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.     

Aromatase inhibitors in postmenopausal breast cancer patients

Aromatase inhibitors (AIs) have greatly enriched the treatment of hormone receptor-positive breast cancer in postmenopausal patients. Before the introduction of the well-tolerated third-generation AIs, tamoxifen was the mainstay of endocrine therapy for hormone receptor-positive breast cancer. Many clinical trials have shown the superiority of AIs compared with tamoxifen in adjuvant breast cancer treatment, as well as their benefit in metastatic breast cancer. NCCN guidelines recommendations for their use are based on the evidence provided by these clinical trials. This discussion reviews the evidence supporting the current guidelines for use of AI therapy in the treatment of hormone receptor-positive postmenopausal breast cancer patients.     

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.     

Emerging role of aromatase inhibitors in the adjuvant setting

Aromatase inhibitors (AIs) have been approved as second-line treatment for estrogen receptor-positive (ER+) metastatic breast cancer after first-line treatment with the selective estrogen receptor modulator (SERM) tamoxifen. Anastrozole and letrozole have also recently been widely approved as first-line endocrine therapy for postmenopausal women with hormone receptor-positive metastatic breast cancer. The three third-generation selective oral AIs approved for use in the United States include two nonsteroidal agents, anastrozole (Arimidex) and letrozole (Femara), and the irreversible steroidal inhibitor exemestane (Aromasin). Several major ongoing clinical trials with a variety of treatment regimens are comparing the relative efficacy of tamoxifen with the steroidal and nonsteroidal AIs in the adjuvant setting. The first strategy compares an AI against tamoxifen directly. Among these are the ATAC (Arimidex, Tamoxifen Alone or in Combination) trial (anastrozole), the BIG FEMTA (Femara-Tamoxifen Breast International Group) trial (letrozole), and the EXEM and TEAM (exemestane) trials. A second strategy is examining the use of an AI as an extension after the initial 5 years of tamoxifen. Examples of this trial design are the MA-17 (letrozole) and the National Surgical Adjuvant Breast and Bowel Project (NSABP B-33, exemestane) trials. A third approach is the use of these agents in sequence with tamoxifen as therapy within the initial 5 postoperative years. Examples of this approach are the International Collaboration Cancer Group trial (tamoxifen for 2-3 years followed by either tamoxifen or exemestane for the remainder of the 5-year period), the BIG FEMTA trial (patients are crossed over from tamoxifen to Ietrozole or letrozole to tamoxifen), and the Arimidex-Nolvadex (ARNO) trial (patients receiving tamoxifen are randomized either to continue with tamoxifen or to switch to anastrozole). A single trial is comparing tamoxifen and anastrozole as initial 5-year therapy, or a combination of the two. The study addressing this design is the ATAC trial. Finally, a small trial in Norway is comparing 2 years of an AI versus a placebo in very low-risk patients with receptor-positive breast tumors. Most adjuvant trials have companion studies associated with the main protocol. These are to determine the end-organ effects of the inhibitors and include measurements of quality of life, bone and lipid metabolism, and endometrial effects. This review addresses the clinical implications of these studies of AIs.     

Implications of first-line adjuvant treatment with aromatase inhibitors in recurrent metastatic breast cancer

The role of adjuvant tamoxifen therapy has gone unchallenged until recently. With the introduction of the selective aromatase inhibitors (AIs), the paradigm for treatment of hormone receptor-positive breast cancer in postmenopausal women is changing. New data from randomized clinical trials have shown the impact of the use of an AI compared with tamoxifen or in sequence with tamoxifen. This review will emphasize some of the highlights from these data sets and the limitations of our current knowledge. Finally, we will discuss the implications of the use of nonselective AIs in the adjuvant setting for the patient who develops recurrent metastatic disease.     

Adjuvant endocrine therapy in hormone receptor-positive postmenopausal breast cancer: evolution of NCCN, ASCO, and St Gallen recommendations

Endocrine therapy has a firm role in adjuvant treatment of women with hormone receptor-positive invasive breast cancer. Until recently, tamoxifen was the most commonly used adjuvant endocrine therapy in premenopausal and postmenopausal women. Several randomized clinical trials have studied the third-generation selective aromatase inhibitors (AIs) (anastrozole, letrozole, and exemestane) as adjuvant endocrine therapy in postmenopausal women. These studies compared therapy with an AI alone versus tamoxifen alone; 2 to 3 years of tamoxifen followed by switching to an AI versus continuation of tamoxifen; or extended therapy with an AI after approximately 5 years of tamoxifen therapy. No statistically significant differences in overall survival were observed. A single trial using extended treatment with an adjuvant AI suggests a small, statistically significant survival advantage in women with axillary lymph node-positive disease while showing no statistically significant decrease in survival with the use of an AI. The toxicities of the AIs are generally acceptable, with fewer endometrial cancers, gynecologic complaints, and thromboembolic events, but more bone fractures and arthralgias compared with tamoxifen alone. Three widely disseminated treatment guidelines, the National Comprehensive Cancer Network Breast Cancer Clinical Practice Guidelines in Oncology, the American Society of Clinical Oncology Technology Assessment on the Use of Aromatase Inhibitors, and the St Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer, now incorporate AIs in the adjuvant therapy of postmenopausal women with estrogen receptor-positive breast cancer.     

Adjuvant endocrine therapy for early breast cancer

Breast cancer is the most common cancer among women and about 80% of breast cancers express hormone receptors. Tamoxifen has been the most important form of adjuvant endocrine therapy over the last 25 years. The third generation aromatase inhibitors (AIs) are a new class of drugs challenging the central role of tamoxifen as adjuvant endocrine treatment in postmenopausal women with hormone receptor-positive breast cancer. Their effectiveness has been demonstrated in first line therapy as well in neoadjuvant setting with a statistically significant superiority over tamoxifen. Here we considered the role of adjuvant AIs in early stage breast cancer with an analysis reviewing the main adjuvant trials. We considered efficacy, side effects, optimal timing, duration of the therapy and whether specific subgroups may achieve particular benefit. In conclusion the upfront use of adjuvant anastrozole or letrozole is superior to tamoxifen with a good relative toxicity profile. Tamoxifen will continue to have a role where recurrence risk is low or if AI is poorly tolerated. Issues including the timing of administration (up-front or sequential), the duration of the therapy and the role of biomarkers such as PgR and HER2 in optimal selection remain unresolved.     

Sequencing of endocrine therapies in breast cancer--integration of recent data

A wide range of endocrine therapies has demonstrated activity in the treatment of hormone receptor-positive metastatic breast cancer and sequential tumor responses to sequential hormonal therapies are common. However, the optimal sequence of the hormonal therapies has not yet been determined. The selection of endocrine therapies in women with hormone receptor-positive breast cancer is strongly influenced by the menopausal status of the patient. For premenopausal women, tamoxifen alone or combined with ovarian suppression using a luteinizing hormone-releasing hormone (LHRH) agonist - such as goserelin or leuprolide - is an appropriate first-line hormonal therapy. Ovarian ablation or megestrol acetate is an appropriate second-line hormonal therapy for premenopausal women treated with tamoxifen as first-line therapy, or ovarian ablation plus an aromatase inhibitor (AI) or megestrol acetate for women treated with first-line tamoxifen plus an LHRH agonist. For postmenopausal women, the non-steroidal AIs anastrozole and letrozole now represent the preferred first-line hormonal treatment for metastatic breast cancer, based upon both efficacy and toxicity considerations. For second-line therapy in postmenopausal women, a number of options now exist, including tamoxifen, the steroidal AI exemestane, and the new agent fulvestrant. Fulvestrant, a novel estrogen receptor (ER) antagonist that downregulates the ER and has no known agonist effects, has been demonstrated to be at least as effective as anastrozole in postmenopausal women whose tumors progress on tamoxifen. The establishment of the optimal sequence of the endocrine therapies should offer significant benefits to women with hormone-sensitive metastatic breast cancer.     

Updates in endocrine therapy for metastatic breast cancer

Endocrine therapy (ET) remains the mainstay of treatment for steroid hormone receptor-positive, human epidermal growth factor 2 (HER2)-negative metastatic breast cancer (MBC). Tumor resistance to hormone therapy has led to the development of novel endocrine drug combinations, transforming the landscape of MBC management. The options for ET are expanding, with promising agents in the pipeline. Although MBC remains incurable, many patients can enjoy years of survival with good quality of life by cycling through the many available agents. With the plethora of available agents and rapid approvals, clinicians look to evidence-based guidelines to assist in treatment selection to maximize patient well-being. In this review, we provide a contemporary review of the advances in ET and a suggested algorithm to guide clinicians in daily management of patients with hormone receptor-positive, HER2-negative MBC. We will discuss landmark trials and highlight their impact in reshaping treatment approaches. Finally, we will provide a glimpse into advances on the horizon and the promise they bring to improve outcomes in patients with advanced breast cancer.     

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.     

Switching trial of adjuvant tamoxifen with an aromatase inhibitor in postmenopausal patients with breast cancer

Tamoxifen is currently a standard of care for postmenopausal patients with breast cancer with hormone receptor-positive tumors who are candidates for adjuvant endocrine therapy. This treatment is highly effective and relatively safe. However, a significant proportion of women are constitutively resistant or become resistant to tamoxifen, despite having hormone receptor-positive tumors. Moreover, the prolonged exposure to tamoxifen can produce severe and life-threatening side effects like endometrial carcinoma or thromboembolic disease. Aromatase inhibitors (AI) have been shown to be quite effective in advanced disease, and also have promising efficacy in early-stage breast cancer as alternatives to tamoxifen. This article reviews the results achieved by AI following 2-3 years or 5 years of tamoxifen. At least 3 trials indicate that switching to an AI following 2-3 years of tamoxifen can produce a substantial benefit. A fourth trial indicates that additional benefit can be achieved by a few years of treatment with an AI after 5 years of tamoxifen. The updated results of previous trials and ongoing trials will soon establish criteria for selecting patients who might be better candidates for sequencing, and to fine tune strategies that are more appropriate.     

Adjuvant endocrine therapy for breast cancer

Endocrine therapy is a critical part of adjuvant therapy in women with hormone receptor-positive breast cancer, and has been shown to reduce the risk of recurrence and death from breast cancer. For decades, 5 years of tamoxifen has been the standard treatment. For premenopausal women, it remains so, and we await the results of ongoing trials to define the role of ovarian suppression or ablation with endocrine therapy. If a woman becomes postmenopausal during treatment, consideration should be given to extended adjuvant therapy with an aromatase inhibitor (AI) for another 5 years. In postmenopausal women, trials have shown that AIs are more beneficial than tamoxifen in preventing disease recurrence.They have been compared as upfront treatment for 5 years, as sequential therapy after 2 to 3 years of tamoxifen, and as extended treatment for 5 years after 5 years of tamoxifen. Among the questions still being studied are the optimal duration of extended adjuvant therapy with AIs, how one AI performs compared to another, and whether there is a benefit to intermittent extended adjuvant treatment.     

A comparison of the efficacy of aromatase inhibitors in second-line treatment of metastatic breast cancer

Randomized clinical trials have established the role of third-generation aromatase inhibitors (AIs) (letrozole, anastrozole, and exemestane) as standard treatment for patients with hormone-sensitive metastatic breast cancer who have experienced disease progression with antiestrogen therapy. Significant gains in clinical efficacy and improved tolerability over progestins (megestrol acetate) and the first-generation AI aminoglutethimide have positioned these agents above previous therapies. Estrogen receptor (ER) status remains the best predictive determinant of endocrine response, and further randomized trials with properly selected patient populations may distinguish individual AIs within this class. A recently completed, randomized, head-to-head phase III trial of letrozole versus anastrozole as second-line endocrine therapy demonstrated a significant difference in objective response rate for letrozole compared with anastrozole (19% versus 12%, respectively; P = 0.014), with similar time to progression. The improved efficacy and safety of AIs as second-line endocrine therapies has spawned trials of their use as first-line endocrine therapy versus tamoxifen for patients with metastatic breast cancer. Based on favorable results from these trials, letrozole and anastrozole have also been approved for use as first-line treatment of postmenopausal women with hormone receptor-positive metastatic breast cancer.     

Adjuvant endocrine therapy for premenopausal women with early breast cancer

Adjuvant endocrine therapy is a pivotal component of treatment for premenopausal women with early-stage hormone receptor-positive breast cancer. Currently, the standard endocrine therapy for premenopausal women is tamoxifen; a role for ovarian suppression or ablation has also been identified. Uncertainty remains about the optimal use of endocrine therapy in this setting. The role of ovarian suppression with tamoxifen or aromatase inhibitor, the optimal duration of adjuvant endocrine therapy and the utility of biomarkers and pharmacogenetic studies to select therapy are questions worthy of further investigation.     

First-Line Treatment of Metastatic Breast Cancer

For many years, tamoxifen was the mainstay of treatment for hormone receptor-positive metastatic breast cancer (MBC). However, in recent years, newer endocrine agents, particularly aromatase inhibitors, have consistently proved their superiority over tamoxifen by improving clinical outcomes. These agents have therefore been incorporated into first-line treatment strategies for endocrine-responsive disease. The chemother-apeutic armamentarium has also been enriched with new agents and combinations that have played a role in improving breast cancer survival in recent decades. However, few chemotherapy clinical trials have claimed a clear survival benefit of one regimen over another. More recently, the development of biologic agents has further widened the spectrum of available therapies. Among these, trastuzumab, a monoclonal antibody against human epidermal growth factor receptor 2 (HER2), has significantly altered the lives of patients with HER2-positive MBC. The transfer of research findings to clinical practice is a delicate process that implies the ability to adequately tailor evidence obtained from well designed clinical trials to the individual patient. This article discusses landmark studies in the treatment of MBC, with emphasis on those treatments used as ‘first-line’ therapy following relapse.     

Emerging data on optimal adjuvant endocrine therapy: Breast International Group trial 1-98/MA.17

In recent years, several major trials have studied aromatase inhibitors (AIs)/inactivators as adjuvant therapy for postmenopausal women with early-stage breast cancer. The AIs have demonstrated improved efficacy compared with 5 years of tamoxifen when used as initial therapy or when used sequentially after 2-3 years. They also improve outcomes when used after 5 years of adjuvant tamoxifen in this patient population. In all cases, AIs improve disease-free survival compared with the standard 5 years of adjuvant tamoxifen, leading to a reassessment of the optimal adjuvant endocrine therapy for postmenopausal patients with breast cancer. The American Society of Clinical Oncology now recommends the inclusion of an AI into the adjuvant regimen at some point for most postmenopausal patients with hormone receptor-positive early-stage breast cancer. However, the optimal duration of AI therapy and the comparative efficacy and safety of the alternative strategies for their incorporation remain matters of debate. In addition, the long-term impact of AIs on other organs, such as the bone and cardiovascular systems, is not completely understood, and longer follow-up of patients from these original trials as well as carefully planned future trials with appropriate substudies are essential to determine the optimal endocrine treatment strategy.     

Safety considerations of adjuvant therapy in early breast cancer in postmenopausal women

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.     

Aromatase inhibitor-induced arthralgia: clinical experience and treatment recommendations

It is well documented that the aromatase inhibitors (AIs) are superior to tamoxifen as adjuvant endocrine therapy in postmenopausal women with hormone receptor-positive breast cancer. However, compared with tamoxifen, an elevated incidence of arthralgia has been observed during AI treatment. Concerns have been raised that AI-induced arthralgia may dissuade patients from completing their full AI treatment course, and may also deter physicians from prescribing an AI if they feel that patients may be at risk of permanent joint damage. Patient education about the possibility of experiencing arthralgia, and effective management of symptoms if they appear, are important in helping patients adhere to AI treatment, and consequently improving breast cancer outcomes. In this paper, we discuss the potential mechanisms behind AI-induced arthralgia, review the frequency with which arthralgia occurs, and propose for the first time an algorithm specifically for the treatment of AI-induced arthralgia. As with joint pain in non-breast cancer patients, a sequential approach to disease management is recommended, involving modifying the patient's lifestyle in addition to taking a stratified approach to pharmacological intervention with analgesia and anti-inflammatory medication. Knowing that joint symptoms can be managed in most patients may encourage patient-physician communication and treatment compliance.     

American Society of Clinical Oncology technology assessment on the use of aromatase inhibitors as adjuvant therapy for postmenopausal women with hormone receptor-positive breast cancer: status report 2004.

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.     

来曲唑在老年乳腺癌新辅助内分泌治疗中的疗效观察

目的探讨来曲唑在老年绝经后乳腺癌新辅助内分泌治疗中的近期疗效,耐受性及与临床病理因素的相关性。方法对58例绝经后激素受体阳性的乳腺癌患者进行来曲唑新辅助内分泌治疗,以他莫昔芬新辅助内分泌治疗为对照组。结果来曲唑组临床疗效显著优于他莫昔芬组（P〈0.05）。来曲唑组临床分期晚,ER及PR均阳性的有效率高,与HER-2表达无关。他莫昔芬组HER-2阳性的有效率低。2组治疗前后Ki-67水平均显著下降,有统计学意义（P〈0.05）。2组未出现明显不良反应。结论绝经后、激素受体阳性的乳腺癌选择来曲唑新辅助内分泌治疗安全,有效,尤其适合有合并症的老年体弱者。