论文部分内容阅读
摘要:肿瘤的生长、浸润与转移离不开新生血管支持,因此抗血管生成治疗成为抗肿瘤治疗的重要策略之一。而血管内皮生长因子( vascular endothelial growth factor,VEGF)在肿瘤血管生成中起到重要作用,所以VEGF/VEGFR (vascular endothelial growth factor receptor,VEGFR)成为抗肿瘤血管生成治疗的重要靶点。乳腺癌是血管依赖性肿瘤,本文就乳腺癌抗血管生成治疗中抗VEGF/VEGFR靶点的研究进展做一综述。
关键词: 肿瘤;乳腺癌;抗血管生成;血管内皮生长因子
Abstract: The growth, infiltration and metastasis of tumor depends on neovascularity. So antiangiogenesis is an important strategy of tumor treatment. And VEGF plays a significant role in the angiogenesis of tumor, so VEGF/VEGFR become an important target of antiangiogenesis. Brest cancer is a tumor which depends on angiogenesis. This review gives a brief background of breast cancer angiogenesis, and focuses on current progress in the field of anti-VEGF/VEGFR strategy for breast cancer and questions for future therapeutic development.
Key word: tumor; breast cancer; antiangiogenesis;vascular endothelial growth factor
早在40年前,Folkman教授首次提出肿瘤生长和转移需要新生血管支持[1],血管形成是在已有血管基础上生成新血管,包括4个步骤:基底细胞降解、内皮细胞迁移和增殖、细胞基质内相互作用和新生血管成熟,这一过程是促血管生成物和抗血管生成物共同作用的结果[2,3]。资料证实乳腺癌是血管依赖性肿瘤,随着乳腺癌病情进展,乳腺癌细胞可表达众多血管生成因子,有针对性的抗血管生成治疗已经在包括乳腺癌在内的多种肿瘤的临床研究中得到了证实。本文将阐述抗VEGF/VEGFR在乳腺癌治疗中的研究进展。
1 概述
乳腺癌细胞在生长过程中常分泌一些促血管生长的细胞因子,如血管内皮细胞生长因子(vascular endothelial growth factor, VEGF)、转化生长因子β(transforming growth factor-β, TGFβ)、碱性成纤维细胞生长因子(basic fibroblast growth factor, bFGF)、胎盘生长因子(Placental growth factor, PIGF)等[4,5]。在血管生成过程中,首先肿瘤局部微环境缺氧导致肿瘤细胞分泌VEGF等多种血管生长因子,这些血管生长因子与内皮细胞表面相应受体结合,刺激内皮细胞增殖、活化,并定向移动。活化的内皮细胞表达多种基质金属蛋白酶(matrixmetalloproteinase, MMPs)降解细胞外基质(extracellularmatrix, ECM),内皮细胞与细胞外基质相互作用,血管腔形成,芽式生长,形成管、袢、网,经过以上一系列复杂有序的过程,肿瘤内新生血管形成。在此过程中,VEGF起重要作用,它在乳腺癌中往往过表达。因此针对VEGF/VEGFR的抗血管生成被认为是抗肿瘤治疗的手段之一,其药物包括抗VEGF(如贝伐珠单抗)、小分子酪氨酸激抑制剂(Tyrosine kinase inhibitors,TKI)(竞争ATP结合VEGF受体抑制信号传输,如sunitinib、sorafenib、pazopanib、vatalanib,和vandetanib)和VEGF-Trap(如aflibercept)。
2 抗VEGF药
2.1 贝伐单抗
贝伐珠单抗(Bevacizumab,Bv)是针对VEGF的重组人源化单克隆抗体,通过与VEGF特异性结合阻断其与受体结合,退化肿瘤血管、“正常化”存活血管,抑制肿瘤血管的新生和再生,减少肿瘤血管生成和抑制肿瘤生长及转移[6,7]。
E2100显示Bv和紫杉醇联合用药组与紫杉醇单药组相比显著延长无进展生存期(progress free survival ,PFS)(11.8个月vs 5.9个月;P <0.001),并提高客观缓解率(object response rate, ORR)(36.9%vs 21.2%;P <0.001)。但总生存期(overall survival,OS)无明显改善[8]。这项研究证明晚期乳腺癌患者在常规化疗中添加Bv能获益。Gray认为每周紫杉醇方案中添加贝伐珠单抗,疾病进展危险性下降52%(HR= 0.48;95%CI:0.385~0.607,P <0.0001),ORR提高1倍(48.9 vs 22.2%;P <0.0001)[9]。根据此临床试验结果,美国FDA批准乳腺癌成为Bv的适应症。而Ⅲ期临床试验AVADO显示对比单药,联合Bv组延长PFS(8.7个月vs 8.0个月;P = 0.0035),同时提高ORR(63.1%vs 44.4%~55.2%;P = 0.0001),但OS无明显改善[10],这项临床试验表明Bv联合紫杉类一线治疗晚期乳腺癌的疗效。另一临床试验RiBBOn-1比较化疗[卡培他滨(Cap)、紫杉类(T)、蒽环类(A)]联合或不联合Bv一线治疗转移性乳腺癌疗效。对比其它各组,联合Bv组的中位PFS显著提高(8.6 vs 5.7个月 Cap,P =0.0002; 9.2 vs. 8.0个月A/T, P =<0.0001),ORR也明显提高(Cap 35.4 vs. 23.6%, P =0.0097;A/T 51.3 vs. 37.9%,P =0.0054),可OS无明显改善[11]。这三项大型研究表明Bv联合标准化疗药物一线治疗晚期乳腺癌都有提高疗效的趋势。 Bv用于三线乳腺癌治疗尚未发现额外获益。一Ⅲ期临床试验显示联合Bv治疗缓解率(response rate,RR)更佳(19.8% vs 9.1%,P=0.001),但PFS和OS无明显改善[12]。这也许是难治性乳腺癌存在多条不同血管生成途径,需要多种抗血管生成药物抑制。
患者对贝伐珠单抗耐受性较好,最常报导的毒性反应包括高血压、蛋白尿、出血、乏力、伤口愈合综合症等。在试验E2100中,3级高血压发生率为15.4%[8]。任何程度蛋白尿均常见,在临床试验AVF2119g中[13],严重蛋白尿(3级或4级)发生率8.3%,27.9%的患者出现严重不良事件(serious adverse event,SAE),最常见的包括中性粒细胞减少性发热、蛋白尿等。而在MO19391中[14],3至4级不良事件6.3%,包括高血压(2.2%)、蛋白尿(0.7%)、肺栓塞(0.5%)和鼻衄(0.4%)。中枢神经系统转移患者中,没有发现中枢神经系统出血现象。总之Bv是安全的晚期乳腺癌药物,其联合标准化疗能改善PFS。虽然2010年12月16日FDA咨询委员会建议删除Bv的一线治疗晚期乳腺癌适应症,但是欧洲医学机构仍认为Bv联合紫杉醇可使晚期乳腺癌患者获益。
还有一些关于Bv的临床试验正在进行中。针对乳腺癌新辅助治疗,NASBP B-40试验评价不同化疗中加入Bv的疗效,GeparQuinto试验则使用Bv加依维莫司和拉帕替尼进行新辅助治疗;而对乳腺癌辅助治疗,ECOG E2104已显示Bv辅助治疗的可行性[15],为进一步研究Bv在乳腺癌辅助治疗中的应用,有两项研究正在进行:一研究BEATRICE;另一Ⅲ期临床研究NSABP BETH;对转移乳腺癌,AVEREL试验评价多西他塞联合或不联合Bv疗效,LEA试验比较来曲唑或氟维司群联合或不联合Bv疗效。
2.2 VEGF-Trap
VEGF-Trap包含VEGFR-1和VEGFR-2细胞外部分区域,并与人IG的Fc片段融合,通过诱骗受体结合所有VEGF亚型和胎盘生长因子(Placental growth factor,PLGF)抑制血管生成[16]。与Bv相比,其与VEGF的亲和力明显提高。
临床前试验中,Le等发现单用VEGF-Trap抑制BT474乳腺癌的肿瘤微血管密度和肿瘤生长,VEGF-Trap能降低人体VEGF和PIGF。他们发现在HER-2阳性的乳腺癌患者中,VEGF-Trap联合曲妥珠单抗比两者单独使用能更有效抑制乳腺癌[17]。目前VEGF-Trap治疗非小细胞肺癌已进入Ⅰ期临床,而对乳腺癌的治疗已进入临床前阶段。
3 酪氨酸激酶抑制剂
3.1 索拉非尼
索拉非尼(Sorafenib)是一多因子抑制剂,其抑制因子包括丝氨酸/苏氨酸因子、受体酪氨酸因子、VEGFR-2,3、血小板源性生长因子受体(platelet derived growth factor receptor, PDGFR)、干细胞受体(c-Kit)和造血细胞的细胞因子受体(CD135)。它通过阻断这些因子和细胞内信号通路抑制肿瘤和血管生成。已批准用于肾细胞癌和不可切除的肝细胞癌,在乳腺癌治疗方面正进行Ⅱ期临床试验。常见不良反应有乏力、皮疹、恶心、手足综合征等。
索拉非尼单药用于转移性乳腺癌的2个Ⅱ期临床试验,N0336试验显示索拉非尼单药治疗乳腺癌患者,没有患者获得部分缓解(partial response,PR)或完全缓解(complete response,CR),仅2人获大于6个月的病情稳定(stable disease,SD),随后终止试验[18]。Bianchi等发现转移乳腺癌患者使用索拉非尼单药治疗后,没有患者CR,1人PR(2%),SD患者中20人持续至少8周(38%)、12人持续至少16周(23%)[19]。这2个临床试验说明单用索拉非尼治疗乳腺癌虽有良好安全性但未显示其疗效,所以研究者建议索拉非尼应联合常规治疗使用。
TIES计划评价索拉非尼联合化疗治疗HER-2阴性转移性乳腺癌疗效和安全性,其包含4个Ⅱb期临床试验[20]。试验NU07B1发现相比单药紫杉醇治疗,Bv联合紫杉醇组提高PFS(6.9 vs. 5.6 个月,P =0.0857)和ORR(67% vs 54%,P=0.0234)[21]。另一试验SOLTI-0701显示,相比单独使用卡培他滨,使用索拉非尼联合卡培他滨的患者也显著延长PFS(6.4 vs. 4.1 个月,P=0.0006)和TTP (6.8 vs 4.2个月,P=0.0005)[22]。另外两个临床试验正在进行中。
索拉非尼联合内分泌治疗也显示较好疗效及耐受性,Ⅰ/Ⅱ期临床试验显示,对芳香化酶抑制剂耐受的激素受体阳性患者,索拉非尼和阿那曲唑联合应用,临床获益率仍有23%,大多数不良事件为1/2级[23]。
3.2 舒尼替尼
舒尼替尼(Sunitib)是多因子抑制剂,其作用靶点在VEGFR-1、2、3酪氨酸因子受体,PDGFR、c-Kit、CD135等。已批准用于肾细胞癌和胃肠道基质肿瘤。最常见的不良反应有腹泻、腹痛、黏膜炎、高血压、手足综合征等。这里有一些数据显示舒尼替尼在乳腺癌治疗中的疗效。
Ⅱ期试验研究舒尼替尼单药对先前有蒽环类或/和紫杉类治疗史的乳腺癌患者的疗效,7人PR(ORR 11%),3人获6个月以上SD且中位PFS 10周、中位OS 38周。有56%的患者因不良事件而调整剂量,主要不良反应为疲劳、恶心、腹泻、黏膜炎症及食欲减退[24]。另一研究显示舒尼替尼联合紫杉醇有良好疗效,在18名转移性乳腺癌患者中,7 (38.9%)人获得ORR(2人CR,5人PR),其中9名三阴性乳腺癌中有3人取得临床反应[25]。 SU1064Ⅲ期试验正在进行,将评价多西他塞联合或不联合舒尼替尼一线治疗转移性乳腺癌疗效,而另一Ⅲ期临床试验将评价卡培他滨联合或不联合舒尼替尼治疗转移乳腺癌疗效及安全性。
4 展望
在抗VEGF/VEGFR药物中,目前大多数药物仍处于试验研究阶段,临床应用仍存在一定问题,乳腺癌患者能否从中受益有待进一步证实。虽最近FDA建议取消贝伐单抗的乳腺癌适应症,但其仍是抗VEGF/VEGFR治疗中重要药物。而索拉菲尼和舒尼替尼对乳腺癌抗血管生成治疗有待Ⅲ期临床试验证实。随着对肿瘤生物学、药物抗肿瘤机制进一步深入, 并通过合理试验设计发现更有效乳腺癌抗血管生成治疗方案,相信在不久的将来,抗血管生成治疗会成为乳腺癌标准治疗方案之一。
参 考 文 献:
[1] Folkman J. Tumor angiogenesis: therapeutic implications. N Engl J Med,1971, 285(21): 1182-1186. PMID: 4938153
[2] Folkman J. New perspectives in clinical oncology from angiogenesis research. Eur J Cancer,1996. 32A(14): 2534-2539. PMID: 9059344
[3] Folkman J. The role of angiogenesis in tumor growth. Semin Cancer Biol,1992. 3(2): 65-71. PMID: 1378311
[4] Gasparini G. Prognostic value of vascular endothelial growth factor in breast cancer. Oncologist,2000. 5 Suppl 1: 37-44.PMID: 10804090
[5] Relf M, LeJeune S, Scott PA, et al. Expression of the angiogenic factors vascular endothelial cell growth factor, acidic and basic fibroblast growth factor, tumor growth factor beta-1, platelet-derived endothelial cell growth factor, placenta growth factor, and pleiotrophin in human primary breast cancer and its relation to angiogenesis. Cancer Res,1997. 57(5): 963-969.PMID: 9041202
[6] Shih T, Lindley C. Bevacizumab: an angiogenesis inhibitor for the treatment of solid malignancies. Clinical Therapeutics, 2006, 8(11): 1779-1802. PMID: 17212999
[7] Ferrara N. Vascular endothelial growth factor: basic science and clinical progress. Endocrine Reviews, 2004, 25(4): 581-611. PMID: 15294883
[8] Miller K, Wang M, Gralow J, et al. Paclitaxel plus bevacizumab versus paclitaxel alone for metastatic breast cancer. N Engl J Med, 2007, 357(26): 2666-2676. PMID: 18160686
[9] Gray R, Bhattacharya S, Bowden C, et al. Independent review of E2100: a Phase III trial of bevacizumab plus paclitaxel versus paclitaxel in women with metastatic breast cancer. J Clin Oncol, 2009, 27(30):4966–4972. PMID: 19720913
[10] Miles DW, Chan A, Dirix LY, et al. Phase III study of bevacizumab plus docetaxel compared with placebo plus docetaxel for the ?rst-line treatment of human epidermal growth factor receptor 2-negative metastatic breast cancer. J Clin Oncol,2010, 28(20): 3239–3247.PMID: 20498403
[11] Robert NJ, Dieras V, Glaspy J, et al. RIBBON-1: randomized, double-blind, placebo-controlled, phase III trial of chemotherapy with or without bevacizumab for first-line treatment of human epidermal growth factor receptor 2-negative, locally recurrent or metastatic breast cancer. J Clin Oncol, 2011, 29 (10): 1252-1260.PMID:21383283 [12] Miller KD, Chap LI, Holmes FA, et al. Randomized phase III trial of capecitabine compared with bevacizumab plus capecitabine in patients with previously treated metastatic breast cancer. J Clin Oncol,2005, 23(4):792–799. PMID: 15681523
[13] Cobleigh MA, Langmuir VK, Sledge GW, et al. A Phase I/II dose-escalation trial of bevacizumab in previously treated metastatic breast cancer. Semin Oncol,2003, 30(5 Suppl 16): 117–124. PMID:14613032
[14] Smith IE, Biganzoli L, Corte?s-Funes H, et al. Primary analysis of study MO19391, an open-label safety study of bevacizumab (B) plus taxane-based therapy as 1st-line treatment of patients (pts) with locally recurrent (LR) or metastatic breast cancer (MBC) [abstract #4118]. Cancer Res,2009, 69(2 Suppl).
[15] Miller KD, O’Neill A, Perez EA, et al. Phase II feasibility trial incorporating bevacizumab into dose-dense doxorubicin and cyclophosphamide followed by paclitaxel in patients with lymph node-positive breast cancer: A trial of the Eastern Cooperative Oncology Group (E2104). J Clin Oncol,(Meeting Abstracts),2008 May 20, 26(15 Suppl):520.
[16] Wulff C, Wilson H, Wiegand SJ,et al. Prevention of thecal angiogenesis, antral follicular growth, and ovulation in the primate by treatment with vascular endothelial growth factor Trap R1R2. Endocrinol, 2002, 143(7):2797-2807. PMID: 12072415
[17] Le XF, Mao W, Lu C, et al. Specific blockade of VEGF and HER2 pathways results in greater growth inhibition of breast cancer xenografts that overexpress HER2. Cell Cycle, 2008, 7(23):3747–3758. PMID: 19029832
[18] Moreno-Aspitia A, Morton RF, Hillman DW et al. Phase II trial of sorafenib in patients with metastatic breast cancer previously exposed to anthracycline or taxanes: North Central Cancer Treatment Group and Mayo Clinic Trial N0336. J Clinic?Oncol, 2009, 27(1): 11-15. PMID: 19047293
[19] Bianchi G, Loibl S, Zamagni C et al. Phase II multicenter, uncontrolled trial of sorafenib in patients with metastatic breast cancer. Anticancer?Drugs, 2009 , 20(7): 616–624. PMID: 19739318
[20] Baselga J, Gianni L, Gradishar WJ et al. Phase IIb double-blind, randomized, Placebo-controlled trials for the efficacy and safety of sorafenib in patients (pts) with metastatic or locally advanced breast cancer (BC): review of the Trials to Investigate the Effects of Sorafenib in BC (TIES) program.
[21] Gradishar WJ, Kaklamani V, Prasad Sahoo T et?al. A double-blind, randomized, Placebo-controlled, Phase IIb study evaluating the efficacy and safety of sorafenib(SOR) in combination with paclitaxel (PAC) as a firstbline therapy in patients (pts) with locally recurrent or metastatic breast cancer (BC). [22] Baselga J, Grupo Espa?ol de Estudio Tratamiento y Otras Estrategias Experimentales en Tumores Sólidos, Roché H et?al.: SOLTI-0701: A multinational double-blind, randomized Phase IIB study evaluating the efficacy and safety of sorafenib compared to placebo when administered in combination with capecitabine in patients with locally advanced or metastatic breast cancer (BC).
[23] Isaacs C, Wilkinson M, Liu MC et?al. Phase I/II study of sorafenib with anastrozole in patients with hormone receptor positive aronatase inhibitor resistant metastatic breast cancer. Breast Cancer Res Treat, 2011, 125(1):137-143. PMID: 20976541
[24] Burstein HJ, Elias AD, Rugo HS, et al. Phase II study of sunitinibmalate, an oral multitargeted tyrosine kinase inhibitor, in patients with metastatic breast cancer previously treated with an anthracycline and a taxane. J Clin Oncol, 2008, 26(11):1810–1816. PMID?:18347007
[25] Kozloff, M, Chuang E, Starr A, et al. An exploratory study of sunitinib plus paclitaxel as first-line treatment for patients with advanced breast cancer. Annals of Oncology, 2010, 21(7): 1436-1441. PMID:20032126
关键词: 肿瘤;乳腺癌;抗血管生成;血管内皮生长因子
Abstract: The growth, infiltration and metastasis of tumor depends on neovascularity. So antiangiogenesis is an important strategy of tumor treatment. And VEGF plays a significant role in the angiogenesis of tumor, so VEGF/VEGFR become an important target of antiangiogenesis. Brest cancer is a tumor which depends on angiogenesis. This review gives a brief background of breast cancer angiogenesis, and focuses on current progress in the field of anti-VEGF/VEGFR strategy for breast cancer and questions for future therapeutic development.
Key word: tumor; breast cancer; antiangiogenesis;vascular endothelial growth factor
早在40年前,Folkman教授首次提出肿瘤生长和转移需要新生血管支持[1],血管形成是在已有血管基础上生成新血管,包括4个步骤:基底细胞降解、内皮细胞迁移和增殖、细胞基质内相互作用和新生血管成熟,这一过程是促血管生成物和抗血管生成物共同作用的结果[2,3]。资料证实乳腺癌是血管依赖性肿瘤,随着乳腺癌病情进展,乳腺癌细胞可表达众多血管生成因子,有针对性的抗血管生成治疗已经在包括乳腺癌在内的多种肿瘤的临床研究中得到了证实。本文将阐述抗VEGF/VEGFR在乳腺癌治疗中的研究进展。
1 概述
乳腺癌细胞在生长过程中常分泌一些促血管生长的细胞因子,如血管内皮细胞生长因子(vascular endothelial growth factor, VEGF)、转化生长因子β(transforming growth factor-β, TGFβ)、碱性成纤维细胞生长因子(basic fibroblast growth factor, bFGF)、胎盘生长因子(Placental growth factor, PIGF)等[4,5]。在血管生成过程中,首先肿瘤局部微环境缺氧导致肿瘤细胞分泌VEGF等多种血管生长因子,这些血管生长因子与内皮细胞表面相应受体结合,刺激内皮细胞增殖、活化,并定向移动。活化的内皮细胞表达多种基质金属蛋白酶(matrixmetalloproteinase, MMPs)降解细胞外基质(extracellularmatrix, ECM),内皮细胞与细胞外基质相互作用,血管腔形成,芽式生长,形成管、袢、网,经过以上一系列复杂有序的过程,肿瘤内新生血管形成。在此过程中,VEGF起重要作用,它在乳腺癌中往往过表达。因此针对VEGF/VEGFR的抗血管生成被认为是抗肿瘤治疗的手段之一,其药物包括抗VEGF(如贝伐珠单抗)、小分子酪氨酸激抑制剂(Tyrosine kinase inhibitors,TKI)(竞争ATP结合VEGF受体抑制信号传输,如sunitinib、sorafenib、pazopanib、vatalanib,和vandetanib)和VEGF-Trap(如aflibercept)。
2 抗VEGF药
2.1 贝伐单抗
贝伐珠单抗(Bevacizumab,Bv)是针对VEGF的重组人源化单克隆抗体,通过与VEGF特异性结合阻断其与受体结合,退化肿瘤血管、“正常化”存活血管,抑制肿瘤血管的新生和再生,减少肿瘤血管生成和抑制肿瘤生长及转移[6,7]。
E2100显示Bv和紫杉醇联合用药组与紫杉醇单药组相比显著延长无进展生存期(progress free survival ,PFS)(11.8个月vs 5.9个月;P <0.001),并提高客观缓解率(object response rate, ORR)(36.9%vs 21.2%;P <0.001)。但总生存期(overall survival,OS)无明显改善[8]。这项研究证明晚期乳腺癌患者在常规化疗中添加Bv能获益。Gray认为每周紫杉醇方案中添加贝伐珠单抗,疾病进展危险性下降52%(HR= 0.48;95%CI:0.385~0.607,P <0.0001),ORR提高1倍(48.9 vs 22.2%;P <0.0001)[9]。根据此临床试验结果,美国FDA批准乳腺癌成为Bv的适应症。而Ⅲ期临床试验AVADO显示对比单药,联合Bv组延长PFS(8.7个月vs 8.0个月;P = 0.0035),同时提高ORR(63.1%vs 44.4%~55.2%;P = 0.0001),但OS无明显改善[10],这项临床试验表明Bv联合紫杉类一线治疗晚期乳腺癌的疗效。另一临床试验RiBBOn-1比较化疗[卡培他滨(Cap)、紫杉类(T)、蒽环类(A)]联合或不联合Bv一线治疗转移性乳腺癌疗效。对比其它各组,联合Bv组的中位PFS显著提高(8.6 vs 5.7个月 Cap,P =0.0002; 9.2 vs. 8.0个月A/T, P =<0.0001),ORR也明显提高(Cap 35.4 vs. 23.6%, P =0.0097;A/T 51.3 vs. 37.9%,P =0.0054),可OS无明显改善[11]。这三项大型研究表明Bv联合标准化疗药物一线治疗晚期乳腺癌都有提高疗效的趋势。 Bv用于三线乳腺癌治疗尚未发现额外获益。一Ⅲ期临床试验显示联合Bv治疗缓解率(response rate,RR)更佳(19.8% vs 9.1%,P=0.001),但PFS和OS无明显改善[12]。这也许是难治性乳腺癌存在多条不同血管生成途径,需要多种抗血管生成药物抑制。
患者对贝伐珠单抗耐受性较好,最常报导的毒性反应包括高血压、蛋白尿、出血、乏力、伤口愈合综合症等。在试验E2100中,3级高血压发生率为15.4%[8]。任何程度蛋白尿均常见,在临床试验AVF2119g中[13],严重蛋白尿(3级或4级)发生率8.3%,27.9%的患者出现严重不良事件(serious adverse event,SAE),最常见的包括中性粒细胞减少性发热、蛋白尿等。而在MO19391中[14],3至4级不良事件6.3%,包括高血压(2.2%)、蛋白尿(0.7%)、肺栓塞(0.5%)和鼻衄(0.4%)。中枢神经系统转移患者中,没有发现中枢神经系统出血现象。总之Bv是安全的晚期乳腺癌药物,其联合标准化疗能改善PFS。虽然2010年12月16日FDA咨询委员会建议删除Bv的一线治疗晚期乳腺癌适应症,但是欧洲医学机构仍认为Bv联合紫杉醇可使晚期乳腺癌患者获益。
还有一些关于Bv的临床试验正在进行中。针对乳腺癌新辅助治疗,NASBP B-40试验评价不同化疗中加入Bv的疗效,GeparQuinto试验则使用Bv加依维莫司和拉帕替尼进行新辅助治疗;而对乳腺癌辅助治疗,ECOG E2104已显示Bv辅助治疗的可行性[15],为进一步研究Bv在乳腺癌辅助治疗中的应用,有两项研究正在进行:一研究BEATRICE;另一Ⅲ期临床研究NSABP BETH;对转移乳腺癌,AVEREL试验评价多西他塞联合或不联合Bv疗效,LEA试验比较来曲唑或氟维司群联合或不联合Bv疗效。
2.2 VEGF-Trap
VEGF-Trap包含VEGFR-1和VEGFR-2细胞外部分区域,并与人IG的Fc片段融合,通过诱骗受体结合所有VEGF亚型和胎盘生长因子(Placental growth factor,PLGF)抑制血管生成[16]。与Bv相比,其与VEGF的亲和力明显提高。
临床前试验中,Le等发现单用VEGF-Trap抑制BT474乳腺癌的肿瘤微血管密度和肿瘤生长,VEGF-Trap能降低人体VEGF和PIGF。他们发现在HER-2阳性的乳腺癌患者中,VEGF-Trap联合曲妥珠单抗比两者单独使用能更有效抑制乳腺癌[17]。目前VEGF-Trap治疗非小细胞肺癌已进入Ⅰ期临床,而对乳腺癌的治疗已进入临床前阶段。
3 酪氨酸激酶抑制剂
3.1 索拉非尼
索拉非尼(Sorafenib)是一多因子抑制剂,其抑制因子包括丝氨酸/苏氨酸因子、受体酪氨酸因子、VEGFR-2,3、血小板源性生长因子受体(platelet derived growth factor receptor, PDGFR)、干细胞受体(c-Kit)和造血细胞的细胞因子受体(CD135)。它通过阻断这些因子和细胞内信号通路抑制肿瘤和血管生成。已批准用于肾细胞癌和不可切除的肝细胞癌,在乳腺癌治疗方面正进行Ⅱ期临床试验。常见不良反应有乏力、皮疹、恶心、手足综合征等。
索拉非尼单药用于转移性乳腺癌的2个Ⅱ期临床试验,N0336试验显示索拉非尼单药治疗乳腺癌患者,没有患者获得部分缓解(partial response,PR)或完全缓解(complete response,CR),仅2人获大于6个月的病情稳定(stable disease,SD),随后终止试验[18]。Bianchi等发现转移乳腺癌患者使用索拉非尼单药治疗后,没有患者CR,1人PR(2%),SD患者中20人持续至少8周(38%)、12人持续至少16周(23%)[19]。这2个临床试验说明单用索拉非尼治疗乳腺癌虽有良好安全性但未显示其疗效,所以研究者建议索拉非尼应联合常规治疗使用。
TIES计划评价索拉非尼联合化疗治疗HER-2阴性转移性乳腺癌疗效和安全性,其包含4个Ⅱb期临床试验[20]。试验NU07B1发现相比单药紫杉醇治疗,Bv联合紫杉醇组提高PFS(6.9 vs. 5.6 个月,P =0.0857)和ORR(67% vs 54%,P=0.0234)[21]。另一试验SOLTI-0701显示,相比单独使用卡培他滨,使用索拉非尼联合卡培他滨的患者也显著延长PFS(6.4 vs. 4.1 个月,P=0.0006)和TTP (6.8 vs 4.2个月,P=0.0005)[22]。另外两个临床试验正在进行中。
索拉非尼联合内分泌治疗也显示较好疗效及耐受性,Ⅰ/Ⅱ期临床试验显示,对芳香化酶抑制剂耐受的激素受体阳性患者,索拉非尼和阿那曲唑联合应用,临床获益率仍有23%,大多数不良事件为1/2级[23]。
3.2 舒尼替尼
舒尼替尼(Sunitib)是多因子抑制剂,其作用靶点在VEGFR-1、2、3酪氨酸因子受体,PDGFR、c-Kit、CD135等。已批准用于肾细胞癌和胃肠道基质肿瘤。最常见的不良反应有腹泻、腹痛、黏膜炎、高血压、手足综合征等。这里有一些数据显示舒尼替尼在乳腺癌治疗中的疗效。
Ⅱ期试验研究舒尼替尼单药对先前有蒽环类或/和紫杉类治疗史的乳腺癌患者的疗效,7人PR(ORR 11%),3人获6个月以上SD且中位PFS 10周、中位OS 38周。有56%的患者因不良事件而调整剂量,主要不良反应为疲劳、恶心、腹泻、黏膜炎症及食欲减退[24]。另一研究显示舒尼替尼联合紫杉醇有良好疗效,在18名转移性乳腺癌患者中,7 (38.9%)人获得ORR(2人CR,5人PR),其中9名三阴性乳腺癌中有3人取得临床反应[25]。 SU1064Ⅲ期试验正在进行,将评价多西他塞联合或不联合舒尼替尼一线治疗转移性乳腺癌疗效,而另一Ⅲ期临床试验将评价卡培他滨联合或不联合舒尼替尼治疗转移乳腺癌疗效及安全性。
4 展望
在抗VEGF/VEGFR药物中,目前大多数药物仍处于试验研究阶段,临床应用仍存在一定问题,乳腺癌患者能否从中受益有待进一步证实。虽最近FDA建议取消贝伐单抗的乳腺癌适应症,但其仍是抗VEGF/VEGFR治疗中重要药物。而索拉菲尼和舒尼替尼对乳腺癌抗血管生成治疗有待Ⅲ期临床试验证实。随着对肿瘤生物学、药物抗肿瘤机制进一步深入, 并通过合理试验设计发现更有效乳腺癌抗血管生成治疗方案,相信在不久的将来,抗血管生成治疗会成为乳腺癌标准治疗方案之一。
参 考 文 献:
[1] Folkman J. Tumor angiogenesis: therapeutic implications. N Engl J Med,1971, 285(21): 1182-1186. PMID: 4938153
[2] Folkman J. New perspectives in clinical oncology from angiogenesis research. Eur J Cancer,1996. 32A(14): 2534-2539. PMID: 9059344
[3] Folkman J. The role of angiogenesis in tumor growth. Semin Cancer Biol,1992. 3(2): 65-71. PMID: 1378311
[4] Gasparini G. Prognostic value of vascular endothelial growth factor in breast cancer. Oncologist,2000. 5 Suppl 1: 37-44.PMID: 10804090
[5] Relf M, LeJeune S, Scott PA, et al. Expression of the angiogenic factors vascular endothelial cell growth factor, acidic and basic fibroblast growth factor, tumor growth factor beta-1, platelet-derived endothelial cell growth factor, placenta growth factor, and pleiotrophin in human primary breast cancer and its relation to angiogenesis. Cancer Res,1997. 57(5): 963-969.PMID: 9041202
[6] Shih T, Lindley C. Bevacizumab: an angiogenesis inhibitor for the treatment of solid malignancies. Clinical Therapeutics, 2006, 8(11): 1779-1802. PMID: 17212999
[7] Ferrara N. Vascular endothelial growth factor: basic science and clinical progress. Endocrine Reviews, 2004, 25(4): 581-611. PMID: 15294883
[8] Miller K, Wang M, Gralow J, et al. Paclitaxel plus bevacizumab versus paclitaxel alone for metastatic breast cancer. N Engl J Med, 2007, 357(26): 2666-2676. PMID: 18160686
[9] Gray R, Bhattacharya S, Bowden C, et al. Independent review of E2100: a Phase III trial of bevacizumab plus paclitaxel versus paclitaxel in women with metastatic breast cancer. J Clin Oncol, 2009, 27(30):4966–4972. PMID: 19720913
[10] Miles DW, Chan A, Dirix LY, et al. Phase III study of bevacizumab plus docetaxel compared with placebo plus docetaxel for the ?rst-line treatment of human epidermal growth factor receptor 2-negative metastatic breast cancer. J Clin Oncol,2010, 28(20): 3239–3247.PMID: 20498403
[11] Robert NJ, Dieras V, Glaspy J, et al. RIBBON-1: randomized, double-blind, placebo-controlled, phase III trial of chemotherapy with or without bevacizumab for first-line treatment of human epidermal growth factor receptor 2-negative, locally recurrent or metastatic breast cancer. J Clin Oncol, 2011, 29 (10): 1252-1260.PMID:21383283 [12] Miller KD, Chap LI, Holmes FA, et al. Randomized phase III trial of capecitabine compared with bevacizumab plus capecitabine in patients with previously treated metastatic breast cancer. J Clin Oncol,2005, 23(4):792–799. PMID: 15681523
[13] Cobleigh MA, Langmuir VK, Sledge GW, et al. A Phase I/II dose-escalation trial of bevacizumab in previously treated metastatic breast cancer. Semin Oncol,2003, 30(5 Suppl 16): 117–124. PMID:14613032
[14] Smith IE, Biganzoli L, Corte?s-Funes H, et al. Primary analysis of study MO19391, an open-label safety study of bevacizumab (B) plus taxane-based therapy as 1st-line treatment of patients (pts) with locally recurrent (LR) or metastatic breast cancer (MBC) [abstract #4118]. Cancer Res,2009, 69(2 Suppl).
[15] Miller KD, O’Neill A, Perez EA, et al. Phase II feasibility trial incorporating bevacizumab into dose-dense doxorubicin and cyclophosphamide followed by paclitaxel in patients with lymph node-positive breast cancer: A trial of the Eastern Cooperative Oncology Group (E2104). J Clin Oncol,(Meeting Abstracts),2008 May 20, 26(15 Suppl):520.
[16] Wulff C, Wilson H, Wiegand SJ,et al. Prevention of thecal angiogenesis, antral follicular growth, and ovulation in the primate by treatment with vascular endothelial growth factor Trap R1R2. Endocrinol, 2002, 143(7):2797-2807. PMID: 12072415
[17] Le XF, Mao W, Lu C, et al. Specific blockade of VEGF and HER2 pathways results in greater growth inhibition of breast cancer xenografts that overexpress HER2. Cell Cycle, 2008, 7(23):3747–3758. PMID: 19029832
[18] Moreno-Aspitia A, Morton RF, Hillman DW et al. Phase II trial of sorafenib in patients with metastatic breast cancer previously exposed to anthracycline or taxanes: North Central Cancer Treatment Group and Mayo Clinic Trial N0336. J Clinic?Oncol, 2009, 27(1): 11-15. PMID: 19047293
[19] Bianchi G, Loibl S, Zamagni C et al. Phase II multicenter, uncontrolled trial of sorafenib in patients with metastatic breast cancer. Anticancer?Drugs, 2009 , 20(7): 616–624. PMID: 19739318
[20] Baselga J, Gianni L, Gradishar WJ et al. Phase IIb double-blind, randomized, Placebo-controlled trials for the efficacy and safety of sorafenib in patients (pts) with metastatic or locally advanced breast cancer (BC): review of the Trials to Investigate the Effects of Sorafenib in BC (TIES) program.
[21] Gradishar WJ, Kaklamani V, Prasad Sahoo T et?al. A double-blind, randomized, Placebo-controlled, Phase IIb study evaluating the efficacy and safety of sorafenib(SOR) in combination with paclitaxel (PAC) as a firstbline therapy in patients (pts) with locally recurrent or metastatic breast cancer (BC). [22] Baselga J, Grupo Espa?ol de Estudio Tratamiento y Otras Estrategias Experimentales en Tumores Sólidos, Roché H et?al.: SOLTI-0701: A multinational double-blind, randomized Phase IIB study evaluating the efficacy and safety of sorafenib compared to placebo when administered in combination with capecitabine in patients with locally advanced or metastatic breast cancer (BC).
[23] Isaacs C, Wilkinson M, Liu MC et?al. Phase I/II study of sorafenib with anastrozole in patients with hormone receptor positive aronatase inhibitor resistant metastatic breast cancer. Breast Cancer Res Treat, 2011, 125(1):137-143. PMID: 20976541
[24] Burstein HJ, Elias AD, Rugo HS, et al. Phase II study of sunitinibmalate, an oral multitargeted tyrosine kinase inhibitor, in patients with metastatic breast cancer previously treated with an anthracycline and a taxane. J Clin Oncol, 2008, 26(11):1810–1816. PMID?:18347007
[25] Kozloff, M, Chuang E, Starr A, et al. An exploratory study of sunitinib plus paclitaxel as first-line treatment for patients with advanced breast cancer. Annals of Oncology, 2010, 21(7): 1436-1441. PMID:20032126