三陰性乳腺癌的生物學特征和治療策略

上海交通大學醫學院附屬瑞金醫院乳腺疾病診治中心 朱麗，唐益清

三陰性乳腺癌(triple negative breast cancer，TNBC)是指雌激素受體(ER)、孕激素受體(PR)和人表皮生長因子受體2(Her-2)均為陰性的乳腺癌。這類乳腺癌占乳腺癌病理類型的10%～23.8%[1-5]，具有特殊的生物學行為和臨床病理特征，預后較其他類型的乳腺癌差，是近年研究的熱點之一。

2000年美國斯坦福大學Perou等[6]通過cDNA微陣列技術分析42例乳腺癌患者的65例手術切除標本的基因表達特征，將乳腺癌分為5個亞型：導管A型(Luminal A)、導管B型(Luminal B)、Her-2過表達型、基底細胞樣型(basal-like phenotype，BP)和正常乳腺樣型。BP乳腺癌分型的金標準是微陣列基因譜分析，而該項技術目前難以在臨床檢測中開展，尋求BP乳腺癌理想的免疫組化標志物是切實可行的方法之一。迄今為止，Nielsen等[7]定義的BP乳腺癌免疫組化標志物最為適宜，即ER、PR和Her-2陰性，細胞角蛋白(cytokeratin，CK)5/6和表皮生長因子受體(epidermal growth factor receptor，EGFR)陽性。同時Nielsen等[7]還將三陰性(triple negative，TN)即ER、PR和Her-2陰性作為BP乳腺癌的主要特征。文獻報道約50%～60%的TN乳腺癌是BP型。故臨床工作中利用免疫組化檢測ER、PR和Her-2這3種標志物，將乳腺癌分為Luminal A型、Luminal B型、Her-2過表達型和TN型[8-10]。但實際上越來越多的研究表明TNBC并非完全等同于BP乳腺癌，兩者之間存在交錯重疊[11-13]。

TNBC成為近年的研究熱點之一，一方面是因為該類患者尚無特異性治療，另一方面是該類患者預后最差。TNBC占全部乳腺癌的10%～17%，常見于較為年輕的(＜50歲)絕經前非洲、非洲裔美國、西班牙和乳腺癌易感基因-1(breast cancer susceptibility gene-1，BRCA1)基因突變攜帶者婦女。韓國報道的TNBC比例為14.7%，日本為15%，復旦大學附屬腫瘤醫院報道的我國最大規模的隨訪資料顯示TNBC比例為18.62%，與西方國家的比例近似。TNBC以侵襲性的臨床表現為特征，與其他類型相比，有著最差的總生存率和無進展生存期，腋窩淋巴結轉移率高，肺轉移的發生較早[14]，與乳腺癌常見的骨轉移相比，TNBC內臟轉移率高[15]，局部復發率高[16]，治療后的1～3年內為TNBC的復發高峰期，多數患者在5年內死亡[17]。與其他類型的乳腺癌相比，TNBC腫瘤直徑大、增殖活性高、常有BRCA1和p53基因突變、常表達EGFR，TNBC最常見的組織病理學類型是浸潤性導管癌和化生性癌[7,16,18-21],多為低分化，有著較高的組織學分級和有絲分裂計數。在影像學檢查方面，一項29例TNBC患者的MRI初步研究表明，28例(97%)為腫塊型病變，表現為典型的惡性增強動力學特征。還有一項研究使用定量18-氟脫氧葡萄糖(18fluorodeoxyglucose，18FDG)正電子發射體層顯像技術檢查TN乳腺癌，發現其對FDG的攝取加強，有著非常高的靈敏度(100%)。

TNBC尚無針對性的治療指南，系統性化療是目前主要的全身性治療手段。臨床研究發現TNBC對新輔助化療較為敏感。Torrisi等[22]給予患者CEF方案(表柔比星25 mg/m2,第1、2天；順鉑60 mg/m2，第1天；5-FU 200 mg/m2，第1～21天)4個療程，然后再給予3個療程紫杉醇(90 mg/m2，第1、8、15天，每28 d為1個療程)，86%的患者經影像學檢查證實為臨床緩解，病理完全緩解(pathological complete response，pCR)率為40%，2年無病生存率(disease free survival，DFS)為87.5%。在輔助化療方面，回顧性分析經蒽環類治療TNBC的資料表明，手術后繼以蒽環類為主的化療方案，并不能改善患者的預后[23]。這可能與p53基因突變相關[24]，故不推薦p53基因突變的TNBC患者使用蒽環類化療方案。Sirohi等[25]的研究發現含鉑類藥物的化療方案可以提高TNBC患者的有效率,Uhm等[26]的回顧性分析并未發現TNBC患者較非TNBC患者對含鉑類藥物化療方案有更高的病理緩解率。兩項回顧性研究發現，大劑量化療(含環磷酰胺和塞替派)能使TNBC患者從中獲益[27,28]。

TNBC因為ER、PR、Her-2均為陰性，無法針對這3個靶點實施靶向治療，但研究發現TNBC常表達EGFR ,這便提示EGFR可能成為TNBC靶向治療的一個重要靶點。EGFR的單克隆抗體西妥昔單抗和EGFR的絡氨酸酶抑制劑吉非替尼和埃羅替尼都是針對EGFR這一靶點的藥物。研究發現西妥昔單抗聯合卡鉑治療晚期TNBC療效優于西妥昔單抗治療疾病進展后加用卡鉑者[29]，其有效率為18%[29]。此外，在預后判斷指標的研究上，發現了多種有意義的分子標志物，如雄激素受體、絲裂原活化蛋白激酶(mitogen- activated protein kinase, MAPK)、ADP-核糖聚合酶1(polyADP- ribose- polymerase-1, PARP1)、CK19、蛋白激酶B(Akt)通路明顯活化等，這都有助于我們尋找潛在的治療靶點和特異性的治療藥物，如EGFR/Her-2抑制劑拉帕替尼、HSP90抑制劑、Ras抑制劑、src和abl激酶抑制劑達沙替尼等。

TNBC具有特殊的生物學特性及臨床病理特征，其CK5/6、EGFR等表達多為陽性,具有高增殖性、分化差等特點,與BP乳腺癌和BRCA1相關性乳腺癌有較多相似之處。TNBC通過新輔助化療可以達到較高的pCR，但是預后與其他亞型的乳腺癌相比仍較差。由于TNBC常高表達EGFR，其他信號傳導通路亦有異常,目前已開展了針對這些靶點的研究,TNBC有望取得更好的預后。

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