液體腫瘤生物指標(biāo)檢測(cè)對(duì)乳腺癌患者的臨床價(jià)值

周金妹 江澤飛

軍事醫(yī)學(xué)科學(xué)院附屬醫(yī)院乳腺腫瘤內(nèi)科，北京 100071

液體腫瘤生物指標(biāo)檢測(cè)對(duì)乳腺癌患者的臨床價(jià)值

周金妹綜述 江澤飛審校

軍事醫(yī)學(xué)科學(xué)院附屬醫(yī)院乳腺腫瘤內(nèi)科，北京 100071

循環(huán)腫瘤標(biāo)志物在乳腺癌中的應(yīng)用受到越來越多的關(guān)注，研究水平已從蛋白質(zhì)水平深入到基因水平，相應(yīng)的檢測(cè)指標(biāo)則從傳統(tǒng)的腫瘤標(biāo)志物擴(kuò)展到相對(duì)特異的HER-2蛋白質(zhì)細(xì)胞外段、循環(huán)腫瘤細(xì)胞、循環(huán)腫瘤DNA及循環(huán)RNA等。作為“液體檢測(cè)”，循環(huán)腫瘤標(biāo)志物的檢測(cè)因其實(shí)時(shí)動(dòng)態(tài)、操作簡便、可重復(fù)性好等優(yōu)勢(shì)，被廣泛應(yīng)用于協(xié)助早期診斷、判斷預(yù)后、預(yù)測(cè)療效、監(jiān)測(cè)疾病復(fù)發(fā)及病情變化等方面。對(duì)循環(huán)腫瘤標(biāo)志物的深入研究，有助于實(shí)現(xiàn)患者的個(gè)體化治療。

乳腺癌；CA15-3；CEA；蛋白質(zhì)細(xì)胞外段；循環(huán)腫瘤細(xì)胞；循環(huán)腫瘤DNA；循環(huán)腫瘤RNA

目前乳腺癌是女性最常見的惡性腫瘤，致死率高，因此其早期診斷、有效隨訪及療效的動(dòng)態(tài)監(jiān)測(cè)一直是臨床科研工作者的研究重點(diǎn)。同時(shí)乳腺癌是一種高度異質(zhì)性的惡性腫瘤，隨著蛋白質(zhì)組學(xué)、分子病理學(xué)及基因組學(xué)的發(fā)展進(jìn)步，乳腺癌的診療已進(jìn)入分子分型指導(dǎo)下的個(gè)體化診療時(shí)代。循環(huán)血中的腫瘤細(xì)胞及其釋放的蛋白、基因片段等，作為循環(huán)腫瘤標(biāo)志物可實(shí)時(shí)動(dòng)態(tài)反映腫瘤負(fù)荷，同時(shí)攜帶大量腫瘤生物學(xué)行為相關(guān)信息，具有預(yù)后、預(yù)測(cè)價(jià)值。鑒于其重要的臨床價(jià)值及操作簡便、可重復(fù)等優(yōu)勢(shì)，目前液體腫瘤生物指標(biāo)檢測(cè)在各階段乳腺癌診療中的應(yīng)用日益廣泛。其檢測(cè)指標(biāo)主要包括傳統(tǒng)的血清標(biāo)志物CA15-3、CEA，相對(duì)特異的蛋白質(zhì)細(xì)胞外段(extracellular domain，ECD)、循環(huán)腫瘤細(xì)胞(circulating tumor cells，CTCs)、循環(huán)腫瘤DNA(circulating tumor DNA，ctDNA)及循環(huán)腫瘤RNA(circulating tumor RNA，ctRNA)等，從蛋白水平的檢測(cè)發(fā)展到基因水平的研究，液體腫瘤生物指標(biāo)檢測(cè)的臨床價(jià)值受到越來越多的關(guān)注，而不同檢測(cè)指標(biāo)的應(yīng)用價(jià)值因自身的特異性及靈敏性而各不相同。

1 CA15-3、CEA的臨床價(jià)值

CA15-3、CEA作為乳腺癌最傳統(tǒng)的血清標(biāo)志物，其檢測(cè)簡便易行，是目前臨床上應(yīng)用最廣泛的動(dòng)態(tài)檢測(cè)指標(biāo)。Lee等［1］的研究指出CA15-3、CEA是乳腺癌患者的獨(dú)立預(yù)后因素。Bahrami等［2］的研究顯示，患者術(shù)后血清CA15-3、CEA水平的動(dòng)態(tài)監(jiān)測(cè)能預(yù)測(cè)復(fù)發(fā)轉(zhuǎn)移，且有研究［3］表明，給予僅有癌標(biāo)升高、無影像學(xué)復(fù)發(fā)證據(jù)的患者干預(yù)治療，能顯著改善預(yù)后。但由于二者檢測(cè)的敏感性和特異性較差，限制了其在乳腺癌早期診療階段的應(yīng)用［4］。CA15-3、CEA在晚期乳腺癌患者的陽性檢出率較高，大量研究表明二者檢測(cè)水平的動(dòng)態(tài)變化與治療療效具有相關(guān)性，在無目標(biāo)病灶者中的臨床價(jià)值更大，且CEA的臨床價(jià)值在CA15-3檢測(cè)值正常者中更為顯著，但由于二者的檢測(cè)值存在“閃爍”現(xiàn)象，目前多數(shù)專家共識(shí)建議其與其他臨床指標(biāo)聯(lián)合應(yīng)用，綜合判定患者的病情變化［4］。

2 HER-2 ECD臨床價(jià)值

HER-2陽性乳腺癌是乳腺癌的一種特殊亞型，其腫瘤侵襲性強(qiáng)、易復(fù)發(fā)，多對(duì)化療及內(nèi)分泌治療耐藥，但可從靶向治療中獲益。目前臨床上一般依據(jù)組織學(xué)HER-2狀態(tài)選擇靶向治療的適用患者群，但由于原發(fā)或繼發(fā)耐藥的存在，幾乎所有患者均不能從靶向治療中持續(xù)獲益，因此探索動(dòng)態(tài)預(yù)測(cè)靶向治療療效的指標(biāo)成為研究熱點(diǎn)。HER-2 ECD在金屬蛋白酶的作用下脫落到外周血中，能被ELISA方法定量檢測(cè)，是乳腺癌相對(duì)特異性的指標(biāo)，能動(dòng)態(tài)反映乳腺癌患者的病情變化，因此其臨床價(jià)值受到越來越多的關(guān)注。

Pedersen等［5］的研究表明，對(duì)組織學(xué)檢測(cè)HER-2陽性患者而言，ECD預(yù)測(cè)復(fù)發(fā)的敏感性優(yōu)于CA153、CEA，但尚無基于ECD檢測(cè)值升高而給予預(yù)先治療致臨床獲益的相關(guān)研究報(bào)道。就曲妥珠單抗靶向治療而言，目前相對(duì)一致的觀點(diǎn)認(rèn)為治療過程中ECD下降者療效較好，但ECD下降的定義尚不明確；而關(guān)于ECD基線檢測(cè)值對(duì)靶向治療療效預(yù)測(cè)的價(jià)值尚無定論［6-8］。就ECD對(duì)拉帕替尼治療療效的預(yù)測(cè)作用而言，Lipton等［9］的研究表明ECD基線檢測(cè)值高者客觀有效率(objective response rate，ORR)高，治療早期ECD檢測(cè)值下降超過20%者ORR升高、無進(jìn)展生存時(shí)間(progression free survival，PFS)延長。同時(shí)部分學(xué)者探討了ECD檢測(cè)值高水平對(duì)組織學(xué)HER-2陰性患者靶向治療療效的預(yù)測(cè)作用。Ardavanis等［10］的研究表明多重解救治療后、組織學(xué)檢測(cè)HER-2陰性而ECD檢測(cè)值呈高水平的患者可能從曲妥珠單抗治療中獲益。Finn等［11］的研究顯示組織學(xué)檢測(cè)HER-2陰性、ECD高表達(dá)的患者未能從拉帕替尼治療中獲益。此外ECD檢測(cè)對(duì)解救化療、內(nèi)分泌治療同樣具有預(yù)測(cè)價(jià)值。絕大多數(shù)研究認(rèn)為，接受解救化療且ECD基線檢測(cè)值高的患者PFS、緩解持續(xù)時(shí)間(duration of response，DOR)較短；同時(shí)大部分研究結(jié)果顯示，ECD基線檢測(cè)值高的患者ORR低［12-13］。研究關(guān)于ECD檢測(cè)對(duì)解救內(nèi)分泌治療療效預(yù)測(cè)作用的結(jié)論相對(duì)一致：ECD基線檢測(cè)值高的患者ORR低，DOR、疾病進(jìn)展時(shí)間(time to progression，TTP)、OS較短［14］。

3 CTCs的臨床價(jià)值

CTCs是指從癌癥原發(fā)部位脫落通過血管或淋巴系統(tǒng)進(jìn)入血液循環(huán)的腫瘤細(xì)胞。國內(nèi)外研究先后證實(shí)了CTCs計(jì)數(shù)、CTCs HER-2對(duì)乳腺癌患者的預(yù)后、預(yù)測(cè)價(jià)值。相較于既往傳統(tǒng)指標(biāo)，CTCs能更好地反映腫瘤的生物學(xué)特性，近年來其分子、基因特性成為研究重點(diǎn)［15-19］。

有研究表明輔助治療前后表達(dá)細(xì)胞角蛋白19信使RNA(cytokeratin-19 mRNA，CK-19 mRNA)的CTCs計(jì)數(shù)高者DFS、OS較短；在三苯氧胺輔助內(nèi)分泌治療過程中，若其持續(xù)存在則預(yù)示疾病的復(fù)發(fā)［20-21］。Xenidis等［22］的后續(xù)研究表明加用紫杉類輔助化療能顯著降低表達(dá)CK-19 mRNA的CTCs的陽性檢出率，提高患者的DFS與OS。此外Georgoulias等［23］的研究表明，對(duì)標(biāo)準(zhǔn)輔助化療結(jié)束后表達(dá)CK-19 mRNA的CTCs檢測(cè)結(jié)果仍陽性的患者給予后續(xù)曲妥珠單抗治療能顯著降低表達(dá)CK-19 mRNA的CTCs的陽性檢出率及個(gè)數(shù)，降低復(fù)發(fā)轉(zhuǎn)移的概率。

就解救階段而言，Liu等［24］的個(gè)案報(bào)道顯示了表達(dá)EGFR的CTCs計(jì)數(shù)的動(dòng)態(tài)變化與拉帕替尼治療療效的相關(guān)性。Gradilone等［25］的研究表明外周血中檢出表達(dá)多重耐藥相關(guān)蛋白(multidrug-resistance-related proteins，MRPs)的CTCs者PFS較短。Yu等［26］的研究表明發(fā)生上皮間質(zhì)細(xì)胞轉(zhuǎn)化的CTCs計(jì)數(shù)與晚期乳腺癌患者的病情變化具有相關(guān)性。另有研究表明CTCs可檢測(cè)到過甲基化的抑癌基因的啟動(dòng)序列，但其臨床價(jià)值亟需大樣本、前瞻性研究進(jìn)一步探索［27］。

4 ctDNA的臨床價(jià)值

基因改變普遍存在于乳腺癌的發(fā)生、發(fā)展過程中，主要包括點(diǎn)突變、過甲基化等形式。ctDNA是指由腫瘤組織釋放到外周血中的DNA片段，所攜帶的腫瘤相關(guān)信息與腫瘤組織具有良好的一致性［28-29］，其對(duì)乳腺癌的臨床價(jià)值成為近年研究的熱點(diǎn)，主要包括早期診斷、判斷預(yù)后、風(fēng)險(xiǎn)評(píng)估、療效監(jiān)測(cè)等方面。

Radpour等［30］的研究表明細(xì)胞周期調(diào)控及DNA損傷修復(fù)相關(guān)基因(p16、p21、BRCA1)、信號(hào)轉(zhuǎn)導(dǎo)相關(guān)基因(APC、BIN1)、侵襲轉(zhuǎn)移相關(guān)基因(CST6、TIMP3)、細(xì)胞解毒相關(guān)基因(GSTP1)、細(xì)胞增殖相關(guān)基因(ESR-b)聯(lián)合檢測(cè)早期乳腺癌的敏感性及特異性均超過90%。Silva等［31］的研究表明，ctDNA是獨(dú)立的預(yù)后因素，ctDNA (同時(shí)在腫瘤組織和血清水平檢測(cè)到的改變/突變基因)檢測(cè)水平高者DFS較短。另有研究先后證實(shí)ctDNA的檢測(cè)對(duì)輔助、新輔助、解救治療的療效有監(jiān)測(cè)作用［32-35］。其中Murtaza等［34］的研究結(jié)果指出患者在解救治療至疾病進(jìn)展的過程中會(huì)獲得與治療藥物相關(guān)的耐藥基因的突變。Dawson等［35］通過標(biāo)記擴(kuò)增深度測(cè)序法(tagged-amplicon deep sequencing，Tam-Seq)檢測(cè)乳腺癌最常見的突變基因PIK3CA、TP53或通過全基因組末端配對(duì)測(cè)序法檢測(cè)腫瘤組織的其他突變基因或結(jié)構(gòu)變異，后續(xù)通過PCR等技術(shù)動(dòng)態(tài)檢測(cè)相應(yīng)的ctDNA水平，結(jié)果表明ctDNA的敏感性及與病情變化的相關(guān)性優(yōu)于CTCs及CA15-3，且ctDNA水平高者OS較短，再次展示了其潛在的臨床價(jià)值。

然而由于乳腺癌發(fā)生、發(fā)展過程中基因改變位點(diǎn)及形式的多樣性，目前尚無明確的敏感性及特異性均能達(dá)到臨床應(yīng)用要求的靶基因，而這也將成為今后研究的重點(diǎn)。

5 RNA的臨床價(jià)值

鑒于并非所有DNA的改變均可導(dǎo)致細(xì)胞表觀遺傳學(xué)的改變，mRNA的改變或許能更好地反映腫瘤的生物學(xué)特性，具有一定的預(yù)后價(jià)值［36］。

相較于m R N A來說，微小R N A (microRNA，miRNA，miR)穩(wěn)定性強(qiáng)，通過調(diào)控多種基因的表達(dá)參與細(xì)胞的生長、凋亡、癌變、侵襲轉(zhuǎn)移等過程。近年來眾多研究證實(shí)了多種miRNA如miR-200b、210、128等對(duì)乳腺癌患者的臨床價(jià)值［37-41］。Cuk等［37］的研究表明miR-148b等微小RNA的檢測(cè)有助于乳腺癌的早期診斷。Buffa等［38］的研究證實(shí)了miR-210、128、27b的獨(dú)立預(yù)后價(jià)值，其高表達(dá)者DFS較短，且與mRNA聯(lián)合檢測(cè)時(shí)預(yù)后價(jià)值更強(qiáng)。Volinia等［39］建立了包含30種mRNA、7種miRNA的聯(lián)合檢測(cè)模型，能較目前常用的MammaPrint and Oncotype DX更好地預(yù)測(cè)患者的復(fù)發(fā)風(fēng)險(xiǎn)。Madhavan等［40］的研究首次證實(shí)了miRNA的檢測(cè)水平與CTCs計(jì)數(shù)的相關(guān)性，并顯示了其對(duì)晚期乳腺癌患者的預(yù)后價(jià)值。同時(shí)有研究結(jié)果顯示，通過調(diào)整miRNA-29b的水平能改變抑癌基因的過甲基化狀態(tài)，從而抑制腫瘤細(xì)胞的生長［41］。

6 小結(jié)與展望

“液體腫瘤學(xué)檢測(cè)”因其簡便易行、侵害性小、實(shí)時(shí)動(dòng)態(tài)佳等優(yōu)勢(shì)受到越來越多的關(guān)注，從蛋白檢測(cè)到基因探索，多層面的循環(huán)腫瘤標(biāo)志物更全面、深入、動(dòng)態(tài)地反映著腫瘤的演變過程，且ctDNA/RNA的敏感性和特異性均較既往指標(biāo)有所提升，顯示預(yù)后、預(yù)測(cè)價(jià)值的同時(shí)展現(xiàn)了早期診斷乳腺癌的臨床價(jià)值。此外，關(guān)于CTCs HER-2、CK-19 mRNA、miRNA的研究結(jié)果更是初步展示了循環(huán)腫瘤標(biāo)志物檢測(cè)對(duì)于傳統(tǒng)治療理念的沖擊，即通過檢測(cè)攜帶腫瘤細(xì)胞生物學(xué)信息的循環(huán)腫瘤標(biāo)志物來實(shí)時(shí)、動(dòng)態(tài)指導(dǎo)個(gè)體化治療，而非僅依靠組織學(xué)及影像學(xué)檢查制定治療策略。但證據(jù)力度、檢測(cè)技術(shù)等多方因素在一定程度上限制了其在臨床的推廣應(yīng)用，因此亟需大樣本、前瞻性臨床研究進(jìn)一步證實(shí)液體腫瘤學(xué)檢測(cè)對(duì)不同類型、不同階段乳腺癌患者的臨床價(jià)值，探索靈敏實(shí)用的靶向標(biāo)志物，從而真正實(shí)現(xiàn)乳腺癌的分類、個(gè)體化治療。

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The clinical value of liquid tumor biomarker detection for breast cancer

ZHOU Jin-mei, JIANG Zefei
(Department of Breast Cancer, Af filiated Hospital of Academy of Military Medical Sciences, Beijing 100071, China)

JIANG Ze-fei E-mail: jiangzf@hotmail.com

Circulating tumor markers have been paid more attention in the application of the treatment for breast cancer, the level of which has extended from protein to gene, including traditional tumor markers, HER-2 extracellular domain, circulating tumor cells, circulating tumor DNA (ctDNA), circulating RNA (ctRNA) and so on. As “l(fā)iquid detection”, the detection of circulating tumor markers with real-time dynamic, easy operation, good reproducibility and other advantages are widely used in aiding early diagnosis, determining prognosis, prospectively predicting response or resistance to speci fic therapies, surveillance after primary surgery, and monitoring therapy in patients with advanced disease, The further study of circulating tumor markers may contribute to patient’s individual treatment.

Breast cancer; CA15-3; Carcino-embryonic antigen; Extracellular domain; Circulating tumor cells; Circulating tumor DNA; Circulating tumor RNA

10.3969/j.issn.1007-3969.2014.08.014

R737.9

A

1007-3639(2014)08-0636-05

2014-02-08

2014-07-05）

江澤飛 E-mail:jiangzf@hotmail.com