芳香化酶抑制剂不同顺序治疗转移性乳腺癌的临床研究

背景与目的:第三代芳香化酶抑制剂(aromatase inhibitors,Als)已经成为治疗复发转移乳腺癌的重要手段.因此本研究旨在通过观察甾体类(依西美坦)和非甾体类(阿那曲唑、来曲唑)3种AIs不同顺序治疗复发转移性乳腺癌患者的疗效,探讨其是否存在交叉耐药.方法:回顾分析既往曾经先后用过甾体类和非甾体类AIs,且能够评价疗效和记录疾病进展时间(time to progression,TTP)和(或)治疗失败时间(time to failure,TTF)的80例复发转移性乳腺癌女性患者,全部患者都有雌激素受体(estrogen receptor,ER)和(或)孕激素受体(progesterone receptor,PR)阳性的结果,主要观察终点为临床获益率(clinical benefit rate,CBR).结果:80例患者中,非甾体类阿那曲唑一线解救的CBR是62.5%(15/24)、来曲唑是71.1%(32/45)、甾体类依西美坦为81.8%(9/11).一线甾体类治疗失败后换用非甾体类的CBR为36.4%(4/11),而一线非甾体类治疗失败后,换用甾体类CBR为24.6%(14/57),一线非甾体类失败后,换用另一种非甾体类的CBR为16.7%(2/12).结论:一种AIs失败后换用另一种AIs仍有获益.总体而言,用药越晚,疗效越差,所以尽早选用疗效相对较高的药物是合适的选择.     

卵巢功能去势联合芳香化酶抑制剂治疗绝经前转移性乳腺癌的临床研究

目的 评价卵巢功能去势联合芳香化酶抑制剂（AI）治疗绝经前转移性乳腺癌患者的临床疗效及预后。方法 140例绝经前激素受体阳性的晚期乳腺癌患者,接受卵巢功能去势（包括双侧卵巢切除手术和戈舍瑞林）联合AI（包括阿那曲唑、来曲唑和依西美坦）的治疗。评价疗效并分析影响预后的因素。结果 全组患者的中位无进展生存时间（PFS）为8.0个月,临床获益率（CBR）为56.3％。接受一线内分泌治疗患者的中位PFS为9.0个月（95％CI：6.3～11.7个月）,接受二线及以上内分泌治疗患者的中位PFS为6.0个月（95％CI：4.1～7.9个月）,两者差异有统计学意义（P=0.002）;两组患者的临床获益时间分别为13.1个月（95％CI：10.9～16.3个月）和9.3个月（95％CI：6.8～11.8个月）,CBR分别为66.7％和35.6％,差异均有统计学意义（P＜0.05）。全组患者的亚组分析显示,单个部位转移、无内脏转移、既往未接受过解救化疗者治疗后获得更长的中位PFS和更好的CBR。Cox多因素生存分析显示,转移灶数目是影响患者PFS的独立预后因素。结论 卵巢功能去势联合AI治疗绝经前激素受体阳性的转移性乳腺癌患者临床疗效肯定,耐受性好,可作为一线治疗的选择。     

芳香化酶抑制剂在绝经后乳腺癌妇女内分泌治疗的策略

在肿瘤治疗领域很少有药物能改变疾病的过程，而第三代芳香化酶抑制剂的出现则改变了乳腺癌的治疗程式。大量随机、前瞻、大样本临床试验结果的出现，使临床医师开始重新认识激素受体阳性和阴性乳腺癌在发病机制、治疗策略和预后方面的不同。     

芳香化酶抑制剂治疗乳腺癌研究进展

第3代芳香化酶抑制剂与其他内分泌制剂相比，具有疗效高、选择性强、毒副作用少等特点，已成为绝经后乳腺癌患者内分泌治疗的主要措施之一。现综述新一代芳香化酶抑制剂的抗肿瘤机制、药理学特性及在绝经后乳腺癌的治疗进展。     

芳香化酶抑制剂治疗乳腺癌研究进展

全文综述了三代芳香化酶抑制剂用于乳腺癌治疗的现状以及最新研究进展。     

芳香化酶抑制剂辅助治疗乳腺癌的远期效果

内分泌治疗是乳腺癌的重要治疗方法，雌激素：抑制能减少乳腺癌发生和抑制乳腺癌进展，尤其是对于激素依赖性的生长和转移。最近一些术后辅助治疗试验将第3代甾体或非甾体类芳香化酶抑制剂的应用和他莫昔芬（一种选择性雌激素受体调节剂）作了比较，结果表明芳香化酶抑制剂对于减少乳腺癌复发和对侧的乳腺癌再发优于他莫昔芬。     

绝经后乳腺癌患者长期应用芳香化酶抑制剂的不良反应及对策

芳香化酶抑制剂（AIs）是绝经后激素受体（HR）阳性乳腺癌患者辅助内分泌治疗的标准用药,包括非甾体类和甾体类,其中阿那曲唑、来曲唑属于非甾体类AIs,依西美坦属于甾体类AIs。在乳腺癌患者AIs类药物长期辅助治疗中,肌肉关节疼痛、骨丢失事件、血脂异常及心血管事件是需要临床医生关注的药物相关不良事件（AEs）。在乳腺癌患者的长期内分泌辅助治疗中,有效管理上述不良事件,有助于改善患者的生活质量,并提高患者的治疗依从性。     

孕激素类药物解救治疗芳香化酶抑制剂耐药的转移性乳腺癌的临床研究

  目的  评价孕激素类药物解救治疗第三代芳香化酶抑制剂(AIs)耐药的复发转移性乳腺癌的临床疗效。  方法  回顾性分析了本院自2000年1月至2010年12月, 87例接受孕激素类药物解救治疗AIs耐药的复发转移性乳腺癌的临床资料, 对临床疗效、影响疗效的因素以及不同孕激素类药物疗效差别等进行了分析。  结果  87例孕激素类药物解救治疗第三代AIs耐药的复发转移性乳腺癌患者, 临床获益率21.8%, 中位无进展生存期(PFS)3.0(2.5~3.5)个月。第三代AIs解救治疗是否获益与孕激素类药物PFS无关(P=0.796), 第三代AIs未获益者后接受孕激素类药物解救治疗仍然有22.8%患者临床获益。两种孕激素类药物甲羟孕酮、甲地孕酮有效率、临床获益率、PFS无差异(P=0.595, 0.737, 0.664)。Cox多因素分析显示孕激素类药物PFS与术后病理分型、同侧腋窝淋巴结转移状态、年龄、ER/PR状态、Her-2状态、是否接受辅助治疗等因素均无关相关性。  结论  孕激素类药物是解救治疗芳香化酶抑制剂(AIs)耐药的转移性乳腺癌的重要治疗选择。      

延长辅助内分泌治疗在激素受体阳性早期乳腺癌治疗中的价值

雌激素受体（estrogen receptor,ER）阳性早期乳腺癌的复发风险一直存在。MA.17试验证明,在淋巴结阳性、雌激素受体阳性的乳腺癌患者中,常规应用5年来曲唑治疗后继续应用他莫昔芬治疗,其无病生存期（disease-free survival,DFS）和整体生存期（overall survival,OS）都得到了明显改善。MA.17R试验证明,完成5年芳香化酶抑制剂治疗的患者,继续随机应用来曲唑或安慰剂,来曲唑组的DFS明显改善。在这些研究中,延长内分泌治疗能减少远期复发的绝对益处是适度的,然而其耐受性和依从性的挑战依然存在。对于完成5年常规内分泌治疗的患者,最终是选择他莫昔芬还是来曲唑来延长治疗,主要应该考虑患者的绝经状态、淋巴结情况、耐受性和潜在的利益大小这些因素。     

芳香化酶抑制剂的耐药机制及对策

芳香化酶抑制剂（aromatase inhibitors，AIs）在绝经后激素反应性乳腺癌妇女的辅助内分泌治疗和解救治疗效果优于三苯氧胺（tamoxifen，TAM）。然而，随着药物治疗的深入，AIs的耐药也逐渐显现。近年研究发现：AIs的原发耐药可能与芳香化酶基因多态性有关，但具体的原理还不甚清楚。AIs的继发耐药可能与雌激素受体（ER）和多个生长因子通路的交叉通话相关。针对AIs的耐药，许多学者进行了逆转耐药的研究，本文就AIs的原发与继发耐药机制及逆转耐药的策略进行综述。     

CDK4/6抑制剂在激素受体阳性进展期乳腺癌治疗中的研究进展

内分泌治疗因其兼具良好的疗效及安全性,是激素受体阳性进展期乳腺癌患者的重要治疗手段。近年来内分泌领域进展迅速,很多新型药物相继出现,其中包括多种可以逆转或延迟内分泌耐药的周期蛋白依赖性激酶(cyclin-dependent kinase,CDK)4/6抑制剂。CDK4/6抑制剂联合内分泌治疗可为激素受体阳性进展期乳腺癌患者带来生存获益、延迟至化疗时间,正逐渐改变国内外激素受体阳性进展期乳腺癌的治疗模式。本文将就CDK4/6抑制剂在激素受体阳性进展期乳腺癌中的治疗进展进行综述。     

Idoxifene versus tamoxifen: a randomized comparison in postmenopausal patients with metastatic breast cancer.

BACKGROUND: More efficacious and safer hormonal agents are needed for breast cancer treatment and prevention. Idoxifene is a novel selective estrogen receptor modulator (SERM) that, in preclinical models, has greater antiestrogenic but lower estrogenic activity than tamoxifen. PATIENTS AND METHODS: Three hundred and twenty-one postmenopausal patients with hormone receptor-positive or -unknown metastatic breast cancer were randomized to receive either tamoxifen or idoxifene as initial endocrine therapy for advanced disease. Data were analyzed based on intention to treat and all the responses were subject to independent review. RESULTS: At the time of a second planned interim analysis, the trial was stopped for economic considerations, not for reasons related to safety or efficacy. Complete data for the 219 patients included in the second interim analysis are fully available and reported here. Median age was 59.1 years for idoxifene patients and 59.9 years for tamoxifen patients. Complete response (CR) plus partial response (PR) rates were as follows: tamoxifen, 9%; idoxifene, 13% (P = 0.39). Clinical benefit rate [CR + PR + stable disease (SD) >or=6 months] was 34.3% for idoxifene and 38.7% for tamoxifen (P = 0.31). Median time to progression and duration of response were 140 days and 151.5 days, respectively, for tamoxifen compared with 166 days and 218 days for idoxifene. None of these endpoints was significantly different for the two drugs, nor was survival. Adverse events (lethal, serious but not lethal and important but not life threatening) were similar in the two arms. CONCLUSIONS: Idoxifene was both active and well tolerated in postmenopausal women with metastatic breast cancer. Idoxifene had similar efficacy and toxicity to tamoxifen in this randomized comparison.     

Aromatase inhibitors in adjuvant therapy for hormone receptor positive breast cancer: a systematic review

BACKGROUND: A systematic review was undertaken to review the evidence for the use of third-generation aromatase inhibitors (anastrozole, letrozole and exemestane) as adjuvant therapy for post-menopausal women with early-stage, hormone receptor-positive breast cancer and to develop and support recommendations for their use, with regard to three areas: aromatase inhibitors compared to tamoxifen, aromatase inhibitors in sequence with tamoxifen for a total of five years, and aromatase inhibitors given after five years of tamoxifen therapy. METHODS: MEDLINE, EMBASE, American Society of Clinical Oncology and San Antonio Breast Cancer Symposium proceedings, and the Cochrane Library were searched to May 2007 for reports of randomized controlled trials that met the inclusion criteria. RESULTS: Nine randomized controlled trials and one meta-analysis of three of these trials were identified that reported efficacy data. Eight of these trials reported significantly improved disease-free survival in the arms that involved aromatase inhibitors. The meta-analysis reported significantly improved overall survival among all patients, as did one individual trial. One trial of five years letrozole or placebo after five years tamoxifen found improved overall survival among node-positive patients. CONCLUSIONS: Aromatase inhibitors provide an alternative to tamoxifen as adjuvant therapy for post-menopausal, hormone-receptor-positive breast cancer patients. The options include anastrozole and letrozole for five years, as well as anastrozole and exemestane following two to three years of tamoxifen, for a total five years of hormonal therapy. Five years of letrozole should be considered following five years of tamoxifen. Patients receiving aromatase inhibitors should be monitored for changes in bone mineral density and for cardiovascular disease risk factors and outcomes.     

Aromatase inhibitors reverse tamoxifen induced endometrial ultrasonographic changes in postmenopausal breast cancer patients

Objective Aromatase inhibitors may decrease endometrial thickness in breast cancer patients previously having short-term tamoxifen treatment. There is a necessity to find out if aromatase inhibitors can also decrease endometrial thickness in patients previously treated with long-term tamoxifen treatment. Methods Prospective comparison of the last ultrasonographic endometrial thickness measurement taken before discontinuation of long-term tamoxifen treatment in 36 postmenopausal breast cancer patients, with further measurements, performed following aromatase inhibitors administration. Results There was a significant decrement of endometrial thickness, following 36.2 ± 16.8 months of tamoxifen treatment, from a mean value of 9.1 ± 5.8 mm, measured at the last ultrasonographic measurement performed before discontinuation of tamoxifen treatment, down to a mean value of 6.0 ± 5.0 mm, measured following 5.8 ± 5.8 months of aromatase inhibitors therapy (P = 0.001). A second ultrasonographic measurement performed in 8 patients following of additional 7.5 ± 4.0 months of aromatase inhibitors treatment revealed further decrement of mean endometrial thickness to 4.8 ± 2.1 mm (P = 0.002 compared to baseline). In 28 patients (77.8%), endometrial thickness was reduced following the administration of aromatase inhibitors, in four patients (11.1%) there was no change in endometrial thickness and four (11.1%) patients demonstrated an increase of endometrial thickness. Conclusions Aromatase inhibitors may reverse endometrial thickening induced by long-term tamoxifen treatment in postmenopausal breast cancer patients.     

Steroid hormone receptor levels and adjuvant tamoxifen in early breast cancer

Summary Ten year disease-free survival (DFS) results of the Naples randomized trial of adjuvant tamoxifen (TM), 30 mg per day for 2 years versus no therapy according to receptor levels, are reported. From Feb. 1, 1978, through Dec. 31, 1983, 308 pre- and postmenopausal patients with early breast cancer entered the trial. Estrogen receptor (ER) data were available on 239 (77.6%) patients, progesterone receptor (PgR) data on 194 (63.0%), and both receptor data on 181 (58.8%).ER and PgR were assayed by dextran-coated charcoal technique in a single laboratory. The effect of adjuvant TM was significantly related to ER and PgR concentration of the primary tumor. The greatest TM benefit on DFS was evident in patients with the highest levels of receptors. The interaction between the treatment effect and receptor concentration was found whether ER and PgR were considered separately or together. Address for reprints: A. Raffaele Bianco, Division of Medical Oncology, University of Naples Medical School II, via S. Pansini, 5-80131 Naples, Italy     

A phase III comparison of two toremifene doses to tamoxifen in postmenopausal women with advanced breast cancer

Efficacy and safety of toremifene 60 and 240mg daily (TOR60 and TOR240) are compared to40 mg tamoxifen daily (TAM40) in postmenopausal womenwith advanced estrogen receptor (ER) positive or ERunknown breast cancer. The study is randomized andopen label in three parallel groups. Primary efficacyvariables are response rate and time to progression.WHO and ECOG criteria were used for measurableand nonmeasurable disease assessment, respectively. Safety was reportedaccording to WHO criteria. Altogether 463 patients wererandomized (157 to TOR60, 157 to TOR240, and149 to TAM40). By data cut-off, after 20.5months median follow-up time, over 70% of thepatients had experienced disease progression. Response rates are20.4%, 28.7%, and 20.8% in TOR60, TOR240, andTAM40, respectively. TOR60 and TAM40 show statistically equivalentefficacy and the difference between TOR240 and TAM40is not significant (P=0.112). Median timesto progression are 4.9 (TOR60), 6.1 (TOR240), and5.0 (TAM40) months and the corresponding hazard ratios(TAM:TOR) 1.015 and 1.124. Again, TOR60 and TAM40are statistically equivalent and the difference between TOR240and TAM40 is not significant (P=0.374).All treatments were well tolerated. As a conclusion,TOR60 and TAM40 show equivalent clinical efficacy andtolerability. The higher dose of toremifene slightly butnot statistically significantly improves response rate and timeto progression. In postmenopausal women, toremifene 60 mgdaily is an effective and safe treatment ofadvanced ER-positive or ER-unknown breast cancer.     

Second- and third-generation aromatase inhibitors as first-line endocrine therapy in postmenopausal metastatic breast cancer patients: a pooled analysis of the randomised trials

The purpose of this study was to estimate in all randomised trials the relative risk of overall response rate (ORR), clinical benefit (CB), time to progression (TTP), overall survival (OS), and toxicity of aromatase inhibitors (AI), compared with tamoxifen (Tam) as first-line endocrine therapy in postmenopausal metastatic breast cancer (PMBC) women. Prospective randomised studies were searched through computerised queries of MEDLINE, EMBASE, and the American Society of Clinical Oncology (ASCO) abstract database. Relative risk, 95% confidence interval, and heterogeneity were derived according to the inverse variance and Mantel-Haenszel method and Q statistics. Six phase III prospective randomised trials including 2787 women were gathered. A significant advantage in ORR (P = 0.042), TTP (P = 0.007), and CB (P = 0.001) in favour of AI over Tam was detected at the fixed effects model. These results were not significant at the random effects model, owing to the significant heterogeneity. On the contrary, no difference was registered for OS (P = 0.743) with no significant heterogeneity. Regarding toxicity, Tam caused more frequently thromboembolic events (P = 0.005) and vaginal bleeding (P = 0.001) compared with AI. Aromatase inhibitors appear to be superior to Tam as first-line endocrine option in PMBC women. Owing to a component of variability between the six studies analysed, the random effects estimates differed from corresponding fixed ones. Investigators should assess heterogeneity of trial results before deriving summary estimates of treatment effect.     

Five years of stable disease with maintenance therapy using bevacizumab and tamoxifen in a patient with metastatic breast cancer

Bevacizumab and Tamoxifen are valid therapeutic options for metastatic breast cancer (mBC) patients. In this report, we describe a 47 year old woman with mBC successfully treated with a maintenance therapy with Bevacizumab+Tamoxifen. A maintenance approach using 2 different drugs with different targets and mechanism of action, such as anti-angiogenic and anti-hormonal treatment is particularly intriguing because they affect different pathways involved in mBC progression. Further studies including a large number of patients are needed, in order to select women who could benefit from this maintenance approach.     

Aromatase inhibitor versus tamoxifen in postmenopausal woman with advanced breast cancer: a literature-based meta-analysis

Clinical trials have reported conflicting results as to whether Aromatase inhibitors (AIs) as first-line hormonal therapy improve outcome over tamoxifen in postmenopausal women with advanced breast cancer. We performed a meta-analysis comparing primary and secondary endpoints of AIs to tamoxifen as first-line hormonal therapy in postmenopausal women with advanced breast cancer. The event-based odds ratio (OR) with 95% confidence interval (95% CI) were derived, and a test of heterogeneity was applied. Six eligible trials (2560 patients) were selected from 488 studies that initially were identified. A significant difference in favoring AIs over tamoxifen was observed in overall response rate (ORR; OR, 1.56; 95% CI, 1.17-2.07; P = .002) and clinical benefit (CB; OR, 1.70; 95% CI, 1.24-2.33; P = .0009).Whereas the trend toward an improved overall survival (OS) rate was not significant (OR, 1.95; 95% CI, 0.88-4.30; P = .10).Toxicities did not differ significantly except vaginal bleeding (OR, 0.30; 95% CI, 0.16-0.56; P = .0002) and thromboembolic event (OR, 0.47; 95% CI, 0.28-0.77; P = .003). AIs appeared to be effective and feasible compared with tamoxifen as first-line hormonal therapy in postmenopausal women with advanced breast cancer. Further prospective, randomized, controlled trials will be necessary.