三陰性乳癌
三陰性乳癌 | |
---|---|
症狀 | 組織細胞突變率高、腫瘤分級高、存在壞死和炎症浸潤,不同亞型有所差異[1] |
類型 | 乳癌、triple-negative breast neoplasm[*] |
風險因素 | |
診斷方法 | 免疫組化[3] |
治療 | 乳房切除術 化學療法 靶向治療 |
預後 | 依照分型有所差異,多數較差 |
盛行率 | 10-20%的乳癌病例 |
分類和外部資源 | |
醫學專科 | 腫瘤學 |
三陰性乳癌(英語:triple-negative breast cancer,TNBC)也稱三陰性乳腺癌,是指缺乏雌激素受體(ER)、孕酮受體(PR)表達與缺乏表皮生長因子受體2(HER2)基因表達的乳癌[1],臨床上一般通過免疫組化確定[3]。這三個基因表達的特徵常見於其它乳癌中,卻少見於此分型中[1],如激素治療等在內的常見乳癌治療方案往往針對這兩種激素受體和HER2基因,因而這些療法對三陰性乳癌患者一般無效[4]。目前主要採取化療對該癌症包括轉移期在內各個階段進行治療[5]。雖然化療可在病理學意義上完全消除許多三陰性乳腺癌患者的腫瘤[1],但因復發率較高,對患者預期生存時間改善不大,這一矛盾現象也被稱為「三陰性悖論」[6]。與其它藥物進行聯合治療已經被臨床試驗證實有效[7]。在美國,超50%的可選擇手術的患者選擇了乳房切除術[4]。
三陰性作為一種侵襲性表型,主要表現為基底樣或正常乳腺樣腫瘤[3],90%為單灶性浸潤性導管癌[3]。該型癌症易發轉移,復發較多且較早,缺乏獲批准的靶向治療方法[4]。該型癌症具有高度異質性,因此可能並非單一疾病,而是不同疾病之集合[8],依據組織學、細胞起源、突變、轉移潛能、疾病進展、治療反應和臨床結果等,還可以分出可以採取不同治療策略的亞型[1][9],如針對BRCA突變的患者已經出現PARP抑制劑等靶向治療藥物[10][11][12]。不同亞型對藥物的反應也不同,如病人無BRCA1/2突變或有腫瘤浸潤淋巴細胞濃度增加,則已有試驗證實卡鉑聯合紫杉醇進行新輔助化療效果更好[13][14]。對於不同亞型的預後也會有所差異,諾丁漢預後指數可以幫助進行預後判斷,但需要更激進治療者除外[15]。
風險因子
該症的風險因子的研究仍然受限於對三陰性乳癌的分型研究與人口統計數據[16]。其在美國乳癌病例中佔15%左右[4],在亞洲的乳癌病例中佔10-17%[9]。多發於年輕女性,可能與BRCA1基因突變相關[2]。非洲裔、西班牙裔等群體在內特定族裔呈現高發,可能與較差社會經濟地位相關[2]。肥胖亦為該疾病的風險因子,身高體重指數較高者易患病[17]。對於不到40歲的女性群體,長期口服避孕藥物是否促進該型癌症發生,目前試驗數據的結果尚存矛盾[16]。
分型及臨床意義
在美國,免疫組學結果顯示激素受體1%陽性以下的乳癌患者視為三陰性患者,過去視為三陰性的對1-10%的陽性表達患者進行激素治療仍然顯示有效[18],但針對三陰性分型的靶向治療藥物是否適用與此類病人難以判斷[1]。
依照病理組織學、基因組學等,三陰性乳腺癌可以分為若干種分型[1][9]。
BRCA基因
BRCA基因突變攜帶者易感於乳腺癌、卵巢癌、胰腺癌和前列腺癌等多種癌症[19],攜帶該突變是三陰性乳癌的風險因子之一。波蘭和澳大利亞的研究顯示,BRCA突變者佔三陰性乳癌群體的10%左右[20]。現有試驗表明,BRCA1突變群體採取添加順鉑的新輔助化療之效果較其他群體更優[21][22],雙側乳房摘除[23]和卵巢摘除[24]對BRCA1基因突變效果亦較好。
超八成的三陰性乳癌表達突變p53蛋白,阻礙正常的DNA修復,突變之p53蛋白被視為三陰性乳癌的病因[25]。用PARP抑制劑誘導DNA單鏈斷裂,破壞無法修復DNA損傷的癌細胞之DNA,可清除腫瘤的發生,而對於有DNA損傷修復能力的普通細胞而無害[25]。BRCA1/2介導了同源重組[26],對BRCA1/2突變攜帶者使用PARP抑制劑,可以致使腫瘤細胞死亡,目前以合成致死性的理論解釋之,即正常之BRCA和PARP同時缺失可以致死[27]。相關藥物已經進入臨床試驗階段並針對BRCA突變者有較好療效[26]。
病理組織學
病理組織學的分型有助於預後的判斷[28]和藥物試驗的篩選[1]。浸潤性導管癌是最常見的形態,轉移率高,預後較差[28]。採用蘇木素-伊紅染色可以識別腺樣囊性癌[1],該分型較其它三陰性乳癌增殖率較低,預後較好[29]。髓樣癌較為罕見,淋巴結很少受累,一般預後良好[28]。化生性的形態亦罕見,多發於老年人,化療效果差,患者診斷後平均生存期不足一年[28]。
此外,以組織學方法進行染色可以識別雄激素受體表達陽性者,佔三陰性患者數量的四分之一左右[30]。雄激素能促髮乳房腫瘤發生,高血漿雄激素水平的女性在絕經後更易患乳腺癌,已證實雄激素可以在動物實驗、體外細胞系中誘發癌症,體重指數增加、飲酒和吸煙可能與體內雄激素水平上升有關[31]。雄激素受體表達陽性的三陰性乳癌患者總生存率較高,預後較好[31]。使用雄激素抑制劑靶向治療三陰性乳腺癌已經進入臨床試驗階段[32]。
分子特徵
三陰性主要為臨床用語,基底樣為cDNA微陣列定義的分子表型[33]。基底樣和三陰性兩個術語被交替使用但有所差異,基底樣分型佔據三陰性乳癌的70-80%,基底樣基因表達可能是三陰性乳癌患者之間的主要生物學差異[34]。依照基因表達圖譜,三陰性乳癌大致可以分為基底樣、非基底樣、Claudin-low型[35]或基底樣免疫激活、基底樣免疫抑制、雄激素受體表達、間葉細胞等分型[36],以及其它的分類方法[37]。不同分型間顯示出的免疫調節、雄激素信號、生長因子通路等差異為藥物研發提供了靶點[38]。
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