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1.
PURPOSE OF REVIEW: Approximately three-quarters of all invasive breast tumors are estrogen and/or progesterone receptor-positive. The selective estrogen receptor modulator tamoxifen has been the preferred endocrine therapy for almost four decades. One of the most significant advances in endocrine therapy for women after menopause with early breast cancer is the introduction of third-generation aromatase inhibitors as an alternative or as an additional treatment to tamoxifen therapy. In making a choice between the use of an aromatase inhibitor or tamoxifen in the adjuvant setting, a careful analysis of both the efficacy data and toxicity profiles of each drug is essential. RECENT FINDINGS: In the adjuvant setting, three major randomized controlled trials have reported on the use of three different aromatase inhibitors for women after menopause with breast cancer. In all of these trials, the third-generation aromatase inhibitors demonstrated significantly improved disease-free survival, either compared with tamoxifen as an initial adjuvant hormonal therapy, or when aromatase inhibitors were given sequentially after tamoxifen therapy. The toxicity data suggest that bone loss, increased fracture rates, and other musculoskeletal disorders are the most serious side effects associated with the use of aromatase inhibitors. Toxicities commonly associated with tamoxifen therapy such as thromboembolic events and endometrial abnormalities are reduced in patients receiving aromatase inhibitors, however. SUMMARY: The present data demonstrate the improved efficacy achieved with third-generation aromatase inhibitors compared with tamoxifen and support the use of these agents in the adjuvant setting. The optimal treatment strategy for whether these agents should be given in place of tamoxifen or as part of a sequential treatment has yet to be defined, however. Moreover, to be able to optimize treatment with aromatase inhibitors, it is imperative to develop interventions to prevent or alleviate treatment related side effects.  相似文献   

2.
Visvanathan K  Davidson NE 《Oncology (Williston Park, N.Y.)》2003,17(3):335-42, 347; discussion 347-50, 354
The aromatase inhibitors are regarded as standard approaches to first- or second-line endocrine therapy in women with hormone-responsive metastatic breast cancer. Their efficacy and apparent lack of toxicity have led to their evaluation as adjuvant therapy. Although initial results with these agents in early breast cancer are promising, our collective long-term experience documenting tamoxifen's benefits and our uncertainty about the long-term effects of aromatase inhibitors suggest that it is too early to recommend their routine use in the adjuvant setting. However, anastrozole is also a reasonable therapeutic option in the adjuvant setting, particularly in individuals with a contraindication to tamoxifen such as those with thromboembolic disease or those who develop breast cancer while receiving tamoxifen or raloxifene (Evista) therapy. Anastrozole (Arimidex) was recently approved by the Food and Drug Administration for the adjuvant treatment of postmenopausal women with hormone-receptor-positive early breast cancer. Ongoing trials are assessing the potential role of aromatase inhibitors in the adjuvant, neoadjuvant, and preventive settings.  相似文献   

3.
Because of its proven efficacy profile based on long-term data, tamoxifen has been the standard adjuvant endocrine therapy for hormone-sensitive early breast cancer for the past 30 years. However, there is well-established evidence that long-term use of tamoxifen is associated with serious side effects. As adjuvant endocrine therapy is generally administered for long periods of time, the safety and tolerability of agents used in this setting are of particular importance. Due to their superior efficacy over tamoxifen, newer agents, such as the third-generation aromatase inhibitors (AIs), are already established therapies for the treatment of advanced breast cancer. In addition, recent trials indicate that the AI anastrozole ('Arimidex') has improved efficacy compared with tamoxifen in the adjuvant setting in postmenopausal women. The other third-generation AIs have reported disease-free survival benefits but not in the absence of prior treatment with tamoxifen; letrozole ('Femara') has been compared with placebo following 5 years of tamoxifen therapy and exemestane ('Aromasin') has been compared with tamoxifen following 2-3 years of prior treatment with tamoxifen. Long-term safety data show that anastrozole also has a more favorable overall safety profile compared with tamoxifen, particularly in terms of life-threatening events such as endometrial cancer and thromboembolism. Anastrozole alone, therefore, provides a new option for adjuvant therapy in postmenopausal women with hormone-receptor-positive early breast cancer. The AIs have differing pharmacological profiles, which may translate into dissimilar adverse event profiles in the adjuvant treatment setting, but patient follow-up in most trials is relatively short to make a valid comparison. It cannot, therefore, be assumed that all AIs will be equally well tolerated in the adjuvant setting. Further data on the long-term safety of AIs other than anastrozole are therefore required to allow overall risk:benefit assessments on these agents to be made.  相似文献   

4.
Recent advances have been made in the hormonal treatment of breast cancer with the advent of third-generation aromatase inhibitors (anastrozole, letrozole, and exemestane). These newer agents have substantial antitumor activity and appear to be as effective as tamoxifen, with fewer adverse effects. Recent reports indicate that anastrozole is more effective than tamoxifen as adjuvant endocrine therapy in postmenopausal women with breast cancer. This report provides an overview of the clinical trials conducted to date with the aromatase inhibitors as first- and second-line therapies, with an emphasis on recently updated analyses comparing anastrozole with tamoxifen in the adjuvant setting.  相似文献   

5.
The current adjuvant therapy for breast cancer is in a continous progress; standard therapeutic strategies include the use of chemotherapy, molecular targeted drugs and hormonal agents, according to well-established prognostic and predictive factors. Among the hormonal drugs, for a long period tamoxifen has been the gold standard of adjuvant therapy in postmenopausal women with hormone receptor-positive (HR+) early breast cancer. In the last years an expanding use of aromatase inhibitors occurred in this subset of patients, because the third-generation class of these agents (anastrozole, letrozole and exemestane) showed to be more effective and safe than tamoxifen and are now recommended as the preferred hormonal approach to postmenopausal hormone-sensitive patients, according to national and international guidelines. Treatment choices with these agents include the use of an aromatase inhibitor as an upfront strategy for 5 years, as a sequential approach after 2–3 years of tamoxifen, or as an extended use after the classical 5 years of tamoxifen. The improved efficacy of aromatase inhibitors over tamoxifen has been largely demonstrated in terms of better disease-free survival, reductions in the occurrence of early distant metastasis as well as improvement of overall survival. Moreover, according to the optimal duration of therapy, presently it is not known whether aromatase inhibitor therapy, as tamoxifen, should be limited to 5 years. In terms of safety profile, the side effects of aromatase inhibitors, as compared with selective estrogen receptor modulators, are different, reflecting the specific mechanism of action of these drugs. There is strong evidence that aromatase inhibitors are well tolerated, with a lower incidence of gynecological symptoms (vaginal bleeding, discharge and endometrial neoplasia), venous thromboembolic events and hot flushes than tamoxifen. On the other hand, the use of aromatase inhibitors has been associated with loss of bone density, arthralgia, myalgia, and a negative effect on lipid metabolism and cardiovascular risk. More extensive and mature studies are necessary to well establish the safety of aromatase inhibitors when given to patients with breast cancer for a long time.  相似文献   

6.
The current adjuvant therapy for breast cancer is in a continous progress; standard therapeutic strategies include the use of chemotherapy, molecular targeted drugs and hormonal agents, according to well-established prognostic and predictive factors. Among the hormonal drugs, for a long period tamoxifen has been the gold standard of adjuvant therapy in postmenopausal women with hormone receptor-positive (HR+) early breast cancer. In the last years an expanding use of aromatase inhibitors occurred in this subset of patients, because the third-generation class of these agents (anastrozole, letrozole and exemestane) showed to be more effective and safe than tamoxifen and are now recommended as the preferred hormonal approach to postmenopausal hormone-sensitive patients, according to national and international guidelines. Treatment choices with these agents include the use of an aromatase inhibitor as an upfront strategy for 5 years, as a sequential approach after 2-3 years of tamoxifen, or as an extended use after the classical 5 years of tamoxifen. The improved efficacy of aromatase inhibitors over tamoxifen has been largely demonstrated in terms of better disease-free survival, reductions in the occurrence of early distant metastasis as well as improvement of overall survival. Moreover, according to the optimal duration of therapy, presently it is not known whether aromatase inhibitor therapy, as tamoxifen, should be limited to 5 years. In terms of safety profile, the side effects of aromatase inhibitors, as compared with selective estrogen receptor modulators, are different, reflecting the specific mechanism of action of these drugs. There is strong evidence that aromatase inhibitors are well tolerated, with a lower incidence of gynecological symptoms (vaginal bleeding, discharge and endometrial neoplasia), venous thromboembolic events and hot flushes than tamoxifen. On the other hand, the use of aromatase inhibitors has been associated with loss of bone density, arthralgia, myalgia, and a negative effect on lipid metabolism and cardiovascular risk. More extensive and mature studies are necessary to well establish the safety of aromatase inhibitors when given to patients with breast cancer for a long time.  相似文献   

7.
PURPOSE: To update the 2003 American Society of Clinical Oncology technology assessment on adjuvant use of aromatase inhibitors. RECOMMENDATIONS: Based on results from multiple large randomized trials, adjuvant therapy for postmenopausal women with hormone receptor-positive breast cancer should include an aromatase inhibitor in order to lower the risk of tumor recurrence. Neither the optimal timing nor duration of aromatase inhibitor therapy is established. Aromatase inhibitors are appropriate as initial treatment for women with contraindications to tamoxifen. For all other postmenopausal women, treatment options include 5 years of aromatase inhibitors treatment or sequential therapy consisting of tamoxifen (for either 2 to 3 years or 5 years) followed by aromatase inhibitors for 2 to 3, or 5 years. Patients intolerant of aromatase inhibitors should receive tamoxifen. There are no data on the use of tamoxifen after an aromatase inhibitor in the adjuvant setting. Women with hormone receptor-negative tumors should not receive adjuvant endocrine therapy. The role of other biomarkers such as progesterone receptor and HER2 status in selecting optimal endocrine therapy remains controversial. Aromatase inhibitors are contraindicated in premenopausal women; there are limited data concerning their role in women with treatment-related amenorrhea. The side effect profiles of tamoxifen and aromatase inhibitors differ. The late consequences of aromatase inhibitor therapy, including osteoporosis, are not well characterized. CONCLUSION: The Panel believes that optimal adjuvant hormonal therapy for a postmenopausal woman with receptor-positive breast cancer includes an aromatase inhibitor as initial therapy or after treatment with tamoxifen. Women with breast cancer and their physicians must weigh the risks and benefits of all therapeutic options.  相似文献   

8.
Kumar S  Leonard RC 《Oncology (Williston Park, N.Y.)》2005,19(11):1425-8, 1433; discussion 1433-41, 1444-6
For many years, tamoxifen has been the gold standard adjuvant hormonal therapy with the greatest impact in early breast cancer for both pre- and postmenopausal women. Tamoxifen-based adjuvant endocrine therapy and chemotherapy have together contributed substantially to the reduction in breast cancer mortality that has occurred in recent years. Over the past few years, the role of aromatase inhibitors has grown in prominence and they are now on the threshold of supplanting tamoxifen as the new gold standard adjuvant therapy for postmenopausal women with estrogen-receptor-positive disease. With extended use of oral antihormones such as tamoxifen, the role of ovarian suppression on the other hand has become less clear in the adjuvant setting. This article reviews the most important data regarding the various adjuvant hormonal treatments in the management of early breast cancer and will also give a brief overview of the role of these agents in the neoadjuvant setting.  相似文献   

9.
In a review of current information on aromatase inhibitors (AIs) and their use in breast cancer treatment and prevention, published reports were obtained through a Medline search. Tamoxifen, a selective estrogen receptor modulator, is approved for use in metastatic breast cancer (MBC), the adjuvant treatment of breast cancer, and the prevention of breast cancer in women at high risk. The 50% reduction in breast cancer incidence seen with tamoxifen is significant for women at increased risk but is accompanied by notable toxicities such as thrombotic events and endometrial cancer. Therefore, the development of other effective agents with less toxicity would be a major advance in breast cancer prevention. Aromatase inhibitors, recently approved for the treatment of MBC and in the adjuvant setting, are proving to be slightly more effective than tamoxifen therapy. These drugs, approved for use in only postmenopausal women, inhibit the enzyme aromatase and thereby lower circulating functional estrogen. To date, the most concerning side effect of these agents is an increase in fracture rate. Compared with tamoxifen, thrombotic events and endometrial cancer rates are much lower. Ongoing data from the Arimidex, Tamoxifen, Alone or in Combination trial continue to favor anastrozole over tamoxifen in the reduction of primary contralateral breast cancers. This information has prompted breast cancer chemoprevention trials with AIs. Although tamoxifen is the gold standard for prevention therapy, results of ongoing studies may indicate a role for AIs in the prevention of breast cancer.  相似文献   

10.
For endocrine therapy of hormone-sensitive advanced breast cancer in postmenopausal women, the third-generation aromatase inhibitors, letrozole, anastrozole, and exemestane, are effective both as alternatives to tamoxifen in first-line treatment and following first-line tamoxifen failure. These three agents are currently being evaluated as adjuvant therapy of early breast cancer, again relative to the standard, tamoxifen. Three treatment strategies are under investigation: replacement of tamoxifen as adjuvant therapy for 5 years (early adjuvant therapy); sequencing of tamoxifen before or after an aromatase inhibitor during the first 5 years (early sequential adjuvant therapy); or following 5 years of tamoxifen (extended adjuvant therapy). Results of the first early adjuvant trial (Arimidex, Tamoxifen Alone or in Combination [ATAC]) demonstrated that anastrozole was significantly more effective than tamoxifen in reducing the risk of disease recurrence. Two trials sequencing 2-3 years of an aromatase inhibitor after 2-3 years of tamoxifen have also reported results. A large trial (International Collaborative Cancer Group [ICCG] trial 96) found switching to exemestane to be significantly superior to continuing on tamoxifen in disease-free survival, and in a small study (Italian Tamoxifen Arimidex [ITA] trial), similarly sequencing anastrozole after tamoxifen significantly reduced the hazard of recurrence compared with remaining on tamoxifen. Extended adjuvant therapy with 5 years of letrozole versus placebo following 5 years of tamoxifen was evaluated in the MA.17 trial. Compared with placebo, letrozole resulted in a significant improvement in disease-free survival that was irrespective of whether patients had lymph node-positive or -negative tumours. Results of these four trials emphasise the important role of aromatase inhibitors in the adjuvant setting, yet the optimal approach still needs to be defined. A number of trials further evaluating the three adjuvant treatment strategies are ongoing.  相似文献   

11.
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.  相似文献   

12.
Untch M  Jackisch C 《Onkologie》2007,30(1-2):55-64
Results from large controlled clinical trials have identified the third-generation aromatase inhibitors (AIs) as the first significant therapeutic advance in the adjuvant treatment of hormone receptor-positive (HR+) early breast cancer in postmenopausal women since the introduction of tamoxifen. Although all 3 agents, letrozole, exemestane and anastrozole, provide benefits compared with a 5-year course of tamoxifen, the optimum strategy for adjuvant AI therapy has not yet been defined. AIs have been studied upfront, in sequence with tamoxifen, in therapy switch strategies after 2-3 years of tamoxifen, and after the completion of standard adjuvant tamoxifen. Clearly, only upfront treatment with an AI can address the peak risk of relapse during the first 2-3 years after surgery, and both letrozole and anastrozole significantly reduce relapses compared with tamoxifen in this setting. Switching to exemestane or anastrozole benefits women who are disease-free following 2-3 years of tamoxifen, and women who have successfully completed the standard 5 years of tamoxifen can benefit from extended adjuvant letrozole therapy. Ongoing studies will help to determine the optimum treatment strategy, and answer other important questions, such as whether the AIs differ clinically, what influence HR expression profiles have on outcomes, and what long-term toxicities may be associated with these highly effective agents.  相似文献   

13.
Mortimer JE  Urban JH 《Oncology (Williston Park, N.Y.)》2003,17(5):652-9; discussion 659, 662, 666 passim
Published literature indicates that the selective estrogen-receptor modulators (SERMs) tamoxifen and raloxifene (Evista) have favorable effects on bone density, lipid profiles, and the incidence of second breast cancers, and unfavorable effects on the incidence of venous thrombosis and hot flushes. Tamoxifen increases the risk of endometrial cancer, but raloxifene does not. The effects of SERMs on sexual function and cognition are unclear. Because the selective antiaromatase agents are relatively new, the long-term effects of these agents on normal tissues are less well established. It appears that the nonsteroidal agents (anastrozole [Arimidex], letrozole [Femara]) and steroidal (exemestane [Aromasin]) antiaromatase agents may have different effects on normal tissues. Preliminary data demonstrate that anastrozole increases the risk of arthralgias and produces a decrease in bone density. In contrast, exemestane appears to favorably affect bone density and lipid profile, similar to tamoxifen and raloxifene. The incidence of contralateral breast cancer is decreased in women on adjuvant anastrozole, but data for the other antiaromatase agents are not yet available. Hot flushes have been reported with the use of selective aromatase inhibitors, but their incidence seems to be comparable to what is reported with SERMs. Antiaromatase agents do not appear to cause venous thrombosis. More information about the effects of the antiaromatase agents on normal tissue will become available as data from ongoing adjuvant and chemoprevention trials are reported. Clinically, we should be conscious of the differences between antiaromatase agents and SERMs and their impact on women's health.  相似文献   

14.
Adjuvant hormonal therapy for postmenopausal women with early stage breast cancer has become far more complex over the past several years. This commentary reviews the current status of the five major trials evaluating the use of the aromatase inhibitors in the adjuvant setting. The data currently available suggest that the aromatase inhibitors are efficacious either as upfront therapy or after a course of tamoxifen. Ongoing trials will compare these approaches and guide the use of these agents in the years to come.  相似文献   

15.
(1) Worldwide, breast cancer is the most common type of cancer in women, and the second most frequently diagnosed cancer overall.(2) Since its approval approximately 20 years ago, a 5-year course of tamoxifen has been the standard adjuvant therapy for patients with hormone-dependent breast cancer.(3) Recently, data from large randomised clinical trials have indicated that the third-generation aromatase inhibitors (letrozole, anastrozole and exemestane) are more effective than tamoxifen as adjuvant therapy in postmenopausal women with operable breast cancer when given either initially, or sequentially following initial tamoxifen therapy, within the first five years post-operatively.(4) One large randomised trial demonstrated that administration of letrozole to high-risk (node-positive) postmenopausal patients who have completed 5 years' adjuvant tamoxifen further prevents late recurrences and contralateral breast cancer, contrary to the lack of obvious benefit of extending tamoxifen treatment to 10 years found in another large randomised study.(5) Aromatase inhibitors and tamoxifen should not be administered concomitantly as this does not provide additional benefit, and a large, randomised study demonstrated reduced disease-free survival with the combination of anastrozole plus tamoxifen compared with anastrozole alone.(6) Further studies are required to establish whether the third-generation aromatase inhibitors prolong overall survival compared with tamoxifen, to evaluate their long-term efficacy and tolerability profiles, and to determine the optimal treatment duration with these agents.  相似文献   

16.
A 5-year regimen of tamoxifen hormone therapy has historically been the recommendation for hormone receptor-positive, postmenopausal women with early-stage breast cancer. With the advent of aromatase inhibitors, there has been extensive work carried out to investigate the role of these agents in the adjuvant setting. Studies have been designed to answer whether these agents should be used upfront (instead of tamoxifen) or in conjunction (either in a switch or extended program). The Arimidex®, Tamoxifen Alone or in Combination (ATAC) trial is a landmark trial that demonstrated the superiority of upfront anastrozole over tamoxifen. This article reviews the trial and discusses both the optimum timing of initiation of aromatase inhibitors and the future approach of more individualized therapy, with the detection of predictive markers.  相似文献   

17.
Endocrine therapies have played an important role in the management of breast cancer for many years. Tamoxifen had been the unchallenged standard in the adjuvant setting until recently. Data from recent clinical trials have emphasized the emerging roles of aromatase inhibitors and ovarian ablation in patients with early breast cancer. This review highlights previous data that led to the recognition of tamoxifen as the gold standard hormonal therapy in the adjuvant treatment of early breast cancer. We then discuss clinical trials demonstrating the impact of aromatase inhibitors as an alternative to tamoxifen or as a component of sequential treatment with tamoxifen in postmenopausal women with early breast cancer. Finally, we review data related to the incorporation of ovarian ablation into the treatment of early breast cancer in premenopausal women.  相似文献   

18.
Epidemiological, experimental and clinical data strongly support the possibility that breast cancer can be prevented by using anti-estrogenic interventions in healthy women. Four trials involving over 25,000 women have so far been reported using tamoxifen 20 mg/day or placebo in healthy women to chemoprevent breast cancer, and several trials utilizing raloxifene or aromatase inhibitors are underway. Interim analyses of the Royal Marsden tamoxifen trial and the Italian national trial showed no effect on the early incidence of breast cancer. The NSABP-P1 showed a 49% reduction in early incidence of breast cancer. This was associated with a reduction in osteoporotic fractures but increases in the risks of endometrial cancer, cataract and thromboembolism. The IBIS trial showed a 32% reduction with a two-fold increase in endometrial cancer and in thromboembolic events. Mortality rates of breast cancer in women receiving tamoxifen prophylactically should be monitored and further follow-up of these trials is needed to determine whether tamoxifen provides an overall health benefit or increase specific or overall survival of breast cancer. High-risk women should not be advised to take anti-estrogens outside of a clinical trial setting.  相似文献   

19.
Tamoxifen has been a standard therapy for breast cancer, but its use is complicated by serious events, including endometrial cancer and thromboembolism. Tamoxifen therapy beyond the recommended 5 years fails to improve disease outcomes, leaving many patients without a treatment option and susceptible to relapse. While all third-generation aromatase inhibitors have proven to be more effective than tamoxifen in reducing recurrence risk, in a variety of settings, there may be some differences in efficacy. For example, there is evidence that letrozole is the most potent suppressor of estrogen levels, and this may translate to greater clinical efficacy. Indeed, letrozole has been consistent at improving outcomes and is approved in a range of treatment settings, including extended adjuvant therapy, where tamoxifen is not indicated, and more recently, in the early adjuvant setting in the United States and Europe. While other potential long-term complications of aromatase inhibitor therapy will require further study, bone loss appears manageable through bisphosphonate therapy. Results of trials currently under way should determine the optimal use of the aromatase inhibitors in breast cancer therapy.  相似文献   

20.
BACKGROUND AND OBJECTIVES: The most powerful predictor of the response of breast cancers to hormonal therapy is the presence of estrogen receptors in the tumor cells. Estrogen receptors are expressed in approximately 35-55% of all breast tumors but up to 80-90% of tumors from women older than 55 years. METHODS: At this time, tamoxifen remains the first-line hormonal therapy for breast cancer of all stages. However, the aromatase inhibitors are evolving into an important treatment option. Aromatase inhibitors prevent the conversion of precursors (androgens) to estrogens. RESULTS: On the basis of several randomized clinical trials, aromatase inhibitors have become established as the second-line therapy for postmenopausal women with advanced breast cancer progressing during tamoxifen therapy. Furthermore, very recent trials support the use of these agents as first-line therapy in place of tamoxifen. CONCLUSIONS: The roles of the selective aromatase inhibitors in the prevention of breast cancer and in the neoadjuvant and adjuvant treatment of early-stage breast cancer are the focus of several planned and ongoing large-scale clinical trials. These trials will answer some of the many questions that remain regarding optimal hormonal therapy for hormone-dependent breast cancer.  相似文献   

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