综述

年轻女性乳腺癌患者双磷酸盐的辅助治疗:雌激素丰富预后不良

Published at: 2014年第1卷第12期

Hamdy A. Azim 1 , Nermine S. Kamal 1 , Rafaat A. Malak 1
1 The Department of Clinical Oncology, Cairo University, Giza, Egypt

简介

与其他的组织不同骨质主要由坚固的矿化组织组成,所以骨质比其他的转移灶更能抵抗肿瘤细胞的侵袭和破坏(1)。引起骨质溶解的主要细胞是破骨细胞(1,2)。因此肿瘤细胞为了能在骨基质中增殖,募集并激活破骨细胞,从而破坏骨基质,这也是癌症诱发骨质破坏的主要细胞学机制(2-4)。骨基质被破坏后会产生一个空间,肿瘤细胞在这个空间内增殖,骨质吸收时释放的细胞因子与肿瘤细胞亦是在这里发生进一步的分子间相互作用,这便产生了一个利于肿瘤侵袭的微环境“土壤种子假说”(3-6)。肿瘤细胞与骨质微环境之间的交互作用详见图1。促进骨转移发生、发展过程的主要细胞是破骨细胞,而双磷酸盐(BP)能抑制破骨细胞引起的骨质溶解,这就是应用双磷酸盐治疗各种癌症引起的骨转移的原理(7,8)。目前已有四种双磷酸盐类药物(氯磷酸盐、帕米磷酸盐、伊班磷酸盐、唑来磷酸)应用于临床治疗乳腺癌引起的骨转移。在安慰剂对照实验中,这些药物都可以显著地降低骨转移引起的骨相关疾病(SRE)的发生,其中唑来磷酸(ZA)的疗效最显著。(与对照组相比,骨相关疾病的发生率降低了41%,与怕米磷酸盐相比降低了20%)(9,10)。双磷酸盐聚集在骨代谢活跃的区域,包括溶骨性的骨转移病灶中。在矿化骨中,两个带负电荷的磷酸基团使这些化合物能与羟磷灰石晶体结构中的钙离子紧密结合(11,12),使得这类药物具有较长的半衰期,甚至可长达一年(如唑来磷酸)(13)。随着骨质的溶解,双磷酸盐便从骨矿中释放出来(11,12)。总之,双磷酸盐类药物均能抑制破骨细胞的形成、迁移和促进破骨细胞的凋亡。双磷酸盐可通过破骨细胞增加护骨素的(OPG)产生(14)。OPG作为可溶性受体是RANKL的诱导受体,是促进破骨细胞激活、活化的关键分子。所以,OPG对生理性和病理性骨溶解都具有抑制作用,是破骨细胞生成的天然抑制因子(5,6)。值得注意的是,双磷酸盐与矿化骨质的亲和力很强,且游离的药物很快会从肾脏中滤除,因此双磷酸盐很快能够从血液中清除(15)。由于双磷酸盐类药物的细胞通透性很弱,在大多组织细胞内的双磷酸盐的含量较低。

Figure 1. Molecular basis of bone metastasis in breast cancer: tumor cell-osteoclast cross talks comments. Diagrammatic illustration of Osteoclasts (OC) activation and its interplay with breast cancer cells and bone microenvironment. OC precursors differentiate from the population of monocytes/macrophages (CFU-M), by virtue of their expression of the receptor RANK. When RANKL (expressed by osteoblasts, and stromal cells) binds to this receptor in the presence of M-CSF, which in turn binds to its receptor, c-Fms, OC precursors differentiate and fuse together to form mature, multinucleated bone-resorbing OCs. Activated osteoclasts will then attach to the bone surface and via a proton pump mechanism it secrets hydrogenions that dissolve bone minerals thus releasing calcium ions into the extracellular space. Osteoclasts also secret proteolytic enzymes like matrix metalloproteinases, collagenases, cathepsins and cysteine proteinases to induce collagen degradation and digestion of the organic matrix. Large amount of TGF-b and IGF II and other cytokines are stored within the mineralized bone matrix, and will be released during the process of OC bone resorption. When breast cancer cells colonize within the bone matrix, they start to secrete PTHrP and other osteolytic cytokines, which stimulate osteoblast production of RANKL while OPG levels are reduced, leading to enhanced osteoclastogenesis and increased bone resorption. Consequently the local milleau will be enriched by growth factors and other products of osteolysis (extracellular Ca++ and collagen fragments) which will induce: 1-stimulation of PTH-rP secretion (via TGF, Ca+ 2), 2-stimulation of tumor growth (via TGF, IGF1) and 3-chemotaxis of circulating tumor cells to arrest in bone matrix (via IGF1, collagen fragments). This evokes further PTH-rP release with worsening osteolysis, in addition to supporting the growth of breast cancer cells within the bone matrix. This reciprocal feedback between tumor cells and the bone microenvironment has been referred to as the “vicious cycle” of bone destruction. PTH-rP, parathyroid hormone related protein; TGFβ, transforming growth factor beta; Ca, calcium; IGF1, insulin growth factor 1; OPG, osteoprotegerin; RANKL, RANK ligand; c-Fms, colony-stimulating factor receptor 1.

双磷酸盐对乳腺癌的抗癌作用

体外及动物实验数据表明,双磷酸盐类药物具有抗肿瘤效应,能够降低骨骼的肿瘤负荷(15,16)。尽管体外研究显示双磷酸盐类药物对骨矿的高亲和力及在其他组织中的浓度较低,具有抗肿瘤作用,但在体研究的证据并不充分(17-19)。双磷酸盐主要通过抑制肿瘤细胞的粘附、侵袭、增殖,并可间接诱导肿瘤细胞的凋亡来发挥直接的抗肿瘤作用(15,16)。含氮的双磷酸盐(N-BP)类药物(如唑来磷酸、帕米磷酸、伊班磷酸)可以作用于法呢基焦磷酸合酶(FPPS),而FPPS是甲羟戊酸途径的关键酶(20,21)。甲羟戊酸途径是产生类固醇的重要代谢通路,维持细胞膜的完整性、调节细胞的新陈代谢,并且对调节蛋白的异戊烯化过程也很关键,参与许多胞内调节细胞增殖的信号通路。抑制甲羟戊酸途径将最终导致破骨细胞的凋亡(20,21)(图2)。甲羟戊酸途径对于肿瘤细胞的新陈代谢和增殖过程也很重要。唑来磷酸对肿瘤细胞中FPPS的抑制作用比其他的双磷酸盐类药物强,无论在体内或体外唑来磷酸都有着最强的抗破骨细胞活性的作用(22)。含氮的双磷酸盐也可通过抗血管生成(23)和免疫调节(24-26)间接地发挥抗肿瘤作用。其免疫调节作用主要归因于双磷酸盐可与破骨细胞同源的单核、巨噬细胞聚集(24)。研究表明治疗剂量的唑来磷酸能够调节单核细胞、巨噬细胞和树突状细胞,并可增强rδT细胞的抗肿瘤作用(16,22,25,27)。

Figure 2. Nitrogen-containing bisphosphonates anti-osteoclastic and anti-tumor molecular mechanism of action. A. BPs localize with a very high affinity to skeletal areas of high bone turnover including osteolytic bone metastases where they are concentrated underneath the activated osteoclasts; B. BPs are subsequently released from the bone mineral during bone resorption; C. BPs are then internalized by the activated osteoclasts; D. Within the osteoclasts (and also breast cancer cells) the N-BPs inhibit the activity of farnesyl diphosphonate (FPP) synthase, a key enzyme in the mevalonate pathway. FPP is necessary for prenylation of small guanine triphosphatases (GTPases)--such as Ras, and Rho, which are involved in intracellular signaling; E. Inhibition of the mevalonate pathway will ultimately cause osteoclasts to undergo apoptosis. Experimental studies have shown that inhibition of this pathway by BPs, will also results in inhibition of malignant cell growth and survival in cell culture and animal models.

尽管双磷酸盐抗肿瘤的具体机制尚不清楚,但近期动物实验数据强烈提示临床剂量双磷酸盐在体内的抗肿瘤作用主要是通过抑制破骨细胞引起的骨溶解而实现的,而非直接的细胞毒作用(28)。这项研究支持的观点是,双磷酸盐能够是通过调节骨质微环境而不一定必须通过直接的细胞毒作用,发挥抑制肿瘤细胞的生长效应。

骨质微环境是防治乳腺癌复发的良好靶点

研究发现,骨髓(BM)中的静止期肿瘤细胞(DTCs)会导致早期乳腺癌(EBC)患者的复发。其他研究发现骨髓中的静止期肿瘤细胞和血液中循环肿瘤细胞相关与预后不良显著相关(29)。实际上,骨髓微环境提供理想的环境使肿瘤细胞逃脱系统的抗肿瘤治疗(30)。在骨髓中骨内膜壁龛和血管壁龛共同发挥作用,保护肿瘤细胞(31)。骨内膜壁龛允许静止期的肿瘤细胞与破骨细胞相互作用,调节干细胞使其复苏。血管壁龛会促进静止期肿瘤细胞与造血干细胞的相互作用。Mead等证实造血干细胞通过调节微环境,产生肿瘤细胞耐药免于细胞毒作用,因此化学治疗和生理性的细胞凋亡调控对肿瘤细胞都无效(32)。虽然激活静止期肿瘤细胞的特异信号还不是很清楚(33,34),但研究人员推测:骨髓中的静止期肿瘤细胞被一种生长因子所激活(34),这种生长因子起源于骨质,并受破骨细胞的调节,从而促进各部位转移灶的形成和肿瘤的局部复发(肿瘤自我播种现象)(35)。

一些包括早期高危乳腺癌患者的二期临床研究发现,联合应用唑来磷酸/伊班磷酸和标准的辅助治疗能有效地减少骨髓中静止期肿瘤细胞的数量和存留时间,而单独应用辅助治疗往往达不到这样的效果(36-39)。虽然这些实验并没有说明静止期肿瘤细胞的减少是否会提高患者的预后,但为干预骨髓微环境对肿瘤细胞的保护,辅助治疗时增加双磷酸盐类药物这一治疗体系必将会得到重视。辅助应用双磷酸盐可以改变骨髓微环境,使其不利于肿瘤细胞的生存,可为防止早期乳腺癌复发提供一个独特的治疗理念(16,28,34)。

雌激素水平低是辅助应用双磷酸盐获益的前提

目前公认雌激素对骨质稳态的维持发挥着关键的作用,能够促进破骨细胞的活化,是绝经后妇女骨溶解的细胞学机制(40,41)。更重要的是,根据推测骨质的溶解会为肿瘤细胞的着床提供良好的环境,增加肿瘤的复发(42,43)。最近,这一推测被MA27实验临床观察结果间接证实,MA27实验的目的是比较阿那曲唑和依西美坦在治疗绝经后的早期乳腺癌患者疗效的差异。这两种芳香化酶抑制剂在无病生存率(DFS)上并没有差别(44)。然而,在接下来的一项探索性分析中发现患有骨质疏松的患者(患者自述)和未经治疗的骨质疏松患者有着相对高的复发风险,而没有骨质疏松和接受治疗的骨质疏松患者复发风险相对较低(45)。这一结果强烈地支持假说:绝经后雌激素的降低和芳香化酶抑制剂(AI)的应用会破坏骨质微环境,提供土壤利于静止期肿瘤细胞的着床和增殖,并且骨质疏松(雌激素减少)会影响早期乳腺癌患者的治疗效果。但应用抗骨溶解治疗后,治疗效果会显著提升。

最近,谢菲尔德大学的研究小组通过一个合理的动物模型模拟了早期乳腺癌的临床情况,发现只有在体内雌激素水平较低时,唑来磷酸才能有效防止乳腺癌的复发,但对于没有切除卵巢的小鼠唑来磷酸没有任何作用(46)。这一研究结果提供了一线的直接证据,证明对于绝经前后的妇女,唑来磷酸的抗肿瘤效果是不同的,只有对于绝经后的妇女,辅助应用双磷酸盐才会发挥抗肿瘤效果,骨髓中唑来磷酸(或许也包括其他双磷酸盐类药物)主要通过抑制受卵巢抑制调节的肿瘤细胞的增殖而发挥作用。因此,雌激素水平减低伴随的骨质溶解似乎是辅助应用双磷酸盐获益的前体条件(16,46,47)。

应用双磷酸盐辅助治疗早期乳腺癌的相关临床试验

前期临床实验证实双磷酸盐在早期乳腺癌中的抗肿瘤效果,有三个随机实验评估了口服氯磷酸盐的疗效。但这三个实验的长期随访数据却呈现了截然不同的结论,前两组实验发现氯磷酸盐在后续随访中有着显著的疗效(48,49),而第三组实验服用氯磷酸盐组比控制对照组10年的无病生存率明显降低(50)。但三个实验的荟萃分析显示,氯磷酸盐不能有效地控制骨转移,也不能提高无病生存率(51)。因此,通过这三个实验并不能得出关键性的结论。

后来的ABCSG-12和 ZO-FAST实验得出了重要的结论:对于体内雌激素水平低的乳腺癌患者,辅助应用唑来磷酸能获得较好的疗效。ABCSG-12实验(52)新增了内分泌治疗(诺雷德抑制卵巢功能联合阿那曲唑或他莫昔芬),研究对象为1,803名患有I期或II期乳腺癌的绝经前妇女,这些患者被随机分成两组,一组应用三年的唑来磷酸,另一组为空白对照组。该研究发现,应用唑来磷酸后,疾病进展的风险降低了36%,更重要的是唑来磷酸组后续7年的无病生存率(HR=0.72; P=0.014)和总生存率 (HR=0.63; P=0.049)有显著的提升(53),这一结果与早期的氯磷酸盐实验是不同的。ZO-FAST实验对象为1,065名I—IIIa期、ER阳性的绝经后患者,主要应用来曲唑,患者被随机分成两组,第一组开始便使用唑来磷酸,第二组延迟应用唑来磷酸,延迟组应用唑来磷酸的指标是发生了非创伤性的骨折或骨质流失达到了一定的标准(54)。在五年随访中,第一组的无病生存率(HR=0.66; log-rank P value=0.0375)有所增加,并且总生存率(HR=0.69; P value=0.196)也有增长的趋势。值得注意的是,这两个实验的患者均给以内分泌治疗,能够显著降低体内雌激素的水平,并诱发骨质流失。入组患者均接受了小剂量的唑来磷酸(每6个月1次),较好的拮抗患者的骨质流失。

这两个实验的不足之处是不能体现双磷酸盐在其他辅助治疗中的疗效(如体内雌激素水平较高的患者或ER阴性的早期乳腺癌患者)。随后的Azure实验证实体内雌激素较低的患者唑来磷酸辅助治疗获益。Azure是III期临床随机实验,观察II/III期乳腺癌患者化疗时辅助应用唑来磷酸(5年中唑来磷酸逐渐减量)的疗效。值得注意的是,Azure实验发现化疗时加用唑来磷酸并不能提高实验患者的无病生存率。但在预先设定的亚组分析中,加用唑来磷酸能显著提高绝经后患者的无病生存期(5年或更长)(校正 HR=0.75;95% CI: 0.59-0.96; P=0.02)(55)。辅助应用双磷酸盐在绝经后妇女获益,在后续的两个三期临床实验研究中得到进一步证实:NSABP B-34(3,323名患者被随机分成两组,一组每天口服氯磷酸盐1,600 mg三年,一组口服安慰剂三年);GAIN实验(3,023名患者被随机分两组,一组每天口服伊班磷酸盐50 mg两年,另一组为观察组)(56,57)。与Azure实验结论一致,这两个实验并没有发现无病生存期的延长,未完成首要观察终点。同样的,这两个实验的预先设定的亚组分析表明对于年龄大于50(在NSABP B-34)和年龄大于60(在GAIN)的患者双磷酸盐有着更好的疗效,换言之,双磷酸盐只对卵巢功能被完全抑制的患者有效。

辅助应用双磷酸盐是否适合年轻的乳腺癌患者?

在ABCSG 12及ZOFAST[及其姐妹实验Z-FAST 和E-ZO-FAST(58,59)]实验中,排除特殊案例后,大部分用来证实双磷酸盐抗肿瘤效果的实验都被设计成“一体适用”的模式(表1),他们没有依据患者疾病的表型、月经的情况、标准辅助治疗的类型等因素将患者区分开来,在我们看来,这就是他们难以得出结论的主要原因。因此,Azure、B34、GAIN这三个大型实验应用了不同种类的双磷酸盐、治疗的疗程也不尽相同(2-5年不等)、并且对绝经的定义也不同,这些因素必然会给联合分析带来困难。尽管如此,近期发表了一个针对这三个大型实验及前三个实验的荟萃分析,该分析主要依据是否绝经来评价双磷酸盐的疗效(60)。作者指出从总体情况上来看,应用双磷酸盐组较对照组并没有取得更好的疗效,但是对绝经后妇女进行亚组间的比较时,双磷酸盐组的无病生存期明显延长[HR=0.81 (0.69-0.95)]。然而,这个荟萃分析得出一个警示性的结论,对于绝经前和围绝经期的妇女,辅助应用双磷酸盐会产生副作用。重要的是,这一观察结果已经被先前的Azure实验强调,Azure实验提示:绝经前妇女应用双磷酸盐后,会促进除骨质以外的部位发生转移性肿瘤,并且这种情况下的转移和肿瘤ER表达状况没有关系,但作者并没有讨论这一点(55)。有趣的是,之前的Finnish实验也曾得到过类似的结论:对于ER阴性的患者,辅助治疗中应用氯磷酸盐后非骨性转移的复发频率较对照组高(10年无病生存期为25% vs. 58%,P=0.004)。更重要的是,这个实验中只有在绝经后并且ER阳性的患者这个亚组中没有观察到氯磷酸盐的副作用(50)。更有趣的是,一些临床前实验也表明辅助应用双磷酸盐如不给予抗肿瘤药物,会增加骨以外部位转移瘤的发生(如长期应用双磷酸盐治疗ER阴性的患者)(19)。当双磷酸盐用于预防骨转移时,这一副作用应当被重视起来(4,50)。根据现有证据,对于绝经前及ER阴性的乳腺癌患者应用双磷酸盐出现的潜在的副作用可能会发生。因此,在这篇文章中,我们希望能提一些关键的问题:当绝经前的乳腺癌患者在辅助治疗阶段应用大剂量的唑来磷酸时,可能是什么因素促使了肿瘤的发展?是高雌激素的微环境、还是由于ER的表型是阴性、还是两者都起着一定的作用?实际上,有许多推测可以解释唑来磷酸辅助治疗对高雌激素状态的反应性较低(61)。应该注意一点,骨髓中肿瘤细胞在静止期时,雌激素和双磷酸盐此时可以相互作用。高雌激素的骨髓微环境似乎可以保护骨内膜壁龛中的静止期肿瘤细胞进行增殖。因为破骨细胞是干细胞休眠、复苏的重要调节因素,并且雌激素可以使骨内膜下的破骨细胞数量增多、活性增强,由此可以证明上述结论(30,62)。这提示对于绝经前患者,双磷酸盐对静止期肿瘤细胞的抑制作用被高水平的雌激素的作用抵消了。

最后,我们认为可以用唑来磷酸引起的免疫改变来解释这种药物对哪个分型的乳腺癌疗效最好。如上所述,唑来磷酸一直被认为可以选择性的刺激rδT细胞,从而在体内发挥很好的抗肿瘤效果(16,22,25,26)。临床上已经证实癌症患者应用唑来磷酸后可以促进rδT细胞的增殖与活化。最近,Benzaid等(27)实验证明,受免疫调节的rδT细胞对ER阳性,HER2阴性的肿瘤细胞敏感。这提示ER阳性的肿瘤类型对唑来磷酸可能获益多。可以推测,由于绝经前的患者中ER阴性患者的比例较高(Azure实验的患者并没有出示数据),多数对rδT细胞调节的细胞毒作用反应不敏感。

另一个受唑来磷酸调节的免疫分子就是上文提到的OPG,这种蛋白能有效抑制骨质溶解。由于OPG具有抑制破骨细胞的功能,因此可以推测其能够对抗肿瘤细胞引起的骨疾病和骨转移(5,6)。据报道唑来磷酸(剂量依赖)(14)和雌激素都可以促进血浆OPG含量的增加(63-65),被认为也是抗溶解作用的机制之一。有趣的是,OPG可以促进血管的生成并能抑制TRAIL诱导的细胞凋亡,对肿瘤细胞亦有保护作用(66-68)。TRAIL(肿瘤坏死因子相关细胞凋亡诱导配合体)是一种能够调节免疫系统发挥抗肿瘤效应的重要分子(66)。重要的是,在某些乳腺癌类型中,血清中OPG含量的增高与预后不良显著相关(69,70)。还有一点应当注意,OPG会优先保护ER阴性的肿瘤细胞株免受TRAIL引起的细胞凋亡(71)。综上所述,我们推测绝经前的患者骨质内外的OPG含量均很高,这是继发于体内雌激素水平较高和唑来磷酸的应用剂量过大。这种情况下,OPG的含量过高会打破其原有的平衡状态,即其对骨质的保护作用和促进肿瘤生长的潜在负作用(68)。实际上在Azure实验中,绝经前患者的骨转移复发率并没有因为应用唑来磷酸而增加,与我们的推测相一致。但是,应用唑来磷酸的患者的骨转移复发率也没有比对照组降低[HR=0.86 (95% CI: 0.63-1.16)]。这再次说明在辅助治疗中大剂量的唑来磷酸时,免疫系统会发挥出截然不同的作用:对ER阳性型的乳腺癌具有抑癌作用(对rδT细胞的细胞毒作用较敏感)、对ER阴性型的乳腺癌则有促进肿瘤细胞的作用(OPG可抑制TRAIL的促凋亡作用)。因为唑来磷酸的剂量可以明显的影响OPG的含量,ABCSG-12和ZOFAST实验中观察到的较好的疗效也可归因如下:应用唑来磷酸仅6个月,体内OPG的含量低;患者体内雌激素含量均较低;对象均为ER阳性的患者,而这些因素在AZURE实验中均未体现。

总之,大量的临床和动物实验都表明,只有对于绝经后的乳腺癌患者,针对于骨质的辅助治疗才能降低复发、死亡率(72)。我们坚信无论在临床上或是生物学上,这一结论都是正确的。现在我们完全将重点放在“雌激素低土壤”上,认为只有雌激素水平低下时辅助应用双磷酸盐才会取得疗效,但我们也应该考虑一下“种子”的重要性,因为这些药物只有作用于ER阳性的乳腺癌类型时才能发挥最大的疗效。最后,绝经前的ER阳性的乳腺癌患者,如果她们应用了黄体生成素释放激素激动剂,或辅助化疗后卵巢功能完全被抑制,那么对于这部分患者我们建议应用小剂量的唑来磷酸(at 4 mg/6 months)。唑来磷酸在这种低浓度下能有效抑制骨质的流失,是患者保护骨质的理想治疗方案。此外,低浓度的唑来磷酸能有效干预肿瘤细胞与骨质微环境之间的相互作用,从而提高了早期乳腺癌患者的无病生存期。ABCSG-12实验是唯一将绝经前妇女(平均45岁)单独列出的实验,证实在依据年龄分组的亚组中只有对于40岁以上的患者(n=1,390; HR=0.66; P=0.013),唑来磷酸才能明显地提高患者的无病生存期(可提高34%)。遗憾的是对于年龄小于40岁的患者(n=413),无病生存期并没有明显的提高(53)。作者认为发生这一现象的主要原因是:40岁以上的患者,卵巢功能被完全抑制。但是这一解释只适用于化疗的患者,对于像ABCSG-12实验中的患者而言(只有少于10%的患者在新辅助治疗中接受了化学治疗),这个解释显然不够合理。此外,对于年龄小于44岁的患者,我们只随访了77名,并且只随访了84个月,这些资料证据显然不够充分,还不能完全否定唑来磷酸对这些患者的疗效。因为只有对于体内雌激素水平低下、骨质流失较快的患者即敏感的患者,辅助应用双磷酸盐才会产生疗效。因此我们推测,双磷酸盐对年轻乳腺癌患者的疗效主要取决于患者的月经状态,而不是年龄。总之,在生物学界有这样一个观念:一种模式不适合所有情况,当面临应用双磷酸盐治疗绝经前乳腺癌患者时,这一总结显得格外贴切。

致谢

声明:本文作者没有利益冲突。

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Cite this article as: Azim HA, Kamal NS, Malak RA. Bisphosphonates in the adjuvant treatment of young women with breast cancer: the estrogen rich is a poor candidate! J Thorac Dis 2013;5(S1):S27-S35. doi: 10.3978/j.issn.2072-1439.2013.06.04

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