三阴性乳腺癌的生物学特征和治疗策略

上海交通大学医学院附属瑞金医院乳腺疾病诊治中心 朱丽，唐益清

三阴性乳腺癌(triple negative breast cancer，TNBC)是指雌激素受体(ER)、孕激素受体(PR)和人表皮生长因子受体2(Her-2)均为阴性的乳腺癌。这类乳腺癌占乳腺癌病理类型的10%～23.8%[1-5]，具有特殊的生物学行为和临床病理特征，预后较其他类型的乳腺癌差，是近年研究的热点之一。

2000年美国斯坦福大学Perou等[6]通过cDNA微阵列技术分析42例乳腺癌患者的65例手术切除标本的基因表达特征，将乳腺癌分为5个亚型：导管A型(Luminal A)、导管B型(Luminal B)、Her-2过表达型、基底细胞样型(basal-like phenotype，BP)和正常乳腺样型。BP乳腺癌分型的金标准是微阵列基因谱分析，而该项技术目前难以在临床检测中开展，寻求BP乳腺癌理想的免疫组化标志物是切实可行的方法之一。迄今为止，Nielsen等[7]定义的BP乳腺癌免疫组化标志物最为适宜，即ER、PR和Her-2阴性，细胞角蛋白(cytokeratin，CK)5/6和表皮生长因子受体(epidermal growth factor receptor，EGFR)阳性。同时Nielsen等[7]还将三阴性(triple negative，TN)即ER、PR和Her-2阴性作为BP乳腺癌的主要特征。文献报道约50%～60%的TN乳腺癌是BP型。故临床工作中利用免疫组化检测ER、PR和Her-2这3种标志物，将乳腺癌分为Luminal A型、Luminal B型、Her-2过表达型和TN型[8-10]。但实际上越来越多的研究表明TNBC并非完全等同于BP乳腺癌，两者之间存在交错重叠[11-13]。

TNBC成为近年的研究热点之一，一方面是因为该类患者尚无特异性治疗，另一方面是该类患者预后最差。TNBC占全部乳腺癌的10%～17%，常见于较为年轻的(＜50岁)绝经前非洲、非洲裔美国、西班牙和乳腺癌易感基因-1(breast cancer susceptibility gene-1，BRCA1)基因突变携带者妇女。韩国报道的TNBC比例为14.7%，日本为15%，复旦大学附属肿瘤医院报道的我国最大规模的随访资料显示TNBC比例为18.62%，与西方国家的比例近似。TNBC以侵袭性的临床表现为特征，与其他类型相比，有着最差的总生存率和无进展生存期，腋窝淋巴结转移率高，肺转移的发生较早[14]，与乳腺癌常见的骨转移相比，TNBC内脏转移率高[15]，局部复发率高[16]，治疗后的1～3年内为TNBC的复发高峰期，多数患者在5年内死亡[17]。与其他类型的乳腺癌相比，TNBC肿瘤直径大、增殖活性高、常有BRCA1和p53基因突变、常表达EGFR，TNBC最常见的组织病理学类型是浸润性导管癌和化生性癌[7,16,18-21],多为低分化，有着较高的组织学分级和有丝分裂计数。在影像学检查方面，一项29例TNBC患者的MRI初步研究表明，28例(97%)为肿块型病变，表现为典型的恶性增强动力学特征。还有一项研究使用定量18-氟脱氧葡萄糖(18fluorodeoxyglucose，18FDG)正电子发射体层显像技术检查TN乳腺癌，发现其对FDG的摄取加强，有着非常高的灵敏度(100%)。

TNBC尚无针对性的治疗指南，系统性化疗是目前主要的全身性治疗手段。临床研究发现TNBC对新辅助化疗较为敏感。Torrisi等[22]给予患者CEF方案(表柔比星25 mg/m2,第1、2天；顺铂60 mg/m2，第1天；5-FU 200 mg/m2，第1～21天)4个疗程，然后再给予3个疗程紫杉醇(90 mg/m2，第1、8、15天，每28 d为1个疗程)，86%的患者经影像学检查证实为临床缓解，病理完全缓解(pathological complete response，pCR)率为40%，2年无病生存率(disease free survival，DFS)为87.5%。在辅助化疗方面，回顾性分析经蒽环类治疗TNBC的资料表明，手术后继以蒽环类为主的化疗方案，并不能改善患者的预后[23]。这可能与p53基因突变相关[24]，故不推荐p53基因突变的TNBC患者使用蒽环类化疗方案。Sirohi等[25]的研究发现含铂类药物的化疗方案可以提高TNBC患者的有效率,Uhm等[26]的回顾性分析并未发现TNBC患者较非TNBC患者对含铂类药物化疗方案有更高的病理缓解率。两项回顾性研究发现，大剂量化疗(含环磷酰胺和塞替派)能使TNBC患者从中获益[27,28]。

TNBC因为ER、PR、Her-2均为阴性，无法针对这3个靶点实施靶向治疗，但研究发现TNBC常表达EGFR ,这便提示EGFR可能成为TNBC靶向治疗的一个重要靶点。EGFR的单克隆抗体西妥昔单抗和EGFR的络氨酸酶抑制剂吉非替尼和埃罗替尼都是针对EGFR这一靶点的药物。研究发现西妥昔单抗联合卡铂治疗晚期TNBC疗效优于西妥昔单抗治疗疾病进展后加用卡铂者[29]，其有效率为18%[29]。此外，在预后判断指标的研究上，发现了多种有意义的分子标志物，如雄激素受体、丝裂原活化蛋白激酶(mitogen- activated protein kinase, MAPK)、ADP-核糖聚合酶1(polyADP- ribose- polymerase-1, PARP1)、CK19、蛋白激酶B(Akt)通路明显活化等，这都有助于我们寻找潜在的治疗靶点和特异性的治疗药物，如EGFR/Her-2抑制剂拉帕替尼、HSP90抑制剂、Ras抑制剂、src和abl激酶抑制剂达沙替尼等。

TNBC具有特殊的生物学特性及临床病理特征，其CK5/6、EGFR等表达多为阳性,具有高增殖性、分化差等特点,与BP乳腺癌和BRCA1相关性乳腺癌有较多相似之处。TNBC通过新辅助化疗可以达到较高的pCR，但是预后与其他亚型的乳腺癌相比仍较差。由于TNBC常高表达EGFR，其他信号传导通路亦有异常,目前已开展了针对这些靶点的研究,TNBC有望取得更好的预后。

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