绝经后Luminal B型乳腺癌的内分泌治疗

目的 探讨芳香化酶抑制剂和三苯氧胺对绝经后Luminal B型乳腺癌患者的疗效.方法 收集天津市肿瘤医院2002年7月至2005年3月间733例术后接受辅助内分泌治疗的原发性乳腺癌患者资料,肿瘤性质均经手术切除病理组织学证实.患者均为绝经后且ER阳性,其中501例接受三苯氧胺治疗,232例接受芳香化酶抑制剂治疗.采用免疫组化SP法进行ER、PR、HER2检测.随访时间36～90个月,中位随访时间46个月.结果 芳香化酶抑制剂治疗组Luminal B型乳腺癌患者三年无瘤生存率高于三苯氧胺组(90.6% vs.88.6%,P=0.038).三苯氧胺组亚组分析显示:LN+/HER2+患者三年无瘤生存率低于LN+/HER2-患者(88.2% vs 90.4%,P=0.037);HER2+/PR+患者高于HER2+/PR-患者(90.8% vs.89.5%,P=0.032).芳香化酶抑制剂组内LN(+)和LN(-)亚组中,HER2(+)患者与HER2(-)患者的三年无瘤生存率差异均无统计学意义(P>0.05);而HER2+/PR+组高于HER2+/PR-组(91.9% vs.90.5%,P=0.029).芳香化酶抑制剂组潮热、阴道出血、静脉血栓形成的发生率低,肌肉骨骼疼痛、骨折的发生率则高于三苯氧胺组(P<0.05).结论 芳香化酶抑制剂对绝经后Luminal B型患者疗效好于三苯氧胺,此效果不受患者腋窝淋巴结状态的影响,且耐受性和安全性较好.     

绝经后Luminal B型乳腺癌的内分泌治疗

目的 探讨芳香化酶抑制剂和三苯氧胺对绝经后Luminal B型乳腺癌患者的疗效.方法 收集天津市肿瘤医院2002年7月至2005年3月间733例术后接受辅助内分泌治疗的原发性乳腺癌患者资料,肿瘤性质均经手术切除病理组织学证实.患者均为绝经后且ER阳性,其中501例接受三苯氧胺治疗,232例接受芳香化酶抑制剂治疗.采用免疫组化SP法进行ER、PR、HER2检测.随访时间36～90个月,中位随访时间46个月.结果 芳香化酶抑制剂治疗组Luminal B型乳腺癌患者三年无瘤生存率高于三苯氧胺组(90.6% vs.88.6%,P=0.038).三苯氧胺组亚组分析显示:LN+/HER2+患者三年无瘤生存率低于LN+/HER2-患者(88.2% vs 90.4%,P=0.037);HER2+/PR+患者高于HER2+/PR-患者(90.8% vs.89.5%,P=0.032).芳香化酶抑制剂组内LN(+)和LN(-)亚组中,HER2(+)患者与HER2(-)患者的三年无瘤生存率差异均无统计学意义(P>0.05);而HER2+/PR+组高于HER2+/PR-组(91.9% vs.90.5%,P=0.029).芳香化酶抑制剂组潮热、阴道出血、静脉血栓形成的发生率低,肌肉骨骼疼痛、骨折的发生率则高于三苯氧胺组(P<0.05).结论 芳香化酶抑制剂对绝经后Luminal B型患者疗效好于三苯氧胺,此效果不受患者腋窝淋巴结状态的影响,且耐受性和安全性较好.     

乳癌内分泌治疗适应证

乳癌的发生发展受内分泌调控,已证实至少有１／３的乳癌患者是激素依赖性的,减低体内雌激素水平,即有利于乳癌的治疗。目前常用的内分泌治疗药物分为抗雌激素类,芳香化酶抑制剂,ＬＨＲＨ类似物,孕激素类等,可根据患者的月经状态,全身状况,激素受体情况,远处转移的受侵器官等情况具体选用。内分泌治疗应用于新辅助治疗及乳癌的预防是目前研究的热点,已有报道证实其可提高乳癌患者的预后并可在一定程度上降低乳癌发生的风险     

乳腺癌内分泌治疗的新概念

对于激素受体阳性的乳癌病人，长期以来三苯氧胺（TAM）一直被视为内分泌治疗的标准选择。但随着芳香化酶抑制剂（Als）一代一代地相继研发成功，新型Als，如：阿那曲唑、来曲唑、依西美坦向TAM的传统地位发起了强有力的挑战。为了及时应用乳癌内分泌治疗的最新研究成果，美国ASCO乳癌专家委员会定期对该领域研究结果进行技术评估，而美国国家综合肿瘤网（NCCN），也会根据最新研究动态，不断更新指南。我们将结合临床体会，解析和总结目前乳腺癌内分泌治疗的新理念。     

乳腺癌内分泌治疗发展与未来

乳腺癌是激素依赖性肿瘤,内分泌药物的选择除了根据患者的年龄、病灶部位、手术到复发的间隔时间以及受体测定等因素外,还要根据不同药物的作用机制以及副反应而定。随着对内分泌治疗药物作用机制的深入研究和大规模临床研究的证实,激素受体阳性乳腺癌的内分泌治疗疗效将不断提高。     

乳腺癌内分泌治疗中三苯氧胺耐药机制的研究进展

乳腺癌内分泌治疗的耐药性影响乳腺癌治疗效果及预后,近年来对耐药性的研究越来越深入,笔者从雌激素受体,内皮生长因子受体及信号传导分子几方面对其耐药性机制进行综述.     

芳香化酶抑制剂新辅助内分泌治疗三苯氧胺耐药的老年性局部晚期乳腺癌的研究

目的探讨芳香抑制剂新辅助内分泌治疗三苯氧胺耐药的老年性局部晚期乳腺癌的临床疗效。方法回顾性分析既往接受三苯氧胺新辅助内分泌治疗失败,后改用芳香化酶抑制剂,且能够评估疗效和记录疾病进展时间的41例老年性局部晚期乳腺癌患者,主要观察终点为临床获益率（Clinical benefit rate,CBR）。结果分别接受阿那曲唑（n=16）、伊西美坦（n=14）和来曲唑（n=11）新辅助内分泌治疗的三组乳腺癌患者的临床病理特征相似（χ2=1.579,P=0.547）,不同的芳香化酶抑制剂均能获得明显改善三苯氧胺治疗失败的老年性局部晚期乳腺癌的治疗效果,其CBR分别为阿那曲唑62.5%,伊西美坦78.57%和来曲唑72.73%,治疗效果相似（χ2=3.787,P=0.327）。结论芳香化酶抑制剂新辅助内分泌治疗三苯氧胺耐药的老年性局部晚期乳腺癌,仍可以获得明显的临床缓解,且不同的芳香化酶抑制剂的CBR相似。     

Luminal A型和HER-2阳性乳腺癌的肿瘤干细胞生物学行为比较

目的:比较人Luminal A型和HER-2阳性乳腺癌的肿瘤干细胞的生物学行为差异。方法:用Luminal A型和HER-2阳性乳腺癌组织培分离并培养原代乳腺癌细胞,获取富含肿瘤干细胞的微球体(MS);用胰酶将MS消化成单细胞(微球体细胞,MSDC),比较两类乳腺癌MSDC的体外增殖和自我更新能力、ALDH1+表型肿瘤干细胞含量,以及移植NOD/SCID小鼠后的成瘤情况。结果:Luminal A型和HER-2阳性乳腺癌组织分离的原代乳腺癌细胞均能培养出MS,但相对于Luminal A型乳腺癌,HER-2阳性乳腺癌来源的MS形成时间短,生成的MS体积大;HER-2阳性乳腺癌来源的MSDC无论在无血清或添加血清的培养基中的增殖与再生能力均明显强于Luminal A型乳腺癌来源的MSDC,且前者含ALDH1表型干细胞比例明显高于后者(均P0.05);HER-2阳性乳腺癌的MSDC在NOD/SCID小鼠体内成瘤能力也强于Luminal A型乳腺癌来源的MSDC。结论:Luminal A型和HER-2阳性乳腺癌分离出来肿瘤干细胞生物学行为存在明显的差异,两者可能有不同肿瘤干细胞起源。     

Luminal B型乳腺癌的临床病理特征

目的:研究Luminal B型乳腺癌的临床病理特点。方法:回顾分析手术治疗的浸润性导管癌497例中Luminal B型乳腺癌200例患者的临床资料。将Luminal B型的乳腺癌进一步分为4组:Luminal B1组,ER和/或PR阳性、HER-2阳性;Luminal B2组,ER阳性、HER-2阴性、PR高表达(≥20%)、Ki-67高表达(≥20%);Luminal B3组,ER阳性、HER-2阴性、PR低表达(20%)、Ki-67高表达(≥20%);Luminal B4组,ER阳性、HER-2阴性、PR低表达(20%)、Ki-67低表达(20%)。分别研究该4组患者年龄、肿瘤大小、有无淋巴结转移及与p53和VEGF表达的关系。结果:在年龄和癌组织p53表达上,Luminal B型乳腺癌4组之间差异有统计学意义(P0.01),其中Luminal B2组中的患者年龄较年轻,多小于53岁(64.44%),其次是Luminal B1组(57.89%),Luminal B3组(43.36%)和Luminal B4组(30.30%);p53的表达在Luminal B1组中阳性表达最多(65.79%),其次是Luminal B3组(56.41%),Luminal B2组(43.33%)和Luminal B4组(27.27%)。在淋巴结转移方面,Luminal B型乳腺癌4组之间差异有统计学意义(P0.05),其中Luminal B3组转移率最高(69.23%),其次是Luminal B2组(54.44%)和Luminal B4组(45.45%),Luminal B1组(36.84%)最低。Luminal B型乳腺癌4组之间在肿瘤大小和VEGF表达方面差异无统计学意义(P0.05)。结论:Luminal B型乳腺癌是由预后不佳的激素受体阳性的乳腺癌组成,根据免疫组化的指标仍可分成不同的亚型,各亚型之间具有不同的临床病理特点。     

Aromatase inhibitors use and risk for cardiovascular disease in breast cancer patients: A population-based cohort study

BackgroundPrior studies regarding use of Aromatase inhibitors (AIs) and risk for cardiovascular disease (CVD) have shown conflicting results. This retrospective cohort study aimed to investigate whether AIs use affects risk for CVD events in postmenopausal breast cancer survivors.MethodsUsing a retrospective cohort study design, four CVD outcomes; heart failure or cardiomyopathy, arrhythmia, acute ischemic heart disease and ischemic stroke or Transient Ischemic Attack were compared with uni- and multivariate Cox regression analyses according to exposure to endocrine therapy (use of AI, tamoxifen or AI/tamoxifen sequentially) or no endocrine therapy.ResultsIn total 15815 postmenopausal women, surgically treated to early breast cancer during 2006–2012, were included. No significantly increased risk for CVD events was observed in patients with AI use in the whole cohort. However, two subgroup analyses showed increased risk for CVD events in the AI/tamoxifen sequential group; heart failure in patients older than 75 years (Hazard Ratio (HR) 2.44; 95% Confidence Interval (CI): 1.32–4.54) and arrhythmia in patients without prior CVD (HR 1.45; 95% CI: 1.01–2.10). An increased risk for arrhythmia and acute ischemic heart disease in patients with at least four years of AI treatment compared with no or short-time exposure was observed (HR 2.12; 95% CI: 1.40–3.25 for arrhythmia; HR 2.03; 95% CI: 1.15–3.58 for ischemic heart disease).ConclusionOur results indicate an increased risk for ischemic heart disease and arrhythmia in patients treated for more than four years with AIs. This should be considered in the risk-benefit assessment concerning endocrine therapy.     

Aromatase inhibitors as solely treatment in postmenopausal breast cancer patients

Several studies evaluating the clinical effectiveness of endocrine therapy alone in breast cancer patients aged 70 years or older reported comparable survival rates to conventional surgical therapy, although the incidence of local recurrences was higher. Primary endocrine therapy is therefore only recommended as an alternative approach in elderly woman with estrogen receptor positive tumors who are deemed inoperable or who refuse surgery. We report our experience with aromatase inhibitors as primary endocrine therapy for estrogen receptor positive breast cancer in postmenopausal woman who are impaired by other diseases, refuse surgery or are of old age. Fifty-six patients with fifty-seven ER+ operable breast cancers who refused surgery, were judged ineligible for surgery because of comorbidity, or were of old age were treated with endocrine therapy using aromatase inhibitors only. Digital mammography and high-end breast ultrasound were used to assess tumor sizes. The mean age of the patients was 74 years (range 52-102 years). All patients suffered from breast cancer. The mean follow-up interval was 40 months (range 5-92 months). Seven patients (12%) achieved complete clinical remission, 31 (57%) partial response giving an overall objective response rate of 69%. In addition, seven (12%) patients showed stable disease, giving a clinical benefit rate (complete remission + partial response + stable disease rate) of 81%. Eleven patients (19%) progressed after an initial partial response or stable disease. Only one patient (2%) progressed on endocrine therapy within the first months. Eventually, 22 (39%) patients underwent surgery after informed consent to achieve better local tumor control. Primary endocrine therapy with aromatase inhibitors may offer an effective and safe alternative to surgery giving a high local control rate in postmenopausal women who refuse surgery, who are judged ineligible for surgery, or are of old age.     

Aromatase inhibitors decrease radiation-induced lung fibrosis: Results of an experimental study

PurposeIn experimental and clinical trials, tamoxifen (TAM) has been shown to increase radiation-induced lung fibrosis (RILF). Furthermore, aromatase inhibitors (AI) have been shown to be superior to TAM in the adjuvant setting and preclinical data suggest that letrozole (LET) sensitizes breast cancer cells to ionizing radiation in other studies. In this experimental study, we evaluated whether AI have any impact on the development of RILF in rats.Materials and methods60 female wistar- albino rats were divided into 6 groups: Control (group A), RT alone (group B), RT + TAM (group C), RT + anastrozole (ANA group D), RT + LET (group E), and RT + exemestane (EXE, group F). RT consisted of 30 Gy in 10 fractions to both lungs with an anterior field at 2 cm depth. Equivalent doses for 60 kg adult dose per day of TAM, ANA, LET, and EXE were calculated according to the mean weight of rats and orally administrated with a feeding tube. Percentage of lung with fibrosis was quantified with image analysis of histological sections of the lung. The mean score values were calculated for each group. the significance of the differences among groups were calculated using one way ANOVA test and Tukey HSD post-hoc test.ResultsMean values of fibrosis were 1.7, 5.9, 6.7, 2.5, 2 and 2.2 for groups A, B, C, D, E, and F, respectively (p = 0.000). TAM increased RT-induced lung fibrosis but without statistical significance. Groups treated with RT + AI showed significantly less lung fibrosis than groups treated with RT alone or RT + TAM (p = 0.000). RT + AI groups showed nearly similar RT-induced lung fibrosis than control group.ConclusionsIn this study, we found that AI decreased RT-induced lung fibrosis to the control group level suggesting protective effect.     

雌、孕激素受体和Her-2阴性乳腺癌的临床病理特征

Objective To study the clinicopathologic characteristics of triple-negative breast cancer (TNBC) and its value in the prediction of prognosis. Method In this study,500 cases of female breast cancers were examined immunohistochcmically for the TNBC. The clinicopathologic characteristics of the 243 TNBC cases were inspected. Results TNBC accounted for 17.6% (88/500) of the 500 breast cancers. The histological types of the TNBC included mainly infihrative ductal carcinoma, metaplastic carcinoma and medullar carcinoma. Among those, histological grade Ⅲ accounted for 72.7% (64/88) of all the TNBC and was more common than that in hormone receptor positive breast cancers (HR+ group ) and Her-2 overexpression breast cancers (Her-2 group)(P=0.000). The positive rates of CK5/6 and EGFR in the TNBC were 30.7% (27/88) and 34.1% (30/88), respectively. The positive rates of ERCC1 and KIT in the TNBC were 28.4% (25/88) and 34.1% (30/88), respectively, Both of which were higher than those in the HR + group and Her-2 group, respectively (P=0.032 and P=0.026). 3-year survival rate of the TNBC was 71.5% and it was lower than that of HR group (P=0.021) and not significantly different from that of Her-2 group (P=0.474). Conclusions TNBC is the breast cancer with high aggressive pathologic futures and poor prognosis. EGFR and ERCC1 expression were positive in a portion of TNBC cases.     

雌、孕激素受体和Her-2阴性乳腺癌的临床病理特征

Objective To study the clinicopathologic characteristics of triple-negative breast cancer (TNBC) and its value in the prediction of prognosis. Method In this study,500 cases of female breast cancers were examined immunohistochcmically for the TNBC. The clinicopathologic characteristics of the 243 TNBC cases were inspected. Results TNBC accounted for 17.6% (88/500) of the 500 breast cancers. The histological types of the TNBC included mainly infihrative ductal carcinoma, metaplastic carcinoma and medullar carcinoma. Among those, histological grade Ⅲ accounted for 72.7% (64/88) of all the TNBC and was more common than that in hormone receptor positive breast cancers (HR+ group ) and Her-2 overexpression breast cancers (Her-2 group)(P=0.000). The positive rates of CK5/6 and EGFR in the TNBC were 30.7% (27/88) and 34.1% (30/88), respectively. The positive rates of ERCC1 and KIT in the TNBC were 28.4% (25/88) and 34.1% (30/88), respectively, Both of which were higher than those in the HR + group and Her-2 group, respectively (P=0.032 and P=0.026). 3-year survival rate of the TNBC was 71.5% and it was lower than that of HR group (P=0.021) and not significantly different from that of Her-2 group (P=0.474). Conclusions TNBC is the breast cancer with high aggressive pathologic futures and poor prognosis. EGFR and ERCC1 expression were positive in a portion of TNBC cases.     

雌、孕激素受体和Her-2阴性乳腺癌的临床病理特征

Objective To study the clinicopathologic characteristics of triple-negative breast cancer (TNBC) and its value in the prediction of prognosis. Method In this study,500 cases of female breast cancers were examined immunohistochcmically for the TNBC. The clinicopathologic characteristics of the 243 TNBC cases were inspected. Results TNBC accounted for 17.6% (88/500) of the 500 breast cancers. The histological types of the TNBC included mainly infihrative ductal carcinoma, metaplastic carcinoma and medullar carcinoma. Among those, histological grade Ⅲ accounted for 72.7% (64/88) of all the TNBC and was more common than that in hormone receptor positive breast cancers (HR+ group ) and Her-2 overexpression breast cancers (Her-2 group)(P=0.000). The positive rates of CK5/6 and EGFR in the TNBC were 30.7% (27/88) and 34.1% (30/88), respectively. The positive rates of ERCC1 and KIT in the TNBC were 28.4% (25/88) and 34.1% (30/88), respectively, Both of which were higher than those in the HR + group and Her-2 group, respectively (P=0.032 and P=0.026). 3-year survival rate of the TNBC was 71.5% and it was lower than that of HR group (P=0.021) and not significantly different from that of Her-2 group (P=0.474). Conclusions TNBC is the breast cancer with high aggressive pathologic futures and poor prognosis. EGFR and ERCC1 expression were positive in a portion of TNBC cases.     

雌、孕激素受体和Her-2阴性乳腺癌的临床病理特征

Objective To study the clinicopathologic characteristics of triple-negative breast cancer (TNBC) and its value in the prediction of prognosis. Method In this study,500 cases of female breast cancers were examined immunohistochcmically for the TNBC. The clinicopathologic characteristics of the 243 TNBC cases were inspected. Results TNBC accounted for 17.6% (88/500) of the 500 breast cancers. The histological types of the TNBC included mainly infihrative ductal carcinoma, metaplastic carcinoma and medullar carcinoma. Among those, histological grade Ⅲ accounted for 72.7% (64/88) of all the TNBC and was more common than that in hormone receptor positive breast cancers (HR+ group ) and Her-2 overexpression breast cancers (Her-2 group)(P=0.000). The positive rates of CK5/6 and EGFR in the TNBC were 30.7% (27/88) and 34.1% (30/88), respectively. The positive rates of ERCC1 and KIT in the TNBC were 28.4% (25/88) and 34.1% (30/88), respectively, Both of which were higher than those in the HR + group and Her-2 group, respectively (P=0.032 and P=0.026). 3-year survival rate of the TNBC was 71.5% and it was lower than that of HR group (P=0.021) and not significantly different from that of Her-2 group (P=0.474). Conclusions TNBC is the breast cancer with high aggressive pathologic futures and poor prognosis. EGFR and ERCC1 expression were positive in a portion of TNBC cases.