
文章信息
- 逆转乳腺癌内分泌治疗耐药研究进展
- Research Progress on Reversing Breast Cancer Resistance to Endocrine Therapy
- 肿瘤防治研究, 2017, 44(11): 759-763
- Cancer Research on Prevention and Treatment, 2017, 44(11): 759-763
- http://www.zlfzyj.com/CN/10.3971/j.issn.1000-8578.2017.17.0535
- 收稿日期: 2017-05-15
- 修回日期: 2017-07-08
2. 050051 石家庄, 河北省人民医院肿瘤四科
2. Fourth Department of Oncology, Hebei General Hospital, Shijiazhuang 050051, China
内分泌治疗以其较好的疗效及耐受性在激素受体(hormone receptor, HR)阳性乳腺癌治疗中占有重要地位,中国乳腺癌内分泌治疗专家共识指出:对于疾病进展缓慢的雌激素受体阳性乳腺癌患者,无论是早期或是无症状的晚期亦或是复发转移性乳腺癌,内分泌治疗都可作为一线首选疗法[1]。常见的内分泌治疗药物包括选择性雌激素受体调制剂(selective estrogen receptor modulator, SERM)、芳香化酶抑制剂(aromatase inhibitors, AIs)、选择性雌激素受体下调剂(selective estrogen receptor down-regulator, SERD)[2],患者对这些药物产生的原发或继发性耐药是临床上面临的重大问题。内分泌耐药机制是复杂多因素的,可由生长因子受体过表达、细胞信号通路成分变化、细胞周期异常、特异性miRNA表达改变以及外泌体在肿瘤细胞间传递耐药分子等方面引起。目前针对耐药发生机制而进行的耐药逆转研究主要从抑制生长因子信号、阻滞备用信号通路、阻滞细胞周期、表观基因修饰、雄激素受体阻滞等方面展开。某些分子靶向药物联合内分泌治疗在临床试验中已看到明确疗效,为将来克服乳腺癌内分泌治疗耐药带来了希望。
1 生长因子信号与内分泌治疗耐药生长因子信号级联系统的异常激活,无论是配体数目增多、受体活性增高或是下游信号分子上调都能轻易导致乳腺癌抗雌激素治疗的失败。目前研究发现,与内分泌耐药相关的生长因子受体主要有人表皮生长因子受体2(human epidermal growth factor receptor 2, HER2)、表皮生长因子受体(epidermal growth factor, EGFR)、胰岛素样生长因子-1受体(insulin-like growth factor 1 receptor, IGF-1R),雌激素受体(estrogen receptor, ER)信号通路与这些生长因子受体信号通路之间的“cross talk”是耐药发生机制之一[3]。
HER2扩增在乳腺癌中约占20%~30%,在ER阳性乳腺癌中约为10%[4]。HER2可激活下游PI3K-AKT-mTOR和Ras-Raf-MAPK信号通路,活化的PI3K-AKT通路使ER特定丝氨酸残基磷酸化引起肿瘤细胞非激素依赖的增殖导致内分泌耐药的产生。TAnDEM是第一个内分泌治疗药物联合抗HER2疗法治疗转移性乳腺癌的Ⅲ期临床试验,比较曲妥珠单抗联合阿那曲唑与阿那曲唑单独用药治疗ER阳性HER2过表达的转移性乳腺癌的效果,结果显示联合用药组无进展生存期(progression-free survival, PFS)明显提高(中位PFS 4.8月vs. 2.4月,P=0.006[5])。EGF30008试验纳入1 286例患者,比较口服来曲唑加拉帕替尼与仅用来曲唑治疗雌激素受体阳性转移性乳腺癌的效果。试验观察到来曲唑加拉帕替尼治疗组PFS延长(8.2 vs.3.0月)以及HER2+患者治疗缓解率的提高,但临床受益仅限于HER2+患者,HER2-者并无明显受益[6]。NCT00429299[7]、CALGB 40302[8]两项试验在不考虑HER2表达情况下评估内分泌联合抗HER2疗法的治疗效果,结果表明患者无明显临床受益。因而,同时抑制ER和HER2带来的预后改善可能只在ER、HER2共表达的患者中,而非HER2阴性患者中。
EGFR可与HER2形成异源二聚体,激活下游MAPK信号通路,促使ER磷酸化,导致内分泌耐药。EGFR抑制剂吉非替尼能通过上调ER表达并抑制MAPK信号转导而逆转他莫昔芬耐药[9]。NCT00077025[10]随机对照双盲临床试验评价内分泌联合吉非替尼治疗绝经后转移性乳腺癌的效果,实验组50例接受来曲唑加吉非替尼,对照组43例接受来曲唑加安慰剂,结果实验组中位无进展生存期为14.7月,对照组为8.4月。AZD8931是双相酪氨酸激酶抑制剂,可同时抑制EGFR和HER2,体外细胞实验中AZD8931可显著抑制乳腺癌他莫昔芬耐药细胞生长,明显延迟小鼠移植瘤内分泌耐药的发生[11],但在一项Ⅱ期临床试验中内分泌联合AZD8931治疗似乎并不能提高患者内分泌治疗的临床受益[12]。
IGF-1R在LuminalA及LuminalB型乳腺癌中表达分别高达84%和76%[13],IGF与IGF-1R结合后激活PI3K/Akt和RAS/MAPK信号通路而使细胞增殖复制[14],高水平的IGF-1R促使ER磷酸化,反过来ER信号也可增强IGF-1R通路的分子表达。有研究证实来曲唑联合IGF-1R抑制剂可协同抑制乳腺癌细胞生长、增殖并诱导凋亡[15]。Ganitumab是IgG1单抗,可阻止IGF-1、IGF-2与IGF-1R结合,Ⅱ期临床试验NCT00626106[16]对比氟维司群或依西美坦联合Ganitumab和单独内分泌治疗ER阳性绝经后晚期乳腺癌患者的疗效,结果发现联合疗法并不比单独内分泌治疗的疗效好,无进展生存期为3.9 vs. 5.7月。
2 PI3K-AKT-mTOR通路与内分泌治疗耐药在乳腺癌中,PI3K/AKT/mTOR是最常发生变化的信号通路,高达70%的乳腺癌中会出现该通路的变化[17],PI3K/AKT/mTOR通路中成分的突变和高度激活与乳腺癌内分泌治疗耐药相关。经PI3K/AKT/mTOR传递的信号可激活非雌激素依赖的ER转录活性,促使细胞在没有雌激素的情况下增殖。新近研究发现,mTOR抑制剂依维莫司作用于芳香化酶抑制剂耐药的MCF-7细胞时,可下调ER水平,诱导细胞发生自噬并增强细胞对内分泌药物的敏感度[18]。有两项研究评估了mTOR抑制剂依维莫司用在AIs治疗过程中发生进展病例中的效果。BOLERO-2[19]对比依西美坦联合依维莫司和依西美坦加安慰剂的疗效,入选病例为来曲唑、阿那曲唑难治性HER2阴性绝经后晚期乳腺癌患者,结果显示联合用药组中位无进展生存期明显延长(中位PFS为7.8 vs. 3.2月,P < 0.0001)。TAMRAD[20]比较他莫昔芬联合依维莫司治疗与他莫昔芬单药的治疗效果,结果显示联合用药组临床获益率(clinical beneficial rate, CBR)为61%,他莫昔芬组为42%(P=0.045)。并且亚组分析显示继发耐药患者联合用药后获益更明显。
也有研究评价PI3K-AKT-mTOR抑制联合内分泌治疗作为一线用药的治疗效果,RAD001试验用来曲唑加依维莫司治疗ER阳性早期乳腺癌,结果显示联合用药4月后,触诊临床缓解率比单独用药明显提高(68% vs. 59%)[21]。另有研究BOLERO-4[22],评估依维莫司加来曲唑一线治疗发生转移或局部晚期乳腺癌,其结果6月及12月的无进展生存率95%CI分别为83.6%和71.4%,CBR为74.3%,预示着依维莫司加来曲唑一线治疗晚期乳腺癌是行之有效的方法。
3 CDKs与内分泌治疗耐药无限复制潜能及紊乱的细胞周期是肿瘤细胞的显著特点,细胞周期素依赖性蛋白激酶(cyclin-dependent kinases, CDKs)是参与细胞周期的重要蛋白激酶,与细胞周期蛋白结合形成异源二聚体促使细胞周期发生时相转变[23]。CDK4/6是细胞由G1期向S期转变的关键调控蛋白,它与cyclin D结合后磷酸化视网膜母细胞瘤蛋白Rb,驱动细胞周期,同时这个过程可被P16抑制[24]。CDK4/6的扩增、cyclin D的过表达、p16和Rb的缺失都会导致细胞周期异常,而细胞周期异常本身就可能是内分泌耐药发生的原因。帕泊昔布是选择性CDK4/6抑制剂,通过抑制CDK4/6阻止Rb蛋白的磷酸化将细胞阻滞于G1期。PALOMA-1[25]是一项Ⅱ期多中心临床试验,比较了来曲唑与来曲唑联合帕泊昔布在ER阳性、HER2阴性的晚期乳腺癌中的治疗效果。实验招募了165例患者,81例接受来曲唑治疗,84例接受来曲唑联合帕泊昔布治疗,结果联合用药组中位PFS比单用来曲唑组明显延长(20.2 vs.10.2月)。PALOMA-3是一项Ⅲ期临床研究对比帕泊昔布联合氟维司群和氟维司群联合安慰剂治疗ER阳性、HER2阴性绝经前或围绝经期乳腺癌患者,结果显示联合治疗组中位无进展生存比单独氟维司群组显著延长(9.5 vs. 4.6月,P < 0.0001),而且肿瘤耐药与否、HR表达情况以及PIK3CA突变状态并不影响联合用药效果[26]。NCT01958021研究用另一种CDK4/6抑制剂Ribociclib加来曲唑一线治疗HR阳性晚期乳腺癌,结果显示患者无进展生存期同样获得明显延长[27]。由于CDK4/6抑制剂疗效显著,相关的多项临床试验正在开展。
4 HDACs与内分泌治疗耐药乳腺癌中ER的表达会因ESR1启动子甲基化或脱乙酰化而被抑制或丢失,这也可能是导致乳腺癌内分泌耐药的原因。组蛋白乙酰转移酶(histone acetyltransferases, HATs)和组蛋白脱乙酰酶(histone deacetylases, HDACs)是影响组蛋白乙酰化的关键酶,现已确认某些特异性HDACs在乳腺肿瘤中异常表达[28]。HDACs抑制剂伏立诺他通过干扰细胞周期可影响乳腺癌细胞的生长、分化、凋亡,他莫昔芬联合HDACs抑制剂比任何单一用药更具抗肿瘤细胞增殖活性[29]。HDACs抑制剂还可通过降低Bcl-2表达及诱导细胞自噬性死亡逆转细胞他莫昔芬耐药[30-31]。NCT00365599是一项Ⅱ期临床试验,评价他莫昔芬联合伏立诺他治疗HR阳性内分泌治疗耐药的转移性乳腺癌,结果显示出19%的客观缓解率和40%的临床获益率,中位进展时间为10.3月,中位生存期为29月,其中组蛋白高度乙酰化及HDAC2的高基线水平与治疗反应性密切相关[32]。
5 AR与内分泌治疗耐药雄激素受体(androgen receptor, AR)在ER阳性乳腺癌中的表达高达90%,其作为乳腺癌预后标识及潜在治疗靶点显示出越来越重要的地位[33]。在AIs耐药的乳腺癌中AR与ER可起相互协调作用[34],AR还可通过活化EGFR促使他莫昔芬表现出激动效应而导致细胞耐药[35]。Cochrane等报道在192例接受他莫昔芬治疗的患者中AR/ER > 2比AR/ER < 2的患者高出4倍的他莫昔芬治疗失败的可能性[36]。Enzalutamide是口服AR抑制剂,NCT02007512这项Ⅱ期随机双盲安慰剂对照评价Enzalutamide加依西美坦治疗HR阳性乳腺癌疗效的临床试验正在进行中。
6 药物代谢与内分泌治疗耐药他莫昔芬在体内主要通过CYP450家族中CYP2D6和CYP3A4代谢为更具活性的4-OH-TAM和吲哚昔芬,但由于CYP2D6基因单核苷酸多态性常导致他莫昔芬治疗结局的差异。直接应用吲哚昔芬可避免因CYP2D6基因多态性引起的个体间药物代谢差异,提高活性药物暴露剂量,增强抗肿瘤活性[37]。研究表明,吲哚昔芬联合拉帕替尼可打破乳腺癌他莫昔芬耐药细胞中ER与HER2间的“cross talk”,克服乳腺癌内分泌耐药[38]。另有研究专门设计合成他莫昔芬类似物绕过CYP2D6代谢过程,经测试该化合物同样能与ER结合,并显示出明显强于他莫昔芬的抗肿瘤增殖活性[39]。
7 总结目前多种针对乳腺癌内分泌耐药的靶向药物正处于临床研究中,不乏这些药物联合内分泌治疗对ER阳性乳腺癌无进展生存有实质性提高。依维莫司联合依西美坦已作为非甾体类AIs治疗绝经后HR阳性晚期乳腺癌继发内分泌耐药后的后续治疗方案,帕泊昔布联合来曲唑可双倍延长无进展生存也已获批一线治疗绝经后ER阳性、HER2阴性的转移性乳腺癌。鉴于细胞信号通路的复杂性和肿瘤细胞的异质性,企图通过单一信号通路的靶向治疗来实现由于各种机制导致的乳腺癌内分泌耐药的逆转或许过于理想化。正如诸多研究所示,任何既定的耐药信号通路阻滞都会补偿性地诱使其他耐药信号通路的产生并促使该信号不断强化。因而未来的研究重点可能是多个通路的平行或垂直的联合网状阻滞,例如现在正在探索的“垂直三联内分泌疗法”,即内分泌治疗外加至少两种信号通路阻滞剂,尤其是CDK4/6抑制剂和PI3K信号通路抑制剂。我们期待未来能有新的方法使ER阳性乳腺癌的治疗有突破性飞跃,并且能有优秀的生物标记来筛选出适合某种治疗的最佳患者群体,最终成功地防止或逆转乳腺癌内分泌耐药。
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