激素受体阳性乳腺癌靶向治疗进展

内分泌治疗是激素受体阳性乳腺癌的主要治疗手段。内分泌耐药是这部分患者肿瘤复发或进展的主要原因。近期研究发现一系列导致激素受体阳性乳腺癌不依赖雌激素的抵抗机制,开发出相应的靶向治疗药物,其中包括细胞周期蛋白依赖性激酶4/6抑制剂、mTOR抑制剂、表皮生长因子受体抑制剂、抗血管生成药物、组蛋白去乙酰化酶抑制剂、成纤维细胞生长因子受体抑制剂、胰岛素样生长因子受体抑制剂,以及免疫检查点抑制剂等。这些药物被用于阻断耐药通路并提高内分泌治疗疗效,其中已经被批准上市的靶向药物有依维莫司和palbociclib。本文将对内分泌联合靶向治疗的药物研究进展进行综述。      

激素受体阳性早期乳腺癌治疗现状与挑战

在早期发现、有效治疗的情况下,早期乳腺癌是可治愈的,长期无病生存应是早期患者所追求的治疗目标.既往认为乳腺癌各亚型中激素受体(hormone receptor,HR)阳性早期乳腺癌预后最好,然而随着人类表皮生长因子受体2(human epidermal growth factor receptor 2,HER2)阳性乳...     

激素受体阳性/人表皮生长因子受体2阳性晚期乳腺癌的多靶向治疗研究进展

在乳腺癌患者中,约20％的患者存在肿瘤细胞人表皮生长因子受体2(HER2)过表达,使得肿瘤侵袭性更强,预后更差.针对这一特点,有靶向治疗方案以控制疾病进展.进一步研究发现,有将近50％的HER2阳性乳腺癌患者同时表达激素受体(HR),HER2与HR在下游通路存在交互作用,而这一特性也与乳腺癌患者的内分泌耐药及抗HER2治疗耐药相关.临床试验证实,针对HR+/HER2+这一亚组,靶向治疗联合内分泌治疗可为患者带来更大的生存获益,目前化疗仍然为该亚组患者的首选治疗方案.本文总结了针对HR+/HER2+晚期乳腺癌治疗的相关文献,探讨靶向治疗联合内分泌治疗是否可作为该亚组治疗的另一优选方案.     

HER2阳性乳腺癌脑转移系统治疗选择研究进展

人表皮生长因子受体2(human epidermal growth factor receptor 2,HER2)阳性乳腺癌患者易发生脑转移。血脑屏障/血肿瘤屏障导致药物递送效率低是脑转移系统治疗过程中面临的主要困境,故长期以来HER2阳性乳腺癌脑转移患者的治疗选择相对较少,预后较差。传统观点认为,大分子药物难以通过血脑屏障,但随着对血脑屏障/血肿瘤屏障特性了解的深入,这种观点逐步得到了改变,尤其是近年来多项临床研究证实了新型抗体偶联药物（antibody-drug conjugates,ADC）在脑转移人群中的疗效,这些发现为HER2阳性乳腺癌脑转移患者带来了更多治疗选择。本文综述了系统治疗药物的作用机制,并着重梳理了当前HER2阳性乳腺癌脑转移患者系统治疗的重要研究进展,以期为中国HER2阳性乳腺癌脑转移的临床治疗实践提供参考。     

激素受体阳性转移性乳腺癌的内分泌治疗

乳腺癌是女性常见的恶性肿瘤,以欧美国家发病率最高。随着我国人民群众生活水平的逐步提高,环境、饮食结构等因素的变化,我国乳腺癌的发病率呈逐年上升趋势。据国家癌症中心和国家卫生和计划生育委员会疾病预防控制局2013年中国肿瘤登记年报报道,全国肿瘤登记地区城市乳腺癌发病率2010年为47.79/10万,农村为27.72/10万 ^{[ 1]} 。2013年中国肿瘤登记年报与2012年相比,癌谱的一大变化是女性癌症发病率上升明显,乳腺癌居女性恶性肿瘤第1位。     

延长内分泌治疗在激素受体阳性早期乳腺癌治疗中的获益分析

目的 探讨延长辅助内分泌治疗能否改善激素受体阳性早期乳腺癌患者的预后,为临床治疗方案提供参考依据.方法 检索PubMed、ASCO会议和圣安东尼奥会议报告,以及相关中文数据库中2018-08-31前发表的临床研究及报告.应用RevMan 5.3软件行Meta分析.结果 共纳入随机对照试验文献13篇,共计32 280例患...     

免疫检查点抑制剂在激素受体阳性乳腺癌新辅助治疗中的研究进展

乳腺癌是全球发病率最高的恶性肿瘤,其中激素受体阳性（hormone receptor positive, HR+）乳腺癌占比最高。针对HR+乳腺癌的新辅助治疗,目前的主流方案是新辅助化疗（neoadjuvant chemotherapy, NACT）和新辅助内分泌治疗（neoadjuvant endocrine therapy, NET）,但两者均有不足。近年来免疫治疗发展迅速,免疫检查点抑制剂（immune checkpoint inhibitors, ICIs）作为主要的免疫治疗方法之一,在乳腺癌治疗中的应用不断前移,在新辅助治疗领域具有广阔的前景。本文就HR+乳腺癌的免疫微环境和ICIs在HR+乳腺癌新辅助治疗中的各种联合方案进行综述,以期为后续的临床研究和应用提供参考。     

三阳性乳腺癌转移的分子机制研究进展

摘 要：三阳性乳腺癌作为一种特殊类型的乳腺癌亚型,其转移性更强且具有更高的侵袭性。大量研究表明,三阳性乳腺通过激素受体的异常表达、上皮细胞间质转化等多种分子机制实现其远端转移和侵袭。全文就三阳性乳腺癌的临床特征及其转移的分子机制进行综述,期望为三阳性乳腺癌的临床治疗提供新的思路。     

哌柏西利联合内分泌治疗晚期激素受体阳性乳腺癌的真实世界研究

目的评价哌柏西利联合内分泌治疗HR+/HER2−晚期乳腺癌患者的疗效及安全性。方法回顾性分析2018年9月15日至2020年10月30日本中心83例采用哌柏西利联合内分泌治疗的HR+/HER2−晚期乳腺癌患者的临床资料,评估其临床疗效、无进展生存期(PFS)及不良反应。结果共纳入的83例HR+/HER2-晚期乳腺癌患者,中位随访时间为15.5个月,一线(n=25)和二线(n=38)采用哌柏西利联合内分泌治疗患者的ORR高于多线治疗患者(n=20),但差异无统计学意义(48.0%vs 44.7%vs 30.0%,P=0.466),3组患者的疾病控制率差异也无统计学意义(96.0%vs 89.5%vs 80.0%,P=0.337)。哌柏西利联合组全人群mPFS为13.0个月(95%CI:11.4~14.6个月),一线/二线治疗患者的mPFS较多线治疗患者延长(20.0个月vs 14.0个月vs 5.0个月,P<0.001),仅有骨转移的患者mPFS优于非骨转移患者(未达到vs 13.0个月;HR=0.42,95%CI:0.22~0.84,P=0.01);无内脏转移患者的mPFS优于存在内脏转移患者,但差异无统计学意义(20.0个月vs 13.0个月;HR=0.65,95%CI:0.35~1.22,P=0.38)。依维莫司联合内分泌治疗耐药患者应用哌柏西利治疗仍可获益(mPFS=5个月)。83例患者采用哌柏西利联合治疗后常见和严重的不良反应均为中性粒细胞减少,其中12例因不良反应下调剂量。结论哌柏西利联合内分泌治疗HR+/HER2-晚期乳腺癌患者的临床疗效显著,尤其是一/二线治疗取得较好疗效,安全性良好。     

乳腺癌内分泌治疗中激素受体问题

雌激素受体(ｅｓｔｒｏｇｅｎｒｅｃｅｐｔｏｒ,ＥＲ)已被作为乳腺癌内分泌治疗和预后评估的一个重要指征。近年来的研究已取得显著进展,特别是有关实际应用中存在的一些问题,许多已有较明确的解释。现就一些有关新认识、新进展做一概要综述。一、雌激素、激素受体与乳腺癌1896年Ｂｅｎｔｓｏｎ发现乳腺细胞的增生及癌变与激素密切相关,并观察到切除卵巢可使进展期乳腺癌消退。1967年Ｊｅｎｓｅｎ发现人类乳腺癌中含有ＥＲ。这一发现把乳腺癌内分泌治疗推向了崭新的阶段,使内分泌治疗变得有的放矢,疗效明显提高。研究证明,有的肿瘤细胞恶变…     

Brain metastases in breast cancer

Despite therapeutic advances, the development of breast cancer brain metastases (BCBM) is still the harbinger of a dismal prognosis. Patient outcomes vary depending on factors, including tumor phenotype, extent of disease within and outside the brain, as well as patient performance status. Treatment includes surgery, radiation therapy and systemic therapy determined by patient and tumor characteristics. Despite these approaches, novel treatments are needed and there is growing interest in systemic therapies. However, the efficacy of pharmacologic agents is hampered by poor penetration of drugs across the blood–brain barrier. Therefore, there is a pressing need for a greater understanding of the natural history of BCBM to guide the development of further therapies. This review analyzes prognosis and treatment of BCBM by tumor phenotype and discusses ongoing research into new therapies.     

Risk factors for brain relapse in patients with metastatic breast cancer.

BACKGROUND: The occurrence of brain metastases is an emerging problem in patients with metastatic breast cancer. In the present study, we looked at risk factors for brain metastasis among patients with metastatic breast cancer. PATIENTS AND METHODS: The risk factors for brain metastasis were first determined in a series of 215 patients with metastatic breast cancer. Risk factors identified in the multivariate analysis were re-evaluated in a confirmatory series of 199 patients with metastatic breast cancer. All the patients had been included in prospective randomized trials that evaluated chemotherapy or endocrine therapy in an adjuvant setting. RESULTS: In the first series, the presence of lung metastases (hazard ratio = 4.3, 95% CI: 1.9-9.3, P=0.0003) and negative hormone receptor status (hazard ratio = 4.2, 95% CI: 1.7-11, P=0.002) were the only predictive factors associated with the occurrence of brain metastases in the multivariate analysis. The second series confirmed that the presence of lung metastases and negative hormone receptor status were associated with the occurrence of brain metastases. CONCLUSION: The presence of lung metastases as the first site of relapse and a negative hormone receptor status are predictive for the occurrence of brain metastases in patients with metastatic breast cancer. A prophylactic treatment should be evaluated in these subsets of patients.     

Incidence of cerebral metastases in patients treated with trastuzumab for metastatic breast cancer

Trastuzumab is an effective treatment for patients with metastatic breast cancer (MBC) that overexpresses HER-2. A high incidence of brain metastases (BM) has been noted in patients receiving trastuzumab. A retrospective chart review was conducted of 100 patients commencing trastuzumab for metastatic breast cancer from July 1999 to December 2002, at the Christie Hospital. Seven patients were excluded; five patients developed central nervous system metastases prior to starting trastuzumab, and inadequate data were available for two. Out of the remaining 93 patients, 23 (25%) have developed BM to date. In all, 46 patients have died, and of these 18 (39%) have been diagnosed with BM prior to death. Of the 23 patients developing BM, 18 (78%) were hormone receptor negative and 18 (78%) had visceral disease. Univariate analysis showed a significant association between the development of cerebral disease and both hormone receptor status and the presence of visceral disease. In conclusion, a high proportion of patients with MBC treated with trastuzumab develop symptomatic cerebral metastases. HER-2-positive breast cancer may have a predilection for the brain, or trastuzumab therapy may change the disease pattern by prolonging survival. New strategies to address this problem require investigation in this group of patients.     

Assessment of prognostic scores in brain metastases from breast cancer

Background

Breast cancer (BC) is the second most common cause of brain metastases (BM). Optimal management of BM from BC is still debated. In an attempt to provide appropriate treatment and to assist with optimal patient selection, several specific prognostic classifications for BM from BC have been established. We evaluated the prognostic value and validity of the 6 proposed scoring systems in an independent population of BC patients with BM.

Methods

We retrospectively reviewed all consecutive BC patients referred to our institution for newly diagnosed BM between October 1995 and July 2011 (n = 149). Each of the 6 scores proposed for BM from BC (Sperduto, Niwinska, Park, Nieder, Le Scodan, and Claude) was applied to this population. The discriminative ability of each score was assessed using the Brier score and the C-index. Individual prognostic values of clinical and histological factors were analyzed using uni- and multivariate analyses.

Results

Median overall survival was 15.1 months (95% CI,11.5–18.7). Sperduto-GPA (P < .001), Nieder (P < .001), Park (P < .001), Claude (P < .001), Niwinska (P < .001), and Le Scodan (P = .034) scores all showed significant prognostic value. The Nieder score showed the best discriminative ability (C-index, 0.672; Brier score error reduction, 16.1%).

Conclusion

The majority of prognostic scores were relevant for patients with BM from BC in our independent population, and the Nieder score seems to present the best predictive value but showed a relatively low positive predictive value. Thus, these results remain insufficient and challenge the routine use of these scoring systems.     

氟维司群500 mg治疗激素受体阳性复发转移性乳腺癌的疗效观察

对于激素受体阳性复发转移性乳腺癌,如果疾病进展较缓慢,无内脏转移危象,内分泌治疗是首选的治疗手段［1］。氟维司群是一种新型的选择性雌激素受体(estrogen receptor,ER)下调剂,它能高亲和力地结合、阻断并下调ER,发挥了完全的抗雌激素作用［2］。氟维司群的疗效具有剂量依赖效应［3］,CONFIRM研究证实,对既往内分泌治疗后进展的绝经期乳腺癌患者采用氟维司群500 mg与250 mg治疗,二者相比,500 mg在无进展生存期(progression-free survival, PFS)及总生存期(overall survival,OS)方面均都有显著优势［4-5］。本研究回顾性分析了500 mg氟维司群在中国ER阳性复发转移性乳腺癌患者中的疗效和安全性,并对可能的影响因素做相关分析。     

Incidence and time trends of brain metastases admissions among breast cancer patients in Sweden

Background:

While treatment for breast cancer has been refined and overall survival has improved, there is concern that the incidence of brain metastases has increased.

Methods:

We identified patients in Sweden with incident breast cancer 1998–2006 in the National Cancer Register, and matched these to the National Patient Register to obtain information on hospital admissions for distant metastases. Hazard ratios (HRs) and 95% confidence intervals (CIs) were computed with Cox regression as estimates of relative risk.

Results:

Among 50 528 breast cancer patients, 696 (1.4%) were admitted with brain metastases during median 3.5 years of follow-up. Admissions for other metastases were found in 3470 (6.9%) patients. Compared with the period 1998–2000, patients diagnosed with breast cancer 2004–2006 were at a 44% increased risk of being admitted with brain metastases (HR 1.44, 95% CI 1.13–1.85).

Conclusion:

The incidence of admissions with brain metastases in breast cancer patients was increasing in the mid-2000s in Sweden. These findings support a true increase in incidence of brain metastases among breast cancer patients.     

Phase II trial of patupilone in patients with brain metastases from breast cancer

Background

For patients with progressive breast cancer brain metastasis (BCBM) after whole brain radiotherapy (WBRT), few options exist. Patupilone is an epothilone that crosses the blood–brain barrier. We hypothesized that patupilone would produce a 35% 3-month CNS progression-free survival in women with BCBM after WBRT.

Methods

This multicenter phase II trial included 2 cohorts. Group A included women with progressive BCBM after WBRT. Group B was an exploratory cohort of patients with either leptomeningeal metastases or untreated brain metastases. The primary goal was to observe a 35% 3-month CNS progression-free survival in Group A. The sample size was 45 for Group A and 10 for Group B. Patients received patupilone 10 mg/m² once every 3 weeks until progression. Responses were scored according to the Macdonald criteria.

Results

Fifty-five patients (45 in Group A, 10 in Group B) enrolled. In Group A, the 3-month CNS progression-free survival was 27%, the median overall survival was 12.7 months, and the overall response rate was 9%. In Group B, which enrolled 5 patients with leptomeningeal disease and 5 with no prior WBRT, no responses occurred and 8 patients had CNS progression before 3 months. Systemic responses occurred in 15% of patients, including a complete response in liver metastases. Diarrhea occurred in 87% of patients; 25% had grade 3 and 4 adverse events.

Conclusions

Patupilone in patients with BCBM did not meet the efficacy criteria and had significant gastrointestinal toxicity. Further study of brain-penetrant agents is warranted for patients with CNS metastases from breast cancer.     

Response of brain metastases from breast cancer to megestrol acetate: A case report

A 56 year old women was treated with megestrol acetate (Megace) 40 mg p.o. q.i.d. for her cerebellar metastasis of primary adenocarcinoma of the breast. She had previously undergone two surgical resections of her brain metastasis, and a course of radiotherapy. After failing to tolerate tamoxifen therapy, she received Megace, with marked improvement in her cerebellar tumor on CT scans. Despite good control of her brain tumor with Megace, she developed progressive neurological symptoms thought to be due to meningeal carcinomatosis, and died two years after initiating Megace therapy. We conclude that Megace could potentially be beneficial in some patients with brain metastases from adenocarcinoma of the breast.     

A phase 2 trial of whole-brain radiotherapy combined with intravenous chemotherapy in patients with brain metastases from breast cancer

BACKGROUND

A study was conducted to determine the efficacy, tolerability, and safety of concurrent cisplatin and vinorelbine chemotherapy and radiotherapy in patients with previously untreated brain metastases from breast cancer.

METHODS

Twenty‐five patients with untreated brain metastases from breast cancer were treated with cisplatin (at a dose of 20 mg/m²/day, Days 1‐5) and vinorelbine (6‐mg/m² bolus on Day 1 and 6 mg/m²/day continuous infusion on Days 1‐5) chemotherapy combined with concurrent 30‐gray fractionated external‐beam radiotherapy. Chemotherapy was given at 3‐week intervals for a total of 4 cycles. Primary endpoint was the rate of radiologic response of brain metastases.

RESULTS

Complete response in the brain was observed in 3 patients, and partial response was noted in 16 patients, yielding a 76% response rate in the brain. The overall systemic response rate was 44%. Progression‐free and overall survival were 3.7 months and 6.5 months, respectively. Overall toxicity was acceptable; nonhematologic grade 3‐4 events were noted in 5 (20%) patients, and there were no toxic deaths.

CONCLUSIONS

Concurrent chemoradiation with cisplatin and vinorelbine for brain metastases from breast cancer appears to be active and well tolerated. Cancer 2008. © 2008 American Cancer Society.     

Cytogenomic profiling of breast cancer brain metastases reveals potential for repurposing targeted therapeutics

Breast cancer brain metastases remain a significant clinical problem. Chemotherapy is ineffective and a lack of treatment options result in poor patient outcomes. Targeted therapeutics have proven to be highly effective in primary breast cancer, but lack of molecular genomic characterization of metastatic brain tumors is hindering the development of new treatment regimens. Here we contribute to fill this void by reporting on gene copy number variation (CNV) in 10 breast cancer metastatic brain tumors, assayed by array comparative genomic hybridization (aCGH). Results were compared to a list of cancer genes verified by others to influence cancer. Cancer gene aberrations were identified in all specimens and pathway-level analysis was applied to aggregate data, which identified stem cell pluripotency pathway enrichment and highlighted recurring, significant amplification of SOX2, PIK3CA, NTRK1, GNAS, CTNNB1, and FGFR1. For a subset of the metastatic brain tumor samples (n=4) we compared patient-matched primary breast cancer specimens. The results of our CGH analysis and validation by alternative methods indicate that oncogenic signals driving growth of metastatic tumors exist in the original cancer. This report contributes support for more rapid development of new treatments of metastatic brain tumors, the use of genomic-based diagnostic tools and repurposed drug treatments.