast cancer is much more emphasized than treatment of established breast cancer.     

Phase I/II study of the anti-oestrogen zindoxifene (D16726) in the treatment of advanced breast cancer. A Cancer Research Campaign Phase I/II Clinical Trials Committee study

We report a phase I/II study of the indole derivative, zindoxifene, an anti-oestrogen with intrinsic oestrogenic activity. We have treated 28 women with advanced breast cancer of whom 26 had received prior endocrine therapy. Oral zindoxifene doses ranged from 10 to 100 mg daily; doses were escalated in some patients. Twenty-five patients were assessed for response; the remaining three patients completed less than 3 weeks of treatment. There were no objective responses; disease stabilised in seven patients for up to 5 months and progressed in the remaining 18. Five patients (including three treated with tamoxifen) responded to subsequent endocrine therapy. Nausea, which was dose-limiting, affected half of the patients treated with 80 mg daily. Metabolites of zindoxifene were detectable in serum at all doses used, and sex hormone binding globulin (SHBG) levels showed a strong tendency to rise at the higher doses, indicating that zindoxifene is absorbed and has biological activity. We conclude that zindoxifene in the doses used in this study has only marginal therapeutic activity in the treatment of advanced breast cancer.     

激素受体阳性晚期乳腺癌内分泌治疗选择

激素受体阳性乳腺癌占所有乳腺癌的70%。内分泌治疗是这个亚型乳腺癌的主要治疗手段,最常见药物有他莫昔芬和芳香酶抑制剂如阿拉曲唑、来曲唑和依西美坦。全文重点总结新型内分泌治疗药物,如雌激素受体降解剂(Fulvestrant),以及新的靶向药物如mTOR抑制剂(Everolimus)、CDK4/6抑制剂(Palbociclib、Ribociclib和Abemaciclib)和PI3K抑制剂(Alpelisib、Buparlisib和Pictilisib)等。新的靶向药物联合内分泌治疗已经改变了临床实践,延长激素受体阳性晚期乳腺癌患者的生存期。     

Superior efficacy of letrozole versus tamoxifen as first-line therapy for postmenopausal women with advanced breast cancer: results of a phase III study of the International Letrozole Breast Cancer Group.

PURPOSE: To compare the efficacy and tolerability of tamoxifen with that of letrozole, an oral aromatase inhibitor, with tamoxifen as first-line therapy in postmenopausal women with advanced breast cancer. PATIENTS AND METHODS: Nine hundred seven patients were randomly assigned letrozole 2.5 mg once daily (453 patients) or tamoxifen 20 mg once daily (454 patients). Patients had estrogen receptor- and/or progesterone receptor-positive tumors, or both receptors were unknown. Recurrence during adjuvant antiestrogen therapy or within the following 12 months or prior endocrine therapy for advanced disease precluded enrollment. One prior chemotherapy regimen for metastatic disease was allowed. The primary end point was time to progression (TTP). Secondary end points included overall objective response rate (ORR), its duration, rate and duration of clinical benefit, time to treatment failure (TTF), overall survival, and tolerability. RESULTS: TTP was significantly longer for letrozole than for tamoxifen (median, 41 v 26 weeks). Treatment with letrozole reduced the risk of progression by 30% (hazards ratio, 0.70; 95% confidence interval, 0.60 to 0.82, P =.0001). TTP was significantly longer for letrozole irrespective of dominant site of disease, receptor status, or prior adjuvant antiestrogen therapy. Similarly, TTF was significantly longer for letrozole (median, 40 v 25 weeks). ORR was higher for letrozole (30% v 20%; P =.0006), as was the rate of clinical benefit (49% v 38%; P =.001). Survival data are currently immature and not reported here. Both treatments were well tolerated. CONCLUSION: Letrozole was significantly superior to tamoxifen in TTP, TTF, ORR, and clinical benefit rate. Our results support its use as first-line endocrine therapy in postmenopausal women with advanced breast cancer.     

Prognostic Significances of Estrogen and Progesterone Receptors in Primary Operable Breast Cancer

Both estrogen and progesterone receptors have been determinedin 613 primary breast cancer patients treated by radical mastectomy.At the cut-off value of 5 fentomoles (fmol) cytosol pro-tein/mgfor both receptors, patients with estrogen or progesterone receptor-positivebreast cancer showed significantly favorable disease-free, overalland post-recurrence survival curves to those of receptor-negativebreast cancer patients. In the patient subgroups: premenopausal,stage III, more than four positive lymph node metastases, postoperativeadjuvant tamoxifen therapy, a significantly favorable prognosiswas recognized in either estrogen or progesterone receptor-positivepatients. Both receptors are thought to be useful prognosticindicators for patients with advanced tumors or for those receivingpostoperative adjuvant tamoxifen therapy. When the cut-off valuewas changed, the maximum significant difference in prognosisbetween receptor-positive and receptor-negative patients wasobserved at 5 fmol cytosol protein/mg for the estrogen receptoror 10 fmol/mg cytosol protein for the progesterone receptor.A more detailed examination should be made on the cut-off valuesof both receptors.     

Aromatase Inhibitors

Endocrine treatment is at the core of therapies against early and advanced breast cancer. Modulators of the estrogen receptor have monopolized the field, offering durable clinical responses with an excellent tolerability profile. The benefits of endocrine therapy, however, are limited to estrogen receptor positive patients. A newer class of drugs, the aromatase inhibitors, have gradually emerged as an alternative endocrine therapy. The advent of third-generation aromatase inhibitors, also known as selective aromatase inhibitors (SAIs), has revolutionized the treatment options available to clinicians and patients. Their potency, increased specificity and overall efficacy have established them as second-line hormonal agents, thus replacing megestrol acetate. A number of large randomized clinical trials have looked into their potential role as first-line agents in advanced breast cancer. These data illustrate that both anastrozole and letrozole have better antitumor activity and better tolerability profiles compared to tamoxifen. In addition, the initial results of a large adjuvant trial of anastrozole versus tamoxifen showed that patients treated with anastrozole had significantly fewer disease recurrences compared with tamoxifen. The overall tolerability profile of anastrozole was also favorable compared to tamoxifen. This review will focus on the latest available clinical data on SAIs as well as the ongoing clinical trials exploring the role of SAIs in the adjuvant setting.     

Aromatase inhibitors for breast cancer: proven efficacy across the spectrum of disease

For more than 100 years, hormonal therapy has been known to be effective in the treatment of breast cancer. Initially, this therapy was dominated by the selective estrogen receptor antagonists such as tamoxifen. Aromatase inhibitors (AIs) are a distinct drug class with demonstrated activity in the treatment of hormone-sensitive breast cancer. All 3 third-generation AIs, exemestane, anastrozole, and letrozole, have been studied in multiple lines of therapy in advanced breast cancer and have demonstrated equivalence or superiority compared with tamoxifen. While initially developed as a treatment option for advanced disease, the AIs have also shown efficacy in the treatment of curable disease, including the neoadjuvant and adjuvant settings. In addition, the AIs demonstrate a tolerable side effect profile in comparison with tamoxifen, and this has led to their early incorporation as standard of care therapy. Given the proven efficacy of AIs across the spectrum of breast cancer, the remaining questions include definitive sequencing strategy, timing, and duration of use. Ongoing trials include head-to-head comparisons between the AIs in early-stage breast cancer; the results of these trials are eagerly anticipated and should further optimize the use of AIs.