Metformin in neoadjuvant systemic therapy of breast cancer patients with metabolic syndrome

Q4 Medicine
R. Liubota, V. Cheshuk, O. Zotov, R. Vereshchako, M. Anikusko, I. Liubota, V. Gur'yanov
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引用次数: 3

Abstract

Received 2018-02-09 Accepted 2018-06-23 INTRODUCTION Breast cancer (BC) is one of the most spread cancers among women worldwide. In 2012 breast cancer incidence was 43.3 per 100 000 in female population, with 1 676 633 new registered cases along with 521 907 deaths from this disease in the world. This accounts for 25.2% of cases and 14.7% of deaths among all cancers in women (1). According to the National Cancer Registry of Ukraine, in 2012 there were 17407 new breast cancer cases and 7727 deaths. This accounts for 19.6% of cases and 20.2% of deaths among all cancers in women in Ukraine. In Ukraine, breast cancer incidence increased from 38.6 cases per 100 000 in female population in 2006 to 41.4 cases in 2011. However, the death rate from breast cancer seems to have a tendency to decrease from 7826 cases in 2006 to 7727 in 2011, or 20.3% (2006) and 20.2% (2011) of the death cases among all cancers in the female population (2, 3). In 2005, in connection with the overall mortality rate the International Diabetes Federation (IDF) defined metabolic syndrome (MS) as one of the main problems of modern medicine. Prevalence of MS has reached pandemic proportions. In developed countries MS was found in 25-35% of the population and in all age groups. This value increased with age and reached 42-43.5% in the age group above 60 years old (4). A number of epidemiological, experimental and clinical studies proved that the metabolic abnormalities, associated with MS, increase the risk of breast cancer and worsen its prognosis. For example, in MS patients decreased sensitivity of the tumor to systemic anticancer therapy, increased rate of postoperative complications as well as reduced overall and disease-free survival compared to patients without MS was reported (5-8). In addition, some drugs that are used in systemic anticancer therapy of breast cancer increase insulin resistance the main pathogenetic link of MS. Specifically, dexamethasone, which is commonly used in breast cancer chemotherapy, causes hyperglycemia. In menopausal women with obesity tamoxifen reduced insulin sensitivity by almost seven fold and increased incidence of type 2 diabetes mellitus compared to women who did not intake tamoxifen (9,10). Experimental studies have found that anti-tumor effect of metformin is associated with activation of AMP-dependent protein kinase (AMPK), which plays a key role in the cell energy balance. Activation of AMPK leads to inhibition of anabolic processes depression of neoglucogenesis in hepatocytes and lipolysis in adipocytes, protein synthesis reduction by inhibiting mTOR (mammalian target of rapamycin), and launching of catabolic processes in the cell (increased glycolysis and fatty acid oxidation), arrest of the cell cycle in G0/G1-phase and the stimulation of the p53-dependent cell autophagy (11, 12). Furthermore, metformin can directly (without AMPK activation) block protein mTOR, which stimulates the biosynthesis of proteins and promotes cell growth and proliferation, thereby demonstrating antiproliferative activity (11). The aim of this prospective randomized trial was to investigate the influence of metformin on the effectiveness of neoadjuvant systemic anticancer therapy of breast cancer patients with metabolic syndrome.
二甲双胍在乳腺癌代谢综合征患者新辅助全身治疗中的应用
乳腺癌(Breast cancer, BC)是全球女性中传播最广泛的癌症之一。2012年,全球乳腺癌发病率为每10万女性人口43.3例,新登记病例1 676 633例,死亡病例521 907例。这占妇女所有癌症病例的25.2%和死亡人数的14.7%(1)。根据乌克兰国家癌症登记处的数据,2012年有17407例新的乳腺癌病例和7727例死亡。这占乌克兰妇女所有癌症病例的19.6%和死亡人数的20.2%。在乌克兰,乳腺癌发病率从2006年每10万女性人口38.6例增加到2011年的41.4例。然而,乳腺癌的死亡率似乎有下降的趋势,从2006年的7826例下降到2011年的7727例,或占女性人口中所有癌症死亡病例的20.3%(2006年)和20.2%(2011年)(2,3)。2005年,关于总死亡率,国际糖尿病联合会(IDF)将代谢综合征(MS)定义为现代医学的主要问题之一。多发性硬化症的流行已达到大流行的程度。在发达国家,25-35%的人口和所有年龄组都有多发性硬化症。这一数值随着年龄的增长而增加,在60岁以上年龄组中达到42-43.5%(4)。多项流行病学、实验和临床研究证明,代谢异常与MS相关,增加了乳腺癌的风险,并使其预后恶化。例如,据报道,与没有多发性硬化症的患者相比,多发性硬化症患者肿瘤对全身抗癌治疗的敏感性降低,术后并发症发生率增加,总生存率和无病生存率降低(5-8)。此外,一些用于乳腺癌全身抗癌治疗的药物增加了ms的主要致病环节胰岛素抵抗,特别是乳腺癌化疗中常用的地塞米松引起高血糖。在绝经期肥胖妇女中,与未服用他莫昔芬的妇女相比,他莫昔芬使胰岛素敏感性降低了近7倍,并增加了2型糖尿病的发病率(9,10)。实验研究发现,二甲双胍的抗肿瘤作用与amp依赖性蛋白激酶(AMPK)的激活有关,AMPK在细胞能量平衡中起关键作用。AMPK的激活可抑制合成代谢过程,抑制肝细胞的新糖生成和脂肪细胞的脂肪分解,通过抑制mTOR(哺乳动物雷帕霉素靶点)减少蛋白质合成,启动细胞内的分解代谢过程(糖酵解和脂肪酸氧化增加),阻滞细胞周期在G0/ g1期,刺激p53依赖性细胞自噬(11,12)。此外,二甲双胍可以直接(不需要AMPK激活)阻断蛋白mTOR,从而刺激蛋白质的生物合成,促进细胞生长和增殖,从而显示出抗增殖活性(11)。这项前瞻性随机试验的目的是研究二甲双胍对乳腺癌代谢综合征患者新辅助全身抗癌治疗效果的影响。
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来源期刊
Archive of Oncology
Archive of Oncology Medicine-Oncology
CiteScore
0.60
自引率
0.00%
发文量
5
审稿时长
12 weeks
期刊介绍: Archive of Oncology is an international oncology journal that publishes original research, editorials, review articles, case (clinical) reports, and news from oncology (medical, surgical, radiation), experimental oncology, cancer epidemiology, and prevention. Letters are also welcomed. Archive of Oncology is covered by Biomedicina Vojvodina, Biomedicina Serbica, Biomedicina Oncologica, EMBASE/Excerpta Medica, ExtraMED and SCOPUS.
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