Recent perspectives of endocrine therapy for breast cancer

The choice of endocrine therapy for breast cancer depends on the menopausal status and stage of disease. Endocrine therapy remains the first choice and most important component in the treatment of hormone sensitive non-life threatening advanced breast cancer. In premenopausal women with metastatic disease, the combination of a luteinizing hormone-releasing hormone (LH-RH) agonist plus tamoxifen is reasonable as first-line endocrine therapy. In postmenopausal patients with recurrent disease progressing after or during adjuvant tamoxifen, third-generation aromatase inhibitors (AIs) are the preferred first-line endocrine treatment. Many premenopausal and postmenopausal women with hormone responsive breast cancer benefit from sequential use of endocrine therapies at the time of disease progression. Recent clinical trials designs have been implemented, employing AIs as monotherapy in postmenopausal breast cancer patients, as first-line adjuvant therapy, and in sequence either 2-3 or 5 years, with initial tamoxifen. Emerging results from these trials indicate an advantage to patients for any of these strategies, and most international guidelines now suggest the use of an AI in the adjuvant setting in postmenopausal women. The use of endocrine treatment for metastatic and early breast cancer will be reviewed here.     

Standards, Options and Recommendations (SOR) for endocrine therapy in patients with non metastatic breast cancer. FNCLCC

CONTEXT: The "Standards, Options and Recommendations" (SOR) project, started in 1993, is a collaboration between the Federation of the French Cancer Centres (FNCLCC), the 20 French Cancer Centres and specialists from French Public Universities, General Hospitals and Private Clinics. The main objective is the development of clinical practice guidelines to improve the quality of health care and outcome for cancer patients. The methodology is based on literature systematic review and critical appraisal by a multidisciplinary group of experts, with feedback from specialists in cancer care delivery. OBJECTIVES: To develop clinical practice guidelines according to the definitions of Standards, Options and Recommendations for endocrine therapy in patients with non metastatic breast cancer. METHODS: Data have been identified by literature search using Medline, Embase, Cancerlit and Cochrane databases - until july 1999 - and the personal reference lists of the expert group. Once the guidelines were defined, the document was submitted for review to 125 independent reviewers. RESULTS: The main recommendations for the endocrine therapy of patients with non metastatic breast cancer are: 1) Endocrine therapy modalities depend on menopausal status or age of women: ovarian suppression for premenopausal women, antiestrogen drug therapy for postmenopausal women (standard). 2) Tamoxifen (20 mg/d - 5 years) is beneficial to women with positive estrogen receptor tumor (standard, level of evidence A). There is no indication of tamoxifen treatment for women with negative estrogen receptor tumor (standard, level of evidence A). 3) For postmenopausal women with positive estrogen receptor tumor, tamoxifen is the standard adjuvant treatment (level of evidence A). For postmenopausal women with negative estrogen receptor, adjuvant chemotherapy has to be considered (option, level of evidence A). No adjuvant treatment has to be considered for women with poor health condition (option). 4) For premenopausal women with estrogen receptor tumor, results of clinical trials of chemotherapy versus endocrine therapy, suggest a benefit for endocrine therapy. However, there is no sufficient evidence to consider endocrine therapy alone as a standard adjuvant treatment. 5) For premenopausal women, chemotherapy + ovarian suppression or chemotherapy + tamoxifen are not better than chemotherapy alone (level of evidence A). 6) For postmenopausal women, administration of chemotherapy plus adjuvant tamoxifen versus the same tamoxifen alone, is of additional benefit in reducing recurrences but not in prolonging overall survival (standard, level of evidence A). 7) Balance of known benefits (delay to recurrence and death) and risks (side-effects of therapy) for adjuvant chemoendocrine therapy has to be taken into consideration before decision making. Chemoendocrine therapy can be indicated for women at high risk of developing metastatic disease (recommendation, experts agreement).     

Advances in endocrine treatments for postmenopausal women with metastatic and early breast cancer

For the past 25 years, the estrogen antagonist tamoxifen has been the hormonal treatment of choice for postmenopausal patients with hormone-sensitive metastatic and early breast cancer (EBC). However, tamoxifen is associated with certain tolerability and safety concerns. In addition, the hormonal options after progression are limited, and thus, alternative endocrine treatments have been developed. This review provides a synopsis of the newer alternatives in endocrine therapy of breast cancer: the aromatase inhibitors (AIs) and fulvestrant Faslodex), the estrogen receptor antagonist that downregulates estrogen and progesterone receptors and has no known agonist activity. The third-generation AIs, anastrozole and letrozole, have been shown to be as effective or more effective than megestrol acetate and tamoxifen as second- and first-line therapies for the treatment of postmenopausal patients with metastatic breast cancer, and exemestane has been approved for second-line use. Fulvestrant has been shown to be as effective as anastrozole as second-line therapy for metastatic breast cancer and has been approved in the U.S. for the treatment of postmenopausal women with hormone-receptor-positive metastatic breast cancer following progression on antiestrogen therapy. Anastrozole is the only AI with published clinical trial data and U.S. Food and Drug Administration approval for adjuvant therapy of postmenopausal women with EBC. The 'Arimidex,' Tamoxifen, Alone or in Combination (ATAC) trial, a double-blind, multicenter trial with 9,366 patients, compared tamoxifen with anastrozole, alone and in combination, as adjuvant endocrine treatment for postmenopausal patients with operable, invasive, EBC. The first analysis (at a median follow-up of 33.3 months) showed longer disease-free survival and, in general, better tolerability with anastrozole than with tamoxifen. This pattern was maintained at later analyses with a median follow-up of 47 months for efficacy and 37 months for safety and tolerability. Although longer follow-up is warranted, anastrozole appears to be a well-documented choice of endocrine adjuvant therapy for postmenopausal women with hormone-responsive breast cancer.     

Sequential hormonal therapy for metastatic breast cancer after adjuvant tamoxifen or anastrozole

The use of adjuvant endocrine therapy in the treatment of hormone receptor-positive, early breast cancer has become important in both pre- and postmenopausal women. Tamoxifen has been the principal adjuvant hormonal therapy in pre- and postmenopausal women with hormone receptor-positive breast cancer for nearly 20 years. Recent data in premenopausal women suggest benefit from ovarian ablation with or without tamoxifen. Early results from the 'Arimidex', Tamoxifen, Alone or in Combination (ATAC) trial have demonstrated that the third-generation, selective aromatase inhibitor (AI) anastrozole ('Arimidex') is a suitable alternative adjuvant therapy for postmenopausal women with hormone receptor-positive disease. After recurrence or relapse on adjuvant endocrine therapy, responses to the sequential use of additional endocrine agents are common. The increase in the number of options now available for adjuvant therapy will have important implications for the selection of the optimal sequence of endocrine agents in the treatment of recurrent breast cancer. Menopausal status is an important factor in determining the endocrine therapy that a patient receives. For premenopausal women, tamoxifen and/or a luteinizing hormone-releasing hormone agonist such as goserelin ('Zoladex') are both options for adjuvant endocrine treatment. After progression on adjuvant and first-line tamoxifen, ovarian ablation is an appropriate second-line therapy. For premenopausal women who have undergone ovarian ablation, the use of third-line therapy with an AI becomes possible. For postmenopausal women, a wide choice of endocrine treatment options is available and an optimal sequence has yet to be determined. Options for first-line therapy of metastatic disease include an AI for women who have received adjuvant tamoxifen or tamoxifen for patients who have received adjuvant anastrozole. In addition, data suggest that fulvestrant ('Faslodex'), a novel estrogen receptor (ER) antagonist that downregulates the ER protein and has no known agonist effects, is a promising therapeutic option that has shown efficacy in the treatment of postmenopausal women with advanced breast cancer. Other agents that may be used in the sequence include the steroidal AI exemestane and the progestin megestrol acetate. The widening range of adjuvant endocrine options therefore represents an opportunity to prolong patient benefits in the treatment of hormone receptor-positive breast cancer, and will require the further refinement of the optimal sequence of endocrine agents for the treatment of recurrent breast cancer.     

Using aromatase inhibitors in the neoadjuvant setting: evolution or revolution?

Despite improvements in the management of patients with early breast cancer, the prognosis for women with locally advanced breast cancer (LABC) remains poor. The potential goals of neoadjuvant treatment for this disease include down-sizing tumours to allow breast conservation as well as the possibility of improving survival rates. Neoadjuvant treatment was initially dominated by chemotherapy, which increased rates of breast conserving surgery, but to date has demonstrated no survival benefit over standard adjuvant chemotherapy. With recent advances in endocrine therapy, and rapid and routine assessment of predictive factors of response such as estrogen (ER), progesterone (PR) and Her2 nu receptor status, endocrine therapy has come to the forefront of research investigating a neoadjuvant alternative to chemotherapy. Early studies of neoadjuvant endocrine therapy mainly evaluated the role of tamoxifen in the treatment of elderly postmenopausal women with LABC who were unselected for ER/PR status and were unsuitable for either surgery or chemotherapy. Response rates in these patients were found to be inferior to those traditionally obtained from trials with neoadjuvant chemotherapy. Paralleling the superiority that third-generation aromatase inhibitors have shown over tamoxifen in the metastatic and adjuvant settings however, AIs have also demonstrated superiority in the neoadjuvant setting. Recent studies have shown response rates for neoadjuvant treatment with aromatase inhibitors in carefully selected hormone receptor positive patients to be comparable to those seen with neoadjuvant chemotherapy. This is particularly important as hormone receptor positive tumours have repeatedly been shown to have lower response rates to neoadjuvant chemotherapy than hormone receptor negative tumours. Neoadjuvant endocrine treatment with aromatase inhibitors has therefore evolved from being an experimental effort to palliate women with LABC unsuitable for surgery or chemotherapy, to representing a viable and possibly preferred alternative for postmenopausal women with hormone receptor positive large tumours or LABC. Further benefits of neoadjuvant trials include allowing the study of predictive biomarkers of disease in order to provide insight into therapy resistance and sensitivity, and identifying promising systemic therapies for additional testing in larger adjuvant trials.     

Role of adjuvant endocrine therapy in early-stage breast cancer

The value of adjuvant endocrine therapy in saving lives of women with estrogen receptor-positive (ER(+)) early-stage breast cancer cannot be disputed. Tamoxifen has proven to be effective in improving relapse-free and overall survival in both pre- and postmenopausal women with ER(+) early-stage breast cancer. In the meta-analysis of the Early Breast Cancer Trialists' Collaborative Group, the proportional reduction in recurrence and mortality for 5 years of tamoxifen therapy was 50% and 28% respectively for patients with ER(+) tumors. These reductions in recurrence and mortality were similar in both lymph node-negative (N(-)) and lymph node-positive (N(+)) patients and translate to an absolute improvement in 10-year survival of approximately 11% in N(+) patients and 6% in N(-) patients. Current data suggest that about 5 years of tamoxifen therapy is the optimal duration of treatment. For women with ER(-)/progesterone receptor-negative (PR(-)) tumors, tamoxifen does not lower the risk of distant metastases or improve survival. In ER(+) patients, the addition of tamoxifen to chemotherapy further lowers the risk of recurrence by about 30% to 40% when compared to chemotherapy alone. In premenopausal women with ER(+) breast cancer, ovarian ablation has proven to be as effective as chemotherapy in improving both relapse-free and overall survival and the potential additive role of ovarian ablation to chemotherapy and/or tamoxifen is presently being explored in clinical trials. The combination of tamoxifen and ovarian ablation is currently being tested and may be superior to tamoxifen alone. In addition, newer, more effective, and less toxic aromatase inhibitors are also being evaluated in clinical trials in the adjuvant setting and have great promise. "Pure" antiestrogens or selective estrogen receptor down-regulators (SERDs) will be studied in adjuvant clinical trials in the near future. Recent data also suggest that molecular markers such as HER-2/neu may predict the response to endocrine therapy, and other predictive factors are currently being evaluated. Lastly, there is renewed interest in neoadjuvant endocrine therapy, a treatment option that may select those patients with early-stage breast cancer most likely to benefit from endocrine therapy.     

Exploring novel targets of basal-like breast carcinoma by comparative gene profiling and mechanism analysis

Current adjuvant treatment modalities for breast cancer that express the estrogen receptor or progesterone receptor include adjuvant anti-estrogen therapies, and tamoxifen and aromatase inhibitors. Bone, including the jaw, is an endocrine-sensitive organ, as are other oral structures. This review examines the potential links between adjuvant anti-estrogen treatments in postmenopausal women with hormone receptor positive breast cancer and oral health. A search of PubMed, EMBASE, CENTRAL, and the Web of Knowledge was conducted using combinations of key terms “breast,” “cancer,” “neoplasm,” “Tamoxifen,” “Aromatase Inhibitor,” “chemotherapy,” “hormone therapy,” “alveolar bone loss,” “postmenopausal bone loss,” “estrogen,” “SERM,” “hormone replacement therapy,” and “quality of life.” We selected articles published in peer-reviewed journals in the English. The authors found no studies reporting on periodontal diseases, alveolar bone loss, oral health, or oral health-related quality of life in association with anti-estrogen breast cancer treatments in postmenopausal women. Periodontal diseases, alveolar bone density, tooth loss, and conditions of the soft tissues of the mouth have all been associated with menopausal status supporting the hypothesis that the soft tissues and bone of the oral cavity could be negatively affected by anti-estrogen therapy. As a conclusion, the impact of adjuvant endocrine breast cancer therapy on the oral health of postmenopausal women is undefined. The structures of the oral cavity are influenced by estrogen; therefore, anti-estrogen therapies may carry the risk of oral toxicities. Oral health care for breast cancer patients is an important but understudied aspect of cancer survivorship.     

Adjuvant Endocrine Therapy of Perimenopausal and Recently Postmenopausal Women With Hormone Receptor-Positive Breast Cancer

Although 5 years of tamoxifen has been the standard adjuvant endocrine therapy for premenopausal women with hormone receptor-positive breast cancer for more than 2 decades, emerging results suggest that either switching to an aromatase inhibitor after 5 years of tamoxifen when postmenopausal or continuing tamoxifen for an additional 5 years can further decrease relapse risk. As a result, more premenopausal breast cancer patients will be continuing adjuvant endocrine therapy through the menopause transition. In this setting, questions arise regarding continued tamoxifen use through 10 years and/or the timing and appropriateness of switching to an aromatase inhibitor. In addition, it is now recognized that estrogen levels substantially decline for approximately 2 years after the last menstrual period and that chemotherapy and/or tamoxifen-induced amenorrhea preclude reliable ovarian function determination. Because aromatase inhibitors are only effective in a low estrogen environment without ovarian estrogen production, determination of the optimal endocrine adjuvant therapy for perimenopausal women and those recently postmenopausal represent a challenge requiring understanding of current clinical study results and the potential for interactions among therapeutic interventions, ovarian function, and clinical outcome. Available options include tamoxifen for 10 years, tamoxifen for 5 years followed by aromatase inhibitors, tamoxifen with a luteinizing hormone-releasing hormone (LHRH) agonist, aromatase inhibitor with an LHRH agonist or aromatase inhibitor with bilateral oophorectomy. Although completed (Austrian Breast Cancer Study Group [ABCSG]-12) and ongoing (SOFT [Suppression of Ovarian Function Trial], TEXT [Tamoxifen and Exemestane Trial]) clinical trials are addressing some issues, many questions will remain requiring individualized clinical judgement. Rationale supporting the available endocrine therapy options in this setting and recommendations for clinical management follow.     

Preclinical and clinical experience with fulvestrant (Faslodex) in postmenopausal women with hormone receptor-positive advanced breast cancer

Fulvestrant (Faslodex) is a new type of estrogen receptor (ER) antagonist that binds, blocks, and degrades the ER, leading to reduced expression of the progesterone receptor (PgR). Unlike the selective ER modulator tamoxifen, fulvestrant is devoid of any known agonist activity. Fulvestrant has a steroidal structure that competitively binds to the ER with an affinity much greater than that of tamoxifen. After binding to fulvestrant, degradation of the ER is accelerated, ultimately resulting in a reduction in cellular ER. Immunohistochemical studies have demonstrated that a single intramuscular injection of fulvestrant results in a dose-dependent decrease in ER and PgR indices and in Ki-67 expression. At the approved 250 mg dose, the decrease in receptor positivity with fulvestrant treatment was greater than that with tamoxifen. Phase III clinical trials have demonstrated the clinical benefit of fulvestrant in the endocrine treatment of breast cancer. Among patients who progressed during adjuvant or first-line endocrine therapy, fulvestrant was at least as effective as anastrozole as second-line treatment for the primary endpoints of objective response and time to progression, and was well tolerated. After a median follow-up of 24.5 months, a combined survival analysis from two Phase III studies has shown that fulvestrant may be considered similar to anastrozole for time to death (27.4 months versus 27.7 months, respectively). For the first-line therapy of advanced breast cancer in postmenopausal women, fulvestrant was shown to be active and well tolerated in a trial that compared fulvestrant 250 mg once monthly and tamoxifen 20 mg once daily. Treatment with fulvestrant has also demonstrated clinical efficacy among patients who progressed following treatment with tamoxifen followed by nonsteroidal aromatase inhibitors. The efficacy of fulvestrant in sequential endocrine therapy and in combination with other agents appears promising and active investigations are ongoing to explore the clinical potential of this novel antiestrogen.     

Aromatase inhibitor plus ovarian suppression as adjuvant therapy in premenopausal women with breast cancer

The goal of adjuvant hormonal therapy for breast cancer is to prevent recurrence by eradicating micrometastatic disease. Recent studies have shown that the use of aromatase inhibitors (AIs) as adjuvant therapy improves outcomes for postmenopausal women with estrogen receptor (ER)-positive breast cancer compared to adjuvant endocrine therapy with tamoxifen alone. The research question has been raised whether AIs would have similar improvements in disease-free survival (DFS) in premenopausal women with ER-positive breast cancer. Combining 2 phase 3 clinical trials (n = 4,690), Pagani and colleagues randomized premenopausal women with ER-positive early breast cancer to exemestane plus ovarian suppression or tamoxifen plus ovarian suppression for a period of 5 y. After a median follow-up of 68 months, DFS was 91.1% in the AI group and 87.3% in the tamoxifen group. In premenopausal women with hormone-receptor-positive early breast cancer, adjuvant treatment with exemestane plus ovarian suppression, as compared with tamoxifen plus ovarian suppression, significantly reduced recurrence.     

369例ER阳性乳腺癌辅助内分泌治疗的前瞻性临床研究

目的 评价ER阳性乳癌根治术后辅助内分泌治疗的效果。方法 ER阳性的根治性术后乳腺癌患者分为内分泌治疗及化疗两组,进行全身辅助治疗。内分泌治疗组194例,服用三苯氧胺（TAM）5年,其中绝经前患者均先切除双侧卵巢后再服用TAM。化疗组175例,主要采用CMFVP或CMF方案。结果 绝经后患者的内分泌治疗组和化疗组5年无病生存率分别为78．4％和45．4％（P＜0．01）,5年总生存率分别为83．3％和52．9％（P＜0．05）;绝经前患者的内分泌治疗组和化疗组5年无病生存率分别为72．8％和35．7％（P＜0．01）。5年总生存率分别为80．7％和60．0％（P＜0．05）。但是Ⅰ期患者及腋淋巴结转移≥8个的患者,两者疗效差异无显著性（P＞0．05）。结论 ER阳性乳腺癌术后辅助内分泌治疗效果优于或等于化疗。     

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.     

Optimizing endocrine therapy for premenopausal and postmenopausal women with breast cancer

The majority of invasive breast cancer patients present with hormone receptor-positive disease, and modulation of estrogen receptor (ER) activation is an essential component of systemic adjuvant therapy for these women. While tamoxifen has traditionally been the primary adjuvant endocrine therapy for all ER-positive women, recent trials evaluating the use of aromatase inhibitors (AIs) have challenged this standard in postmenopausal women, and ongoing trials are examining the optimal use of endocrine therapy in younger women. Issues regarding the optimal approach to endocrine therapy in both pre- and postmenopausal women are examined in this review.     

Postmenopausal Metastatic Breast Cancer

Endocrine therapy and chemotherapy play important roles in the management of postmenopausal women with metastatic breast cancer. This paper specifically reviews the indications and options for first-line treatment of metastatic breast cancer and recent advances are highlighted, with particular attention to randomized, controlled, phase III clinical trials. Until recently, tamoxifen was standard first-line endocrine treatment for patients with metastatic breast cancer. Now, potent third generation aromatase inhibitors, such as letrozole and anastrozole, have shown superiority to tamoxifen as first-line endocrine treatment and provide an alternative for postmenopausal women. The most active chemotherapy agents for patients with advanced breast cancer have, until recently, been the anthracyclines, doxorubicin and epirubicin. However, their increasing use in the adjuvant setting has resulted in a need for novel active non-cross-resistant cytotoxic drugs for metastatic breast cancer. Real progress has been made with the introduction of the taxanes, paclitaxel and docetaxel. Other developments include the use of single agent cytotoxics such as vinorelbine, the oral fluoropyrimidine capecitabine and gemcitabine, all of which have some activity following either taxanes or anthracyclines, along with a low toxicity profile. Bisphosphonates are bone-specific palliative treatments that have been instituted on the basis of their impact on symptoms and skeletal related morbidity. Finally, the era of biological therapy in the clinic for patients with breast cancer has been heralded with the development and introduction of trastuzumab, a humanized monoclonal antibody which targets the cell surface growth factor receptor HER2/neu. Importantly, each of these new treatment options has provided an incremental improvement in efficacy over previous standard first-line therapies.     

“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.     

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.     

Adjuvant chemoendocrine therapy for early breast-cancer - is it worthwhile - (review)

The overview published in 1999 by the Early Breast Cancer Trialist' Cooperative Group demonstrated that systemic therapy after surgical removal of primary breast tumors prolongs both disease-free and overall survival of patients when compared with no systemic therapy, Specifically, both chemotherapy and ovarian ablation in patients aged less than 50 and tamoxifen in those aged 50 or more achieve a reduction of one-fifth to one-fourth in the annual odds of recurrence or death from any cause. The relative effect of different therapies is independent of the stage of the disease, while the absolute benefit depends not only upon the relative effect of treatment but also upon the baseline prognosis of patients. The overview did not report a direct estimation of the effect of combined chemoendocrine adjuvant therapy. Among the effects that may confound the evaluation of chemoendocrine adjuvant therapy are: (a) the possibility of biological interactions between drugs; (b) the presence on tumor cells of steroid hormone receptors; (c) the suppression of ovarian activity induced by chemotherapy in most premenopausal patients; (d) the scheduling of chemotherapy and endocrine therapy. Based on data of the overview, relevant questions are: (i) does the addition of endocrine therapy (tamoxifen dr ovarian ablation) to chemotherapy improve the outcome of premenopausal patients? (ii) does the addition of chemotherapy to tamoxifen improve the outcome of postmenopausal patients? We have reviewed single randomised trials in an attempt to answer these questions. In premenopausal patients, the addition of tamoxifen to chemotherapy probably induces only small advantages. The addition of ovarian ablation to chemotherapy could improve survival. The relationship between oophorectomy and receptor status has not been extensively studied; however, the addition of oophorectomy, like the addition of tamoxifen, to chemotherapy could be cost effective in cases of estrogen receptor-positive tumors. The effect of tamoxifen in association with ovarian ablation, after chemotherapy, has not yet been studied. In postmenopausal patients the addition of chemotherapy to tamoxifen is debated. The role of receptor status seems to be important in these patients. Most studies found that chemotherapy does not significantly increase the effect of tamoxifen in the subgroup of patients with receptor-positive tumors, while it does increase toxicity. On the contrary, the addition of chemotherapy to tamoxifen, in patients with receptor-negative tumors could significantly improve results.     

Aromatase and aromatase inhibitors

Aromatase inhibition provides both paracrine/intracrine and endocrine treatment. Recent accumulated data clarified that 3rd generation aromatase inhibitors potently suppress intratumoral estrogen synthesis particularly in postmenopausal patients. In the 2nd-line treatment for metastatic breast cancer patients, aromatase inhibitors achieved results antitumor activity at least equal to and sometimes better than that of tamoxifen. In the first-line treatment for metastatic breast cancer patients, a recent pivotal study clearly demonstrated that aromatase inhibitor was superior to tamoxifen. Based upon these results, various adjuvant trials which compare aromatase inhibitors with tamoxifen and attempt to determine optimal combination therapies and treatment periods with aromatase inhibitors are currently being conducted. In addition, preliminary studies conducted in neoadjuvant setting indicated that aromatase inhibitors showed an extremely high response rate, which predicts a future paradigm, that neoadjuvant therapy using aromatase inhibitors singly or in combination may become standard for hormone-responsive and post-menopausal breast cancer patients.     

绝经前激素受体阳性乳腺癌内分泌治疗现状

内分泌治疗是激素受体阳性乳腺癌患者术后辅助治疗的重要手段之一。在内分泌治疗的背景下,接受5年他莫昔芬治疗一直是绝经前患者的标准治疗方案。近年来,这一标准受到挑战。许多大型随机临床试验结果为绝经前患者辅助内分泌治疗提出了新的选择。本文拟将绝经前激素受体阳性乳腺癌患者的内分泌治疗现状做一综述。     

Breast cancer adjuvant endocrine therapy

Adjuvant endocrine therapy with the selective estrogen receptor modulator, tamoxifen, has significantly improved mortality from early-stage breast cancer for both pre- and postmenopausal women with hormone receptor-positive breast cancer. Recent large clinical trials have demonstrated a clear and consistent benefit for the incorporation of aromatase inhibitor (AI) therapy within adjuvant endocrine regimens for postmenopausal women. The AIs, which are associated with myalgias, arthralgias, and a reduction in bone mineral density, are generally well tolerated and have lower risks of endometrial carcinoma and thromboembolic events than tamoxifen. Data are awaited from ongoing trials to better define the optimal sequencing strategy, duration, and AI agent. Attempts to further optimize adjuvant endocrine therapy by identifying predictive biomarkers of response, as well as by developing strategies to overcome endocrine resistance are underway. In premenopausal women AI monotherapy is currently contraindicated and tamoxifen remains the standard of care. The role of ovarian function suppression in addition to tamoxifen or combined with AI therapy is being explored. The hope is that continued advances in endocrine therapy will translate into improved survival among both pre- and postmenopausal women with receptor-positive breast cancer.