精準(zhǔn)醫(yī)學(xué)背景下CTC檢測(cè)的應(yīng)用

高陽(yáng)張景春康熙雄

1 首都醫(yī)科大學(xué)附屬北京天壇醫(yī)院 首都醫(yī)科大學(xué)檢驗(yàn)診斷學(xué)系 （北京 100020）

2 杭州華得森生物技術(shù)有限公司 （浙江 杭州 310051）

3 吉林大學(xué)附屬中日聯(lián)誼醫(yī)院 （吉林 長(zhǎng)春 130033）

精準(zhǔn)醫(yī)學(xué)背景下CTC檢測(cè)的應(yīng)用

高陽(yáng)1,2張景春3康熙雄1

1 首都醫(yī)科大學(xué)附屬北京天壇醫(yī)院 首都醫(yī)科大學(xué)檢驗(yàn)診斷學(xué)系 （北京 100020）

2 杭州華得森生物技術(shù)有限公司 （浙江 杭州 310051）

3 吉林大學(xué)附屬中日聯(lián)誼醫(yī)院 （吉林 長(zhǎng)春 130033）

精準(zhǔn)醫(yī)學(xué)是隨著科學(xué)技術(shù)不斷發(fā)展，人們對(duì)健康需求的不斷提高，而逐漸興起的新的醫(yī)療理念和模式，主要基于分子病理醫(yī)學(xué)和最先進(jìn)的醫(yī)學(xué)檢測(cè)技術(shù)，通過對(duì)患者進(jìn)行基因組、轉(zhuǎn)錄組、蛋白組、表觀遺傳學(xué)、分子影像學(xué)和分子病理學(xué)檢測(cè)，結(jié)合患者病例病理信息，為患者制定針對(duì)個(gè)體疾病特征的最優(yōu)化治療方案，以追求最大的治療效果和最低毒副作用。腫瘤精準(zhǔn)醫(yī)學(xué)的發(fā)展方向之一就是無創(chuàng)診療，其中液體活檢愈來愈受醫(yī)療診斷業(yè)界關(guān)注，液體活檢通過無創(chuàng)方式檢測(cè)體液（主要為外周血、唾液、尿液、胸腹腔積液等）中的循環(huán)腫瘤細(xì)胞（CTC）、循環(huán)腫瘤DNA（ctDNA）、外泌體（Exsome）等腫瘤來源的生物標(biāo)志物，動(dòng)態(tài)反應(yīng)腫瘤的疾病進(jìn)展，為腫瘤的早期診斷、預(yù)后評(píng)估、療效監(jiān)測(cè)、復(fù)發(fā)轉(zhuǎn)移檢測(cè)、實(shí)時(shí)動(dòng)態(tài)監(jiān)測(cè)和個(gè)體化診療等，為腫瘤診療提供了一種簡(jiǎn)便快捷的手段。

精準(zhǔn)醫(yī)學(xué) 液體活檢 循環(huán)腫瘤細(xì)胞

隨著基因檢測(cè)等新技術(shù)的飛速發(fā)展，越來越多的精準(zhǔn)醫(yī)學(xué)、精準(zhǔn)醫(yī)療診斷產(chǎn)品涌入臨床檢驗(yàn)，這種通過各種高端檢測(cè)技術(shù)，實(shí)現(xiàn)個(gè)性化診療的手段，已經(jīng)被大家所認(rèn)識(shí)并接受。但在全民提倡的精準(zhǔn)醫(yī)學(xué)背景下，所謂的精準(zhǔn)技術(shù)、精準(zhǔn)服務(wù)到底體現(xiàn)在哪里，如何去實(shí)現(xiàn)，是每個(gè)醫(yī)療專業(yè)人員十分關(guān)心的問題。精準(zhǔn)醫(yī)療是一個(gè)被賦予了很多期望并可能改變醫(yī)療認(rèn)知的新興領(lǐng)域，雖然探索之路還面臨很多困難，但希望研究者可以利用現(xiàn)有迅速發(fā)展的技術(shù)平臺(tái)，不斷積累健康數(shù)據(jù)，覆蓋更多的醫(yī)療和健康領(lǐng)域。

1.精準(zhǔn)醫(yī)療應(yīng)用的主要領(lǐng)域

根據(jù)應(yīng)用范圍來看，可以總結(jié)為四大領(lǐng)域：①與新生兒相關(guān)的疾病領(lǐng)域，如體外受精的卵母細(xì)胞選擇、孕婦產(chǎn)前診斷、新生兒先天性代謝、先天性免疫缺陷、單基因遺傳等疾病的篩查；②對(duì)人的分型，過去用ABO血型和肝臟移植的HLA分型，現(xiàn)在可以通過基因測(cè)序進(jìn)行藥物代謝分型，把人群分為快、中、慢幾種代謝類型等；③生物藥物、可提前篩查抗體藥物的適用人物；④在腫瘤的篩查，診斷和評(píng)價(jià)上進(jìn)行精細(xì)的指導(dǎo)治療。

2.循環(huán)腫瘤細(xì)胞（CTC）檢測(cè)起源及現(xiàn)狀

醫(yī)學(xué)檢驗(yàn)已成為一門學(xué)科，在臨床診斷中起著決定性的指導(dǎo)作用。一些精準(zhǔn)醫(yī)療產(chǎn)品也層出不窮。目前，臨床應(yīng)用最多的是基于循環(huán)腫瘤細(xì)胞（Circulating Tumor Cell，CTC）和ctDNA的精準(zhǔn)診療檢測(cè)產(chǎn)品。在1896年，澳大利亞學(xué)者Ashworth發(fā)現(xiàn)血液中存在的一些血細(xì)胞同尸檢發(fā)現(xiàn)的腫瘤細(xì)胞相似，首次提出CTC的概念[1]。CTC目前定義為自發(fā)或因診療操作由實(shí)體瘤或轉(zhuǎn)移灶釋放進(jìn)入外周血循環(huán)的腫瘤細(xì)胞。進(jìn)入循環(huán)的腫瘤細(xì)胞絕大多數(shù)在短期內(nèi)死亡，只有極少數(shù)具有高度活力、高度轉(zhuǎn)移潛能的腫瘤細(xì)胞在循環(huán)系統(tǒng)中存活下來，相互聚集形成微小癌栓，并在一定條件下發(fā)展為轉(zhuǎn)移灶，也就是腫瘤可怕的血行轉(zhuǎn)移和復(fù)發(fā)。

很多研究證明，外周血CTC存在于乳腺癌、肺癌、前列腺癌、結(jié)直腸癌、胃癌和卵巢癌等多種惡性腫瘤中，與患者的臨床分期、無進(jìn)展生存期、總生存期、藥物療效以及早期復(fù)發(fā)和轉(zhuǎn)移均密切相關(guān)，對(duì)外周血中CTC的檢測(cè)有助于早期發(fā)現(xiàn)腫瘤的微轉(zhuǎn)移、監(jiān)測(cè)術(shù)后復(fù)發(fā)、評(píng)估療效及預(yù)后，以及選擇合適的個(gè)體化治療[2-39]。因而這種檢測(cè)技術(shù)有望成為實(shí)時(shí)的“液體活檢”，已備受關(guān)注。

由于CTC在血液中的比例極少（幾十萬分之一），則對(duì)于CTC富集方面是需要攻克的難題。目前CTC富集方法主要有免疫磁性分離法和基于形態(tài)學(xué)的富集法。前者的白血球污染問題，而后者由于腫瘤細(xì)胞的大小沒有定義，所以其分離靈敏性受到質(zhì)疑。采用流式分選也可得到CTC，但由于細(xì)胞在流式分選系統(tǒng)中承受的各種外力導(dǎo)致細(xì)胞損傷，沒有活性。如何有效地富集到高純度、有活性的CTC成為了一個(gè)重大挑戰(zhàn)！

美國(guó)FDA于2004年認(rèn)證了CTC檢測(cè)技術(shù)的第一款上市設(shè)備美國(guó)上市公司強(qiáng)生的CellSearch分析系統(tǒng)，并分別在2004年、2007年和2008年批準(zhǔn)采用CellSearch檢測(cè)系統(tǒng)用于轉(zhuǎn)移性乳腺癌、轉(zhuǎn)移性結(jié)直腸癌及轉(zhuǎn)移性前列腺癌的預(yù)后評(píng)估，無進(jìn)展生存（PFS）期和總生存（OS）期的預(yù)測(cè)，拉開了全球CTC的臨床研究和應(yīng)用的序幕。其中CTC細(xì)胞計(jì)數(shù)是目前唯一獲得FDA認(rèn)證的CTC臨床應(yīng)用領(lǐng)域，可以作為臨床上乳腺癌、前列腺癌以及腸癌的輔助診斷指標(biāo)之一。

2012年8月，中國(guó)國(guó)家食品藥品監(jiān)督管理局（CFDA）正式批準(zhǔn)CellSearch CTC檢測(cè)與分析系統(tǒng)用于轉(zhuǎn)移性乳腺癌患者的預(yù)后分析，這是中國(guó)首次批準(zhǔn)CTC檢測(cè)進(jìn)入臨床應(yīng)用。目前，CTC檢測(cè)在基礎(chǔ)臨床研究及臨床應(yīng)用方面得到越來越多的重視。

國(guó)內(nèi)各省腫瘤醫(yī)院、大型綜合性三甲醫(yī)院和部分二甲以上的醫(yī)院都已經(jīng)開展CTC檢測(cè)，或正籌備開展CTC臨床檢測(cè)服務(wù)和各種科研應(yīng)用。CTC檢測(cè)是一種安全可靠的被美國(guó)FDA批準(zhǔn)的癌癥臨床輔助診斷手段。CellSearch CTC檢測(cè)儀器和試劑雖搶占了先機(jī)，但隨著臨床單位對(duì)CTC檢測(cè)方法及結(jié)果的更高要求，對(duì)后續(xù)的精準(zhǔn)治療方面有著更深的需求下，中國(guó)國(guó)內(nèi)其他相關(guān)檢測(cè)儀器和試劑隨著注冊(cè)臨床試驗(yàn)的進(jìn)行，已經(jīng)陸續(xù)取得了CFDA的注冊(cè)認(rèn)可。未來更先進(jìn)和小巧的CTC檢測(cè)儀器將踴躍出現(xiàn)，后來居上，搶占市場(chǎng)。CTC檢測(cè)將會(huì)在中國(guó)得到越來越多的重視，并迎來更加廣闊的臨床及科研應(yīng)用前景，

雖然CTC已被FDA批準(zhǔn)應(yīng)用于轉(zhuǎn)移性乳腺癌、轉(zhuǎn)移性直結(jié)腸癌、轉(zhuǎn)移性前列腺癌的檢測(cè)，其臨床應(yīng)用仍然面臨諸多挑戰(zhàn)。各實(shí)驗(yàn)室CTC分析方法和結(jié)果解讀的標(biāo)準(zhǔn)化是亟需解決的問題。

3.國(guó)內(nèi)市場(chǎng)主要CTC檢測(cè)平臺(tái)

在國(guó)內(nèi)市場(chǎng)上，已有多家公司推廣了CTC檢測(cè)平臺(tái)，見表1。

目前國(guó)內(nèi)已有上百家醫(yī)院開展了CTC檢測(cè)項(xiàng)目，如中國(guó)人民解放軍第三〇七醫(yī)院，復(fù)旦大學(xué)附屬腫瘤醫(yī)院，中山大學(xué)附屬孫逸仙紀(jì)念醫(yī)院，天津腫瘤醫(yī)院等醫(yī)院，以及湖北省同濟(jì)醫(yī)院、協(xié)和醫(yī)院、武漢大學(xué)中南醫(yī)院、江漢大學(xué)實(shí)驗(yàn)室等。

4.CTC檢測(cè)的價(jià)值及前景

CTC檢測(cè)具有良好的社會(huì)效益和經(jīng)濟(jì)效益，是腫瘤?？漆t(yī)院不可或缺的檢驗(yàn)檢測(cè)項(xiàng)目。該技術(shù)的全球市場(chǎng)2012年達(dá)到近28億美元的規(guī)模，2013年達(dá)到37億美元。今后該市場(chǎng)以年復(fù)合成長(zhǎng)率18.9%的速度增長(zhǎng)，預(yù)計(jì)2018年將達(dá)到89億美元的規(guī)模。

目前，國(guó)內(nèi)各省市對(duì)于CTC檢測(cè)尚無明確醫(yī)療服務(wù)收費(fèi)標(biāo)準(zhǔn)，現(xiàn)階段各省多數(shù)定價(jià)無法統(tǒng)一，而且收費(fèi)較高。據(jù)悉，浙江省已開展CTC檢測(cè)的醫(yī)療檢測(cè)機(jī)構(gòu)的服務(wù)收費(fèi)為6240元/測(cè)試，上海CTC檢測(cè)服務(wù)收費(fèi)為4800元/測(cè)試左右，個(gè)別省市CTC檢測(cè)服務(wù)收費(fèi)為4600元/測(cè)試左右。未來CTC在臨床應(yīng)用還需要多方面的努力才能順利普及開展。

從宏觀的角度分析精準(zhǔn)醫(yī)學(xué)，應(yīng)該體現(xiàn)在檢測(cè)平臺(tái)、醫(yī)療數(shù)據(jù)平臺(tái)、分子病理平臺(tái)、臨床科研平臺(tái)多方面發(fā)展，發(fā)現(xiàn)更多的如KRAS/EGFR等個(gè)體化基因標(biāo)志物，希望通過臨床的開展，大數(shù)據(jù)的算法，對(duì)疾病的發(fā)生發(fā)展規(guī)律或者個(gè)體健康和疾病進(jìn)行預(yù)測(cè)，甚至開拓新的醫(yī)學(xué)預(yù)測(cè)學(xué)科建設(shè)。隨著國(guó)家政策對(duì)精準(zhǔn)醫(yī)學(xué)的扶持，希望新的檢測(cè)技術(shù)能為精準(zhǔn)醫(yī)學(xué)在臨床的應(yīng)用提供更多更廣的空間。

表1. 國(guó)內(nèi)宣傳CTC項(xiàng)目及平臺(tái)的部分廠家

表2. 部分已開展CTC檢測(cè)的醫(yī)療檢測(cè)機(jī)構(gòu)

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Application of CTC Detection in Precision Medical Background

GAO Yang1,2ZHANG Jing-chun3KANG Xi-xiong1
1 Capital Medical University Beijing Tiantan Hospital Laboratory Diagnosis Department (Beijing 100020)
2 Hangzhou Waston Biotech. INC (Zhejiang Hangzhou 310051)
3 Jilin Univercity China-Japan Fellowship Hospital (Jilin Changchun 130033)

Precision medicine is a new medical concepts and models, which gradual rise with the continuous development of science and technology, and the people's health needs. It mainly based on molecular pathology and the most advanced medical testing technology, through the genomics, proteomics, epigenetics, molecular imaging and molecular pathology, combined with patient case and pathology information, for patients with the development of individual disease for the characteristics of the optimal treatment program, to pursue the greatest therapeutic effect and the lowest side effects. One of the directions of development of tumor precision medicine is noninvasive diagnosis, in which liquid biopsy is increasingly concerned by the medical diagnosis. Liquid biopsy provides a simple and quick means for cancer diagnosis and treatment, by detecting the circulating tumor cell (CTC), circulating tumor DNA (ctDNA), exosomes and other tumor-derived biomarkers, which come from body fuids (mainly peripheral blood, saliva, urine, pleural effusion, etc.), in a relatively noninvasive way, dynamic response of tumor disease progression, for the early diagnosis of cancer, prognosis evaluation, effcacy monitoring, recurrence and metastasis detection, real-time dynamic monitoring and individual diagnosis and treatment.

precision medicine, liquid biopsy, circulating tumor cell (CTC)

1006-6586(2017)11-0014-04

R197.39

A

2017-04-18