氟维司群治疗乳腺癌的若干问题

氟维司群是一种新型甾体雌激素受体拮抗药,可在细胞水平下调雌激素受体和孕激素受体数量,且无激动效应。氟维司群对激素受体阳性的乳腺癌疗效确切,耐受性好,是一种新的内分泌治疗药物。本文回顾氟维司群治疗乳腺癌的临床研究进展,讨论若干临床应用关键问题。     

FDA批准mTOR抑制剂依维莫司治疗乳腺癌

近日美国食品药品管理局（FDA）宣布,已批准依维莫司的适应证扩大至治疗激素受体阳性、HER2阴性晚期乳腺癌绝经后女性患者。依维莫司（Afinitor）为哺乳动物雷帕霉素靶蛋白（mTOR）抑制剂,此次获准可与依西美坦（Aromasin）联合用于来曲唑（Femara）或阿那曲唑（Arimidex）治疗后复发或出现疾病进展的上述女性患者。该药物是首个被批准用于激素受体阳性乳腺癌的mTOR抑制剂。     

阿贝西利治疗激素受体阳性乳腺癌的临床研究进展

目前全球有4款获批治疗乳腺癌的细胞周期蛋白依赖性激酶（CDK）4/6抑制剂，分别是哌柏西利、瑞博西利、阿贝西利和达尔西利。其中，阿贝西利是继哌柏西利和瑞博西利之后第3个进入市场的CDK4/6抑制剂，可联合芳香化酶抑制剂（AI）或他莫昔芬作为激素受体阳性（HR⁺）、人表皮生长因子受体2阴性（HER2^-）早期高危乳腺癌成人患者的辅助治疗，还可联合氟维司群或AI治疗HR⁺/HER2^-局部晚期或转移性乳腺癌。就阿贝西利治疗激素受体阳性乳腺癌的临床研究进展作以综述，以期为临床治疗提供参考。     

晚期乳腺癌治疗药物依维莫司

诺华制药公司开发的依维莫司(商品名:Afinitor)于2012年7月20日获美国FDA批准,与依西美坦(商品名:Aromasin)联用于治疗激素受体阳性、HER2 阴性的绝经后晚期乳腺癌患者.FDA药物评价和研究中心血液和肿瘤学产品办公室主任Richard Pazdur博士称,这是mTOR抑制剂类药物首次获准用于激素受体阳性的绝经后晚期乳腺癌患者的治疗.     

氟维司群治疗受体阳性转移性乳腺癌患者的疗效及安全性

目的探讨氟维司群（FUL）对受体阳性转移性乳腺癌（MBC）患者的疗效及安全性。方法 24例患者接受氟维司群治疗,0、14及28 d各肌内注射250 mg,随后每28天肌内注射250 mg,直至肿瘤进展。主要研究终点为至疾病进展时间（TTP）,次要终点为客观有效率（ORR）及临床获益率（CBR）。结果本组24例患者中位TTP为4.4个月,ORR为8.3%（2/24）,CBR为25.0%,其中部分缓解（PR）2例,疾病稳定（SD）超过24周4例。氟维司群的疗效与患者术后无病生存期（DFS）及解救治疗线数等因素相关。全组不良反应较轻微。结论氟维司群是治疗MBC患者的有效内分泌治疗药物,安全性较好。     

依维莫司治疗晚期乳腺癌激素受体阳性患者中位生存期的影响因素分析

目的探究依维莫司治疗晚期乳腺癌激素受体(HR)阳性人表皮生长因子受体(HER-2)阴性患者中位生存期(mPFS)的影响因素。方法选择本院在2018年2月至2019年2月收治的98例采用依维莫司联合内分泌治疗的晚期HR(+)HER-2(-)乳腺癌患者,根据mPFS是否>3个月分为长期生存组(61例)与短期生存组(37例)。单因素分析影响mPFS的可能因素,进入多因素Logistic回归方程,总结影响晚期乳腺癌患者mPFS的可能因素。结果单因素分析显示,2组患者年龄、肿瘤类型、转移部位数目、既往化疗情况等因素均不会对mPFS造成影响(P>0.05),是否向远处转移、对内分泌治疗是否敏感对mPFS有明显影响(P<0.05);多因素分析显示,是否向远处转移、对内分泌治疗是否敏感均为影响晚期HR(+)HER-2(-)乳腺癌患者mPFS的相关危险因素(P<0.05)。结论内分泌治疗联合依维莫司可通过改善晚期HR(+)HER-2(-)乳腺癌患者的内分泌治疗耐药性,而延长其mPFS。     

口服选择性雌激素受体降解剂抗乳腺癌新药艾拉司群

选择性雌激素受体降解剂(selective estrogen receptor degrader,SERD)是雌激素受体(estrogen receptor,ER)阳性的晚期乳腺癌(breast cancer)内分泌治疗的常用药物。艾拉司群(elacestrant)是治疗晚期乳腺癌ER阳性,人表皮细胞生长因子受体(human epidermal growth factor receptor,HER)2阴性的新型口服SERD,疗效优于其他内分泌治疗,可显著改善患者中位无进展生存期,且对于ER基因α突变的乳腺癌患者有效。艾拉司群的上市将为ER阳性、HER2阴性的晚期乳腺癌患者提供更有效的治疗药物选择。     

哌柏西利治疗乳腺癌的临床研究进展

哌柏西利是一种同类首创的细胞周期蛋白依赖性激酶4/6抑制剂，是抗肿瘤药物发展史上一个重要的里程碑。哌柏西利联合芳香化酶抑制剂或氟维司群作为一线、二线或后线治疗，对激素受体阳性、人表皮生长因子受体-2阴性的局部晚期或转移性乳腺癌有良好的疗效和安全性，应用前景较好。本文总结了哌柏西利相关的临床研究和安全性研究等问题。     

四个新获准上市或新增适应证的抗肿瘤药物

诺华制药公司开发的依维莫司（商品名：Afinitor）于2012年7月20日获美国FDA批准,与依西美坦（商品名：Aromasin）联用于治疗激素受体阳性、HER2阴性的绝经后晚期乳腺癌患者。FDA药物评价和研究中心血液和肿瘤学产品办公室主任RichardPazdur博士称,这是mTOR抑制剂类药物首次获准用于激素受体阳性的绝经后晚期乳腺癌患者的治疗。     

欧盟批准乳腺癌治疗药物氟维司群

阿斯利康公司近日宣布,欧盟批准了Faslodex(fulvestrant,氟维司群) 用于接受过抗雌激素治疗的绝经后妇女的晚期乳腺癌治疗。Faslodex是一类新型的雌激素受体阻断剂,用于抗雌激素疗法治疗无效、雌激素受体呈阳性的绝经后晚期乳腺癌的治疗。其作用机制与芳香酶抑制剂不同,芳香酶抑制剂是减少妇女体内雌激素的浓度,该药物的作用机制是阻断雌激素与受体结合。芳香酶抑制剂和他莫昔芬(tamoxifen)都是治疗晚期乳腺癌的标准疗法,且耐受性良好,但是肿瘤细胞有时能够产生对芳香酶抑制剂和他莫昔芬的耐药性。Faslodex的上市为患有乳腺癌的绝经后妇女…     

Fulvestrant: a new type of estrogen receptor antagonist for the treatment of advanced breast cancer

Postmenopausal women with hormone receptor- positive tumors are candidates for endocrine treatment. Current treatment options include the selective estrogen receptor modulators (e.g., tamoxifen and toremifene), which inhibit estrogen receptor signaling, and the aromatase inhibitors (e.g., anastrozole and letrozole), which prevent the conversion of androgens into estrogen in postmenopausal women. As most patients eventually become resistant to endocrine agents, there is a need for new treatments that are effective, well tolerated and lack cross-resistance with currently available therapies. This review describes the development of fulvestrant (Faslodex), a new type of endocrine agent, which is an estrogen receptor antagonist with no agonist effects. Phase III clinical trials have found that fulvestrant is as effective and well tolerated as anastrozole for treating postmenopausal patients with advanced breast cancer who have progressed on one prior endocrine therapy. In addition, fulvestrant has first-line efficacy similar to that of tamoxifen in patients with estrogen receptor-positive and/or progesterone receptor-positive breast cancer. Moreover, in a compassionate-use program, it has become clear that fulvestrant is not cross-resistant with other therapies. Therefore, fulvestrant is a versatile new treatment option for postmenopausal women with advanced breast cancer who have progressed on prior endocrine therapy.     

An evaluation of fulvestrant for the treatment of metastatic breast cancer

ABSTRACT

Introduction: Fulvestrant is currently the only selective estrogen receptor degrader (SERD) that is approved for clinical use in estrogen receptor (ER) positive advanced breast cancer (ABC). The drug is approved as single-agent therapy in the first and second-line setting of metastatic ER-positive breast cancer.

Areas covered: In this review, the authors review the preclinical studies that were pivotal in the development of fulvestrant, the pharmacologic properties of the drug, and the key clinical trials that resulted in its approval for clinical use. The authors discuss mechanisms of endocrine resistance and potential targets for endocrine refractory disease while highlighting ongoing studies that assess fulvestrant use with novel agents.

Expert opinion: While fulvestrant has limited use in the first-line setting in advanced breast cancer, it is most frequently used in the second line after progression with aromatase inhibitors. The combination of fulvestrant with CDK4/6 inhibitors has shown a clear benefit over monotherapy in patients who progress on prior endocrine therapy. Further study is necessary to assess if patient outcomes can be enhanced by optimizing the sequence of endocrine therapies, targeting resistance pathways with novel agents, and development of new agents in the SERD class.     

Emerging data on the efficacy and safety of fulvestrant, a unique antiestrogen therapy for advanced breast cancer

INTRODUCTION: Fulvestrant is an antiestrogen therapy with a unique mechanism of action. Unlike the selective estrogen receptor modulator tamoxifen, fulvestrant has no known estrogen agonist activity and is considered a pure antiestrogen. Its primary mechanism of action is thought to result from downregulation of the estrogen receptor (ER). Considerable data have demonstrated the efficacy of fulvestrant in postmenopausal women with ER-positive advanced breast cancer, both in the first-line setting and following disease progression on tamoxifen or aromatase inhibitors. Recent studies report improved benefit with alternative dosing strategies. At all administration schedules, fulvestrant has an excellent safety profile with no significant adverse effects. AREAS COVERED: This article provides a review of the mechanism of action of fulvestrant and the preclinical and clinical data evaluating its use as a form of endocrine therapy. The reader will gain insight into the pharmacologic properties of the drug and its role in the treatment of advanced hormone receptor-positive breast cancer in postmenopausal women. EXPERT OPINION: Based on data demonstrating the efficacy of fulvestrant, including prolonged clinical benefit in many patients, this well-tolerated antiestrogen is an important therapy for breast cancer. The optimal position of fulvestrant in the sequence of endocrine therapies for postmenopausal women and its role in combination regimens are not yet resolved.     

Fulvestrant for the treatment of endometrial cancer

Introduction: About one third of patients with endometrial cancer (EC) relapse and face a limited prognosis, if surgery or radiotherapy are not feasible. The remaining therapeutic options are chemotherapy and endocrine therapy.

Areas covered: This review summarizes the development of the first selective estrogen receptor (ER) down-regulator fulvestrant. This article provides its mechanism of action, pharmacokinetics and the available preclinical and clinical data. Furthermore, this review provides an overview of the market of treatments for recurrent or metastatic EC (RMEC) while also taking into account studies of fulvestrant in metastatic breast cancer.

Expert opinion: Even if fulvestrant showed only marginal activity in two phase II trials, it shouldn’t be abandoned but instead further developed in EC. Firstly, the dose of fulvestrant used in these trials was too low from today’s point of view. Secondly, the available literature on other endocrine agents is full of limitations and does not provide a gold standard. Furthermore, given the activity of mTOR inhibitors in EC, there may also be synergistic effects, given the cross-regulation of ER and the PI3K/AKT/mTOR pathway. The authors suggest that a prospective, phase II trial in ER positive RMEC would help to further explore the efficacy and tolerability of fulvestrant together with a mTOR inhibitor.     

Emerging data on the efficacy and safety of fulvestrant,a unique antiestrogen therapy for advanced breast cancer

Introduction: Fulvestrant is an antiestrogen therapy with a unique mechanism of action. Unlike the selective estrogen receptor modulator tamoxifen, fulvestrant has no known estrogen agonist activity and is considered a pure antiestrogen. Its primary mechanism of action is thought to result from downregulation of the estrogen receptor (ER). Considerable data have demonstrated the efficacy of fulvestrant in postmenopausal women with ER-positive advanced breast cancer, both in the first-line setting and following disease progression on tamoxifen or aromatase inhibitors. Recent studies report improved benefit with alternative dosing strategies. At all administration schedules, fulvestrant has an excellent safety profile with no significant adverse effects.

Areas covered: This article provides a review of the mechanism of action of fulvestrant and the preclinical and clinical data evaluating its use as a form of endocrine therapy. The reader will gain insight into the pharmacologic properties of the drug and its role in the treatment of advanced hormone receptor-positive breast cancer in postmenopausal women.

Expert opinion: Based on data demonstrating the efficacy of fulvestrant, including prolonged clinical benefit in many patients, this well-tolerated antiestrogen is an important therapy for breast cancer. The optimal position of fulvestrant in the sequence of endocrine therapies for postmenopausal women and its role in combination regimens are not yet resolved.     

Fulvestrant: a review of its use in the management of hormone receptor-positive metastatic breast cancer in postmenopausal women

Fulvestrant (Faslodex?) is an intramuscularly administered steroidal estrogen receptor antagonist that is devoid of any known estrogen agonist effects. It is indicated as second-line therapy for the treatment of postmenopausal women with hormone receptor-positive advanced breast cancer who have progressed following prior endocrine therapy. In well designed, randomized clinical trials, regimens of fulvestrant 250 and 500 mg provided effective second-line therapy for postmenopausal women with advanced breast cancer who had progressed following prior endocrine therapy. Moreover, fulvestrant 250 mg monthly (with or without a loading dose) was as effective as aromatase inhibitor therapy. However, fulvestrant is absorbed slowly, and greater steady-state concentrations are achieved more rapidly when using a higher dosage with a loading dose regimen. Consequently, a regimen of fulvestrant 500 mg monthly with a loading dose was significantly more effective than a regimen of 250 mg monthly in postmenopausal women with disease progression. Limited data also indicate a potential role for the fulvestrant 500 mg regimen as first-line therapy. Fulvestrant is generally well tolerated with no additional adverse events noted with the high-dose regimen compared with the 250 mg regimens. Furthermore, the incidence of joint disorders was shown to be significantly lower with fulvestrant 250 mg monthly than with anastrozole. Treatment with fulvestrant is not associated with any clinically significant effects on endometrial thickening, bone-specific turnover markers or sex hormone levels. In conclusion, a monthly regimen of intramuscular fulvestrant 500 mg with a loading dose provides effective and well tolerated second-line therapy for postmenopausal women with advanced breast cancer who have progressed following prior endocrine therapy and is now the approved optimal dose.     

Fulvestrant – a new treatment for postmenopausal women with hormone-sensitive advanced breast cancer

Approximately 75% of breast tumours in postmenopausal women are positive for the oestrogen receptor (ER) and/or the progesterone receptor (PgR) and are, therefore, potential candidates for endocrine treatment. Fulvestrant is a new type of ER antagonist with no agonist effects and a novel mode of action; it binds, blocks and degrades the ER, leading to a reduction in cellular ER and, consequently, in PgR levels. This novel mode of action results in a lack of cross-resistance with other commonly used endocrine treatments. In Phase III trials in postmenopausal women with advanced breast cancer progressing on prior anti-oestrogen therapy, fulvestrant was at least as effective as the third-generation aromatase inhibitor, anastrozole, in terms of time to progression and objective response, and was associated with similar overall survival. In the first-line setting, fulvestrant showed similar efficacy to tamoxifen in patients with ER-positive and/or PgR-positive disease. Efficacy in more heavily pretreated patients has also been demonstrated in the fulvestrant compassionate use programme. Fulvestrant is well tolerated, being associated with a significantly lower incidence of joint disorders compared with anastrozole, and a lower incidence of hot flushes compared with tamoxifen. Fulvestrant, therefore, provides clinicians with a useful additional treatment for hormone-sensitive advanced breast cancer in postmenopausal women. Ongoing trials will help to clarify the optimal position of fulvestrant in the endocrine treatment sequence for these patients.     

Fulvestrant - a new treatment for postmenopausal women with hormone-sensitive advanced breast cancer

Approximately 75% of breast tumours in postmenopausal women are positive for the oestrogen receptor (ER) and/or the progesterone receptor (PgR) and are, therefore, potential candidates for endocrine treatment. Fulvestrant is a new type of ER antagonist with no agonist effects and a novel mode of action; it binds, blocks and degrades the ER, leading to a reduction in cellular ER and, consequently, in PgR levels. This novel mode of action results in a lack of cross-resistance with other commonly used endocrine treatments. In Phase III trials in postmenopausal women with advanced breast cancer progressing on prior anti-oestrogen therapy, fulvestrant was at least as effective as the third-generation aromatase inhibitor, anastrozole, in terms of time to progression and objective response, and was associated with similar overall survival. In the first-line setting, fulvestrant showed similar efficacy to tamoxifen in patients with ER-positive and/or PgR-positive disease. Efficacy in more heavily pretreated patients has also been demonstrated in the fulvestrant compassionate use programme. Fulvestrant is well tolerated, being associated with a significantly lower incidence of joint disorders compared with anastrozole, and a lower incidence of hot flushes compared with tamoxifen. Fulvestrant, therefore, provides clinicians with a useful additional treatment for hormone-sensitive advanced breast cancer in postmenopausal women. Ongoing trials will help to clarify the optimal position of fulvestrant in the endocrine treatment sequence for these patients.