转移性乳腺癌治疗的一般原则－－丘嫦译 陈前军校

丘嫦 译　陈前军校

广州中医药大学广东省中医院大学城医院乳腺科 （广州  510006）

作者：Daniel F Hayes；MD Section Editor；Julie R Gralow, MD；Deputy Editor；Rachel Lerner, MD, MS广东省中医院乳腺科陈前军

引言

虽然转移性乳腺不可治愈，但新的全身系统治疗方法的运用对改善生存率有意义^[1-3]。改善中位生存期接近2年，它的范围从几个月至几年^[4]。治疗策略的选择依靠肿瘤的生物学特性和临床因素，目的就是使策略具有个性化。虽然一部分肿瘤转移患者从局部的强化治疗中获益，但现在越来越多的转移性乳腺癌患者接受包括化疗、内分泌治疗、和/或生物治疗，和支持疗法的全身系统治疗^[5,6]。转移性乳腺癌治疗的一般原则将在这里介绍。单药/联合化疗、内分泌治疗、生物治疗和如何进行选择，局部治疗方法如抑制破骨细胞（二膦酸盐和受体激活核因子kappa- B[RANK]配体抑制剂）和支持治疗，将分别进行讨论。

治疗目标

转移性乳腺癌全身治疗最主要的目标是延长生存时间，减轻症状和维持/改善生活质量，尽管需遭受治疗带来的毒副作用^[7-9]。转移性乳腺癌的中位生存期为18至24个月，虽然有些患者可长期生存^[1-4,10]。没有一项前瞻性随机临床试验表明全身治疗与单独的最佳支持治疗相比可延长生存期^[7]。然而，随着时间的推移，全身治疗对转移性乳腺癌患者的中位生存期似乎有所改善，这已归因于新的，更有效的药物，其中包括紫杉烷类化合物，芳香酶抑制剂，曲妥珠单抗^[1,2,11-13]。举个例子，来自不列颠哥伦比亚省乳腺癌的成果数据库，1997-2001年之间确诊的患者比1991-1995年之间确诊的有较好的2年总生存数（45％比34％）^[1]。

评定疗效的最佳措施是有争议的。整体存活率是评定疗法的金标准，但它需要长期随访，并且后续治疗的效果可能被稀释。然而，它没有其他的终末点，包括无进展生存期，肿瘤进展时间，或已被证明是一个良好的替代总生存期的客观应答率^[14]。比较客观应答率往往是用来确定相对的治疗效果。但很高的应答率不一定转化为临床上有意义的生存率增加^[14-16]。此外，对于不可预测的疾病，与病情稳定和疾病进展相比，症状的缓解可能是临床上重要的疗效评定指标^[17]。

肿瘤生物学和风险评估

生物学标志物，如激素受体状态、人体表皮生长因子受体2（HER2）的过度表达、肿瘤负荷是预后和预测的指标，也是选择合适治疗时重要的因素。

疾病评估

转移性疾病程度的全面评估，包括重新活检疑似病灶和重新测定分子标记，尤其是雌激素受体（ER），孕激素受体（PR），HER2过度表达。原发性和转移性疾病之间的这些指标有可能不一致^[18-22]。举个例子，两个前瞻性研究的汇总分析，ER，PR和HER2的原发性及复发性疾病之间的不一致率分别为13%，28%和5％^[19]。在这项研究中，需要活检立即改变病人治疗策略的为6.3%。不过，新转移灶受体的确定以及由此产生的治疗策略的变化，是否将最终导致患者的生活和生存质量的改善，这一点目前尚不清楚。

预后

疾病进展率和生存率预测的临床因素包括初始治疗方案和复发间隔，转移部位数量，是否合并内脏受累和肿瘤生物标志物之间的不同。比如：

1）无复发间隔2≥年比短时间内复发的预后较好。

2）肝和/或淋巴管炎肺疾病的患者有更短的无进展生存期和总生存率，而涉及胸壁，骨或淋巴结转移的患者不同，它的无进展生存期可延长^[23,24,27]。肺淋巴管转移，骨髓置换，癌性脑膜炎或有症状的肝转移被归类为内脏危象^[28]。没有内脏危象但具有不良预后特征的可做为另一种类型。

3）激素受体阳性的病人一般认为预后良好，ER和PR阳性的肿瘤患者的生存期明显长于单激素受体阳性肿瘤（ER +/公关或ER-/PR）_[29]。HER2过度表达或三阴性（ER，PR，HER2的）的转移性乳腺癌患者生存率缩短^[25,30,31]。特定的分子表型相关的预后将分别讨论。

4）其他不良预后因素包括体重减轻，状态不佳,乳酸脱氢酶升高^[23,32]。年龄小于35岁是早期乳腺癌妇女的不良预后因素，但年龄对复发后生存率的影响是不确定的^[25,33]。同样，在诊断过程中，肿瘤复发后没有可靠的预后指标。

治疗反应的预测

激素受体状态和HER2过度表达对于转移性乳腺癌患者是最重要的治疗反应预测指标。

激素受体---激素受体状态是反应激素治疗的重要预测因子^[34,35]。70％的肿瘤患者可能表达ER和PR两种受体，40％为ER+/PR-或ER-/PR+，低于10％ 为ER-/PR-^[36,37]。 ER受体状态预测内分泌治疗的分子基础将分开讨论。预测转移性乳腺癌患者对激素治疗反应性的其他指标还包括无复发间隔期长，仅有骨与软组织的转移，转移前对内分泌治疗敏感^[38,39]。一些数据表明， ER受体阳性的肿瘤患者较ER受体阴性的对细胞毒性化疗反应性较低^[35,40-42]。

HER- 2过度表达---- HER2过度表达可预测HER2的靶向治疗反应性；如人单克隆抗体曲妥珠单抗和小分子酪氨酸激酶抑制剂拉帕替尼。这些药物只对HER2高表达（免疫组化3 +）或基因扩增的（如荧光原位杂交[FISH]检测）的肿瘤有效。

一些证据表明，HER2过度表达的肿瘤内分泌治疗反应性较低，尽管现有的数据不足以运用HER2状态预测内分泌治疗抵抗^[43,44]。HER2检测和HER2状态对预测HER2基因导向治疗的作用，化疗和内分泌治疗将分别详细讨论。

化疗反应

预测化疗反应不佳的指标有化疗前晚期疾病的进展程度，完成辅助化疗后12月内复发和存在多种疾病，尤其是内脏受累 ^{[23,24,32,45-52]} 。增加细胞增殖的标记如流式细胞仪使高S期分级增加摄取放射性标记的胸腺嘧啶，和免疫组织化学染色的增殖抗原Ki67，这些都与较高的化疗反应率相关^[53-55]。相比之下，P-糖蛋白（gp170）过度表达，药物排泵介导的多药耐药（MDR），或有p53基因突变的乳腺癌可能对化疗的反应性较低^[56-59]。目前，这些标记还没有运用于临床的决策。另一个可行的方法是使用化疗敏感性和耐药性分析^[60-62]。然而，这些检测的临床效用尚不清楚^[56,63,64]。下面讨论在转移性乳腺癌治疗过程中循环肿瘤细胞的检测和监测。

治疗策略的选择

上文所述是治疗转移性乳腺癌选择时很重要需牢记的要点，这些措施包括：

1）治疗的目的是能减轻症状，延长生存期，并保持生活质量。

2）内脏转移和无病间期短的患者肿瘤特性侵犯性强，而仅有软组织和骨转移患者的表型较为懒惰。

3）激素受体状态和人表皮生长因子受体2（HER2）的过度表达对于预测预后和治疗反应的可能性很重要。

4）激素受体（雌激素受体[ER]和/或孕激素受体[PR）状态是反应内分泌治疗的主要决定因子。

5）同样，HER2过度表达必然反映HER2靶向疗法。

基于这些原则，可以选择个性化的治疗。内分泌治疗最适用于与激素受体阳性的乳腺癌患者而非激素受体阴性患者。 HER2基因靶向治疗只适合HER2高表达的肿瘤患者。最后，化疗对激素不敏感的转移性乳腺癌有治疗反应（即激素受体阴性的乳腺癌患者和对内分泌治疗耐药的激素受体阳性患者）。但是，它不太清楚对于激素受体阳性的转移性乳腺癌患该如何选择内分泌治疗与化疗作为初始治疗。同样，当使用单药与联合化疗，如何以最佳方式结合生物疗法，并且相结合的方式是否可以受益，这些还不太明确，

内分泌治疗与化疗

普遍认为化疗比内分泌治疗应答率高和反应更快速，结果那些预后较差的激素受体阳性的转移性乳腺癌患者往往选择化疗作为初始治疗，特别有内脏转移的。一项包含8个规模较小的随机试验的荟萃分析中，所有在1995年以前公布，比较单纯化疗与单纯内分泌治疗的效果^[65]。对反应率的汇总估计显示了化疗与内分泌治疗（相对危险度1.25，95％可信区间1.01-1.54）的优势，虽然两个最大的试验的结果相反^[66,67]。总生存期无显著差异（HR 0.94，95％可信区间0.79-1.12），在亚组分析中，没有明确显示年龄、绝经状态、或转移性疾病对这两种治疗疗效的影响。对比生活质量和毒性都是极微的。

这些研究结果的一个主要限制是，在这些试验中大多数患者激素受体状态不明，导致激素受体状态对内分泌治疗反应的预测值没有显示出来。然而，化疗依然是进展迅速的有症状的疾病或内脏危机（器官功能障碍）的患者初始治疗的首选方式，可以实现可能性更高的化疗反应率。化疗和内分泌治疗联合运用时对生存率无获益。

序贯单药与联合化疗

在2005年出版的荟萃分析比较中，联合化疗的总应答率显着增高（OR 1.28，95％CI 1.15-1.42），改善总生存率（死亡OR0.88，95％CI 0.83-0.93），并显着降低疾病的进展速度（HR 0.78，95％CI 0.73-0.83）[68]。然而，这种适度的生存改善伴随着明显的药物毒性，包括白细胞减少，恶心，呕吐。这一荟萃分析的结果是局限的，近代的化疗药物不能很好地纳入试验并且交叉率是未知。

1）一些新制剂的临床试验，如卡培他滨，多西紫杉醇，长春瑞滨，吉西他滨，联合化疗与单药化疗的总生存率没有发现差异，或略有几个月的改善，并有更严重的毒副作用^{[69 - 71]}。

2）这些适度的生存获益，初始联合化疗与单药化疗相比，其有利的微小的生存获益可能不被发现，如果允许多次交叉试验直接比较结合序贯疗法治疗并不能显示初始联合治疗的生存获益^[72-75]。

举个例子，东部肿瘤协作组（ECOG）试验E1193中，739例转移性乳腺癌患者随机分组给予单纯阿霉素、紫杉醇，或联合阿霉素、紫杉醇[72]。接受单药治疗的患者进展时间超过替代剂。虽然阿霉素和紫杉醇的初始联合治疗，与两种药物单纯化疗相比具有显着较高的应答率（47％：36和34％）和治疗失败的时间（8个月：5.8和6个月），三组中位总生存期相似（分别为22、19、22个月）。联合化疗没有明显的生存优势，单药序贯疗法通常是首选。单药治疗毒性较低并且生活质量较高^[76-78]。然而，对于需要快速控制症状或疾病迅速进展或内脏危机的的患者，联合治疗可能是一个更合适一线选择，因为客观反应的可能较大。提供更多联合化疗的试验并没有显示其引起进展时间或整体生存时间的进一步改善^[79]。事实上，回顾所有的随机试验，比较2000年和2007年之间的转移性乳腺癌的化疗方案，几乎没有发现共同化疗方案之间的主要生存差异的证据^[80]。

联合的治疗方法

理论上，联合化疗，生物治疗，和/或内分泌治疗，可能增加疗效，但它也可能导致毒性增加。临床试验不能表明同时进行化疗和内分泌治疗的的生存优势超过单纯化疗或内分泌治疗^[7,67,81]。然而，HER-2靶向治疗，即曲妥珠单抗和拉帕替尼已成功表明可以有效地联合化疗、内分泌治疗。

生物治疗

目前，分子靶向药物（或生物治疗）已证明对转移性乳腺癌有效的是HER2靶向剂，如曲妥珠单抗，拉帕替尼和贝伐单抗。这些生物制剂在转移性乳腺癌的运用在分别详细讨论。

破骨细胞抑制剂

骨转移患者应及时予破骨细胞抑制剂治疗（二膦酸盐或RANK配体抑制）减少骨转移疾病的发生率，如骨折，需要手术或放射，脊髓压迫症，和恶性高钙血症。

治疗分析

上面讨论的问题可以概括并表明了转移性乳腺癌患者根据激素受体和人表皮生长因子受体2（HER2）的肿瘤状态进行临床决策。

激素受体阳性、HER2阴性的患者---尽管上面所述的局限性，但证据表明化疗比内分泌具有更高的应答率。因此，肿瘤迅速进展，有症状的疾病或终末器官功能障碍的内脏转移，最好的治疗是一线化疗。化疗应答稳定后（通常是4-6个月），更换为内分泌维持治疗的是一个普遍采用的策略，它可以减少治疗的副作用而不影响整体生存^[7,82,83]。一线内分泌治疗可能对其他病人更合适，因为其总体上毒副作用较温和。如果初始一线内分泌治疗后病情进展迅速（数个月内），建议化疗作为二线治疗方案，而不是转换内分泌治疗方案。如果初始内分泌治疗后的疾病进展期较长（大于6个月），更改为二线内分泌治疗是合理的。

激素受体阳性HER2阳性患者---对这些病人的治疗方案，包括化疗，内分泌治疗，HER2靶向治疗。 HER2基因靶向治疗已显示出可以提高HER2基因过度表达的肿瘤患者的生存率，因此应作为这些患者的一线治疗方案。是否HER2基因靶向治疗联合化疗比内分泌治疗作为一线治疗更好，目前尚不清楚。 HER-2靶向治疗结合化疗或内分泌治疗将分开讨论。

激素受体阴性HER2阴性的患者---三阴性乳腺癌（ER -，PR -，HER - 2）有一个特别积极的的亚型，建议一线化疗主案。是滞联合或序贯化疗应根据症状、转移部位和疾病负荷，以及病人的相关因素（即喜好，目标，和整体健康）。

激素受体阴性的HER2阳性患者 - 建议对这些患者联合HER2靶向治疗和化疗。

监测治疗 - 仔细评估对治疗的反应性将有助于决定治疗时间和后续治疗的选择。然而，监测转移性乳腺癌患者最好的办法并没有很好地建立。

病史和检查

如果主要目标的症状的缓解，临床病史可能就足够确定治疗的成功。如果疾病是很容易的观察的（例如，胸壁结节，可扪及淋巴结肿大），体格检查允许反应疾病的客观指标。可触及病变，血清标志物和影像学检查明显减少可以清楚地表明疾病的明显缓解。然而，许多患者疾病症状更细微，或症状可能与治疗毒反应或其他非恶性条件相混淆。此外，近一半的转移性乳腺癌患者的疾病是不能通过体检检查出来的。在这些患者中，肿瘤标志物或放射学的变化对确立治疗的反应性至关重要。

肿瘤标志物

测定血清肿瘤标志物（如MUC - 1基因产生的CA15 - 3和CA27.29，和CEA），可以帮助评估反应性，但如果特别的疾病运用一般的标准不能进行评估^[43，84]。灵活地运用肿瘤标志物的测定，可能会减少影像学的定期评价^[85]。MUC-1和CEA其中一项是合理的^[43]。如果MUC-1含量升高，测定CEA的没用意义，但如果MUC-1含量没有升高，那么监测CEA水平可能是有意义的。肿瘤标志物升高，偶尔可能会失真。高达20％的患者经过成功的系统治疗后，可能会开始治疗后的第一个或两个月瞬时增加（标记为“闪光”），可能由于细胞溶解释放了抗原^[86,87]。肝功能异常的患者标志物水平升高也可能出现假阳性，因为它们是经过肝脏代谢[86]。维生素B12缺乏和巨幼细胞性贫血，以及地中海贫血或镰状细胞病的患者，它们的CA15-3水平也可能出现升高^[88-90]。

影像学研究

平片，计算机断层扫描（CT）扫描或磁共振成像（MRI）可允许进行肿瘤反应的评估。定期骨扫描是可获益的，但可能会产生误导。锝（Tc99）在成骨细胞而不是肿瘤细胞中积，经过治疗后有反应的患者，在开始治疗前2月可能会出现一个“显像愈合耀斑”的现象，这种情况会持续12个月^[91,92]。综合正电子发射断层扫描（PET）/计算机断层扫描（CT）作为一个全身检查来监测转移性乳腺癌治疗反应性是推广的，因为它具有较高的敏度性和特异性并且可靠地评估反应性^[93-95]。一些关于全身治疗治疗骨转移引起的代谢改变的证据（[SUV]）即在标准摄取值的变化）表明它们能可靠地预测反应持续时间或进展时间^[96-98]。然而，许多综合性的PET/CT扫描仪在临床使用时首先局部进行CT扫描（确定的PET异常的地方）和不使用更高的分辨率，细切，增强CT扫描。这些评估反应性的方法（标准CT和PET/CT）应牢记。

循环肿瘤细胞

检测转移性乳腺癌患者（≥5的CTC）血液样本的循环肿瘤细胞（CTCS）已被证明是一个无进展生存期（PFS）和总生存期的预测值^[99-105]。此外，在治疗过程中CTCs持续升高，可以预测疾病进展和死亡率。举个例子，在一项前瞻性试验中177例转移性乳腺癌开始进行新的治疗表明CTCs是一个预后值和预测值^[100]。CTCs在基线水平（定义为≥5％/7.5ml）升高比较低或没有检测到预测无进展生存期（3月：7月）和总生存率明显减小（10月：22个月）。CTCs升高的患者在第一次随访（开始治疗后3-5周）的PFS（2月：7月）和总生存期（8月：≥18月）较差，而那些较基线水平降低的CTCs的PFS和总生存期有改善。从这个试验和其他试验的后续分析表明CTCs在治疗期间的任何时间点的水平升高与肿瘤进展相关，并且早于影像学可靠地估计病情恶化^{[102,105,106]}。虽然这些结果是耐人寻味的，但疾病进展缺乏客观证据的情况下持续升高的CTC仍然不知它是否是治疗早期的变化^[107，108]。是否CTCs的测定优于肿瘤标志物（如CA15- 3，CA27.29）目前还不清楚^[109]。 在2007年召开的ASCO，一位专家就乳腺癌的肿瘤标志物方面指出，建议转移性乳腺癌患者常规测量CTC的数据不足还需进一步验证。在乳腺癌通常用免疫学和RNA为基础的的方法检测循环肿瘤细胞。一种方法是（RT-PCR）研究mRNA的表达的4个标记基因，CK19，P1B，PS2和EGP2^[99、110]。市售CellSearch系统采用免疫标本，利用上皮细胞粘附分子（EpCAM的）和细胞荧光标记的单克隆抗体从粒细胞（CD45）区分上皮细胞（cytokeratins8,18,and19）^[104]。

结论和建议---全身治疗转移性乳腺癌的目标是延长生存期，减轻症状，并维持或改善生活质量。

1）激素受体状态，人表皮生长因子受体2（HER2）的过度表达，肿瘤的负荷，无病间期在选择合适的治疗时是很重要的预后和预测指标。

2）由于激素受体和HER2状态在选择治疗时重要性，乳腺癌在确诊后应重复检测激素受体和HER2，因为原发肿瘤和转移之间的肿瘤表达有不一致的。

3）对于进展迅速、有症状的内脏转移或内脏转移器官功能障碍的激素阳性的转移性乳腺癌患者，我们建议一线治疗为化疗，而不是内分泌治疗（1B级）。其他的激素阳性转移性乳腺癌患者首先应及时行内分泌治疗。

4）我们建议大部分移转性乳腺癌患者接受序贯单药化疗（2B级）。联合化疗可能适合进展迅速的疾病，内脏危机，或需要快速控制症状的患者。

5）我们建议HER2阳性乳腺癌患者，不论激素受体状态， HER2靶向治疗作为一线治疗方案（1A级）

6）仔细评估治疗的反应性将有助于持续治疗和后续治疗的决定。临床医生可以使用病史，体格检查，影像学，肿瘤标志物，和/或循环肿瘤细胞（CTCS）监测治疗反应。

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