Curcumin-derivative nanomicelles for the treatment of triple negative breast cancer

Abstract

Background: Triple negative breast cancer (TNBC) is a subtype of breast cancer characterized by its poor outcome and a lack of targeted therapies. Recently, our laboratory has developed a second generation curcumin derivative, 3,5-bis(3,4,5-trimethoxybenzylidene)-1-methylpiperidine-4-one (RL71) that shows potent in vitro cytotoxicity. RL71 is hydrophobic with poor bioavailability which limits its clinical development.

Purpose: We have designed styrene-co-maleic acid (SMA) micelles encapsulating 5, 10 or 15% RL71 by weight/weight ratio to improve its solubility and pharmacokinetic profile.

Methods: The micelles charge, size and release rate were characterized. We evaluated their cytotoxicity against TNBC cell lines. The internalization of the drug inside the cells was measured by HPLC and the efficiency of the micelles was tested using a tumor spheroid model.

Results: The micelles exhibited mean diameters of 125–185?nm and had a neutral charge. SMA-RL71 micelles have a cytotoxicity profile comparable to the free drug against several TNBC cell lines. Moreover, the 15% loaded micelles increased the stability of RL71 and demonstrated higher activity in a tumor spheroid model.

Conclusion: The current study demonstrates the efficiency of SMA for drug delivery, the influence of physicochemical characteristics on cytotoxicity, and provides the basis for preclinical testing in vivo.     

Curcumin-induced antitumor effects on triple-negative breast cancer patient-derived xenograft tumor mice through inhibiting salt-induced kinase-3 protein

This study demonstrated for the first time that curcumin effectively inhibits the growth of triple-negative breast cancer (TNBC) tumors by inhibiting the expression of salt-induced kinase-3 (SIK3) protein in patient-derived xenografted tumor mice (TNBC-PDX). For TNBC patients, chemotherapy is the only option for postoperative adjuvant treatment. In this study, we detected the SIK3 mRNA expression in paired-breast cancer tissues by qPCR analysis. The results revealed that SIK3 mRNA expression was significantly higher in tumor tissues when compared to the normal adjacent tissues (73.25 times, n = 183). Thus, it is proposed for the first time that the antitumor effect induced by curcumin by targeting SIK3 can be used as a novel strategy for the therapy of TNBC tumors. In vitro mechanism studies have shown that curcumin (>25 μM) inhibits the SIK3-mediated cyclin D upregulation, thereby inhibiting the G1/S cell cycle and arresting TNBC (MDA-MB-231) cancer cell growth. The SIK3 overexpression was associated with increased mesenchymal markers (i.e., Vimentin, α-SMA, MMP3, and Twist) during epithelial–mesenchymal transition (EMT). Our results demonstrated that curcumin inhibits the SIK3-mediated EMT, effectively attenuating the tumor migration. For clinical indications, dietary nutrients (such as curcumin) as an adjuvant to chemotherapy should be helpful to TNBC patients because the current trend is to shrink the tumor with preoperative chemotherapy and then perform surgery. In addition, from the perspective of chemoprevention, curcumin has excellent clinical application value.     

Co-delivery of gambogic acid and TRAIL plasmid by hyaluronic acid grafted PEI-PLGA nanoparticles for the treatment of triple negative breast cancer

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-based combination therapy and gene therapy are new strategies to potentially overcome the limitations of TRAIL, however, the lack of efficient and low toxic vectors remains the major obstacle. In this study, we developed a hyaluronic acid (HA)-decorated polyethylenimine-poly(d,l-lactide-co-glycolide) (PEI-PLGA) nanoparticle (NP) system for targeted co-delivery of TRAIL plasmid (pTRAIL) and gambogic acid (GA) in triple-negative breast cancer (TNBC) therapy. GA was encapsulated into the core of the PEI-PLGA NPs while pTRAIL was adsorbed onto the positive NP surface via charge adsorption. The coating of HA on PEI-PLGA NPs functions as a targeting ligand by binding to CD44 receptor of TNBC cells and a shell to neutralize the excess positive charge of inner NPs. The resultant pTRAIL and GA co-loaded HA-coated PEI-PLGA NPs exhibited spherical shape (121.5?nm) and could promote the internalization of loaded cargoes into TNBC cells through the CD44-dependent endocytic pathway. The dual drug-loaded NPs significantly augmented apoptotic cell death in vitro and inhibited TNBC tumor growth in vivo. This multifunctional NP system efficiently co-delivered GA and pTRAIL, thus representing a promising strategy to treat TNBC and bringing forth a platform strategy for co-delivery of therapeutic DNA and chemotherapeutic agents in combinatorial TNBC therapy.     

槐耳颗粒联合DC-CIK细胞对乳腺癌MDA-MB-231干细胞体内外杀伤作用研究

目的 探究白屈菜红碱（CHE）对腺样囊性癌细胞（ACC2）生长的抑制作用及机制。方法 利用CCK8法、EdU法、Hoechst33342/PI双染色法、试剂盒法检测CHE对ACC2细胞活力、细胞增殖、细胞凋亡和活性氧（ROS）水平的影响;通过Western blotting技术检测CHE对Cleaved-Caspase 3、PARP、NF-κB、p-JNK、p-p38蛋白表达的影响;利用斑马鱼移植瘤模型检测CHE对斑马鱼体内ACC2细胞生长的抑制作用。结果 CCK-8结果显示：与对照组比较,2、3、4、5、6、7、8、9、10 μmol/L的CHE显著降低ACC2细胞的存活率（P<0.05、0.01）,且呈浓度相关性; ROS检测结果显示：与对照组比较,5、8 μmol/L的CHE导致ACC2细胞内的ROS水平显著上升（P<0.05、0.01）; EdU增殖检测结果表明：与对照组比较,5、8 μmol/L的CHE致使ACC2细胞的增殖能力显著下降（P<0.01）;Hoechst/PI染色结果显示：与对照组比较,CHE 5、8 μmol/L组ACC2细胞凋亡率显著上升（P<0.01）。抗氧化剂N-乙酰半胱氨酸（NAC）显著抑制CHE诱导的ROS水平升高、细胞凋亡增加（P<0.01）;Western blotting结果显示：2、5、8 μmol/L的CHE能够显著上调Cleaved-Caspase 3、PARP、NF-κB蛋白的表达（P<0.01）,且呈现浓度相关性,5、8 μmol/L的CHE能够显著上调p-JNK的蛋白表达（P<0.01）,8 μmol/L的CHE能够显著上调p-p38的蛋白表达（P<0.01）;NAC显著降低由CHE导致的Cleaved-Caspase 3、PARP、NF-κB、p-JNK、p-p38蛋白表达增加（P<0.01）,5、8 μmol/L CHE能够有效抑制斑马鱼体内肿瘤的生长（P<0.01）。结论 体外及斑马鱼移植瘤模型证明,CHE可以有效抑制ACC2细胞生长,其机制与提高细胞ROS水平,上调NF-κB、p-JNK、p-p38表达,从而抑制细胞增殖、诱导细胞凋亡相关。     

CD44 directed nanomicellar payload delivery platform for selective anticancer effect and tumor specific imaging of triple negative breast cancer

Triple negative breast cancer (TNBC) is a highly aggressive tumor subtype, lacking estrogen, progesterone and human epidermal growth factor-2 (HER-2) receptors. Thus, early detection and targeted therapy of TNBC is an urgent need. Herein, we have developed a CD44 targeting Hyaluronic Acid (HA) decorated biocompatible oligomer, containing FDA approved vitamin E TPGS and Styrene Maleic Anhydride (SMA) (HA-SMA-TPGS) for targeting TNBC. The self-assembling HA-SMA-TPGS was encapsulated with poorly water soluble, potent curcumin analogue (CDF) to form nanomicelles (NM), HA-SMA-TPGS-CDF has demonstrated excellent nanoparticle characteristics for parenteral delivery. The targeted NM can selectively kill TNBC cells through CD44 mediated apoptosis pathway. Tumor imaging using phase-2 clinical trial near infrared (NIR)-fluorescent dye (S0456) conjugate, HA-SMA-TPGS-S0456 showed excellent TNBC tumor accumulation with minimum liver and spleen uptake. To our best of knowledge, for the first time, we are reporting a promising platform for CD44 mediated multimodal NIR imaging and cytotoxin delivery to TNBC.     

全身化疗联合调强放射治疗对复发性晚期三阴性乳腺癌的疗效分析

目的 探讨全身化疗联合调强放射治疗对复发性晚期三阴性乳腺癌（TNBC）的疗效。方法 采用回顾性研究方法,选择122例在我院诊治的复发性晚期TNBC患者作为研究对象,根据治疗方法的不同分为观察组（62例）与对照组（60例）。对照组给予全身化疗治疗,观察组在对照组的基础上联合调强放射治疗。比较两组患者的疗效、毒副反应、免疫功能以及预后。结果 观察组患者治疗总有效率显著高于对照组（67.7% vs. 33.3%, P<0.05）。两组患者治疗期间骨髓抑制、消化道反应、脱发等毒副反应发生率比较,差异均无统计学意义（P>0.05）。观察组患者治疗后CD3⁺、CD4⁺水平显著高于治疗前,并显著高于对照组（P<0.05）,而对照组治疗前后CD3⁺、CD4⁺水平比较,差异无统计学意义（P>0.05）。观察组患者总生存期及无进展生存期均显著长于对照组（P<0.05）。结论 全身化疗联合调强放射治疗可提高复发性晚期TNBC患者的疗效,改善其免疫功能,延长其总生存期及无进展生存期,且不增加毒副反应。     

cMET in triple-negative breast cancer: is it a therapeutic target for this subset of breast cancer patients?

Introduction: The identification and validation of a targeted therapy for triple-negative breast cancer (TNBC) is currently one of the most urgent needs in breast cancer therapeutics. The cMET oncogene encodes a membrane-bound tyrosine kinase implicated in the formation and/or progression of several cancer types, including TNBC. Currently, inhibitors targeting cMET are undergoing clinical trials for a variety of cancers, including TNBC. These include anti-cMET and anti-hepatocyte growth factor (HGF) monoclonal antibodies and tyrosine kinase inhibitors.

Areas covered: This article reviews the structure and mode of action of cMET, the role of cMET in cancer formation/development, with particular emphasis on its role in basal/TNBC and its potential as a therapeutic target for this subtype of breast cancer.

Expert opinion: Due to cancer heterogeneity, it is unlikely that all TNBC patients will be responsive to anti-cMET drugs. Therefore, if cMET is to be used as a target for treatment, it will be important to identify predictive biomarkers to select, upfront, those patients likely to benefit. Potential predictive biomarkers for anti-cMET treatments in basal/TNBC include cMET, phospho-cMET, downstream signaling proteins or HGF. These putative predictive biomarkers should be evaluated in a large panel of basal/TNBC cell lines before incorporation into clinical trials involving anti-cMET drugs.     

The apple polyphenol phloretin inhibits breast cancer cell migration and proliferation via inhibition of signals by type 2 glucose transporter

Human triple-negative breast cancer (TNBC) is the most aggressive and poorly understood subclass of breast cancer. Glucose transporters (GLUTs) are required for glucose uptake in malignant cancer cells and are ideal targets for cancer therapy. To determine whether the inhibition of GLUTs could be used in TNBC cell therapy, the apple polyphenol phloretin (Ph) was used as a specific antagonist of GLUT2 protein function in human TNBC cells. Interestingly, we found that Ph (10–150 μM, for 24 h) inhibited cell growth and arrested the cell cycle in MDA-MB-231 cells in a p53 mutant-dependent manner, which was confirmed by pre-treatment of the cells with a p53-specific dominant-negative expression vector. We also found that Ph treatment (10–150 μM, for 24 h) significantly decreased the migratory activity of the MDA-MB-231 cells through the inhibition of paxillin/FAK, Src, and alpha smooth muscle actin (α-sMA) and through the activation of E-cadherin. Furthermore, the anti-tumorigenic effect of Ph (10, 50 mg/kg or DMSO twice a week for six weeks) was demonstrated in vivo using BALB/c nude mice bearing MDA-MB-231 tumor xenografts. A decrease in N-cadherin, vimentin and an increase in p53, p21 and E-cadherin were detected in the tumor tissues. In conclusion, inhibition of GLUT2 by the apple polyphenol Ph could potentially suppress TNBC tumor cell growth and metastasis.     

Cholesterol-conjugated poly(D,L-lactide)-based micelles as a nanocarrier system for effective delivery of curcumin in cancer therapy

Polymeric micelles have been widely explored preclinically as suitable delivery systems for poorly soluble chemotherapeutic drugs in cancer therapy. The present study reported the development of cholesterol (Ch)-conjugated poly(D,L-Lactide) (PLA)-based polymeric micelles (mPEG–PLA-Ch) for effective encapsulation and delivery of curcumin (CUR) at the tumor site. Cholesterol conjugation dramatically affected the particle size and improved drug loading (DL) and encapsulation efficiency (EE). mPEG–PLA-Ch-CUR showed bigger hydrodynamic diameter (104.6?±?2.1?nm, and 169.3?±?1.52?nm for mPEG–PLA and mPEG–PLA-Ch, respectively) due to increased size of the hydrophobic core. The newly developed polymer exhibited low critical micelles concentration (CMC) (25?μg/mL) which is close to lipid-based polymer, PEG-phosphatidyl ethanolamine (12.5?μg/mL) compared to mPEG–PLA (50?μg/mL). mPEG–PLA-Ch micelles exhibited relatively higher EE (93.74?±?1.6%) and DL (11.86?±?0.8%) compared to mPEG–PLA micelles (EE 91.89?±?1.2% and DL 11.06?±?0.8%). mPEG–PLA-Ch micelles were internalized by the cancer cells effectively and exhibited higher cytotoxicity compared to free CUR in both, murine melanoma (B16F10) and human breast cancer (MDA-MB-231) cells. mPEG–PLA-Ch exhibited satisfactory hemocompatibility indicating their potential for systemic application. Further, mPEG–PLA-Ch-CUR demonstrated higher rate of reduction of tumor volume in B16F10-xenografted tumor-bearing mice compared to free CUR. At the end of 22 days, the tumor reduced to 1.87-fold (627.72?±?0.9?mm³ versus 1174.68?±?1.64?mm³) compared to the treatment with free CUR. In conclusion, the experimental data in vitro and in vivo indicated that the newly developed CUR-mPEG–PLA-Ch micelles may have promising applications in solid tumors.     

Oridonin inhibits 4T1 tumor growth by suppressing Treg differentiation via TGF-β receptor

The Chinese herbal medicine oridonin has potent anti-inflammatory and antitumor activities. In addition, oridonin treatment effectively suppresses breast cancer growth. However, the underlying mechanisms are poorly defined. Here, we reported that oridonin decreased Treg differentiation in vitro and in vivo. Oridonin inhibition of Treg differentiation was dependent on decreasing TGF-β receptor expression. Oridonin attenuated Tregs’ immunosuppressive ability; thus, oridonin did not inhibit CD8⁺ T cell proliferation very well in vitro. Oridonin greatly delayed the progression of 4T1 tumors in vivo. In addition, oridonin combined with anti-PD-1 activated a robust antitumor immune response and suppressed 4T1 tumor growth. Therefore, our results indicate that oridonin inhibits TNBC growth by modulating Treg differentiation, which provides new directions for the clinical treatment of TNBC.     

Tea polyphenol epigallocatechin-3-gallate inhibits cell proliferation in a patient-derived triple-negative breast cancer xenograft mouse model via inhibition of proline-dehydrogenase-induced effects

Triple-negative breast cancers (TNBCs) lack specific targeted therapy options and have evolved into highly chemo-resistant tumors that metastasize to multiple organs. The present study demonstrated that the proline dehydrogenase (PRODH) mRNA level in paired (tumor vs. normal) human breast tissue samples (n=234) was 6.6-fold greater than normal cells (*p=0.021). We established stable PRODH-overexpressing TNBC (HS578T) cells, and the malignant phenotypes were evaluated using soft agar colony formation and Transwell migration assays. The results demonstrated that PRODH induced epithelial-mesenchymal transition in cancer cells and increased cell proliferation. The present study found that the tea polyphenol epigallocatechin-3-gallate (EGCG) significantly inhibited PRODH and its regulated proteins, such as alpha-smooth muscle actin (alpha-SMA) expression in TNBC cells. These findings support the targeting of the PRODH signaling pathway as a potential therapeutic strategy in preventing cancer cell metastasis. The patient-derived xenograft (PDX) mouse model is highly relevant to real human tumor growth. We established a TNBC-PDX (F4, n=4 in each group)mouse model. The PDX mice were treated with EGCG (50 mg/kg), and the results indicated that EGCG significantly inhibited PDX tumor growth (*p = 0.013). These experiments provide additional evidence to evaluate the antitumor effects of EGCG-induced PRODH inhibition for clinical therapeutic application, especially in TNBC patients.     

Toxicity and efficacy evaluation of multiple targeted polymalic acid conjugates for triple-negative breast cancer treatment

Abstract

Engineered nanoparticles are widely used for delivery of drugs but frequently lack proof of safety for cancer patient’s treatment. All-in-one covalent nanodrugs of the third generation have been synthesized based on a poly(β-l-malic acid) (PMLA) platform, targeting human triple-negative breast cancer (TNBC). They significantly inhibited tumor growth in nude mice by blocking synthesis of epidermal growth factor receptor, and α4 and β1 chains of laminin-411, the tumor vascular wall protein and angiogenesis marker. PMLA and nanodrug biocompatibility and toxicity at low and high dosages were evaluated in vitro and in vivo. The dual-action nanodrug and single-action precursor nanoconjugates were assessed under in vitro conditions and in vivo with multiple treatment regimens (6 and 12 treatments). The monitoring of TNBC treatment in vivo with different drugs included blood hematologic and immunologic analysis after multiple intravenous administrations. The present study demonstrates that the dual-action nanoconjugate is highly effective in preclinical TNBC treatment without side effects, supported by hematologic and immunologic assays data. PMLA-based nanodrugs of the Polycefin? family passed multiple toxicity and efficacy tests in vitro and in vivo on preclinical level and may prove to be optimized and efficacious for the treatment of cancer patients in the future.     

小金片联合NX方案治疗紫杉类及蒽环类耐药晚期乳腺癌的临床研究

目的 观察小金片联合NX化疗方案(长春瑞滨联合卡培他滨)治疗紫杉类及蒽环类耐药晚期乳腺癌的临床效果.方法 选取2019年1月—2020年1月南阳市第二人民医院收治的100例紫杉类及蒽环类耐药晚期乳腺癌患者,根据信封抽签法分为对照组和治疗组,每组各50例.对照组给予NX化疗方案治疗,第1、8天静脉滴注酒石酸长春瑞滨注射液...     

Development and characterization of octreotide-modified curcumin plus docetaxel micelles for potential treatment of non-small-cell lung cancer

We prepared octreotide (OCT)-modified curcumin plus docetaxel micelles to enhance active targeting and inhibit tumor metastasis by destroying vasculogenic mimicry (VM) channels. Soluplus was applied as an amphiphilic material to form micelles via film dispersion. The cytotoxic effects, active cellular targeting, and inhibitory effects on metastasis were systematically evaluated in vitro using A549 cells, and in vivo antitumor effects were evaluated using xenograft tumor-bearing mice. In vitro assays indicated that the OCT-modified curcumin plus docetaxel micelles showed robust cytotoxicity on A549 cells and effectively inhibited VM channels and tumor metastasis. Studying the mechanism of action indicated that OCT-modified curcumin plus docetaxel micelles downregulated MMP-2 and HIF-1α. In vivo assays indicated that OCT-modified curcumin plus docetaxel micelles increased drug accumulation at tumor sites and showed obvious antitumor efficacy. The developed OCT-modified curcumin plus docetaxel micelles may offer a promising treatment strategy for non-small-cell lung cancer.     

Improved delivery of miR-1296 loaded cationic nanoliposomes for effective suppression of triple negative breast cancer

Nowadays, microRNA is considered an attractive strategy for the effective treatment of cancer. A significant delivery of microRNA for cancer therapy remains a significant obstacle to target cancer cells. The restoring microRNA-1296 (miR-1296) has immense therapeutic efficacy in triple-negative breast cancer (TNBC). TNBC is an aggressive subtype of breast tumors with the progression of malignant transformation. This study aimed to develop a cationic nanoliposome that can serve as a miR-1296 carrier and studied its efficiency in TNBC. The efficacy of miR-1296 liposomes was evaluated on its apoptotic effect, cellular uptake, and potential chemotherapy sensitization in the TNBC cell line (MDA-MB-231). For in vitro viability study, the apoptotic effect was performed to validate protein expression using Alamar blue kit and western blot. The transfection of miR-1296 into TNBC cells was also investigated using cisplatin as a TNBC resistance drug. The fluorescent miR-1296-cy3 liposome was used for cellular uptake study. The miR-liposome was successfully prepared with a particle size of 123.6 ± 1.3 nm and encapsulation efficiency of 94.33%. A dose of 0.5 uM has significantly reduced the viability of MDA-MB-231 to be 33.45%±5.29 (P < 0.001). This result was validated by down-expression of CCND1, and PARP1, the miR-1296 receptor, and apoptosis marker. The image of the miR-1296-cy3 liposome showed cytoplasmic intracellular localization. It was found high sensitization of TNBC cell line for miR-1296 liposome compared to cisplatin (P < 0.001). Future in vivo research may answer questions concerning safety and stability. This study demonstrates that miR-191 liposomes may have promising clinical applications for TNBC therapy.     

三阴性乳腺癌与非三阴性乳腺癌的超声特征对比分析

目的对比分析三阴性乳腺癌（TNBC）和非三阴性乳腺癌（NTNBC）的超声和病理学特征差异。方法将135例经病理证实的乳腺癌患者根据术后免疫组织化学结果分为TNBC组和NTNBC组,对比分析两组患者病灶的超声表现及临床病理特征。结果 135例乳腺癌病例中,TNBC患者占26.67%,NTNBC患者占73.33%;TNBC组和NTNBC组腋窝淋巴结转移率分别为58.33%和40.40%,差异有统计学意义（P〈0.05）;两组浸润性导管癌和非浸润性导管癌的比例相似,两组间病理类型比较,差异无统计学意义（P〉0.05）。TNBC组患者肿块边缘毛刺征、肿块内部微钙化及血流分级为Ⅱ～Ⅲ级者所占比例均明显低于NTNBC组,差异有统计学意义（P〈0.05）;两组肿块直径〉2cm者比例及肿块后方无回声衰减者比例差异无统计学意义（P〉0.05）。结论 TNBC患者的淋巴结转移率高于NTNBC患者,且TNBC患者缺少毛刺征、微钙化、丰富的血流等典型的乳腺癌超声表现,诊断检测时应注意与良性肿块间的区别,以免漏诊。     

Sacituzumab for the treatment of triple-negative breast cancer: the poster child of future therapy?

Introduction: Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer that disproportionately impacts younger women and is associated with a poor prognosis. Systemic treatment options for metastatic TNBC (mTNBC) are limited to cytotoxic chemotherapy agents with low response rates. This encouraged the clinical development of sacituzumab govitecan (IMMU-132), an antibody-drug conjugate targeting Trop-2, a potential target in epithelial cancer such as TNBC.

Areas covered: We summarize the key features, pharmacokinetics, and the safety and efficacy data of sacituzumab govitecan. We also discuss the future directions of this novel therapeutic agent for mTNBC.

Expert opinion: Based on the efficacy and tolerability observed in the phase 1/2 clinical trial, sacituzumab govitecan was granted breakthrough therapy designation by the Food and Drug Administration as ≥3^rd line therapy for mTNBC. Novel treatment modalities for the management of mTNBC are necessary to improve the care of this aggressive disease. Sacituzumab govitecan represents an important advance in the treatment of mTNBC because of its efficacy and tolerability.     

Multifunctional polymeric micelle-based chemo-immunotherapy with immune checkpoint blockade for efficient treatment of orthotopic and metastatic breast cancer

Immunotherapy has become a highly promising paradigm for cancer treatment. Herein, a chemo-immunotherapy was developed by encapsulating chemotherapeutic drug doxorubicin (DOX) and Toll-like receptor 7 agonist imiquimod (IMQ) in low molecular weight heparin (LMWH)-d-α-tocopheryl succinate (TOS) micelles (LT). In this process, LMWH and TOS were conjugated by ester bond and they were not only served as the hydrophilic and hydrophobic segments of the carrier, but also exhibited strong anti-metastasis effect. The direct killing of tumor cells mediated by DOX-loaded micelles (LT-DOX) generated tumor-associated antigens, initiating tumor-specific immune responses in combination with IMQ-loaded micelles (LT-IMQ). Furthermore, the blockade of immune checkpoint with programmed cell death ligand 1 (PD-L1) antibody further elevated the immune responses by up-regulating the maturation of DCs as well as the ratios of CD8⁺ CTLs/T_reg and CD4⁺ T_eff/T_reg. Therefore, such a multifunctional strategy exhibited great potential for inhibiting the growth of orthotopic and metastatic breast cancer.     

复方苦参注射液联合ET方案治疗乳腺癌的临床研究

目的探讨复方苦参注射液联合ET方案(表柔比星联合多西他赛)治疗乳腺癌的临床疗效。方法选取2016年1月—2017年12月邳州市中医院收治的94例晚期乳腺癌患者作为研究对象,将所有患者随机分为对照组和治疗组。每组各47例。对照组患者给予ET方案治疗,静脉滴注注射用盐酸表柔比星70 mg/m~2,连续3 d,4周后重复1次;静脉滴注多西他赛注射液75mg/m~2,1次/周,连用6周,停2周。治疗组患者在对照组治疗的基础上第1～10天静脉滴注复方苦参注射液,20 mL用氯化钠注射液200 mL稀释。8周为1个疗程,两组患者均治疗2个疗程。观察两组近期临床疗效,比较两组患者的无进展生存期(PFS)、总生存期(OS)、生存质量测定量表简表(QOL-BREF)评分、肿瘤标志物和免疫因子水平。结果治疗后,对照组的临床缓解率为38.3%,疾病控制率为72.3%,分别显著低于治疗组的57.4%、89.4%,两组比较差异具有统计学意义(P0.05)。治疗后,治疗组患者的PFS、OS显著高于对照组,两组比较差异具有统计学意义(P0.05)。治疗后,治疗组的QOL-BREF评分显著升高,同组比较差异具有统计学意义(P0.05),且治疗后治疗组QOL-BREF评分显著高于对照组,两组比较差异具有统计学意义(P0.05)。治疗后,两组血清癌胚抗原(CEA)、糖类抗原153(CA153)和糖类抗原125(CA125)水平均显著降低,同组治疗前后比较差异具有统计学意义(P0.05);且治疗后治疗组的肿瘤标志物水平均显著低于对照组,两组比较差异具有统计学意义(P0.05)。治疗后,治疗组的CD3~+、CD4~+和CD4~+/CD8~+水平均显著升高,CD8~+水平显著降低,同组治疗前后比较差异具有统计学意义(P0.05);且治疗后治疗组免疫因子水平显著优于对照组,两组比较差异具有统计学意义(P0.05)。结论复方苦参注射液联合ET方案治疗晚期乳腺癌疗效确切,能降低肿瘤标志物水平,提高免疫功能,延长患者PFS和OS,提高患者生活质量,具有一定的临床推广应用价值。     

Patient survival and healthcare utilization costs after diagnosis of triple-negative breast cancer in a United States managed care cancer registry

Abstract

Background:

Triple-negative breast cancer (TNBC) makes up 10–17% of all breast cancers and, due to lack of receptor expression, is unresponsive to therapies that target hormonal receptors or HER2. Unique in its tumor aggression and high rates of recurrence, TNBC is less likely to be detected by mammogram and has a poorer prognosis than other breast cancer subtypes (non-TNBC).