戈舍瑞林联合三苯氧胺治疗绝经前ER~＋PR~＋及ER~＋PR~-复发转移性乳腺癌疗效观察

目的：探讨戈舍瑞林联合三苯氧胺辅助内分泌治疗绝经前雌激素（ER）、孕激素（PR）双阳性及ER＋/PR-两种复发转移乳腺癌的临床疗效,对比两种乳腺癌的治疗效果。方法：将104例绝经前、原癌基因（c-erbB-2）均为（＋）、淋巴结1-3个阳性的复发转移乳腺癌患者分成两组,52例ER＋/PR＋,52例为ER＋/PR-。两组患者均为手术后和辅助化疗后发现复发转移的乳腺癌接受戈舍瑞林3.6mg皮下注射,每28天1次,连续6个月以上;联合三苯氧胺口服,10mg/次,每日2次,连用6个月以上。结果：104例患者完全缓解（CR）3例,部分缓解（PR）31例,稳定（SD）31例,进展（PD）39例,总有效率（OR=CR＋PR）为32.7%,临床获益率（CBR=CR＋PR＋SD≥6个月）62.5%;其中ER＋、PR-组,CR 2例,PR 21例,SD 16例,PD 13例,OR为44.1%,CBR 74.9%;ER＋、PR-组CR 1例,PR 10例,SD 15例,PD 26例,OR 21.1%,CBR 49.9%。结论：戈舍瑞林联合三苯氧胺辅助内分泌治疗绝经前ER阳性、淋巴结1-3阳性、复发转移性的乳腺癌患者临床疗效显著,而ER＋/PR＋组患者效果明显优于ER＋、PR-组患者,临床治疗效果更佳。对于在辅助内分泌治疗期间发生PD,应立即中止辅助内分泌治疗,进行手术、解救化疗、放疗或分子靶向等治疗后再序贯内分泌治疗。     

戈舍瑞林联合内分泌治疗高复发风险绝经前乳腺癌的临床研究

背景与目的:具有高复发风险因素的绝经前乳腺癌患者预后至今仍不理想,促黄体激素释放激素类似物(luteinizing hormone-releasing hormone,LHRH)与手术去势作用相似,是一种有效的乳腺癌治疗方法.本研究旨在探讨戈舍瑞林(goserelin)联合内分泌治疗在绝经前高危乳腺癌患者综合治疗中的作用.方法:回顾性分析72例完成标准治疗后予戈舍瑞林联合他莫两芬(tamoxifen,TAM)或芳香化酶抑制剂(aromatase inhibitors,Als)治疗的具有高复发风险因素绝经前乳腺癌患者的临床资料,并以UICC 2002年标准分期、确诊时间、年龄及激素受体情况等指标,采用逐一配对的方法选取间期单用TAM治疗的72例患者作为对照,比较两组的近和远期疗效,探讨影响生存的预后因素,同时观察戈舍瑞林的相关不良反应.结果:戈舍瑞林组与对照组患者经比较,5年无病生存率(84.7%和58.3%,P=0.011)及总生存率(88.9%和80.1%,P=0.049)差异均有统计学意义.多因素COX回归分析表明是否使用戈舍瑞林是两组患者无病生存的独立预后因素(HR=0.315;95%CI=0.103～0.090;P=0.029),戈舍瑞林可使具有高复发风险因素的绝经前乳腺癌患者复发转移风险下降68%.用药期间无明显不良反应发生.结论:标准治疗后予戈舍瑞林联合TAM或AIs可提高具有年龄≤35岁,淋巴结转移数目>10个等高复发风险因素激素受体阳性乳腺癌患者的无病生存时间,并有改善其总生存的趋势,临床不良反应少且较易耐受.     

戈舍瑞林联合内分泌药物治疗绝经前晚期乳腺癌的临床研究

背景与目的:目前绝经前晚期乳腺癌的疗效仍不甚理想,卵巢去势是激素受体阳性晚期乳腺癌的有效治疗手段之一,卵巢去势药物促黄体激素释放激素类似物(luteinizing hormone-releasing hormone,LHRH),如戈舍瑞林,与手术或放疗去势疗效相当.本研究旨在探讨戈舍瑞林联合内分泌药物治疗激素受体阳性的绝经前晚期乳腺癌的疗效.方法:戈舍瑞林联合内分泌药物治疗组30例,个体匹配,选取同期30例应用三苯氧胺治疗的患者作为对照组,采用Kaplan-Meier法计算生存率,用log-rank方式进行差异的显著性检验,主要研究指标为无疾病再次进展生存时间(progression-free survival,PFS)和总生存时间(overall survival,OS).结果:治疗组和对照组的中位PFS分别为47.9个月和16.7个月,1,2和3年无疾病再次进展生存率分别为86.7% vs 58.9%,73.0% vs 43.1%和62.6% vs 38.3%(P=O.039);治疗组和对照组1、2和3年的总生存率分别为100% vs 83.3%、82.9% vs 57.5%和79.1% vs 48.9%(P=0.010).年龄＜40岁的患者,治疗组的PFS(P=O.027)和OS(P=0.007)较对照组显著提高,年龄≧40岁的患者使用戈舍瑞林则对预后无影响(P>O.05).疾病再次进展后继续使用戈舍瑞林中位生存时间较未使用者显著延长(28.2个月 vs 7.0个月),具有潜在受益(P=0.070).结论:对于激素受体阳性的绝经前晚期乳腺癌,戈舍瑞林联合内分泌药物可作为年龄＜40岁患者的标准内分泌治疗方法,对于出现疾病再次进展的患者,建议继续使用戈舍瑞林.     

戈舍瑞林用于乳腺癌治疗的研究进展

综述戈舍瑞林的抗肿瘤机制，临床前研究以及临床研究的现状，研究证明戈舍瑞林是一种安全、有效、可逆的卵巢功能抑制药物，对绝经前晚期乳腺癌患者，戈舍瑞林单药或戈舍瑞林和三苯氧胺联用至少能达到同卵巢去势或CMF化疗相同的疗效；用作绝经前乳腺癌患者术后辅助治疗。对雌激素受体阳性腋淋巴结有转移的患者，戈舍瑞林可获得和CMF化疗方案同样的疗效，但戈舍瑞林副作用少于卵巢去势或CMF化疗。     

戈舍瑞林在绝经前乳腺癌内分泌治疗中对卵巢功能抑制作用的前瞻性临床研究

乳腺癌是一种激素依赖性的疾病,辅助内分泌治疗在预防术后复发和转移中起着重要作用。目前临床研究和应用较多的药物是第三代芳香化酶抑制剂,主要适用于绝经后激素受体阳性的乳腺癌患者。而我国的乳腺癌患者中约有60％～70％处于绝经前期,其中约60％的患者雌激素受体阳性。     

弗隆与三苯氧胺内分泌治疗序次对绝经后乳腺癌患者预后的影响

三苯氧胺 (TAM )已成为各期乳腺癌患者优先的一线内分泌治疗选择。第 3代芳香化酶抑制剂如弗隆(letrozole)、瑞宁得 (anatrozole)等 ,因其疗效和耐受性方面的优势 ,已有取代TAM成为进展期乳腺癌一线治疗的可能。ILBCG(TheInternationalLetrozolBreastCancerGroup)开展的一项双盲随机化Ⅲ期临床试验比较了弗隆 (n =4 5 3)与TAM (n =4 5 4)作为一线治疗用于绝经后进展期乳腺癌的结果。显示弗隆在病情进展时间 (TTP)、治疗失败时间 (TTF)、客观缓解率和临床获益率 (CBR)方面均优于TAM ;进一步进行交叉分组 ,即原先接受弗隆一线治…     

戈舍瑞林治疗乳腺癌研究的回顾与展望

1977年明确促黄体激素释放激素 (ｌｕｔｅｉｎｉｚｉｎｇｈｏｒｍｏｎｅ ｒｅ ｌｅａｓｉｎｇｈｏｒｍｏｎｅ ,ＬＨＲＨ )化学结构后 ,ＬＨＲＨ类似物 (ＬＨＲＨ Ａ )的合成开辟了乳腺癌辅助治疗的新途径。目前研究开发的ＬＨＲＨ -Ａ有戈舍瑞林 ( ｇｏｓｅｒｅｌｉｎ ,商品名ｚｏｌａｄｅｘ)、亮丙瑞林(ｌｅｕｐｒｏｒｅｌｉｎ)、曲普瑞林 (ｔｒｉｐｔｏｒｅｌｉｎ ,商品名ｄｅｃａｐｅｐｔｙｌ ,达必佳 )、布舍瑞林 (ｂｕｓｅｒｅｌｉｎ)等 ,其中戈舍瑞林是目前ＬＨＲＨ -Ａ中研究较为成熟的 1种 ,现对该药治疗乳腺癌的研究现状综述如下。…     

来曲唑与三苯氧胺在绝经后期乳腺癌新辅助内分泌治疗中的疗效对比

目的 比较来曲唑与三苯氧胺用于绝经后期乳腺癌新辅助内分泌治疗的近期疗效和毒副反应.方法将收治的绝经后期、ER阳性、有合并症的55例乳腺癌随机分为两组,并行新辅助内分泌治疗.来曲唑组25例:2.5 mg/次,1次/d,连续60 ～90 d;三苯氧胺组30例:10mg/次,2次/d,连续60～90 d.比较两组的近期疗效和...     

戈舍瑞林联合来曲唑治疗高复发风险绝经前乳腺癌的疗效观察

目的:比较戈舍瑞林联合三苯氧胺(TAM)与联合芳香化酶抑制剂(A1)来曲唑治疗高复发风险绝经前乳腺癌的临床疗效.方法:收集2003-06-01-2007-06-01大连市中心医院治疗的50例有高复发风险激素受体阳性的绝经前乳腺癌患者进行回顾性研究.所有患者均为标准治疗后给予戈舍瑞林(3.6 mg,每28～30 d皮下注射1次,至少1年),其中联合应用TAM(20 mg/d,连续5年)的为TAM组(n=25),联合应用来曲唑(2.5 mg/d,连续5年)的为AI组(n=25),评价两组的临床疗效和不良反应.结果:AI组患者无进展生存期(PFS)为11～74个月(中位PFS为72个月),高于TAM组的10～74个月(中位PFS为49个月),x2=5.90,P=0.015 2;两组患者总生存期(OS)分别为28～80和25～78个月,差异无统计学意义,x2=1.56,P=0.2115.两组患者用药后主要不良反应为骨关节疼痛不适感、潮热或多汗、阴道干涩和焦虑易怒等,差异无统计学意义,P＞0.05.结论:戈舍瑞林联合AI治疗高复发风险激素受体阳性的绝经前乳腺癌患者,疗效明显优于戈舍瑞林联合TAM,而且不良反应可耐受.     

戈舍瑞林联合阿那曲唑作为一线内分泌方案治疗绝经前伴中、高危复发转移因素乳腺癌的临床研究

背景与目的:现已证实治疗绝经前乳腺癌患者,阿那曲唑疗效优于他莫昔芬,并有研究表明戈舍瑞林为安全有效的卵巢去势药物,然而两者联用作为乳腺癌内分泌治疗一线方案则鲜有报道.本研究旨在观察分析戈舍瑞林联合阿那曲唑作为绝经前伴中、高危复发转移因素的乳腺癌一线内分泌治疗临床疗效和预后.方法:分析本中心2002年至今应用戈舍瑞林联合阿那曲唑作为绝经前伴中、高危复发转移因素的68例乳腺癌患者一线内分泌治疗方案的疗效和预后:应用戈舍瑞林3.6 mg,每28 d皮下注射1次;阿那曲唑1 mg口服,每天1次;28 d为1个周期.所有患者按期评价疗效和不良反应.结果:68例患者中2例出现肿瘤复发转移,其余66例患者随访至今未出现肿瘤复发转移;中位治疗时间为3.6年,中位随访时间为48个月,无病生存率(disease-free survival,DFS)为97.1%,总生存率(overall survival,OS)为98.5%.结论:戈舍瑞林联合阿那曲唑治疗绝经前伴有中、高危复发转移因素乳腺癌疗效肯定,不良反应较轻,是一种有效的一线内分泌治疗药物.     

Clinical and endocrine data for goserelin plus anastrozole as second-line endocrine therapy for premenopausal advanced breast cancer

A total of 16 premenopausal women with metastatic breast cancer (N=13) or locally advanced primary breast cancer (N=3) were treated with a combination of a gonadotropin-releasing hormone agonist goserelin, and a selective aromatase inhibitor anastrozole. All had previously been treated with goserelin and tamoxifen. In all, 12 patients (75%) achieved objective response or durable stable disease at 6 months, with a median duration of remission of 17+ months (range 6-47 months). Four patients still have clinical benefit. Introduction of goserelin and tamoxifen resulted in an 89% reduction in mean oestradiol levels (pretreatment vs 6 months=224 vs 24 pmol l(-1)) (P<0.0001). Substitution of tamoxifen by anastrozole on progression resulted in a further 76% fall (to 6 pmol l(-1) at 3 months) (P<0.0001). Treatment with goserelin and tamoxifen led to a 90% fall in the mean follicle-stimulating hormone (P<0.001). This was reversed once therapy was changed to goserelin and anastrozole. A similar initial reduction was seen in the mean luteinising hormone levels, but substitution of tamoxifen by anastrozole on progression resulted in no significant change. Goserelin and tamoxifen did not lead to any significant change in testosterone and androstenedione levels. The combined use of goserelin and anastrozole as second-line endocrine therapy produces a significant clinical response of worthwhile duration, with demonstrable endocrine changes, in premenopausal women with advanced breast cancer, and offers them another therapeutic option. Further studies involving more patients and longer follow-up are indicated.     

Combined effects of goserelin and tamoxifen on estradiol level,breast density,and endometrial thickness in premenopausal and perimenopausal women with early-stage hormone receptor-positive breast cancer: a randomised controlled clinical trial

Background:

This study is to investigate the effects of geserelin+tamoxifen (TAM) on estradiol level, breast density (BD), endometrial thickness (ET), and blood lipids in premenopausal and perimenopausal women with hormone receptor-positive early-stage breast cancer.

Methods:

This study recruited 110 premenopausal and perimenopausal patients with hormone receptor-positive early-stage breast cancer between 22 June 2008 and 31 December 2009 and randomly assigned them to receive either goserelin plus TAM or TAM alone for 1.5 years. Blood levels of sex hormones and lipids and ET were determined at 0, 3, 6, 12, and 18 months. Contralateral BD was also measured at 0, 12, and 18 months.

Results:

Five participants dropped out of the goserelin plus TAM group, and two participants dropped out of the TAM-alone group before initiation of endocrine therapy. The rest of patients received scheduled treatment and 3 years of median follow-up. No serious adverse effects were observed, and only two local recurrences have been observed in these patients. Estradiol level and BD were lower in the goserelin plus TAM group than in the TAM-alone group (P<0.05). The endometrium in the goserelin plus TAM group was significantly thinner than that in the TAM-alone group (P<0.05), and women in the TAM-alone group exhibited endometrial thickening over the course of the study. Furthermore, no significant differences in blood lipid levels were reported between the two groups.

Conclusion:

The data from the current study demonstrated that the addition of goserelin to TAM results in downregulation of estradiol level, followed by significant reduction in BD and ET in premenopausal and perimenopausal women with hormone receptor-positive breast cancer, which may eventually lead to better outcome in these patients.     

Anti-tumor and endocrine effects of chronic LHRH agonist treatment (Buserelin) with or without tamoxifen in premenopausal metastatic breast cancer

Summary Seventeen premenopausal women with metastatic breast cancer were treated with the potent Luteinizing Hormone Releasing Hormone (LHRH) agonist Buserelin as a first-line agent. Twelve patients (group A) were treated with Buserelin alone and five patients (group B) with the combination of Buserelin and tamoxifen from the start of treatment. In nine patients of group A tamoxifen was added to Buserelin later on because of tumor progression or recurrent peaks of plasma estradiol (E₂). Chronic intranasal therapy with Buserelin alone, preceeded by parenteral administration, caused an objective remission in four patients (2 × C.R., 2 × P.R.) and stable disease in four further patients without causing side effects. The longest duration of response until now is more than 29 months. After addition of tamoxifen a partial response occurred in two more patients of group A. Anovulation with suppressed progesterone secretion was reached in all patients treated with Buserelin alone, but transient peaks of E₂ occurred in the majority (60%) of the patients. Addition of tamoxifen to Buserelin treatment caused disappearance of E₂ peaks in 2 patients, but also reappearance of progesterone secretion with recurring E₂ peaks in 3 other patients; in one case hyperstimulation of the ovaries was observed without progression of tumor growth. In group B only one woman showed a complete castration effect, while in four patients progesterone secretion was not (completely) suppressed. In two of these five patients an objective response occurred. In conclusion, Buserelin appears effective in the treatment of premenopausal women with metastatic breast carcinoma, but with the regimen used close control of endocrine parameters is necessary because of the variation in hormonal response with a risk of (hyper)stimulation of the ovaries, especially during combination therapy with tamoxifen.     

Combined endocrine treatment of elderly postmenopausal patients with metastatic breast cancer; A randomized trial of tamoxifen vs. tamoxifen + aminoglutethimide and hydrocortisone and tamoxifen + fluoxymesterone in women above 65 years of age

The efficacy of combined endocrine therapy with tamoxifen (TAM), aminoglutethimide (AG), and hydrocortisone (H) or tamoxifen and fluoxymesterone (FLU) was evaluated against treatment with tamoxifen alone in 311 patients above 65 years of age with a first recurrence of a metastatic breast cancer. A total of 279 patients were eligible. The response rates were assessed for 258 fully evaluable patients and were the following for the TAM (N=94), the TAM+AG+H (N=83), and the TAM+FLU (N=81) groups, respectively, PR: 14, 18, and 21%, and CR: 20, 11, and 23%. The overall response rates are not statistically different (p=0.30). The 95% CL of difference in response rates for TAM vs. TAM+AG+H are –9–19% and for TAM vs. TAM+FLU –4–25%. Time to treatment failure was comparable with median values of 9.2, 7.7, and 9.2 months in the TAM, TAM+AG+H, and TAM+FLU group, respectively (p=0.17). The corresponding figures for survival are median times of 22.0, 24.1, and 21.1 months with a p-value of 0.62. Toxicity was more pronounced in both the combined treatment groups, and could in most instances be attributed to treatment with either AG+H or FLU. Currently, new specific aromatase inhibitors with lesser toxicity than AG are being evaluated in combination with TAM for treatment of primary and metastatic breast cancer. In conclusion, the simultaneous use of TAM and AG+H or FLU does not seem to improve the therapeutic efficacy in elderly postmenopausal patients with metastatic disease. So far, combined endocrine therapy in this group of patients should only be used in the context of clinical trials.     

他莫昔芬治疗芳香化酶抑制剂耐药的激素受体阳性绝经后转移性乳腺癌患者的临床研究

目的:探讨他莫昔芬治疗芳香化酶抑制剂（AIs）耐药的激素受体阳性（HR+）绝经后转移性乳腺癌（MBC）患者的疗效和安全性。方法:回顾性分析他莫昔芬治疗AIs耐药的30例HR+绝经后MBC患者的临床资料,观察终点为缓解率（RR）、临床获益率（CBR）、疾病进展时间（TTP）和安全性。结果:30例患者中,CR 1例,PR 9例,SD 15例,RR为33.3%,CBR 为50%,中位TTP 6.1个月。23例骨和/或软组织转移患者中,RR为34.8%,CBR为52.2%,中位TTP 7.3个月;7例肝脏和/或肺部转移患者中,RR为28.6%,CBR为42.8%,中位TTP 4.8个月（P=0.019）。不良反应多为面部潮红、阴道干燥、白带增多、阴道出血、恶心、呕吐、腹泻等,均为I、II级。结论:他莫昔芬治疗AIs耐药的HR+绝经后MBC患者安全有效,可改善患者预后。     

Use of goserelin in the treatment of breast cancer

Gonadotropin-releasing hormone analogs are, alongside tamoxifen, one of the most commonly used drugs in the treatment of pre-/perimenopausal endocrine-responsive breast cancer. Goserelin, as a principal agent of this class of drugs, is mainly investigated in clinical trials. The indirect comparison of goserelin with tamoxifen as a single drug in the adjuvant setting showed similar efficacy. Furthermore, goserelin is as effective as cyclophosphamide, methotrexate and 5-fluorouracil chemotherapy, and total endocrine blockade as a combination of gonadotropin-releasing hormone analog and tamoxifen showed a comparable benefit with anthracycline-containing adjuvant chemotherapy. Goserelin administered after cessation of chemotherapy leads to a further improvement and may be equieffective as tamoxifen or a combination of both. Data concerning taxane-based and dose-dense chemotherapy as well as combination of gonadotropin-releasing hormone analogs with third-generation aromatase inhibitors are still lacking (ongoing suppression of ovarian function, tamoxifen and exemestane, and premenopausal endocrine-responsive chemotherapy trials). Moreover, duration of therapy with gonadotropin-releasing hormone analogs (2–3 years or longer) is still a matter of debate. Palliative endocrine treatment is standard in the first-line therapy of patients without life-threatening disease and endocrine-responsive breast cancer. Treatment decisions depend upon adjuvant endocrine pretreatment. Clinical data regarding ovarian protection by synchronous use of gonadotropin-releasing hormone in young breast cancer patients receiving chemotherapy are incoherent.     

Tamoxifen as initial endocrine therapy for metastatic breast cancer: Long term follow-up of two Piedmont Oncology Association (POA) trials

Purpose: To examine the outcomes of endocrine naive patients treated with tamoxifen as initial endocrine therapy for metastatic breast cancer. Data were obtained from the long-term follow-up of two previously published randomized trials. Patients and methods: All patients received tamoxifen 20 mg po in a single daily dose. Eligibility required patients to be age 18, performance status 0—3, and estrogen or progesterone receptor positive or unknown. Patients were ineligible if they had any prior endocrine therapy in either the adjuvant or metastatic setting. Results: 156 patients have been followed for a median of 8.3 years. Median age was 61 years, 83% were 50 years, 84% performance status of 0–1, 43% were both ER and PR positive, 33% had prior chemotherapy, 62% had a disease-free interval of > 2 years, and 59% had only one metastatic site. The complete (14%) and partial (6%) response rate for 147 evaluable patients was 20% (95% CI for CR + PR of 14–27%). Multivariate analysis revealed that improved response was related to soft tissue involvement and positive PR status. The majority of patients with soft tissue, nodal or lung metastases had responses noted within three months. Median time to disease progression was 6.7 months. Multivariate analysis revealed that older patients, those with one metastatic site and those with positive PR status had the longest time to progression. Median survival was 27.2 months. Better performance status, fewer metastatic sites and being PR positive were associated with significantly improved survival. Conclusion: The patient population in this series is not likely to be studied in future trials because of the wide use of tamoxifen in the adjuvant setting. In a small percentage of patients with metastatic breast cancer, tamoxifen therapy is associated with prolonged remission and survival. Pretreatment characteristics can help identify such patients.     

Insights on adjuvant endocrine therapy for premenopausal and postmenopausal breast cancer

In 2005, cancer accounted for 13% of all deaths worldwide. Breast cancer is the number-one cause of cancer-related death among women in the USA, affecting 178,480 of them in 2007. As 75% of tumors in postmenopausal women and half in premenopausal women express estrogen receptor, endocrine therapy plays a significant role as a systemic treatment. Robust datasets have demonstrated the impact of tamoxifen in reducing breast cancer recurrence and mortality, regardless of the age of the patient. Other estrogen-deprivation strategies, such as aromatase inhibitors in postmenopausal women and luteinizing hormone-releasing hormone agonists in premenopausal women, are being increasingly used for estrogen receptor-positive breast cancer. This review discusses basic principles regarding endocrine therapy, the need for accurate estrogen receptor testing and the role of menopause in therapy selection.     

乳腺癌内分泌治疗耐药相关机制的研究进展

内分泌治疗作为雌激素受体（estrogen receptor,ER）阳性乳腺癌的主要治疗方案被广泛应用。他莫西芬（tamoxifen,Tam）是乳腺癌内分泌治疗最常用的药物,它通过与雌激素竞争性结合ERα来降低雌激素的生物学活性,抑制细胞的增殖,从而治疗乳腺癌。然而,肿瘤细胞所表现出的原发性或获得性的他莫西芬耐药使得其临床应用受到了限制,寻找克服他莫西芬耐药的治疗策略已经刻不容缓。目前为止,他莫西芬耐药的相关机制已部分明确,但仍需进一步研究。有证据表明ERα、生长因子受体信号通路及microRNA的表达异常等多种机制均与他莫西芬耐药有关。本文对他莫西芬耐药的相关机制进行了具体分析,以期为ER阳性乳腺癌的治疗提供新思路。