肖 毅 江一舟 邵志敏

(1復(fù)旦大學(xué)附屬腫瘤醫(yī)院乳腺外科 上海 200032; 2復(fù)旦大學(xué)腫瘤研究所 上海 200032)

專家簡(jiǎn)介邵志敏,首批教育部長(zhǎng)江學(xué)者特聘教授,國家杰出青年基金獲得者,復(fù)旦大學(xué)特聘教授。現(xiàn)任復(fù)旦大學(xué)腫瘤研究所長(zhǎng)、乳腺癌研究所所長(zhǎng),大外科主任兼乳腺外科主任,中國抗癌協(xié)會(huì)乳腺癌專業(yè)委員會(huì)名譽(yù)主委,中華醫(yī)學(xué)會(huì)腫瘤學(xué)分會(huì)副主任委員,上海市抗癌協(xié)會(huì)乳腺癌專業(yè)委員會(huì)名譽(yù)主任委員,上海市醫(yī)學(xué)會(huì)腫瘤?？莆瘑T會(huì)主任委員,第八屆亞洲乳腺癌協(xié)會(huì)主席、St.Gallen乳腺癌大會(huì)專家團(tuán)成員。主要從事乳腺癌的臨床和基礎(chǔ)研究,建立適合中國人群的早期篩查和診療流程,開展臨床試驗(yàn)提高乳腺癌患者的預(yù)后,科研重點(diǎn)為乳腺癌的轉(zhuǎn)化研究和乳腺癌轉(zhuǎn)移機(jī)制研究等。已發(fā)表有關(guān)乳腺癌研究的論著近350篇,其中SCI收錄100余篇,被世界醫(yī)學(xué)文獻(xiàn)引用逾3 000次,主編專著4本。并多次獲得衛(wèi)生部科技進(jìn)步一等獎(jiǎng),上海市科技進(jìn)步一、二、三等獎(jiǎng),國家科技進(jìn)步二等獎(jiǎng),教育部科技進(jìn)步一、二等獎(jiǎng),領(lǐng)銜團(tuán)隊(duì)分別入選教育部創(chuàng)新團(tuán)隊(duì),上海市乳腺腫瘤重點(diǎn)實(shí)驗(yàn)室及上海市教委“重中之重臨床醫(yī)學(xué)中心B類”項(xiàng)目、上海市重要疾病聯(lián)合攻關(guān)項(xiàng)目。先后主持國家杰青基金、國自然、十五攻關(guān)課題,衛(wèi)生部臨床重點(diǎn)項(xiàng)目、211工程II、985、973課題及其他省部級(jí)項(xiàng)目30余項(xiàng)。

上海醫(yī)學(xué)院創(chuàng)建90周年寄語雄關(guān)漫道真如鐵,而今邁步從頭越。祝上醫(yī)在新的90年中再創(chuàng)輝煌！

乳腺癌的精準(zhǔn)醫(yī)學(xué)研究

肖 毅1,2江一舟1,2邵志敏1,2△

(1復(fù)旦大學(xué)附屬腫瘤醫(yī)院乳腺外科 上海 200032;2復(fù)旦大學(xué)腫瘤研究所 上海 200032)

乳腺癌是最常見的女性惡性腫瘤,近年來在我國發(fā)病率逐年上升。循證醫(yī)學(xué)在乳腺癌的綜合治療領(lǐng)域取得了豐碩成果,奠定了乳腺癌規(guī)范化治療的基礎(chǔ)。精準(zhǔn)醫(yī)學(xué)則為乳腺癌更加精細(xì)化、個(gè)體化的治療提供了契機(jī)。多組學(xué)研究、ctDNA研究、腫瘤內(nèi)部異質(zhì)性研究和腫瘤與微環(huán)境交互作用的研究是乳腺癌精準(zhǔn)治療領(lǐng)域具有廣闊前景的研究方向。

乳腺癌; 精準(zhǔn)醫(yī)學(xué); 組學(xué)

乳腺癌是目前全球范圍內(nèi)最常見的女性惡性腫瘤[1],2012年全球新增乳腺癌病例170萬例,因乳腺癌死亡病例52.2萬例,居女性癌癥死因第2位[2]。在中國,隨著社會(huì)經(jīng)濟(jì)的發(fā)展和人民生活方式的改變,乳腺癌發(fā)病率逐年上升,在大中城市尤為突出[3]。乳腺癌同時(shí)也是一類被深入研究并具有精確管控前景的疾病[1,4]?；诒磉_(dá)譜信息,乳腺癌可被分為L(zhǎng)uminal A、Luminal B、HER2過表達(dá)和Basal-like型,各亞型具有其特異性腫瘤生物學(xué)特征[5-6]。在循證醫(yī)學(xué)時(shí)代,隨著“乳腺癌是一種全身性疾病”理念的提出和臨床試驗(yàn)的進(jìn)行,基于免疫組化分型對(duì)患者進(jìn)行手術(shù)、放療、內(nèi)分泌治療、化療或靶向治療已取得豐碩成果,奠定了乳腺癌“分類而治”的基礎(chǔ)[1,4]。盡管如此,循證醫(yī)學(xué)時(shí)代對(duì)乳腺癌的管理模式仍顯得相對(duì)粗放,對(duì)遠(yuǎn)期復(fù)發(fā)風(fēng)險(xiǎn)高的Luminal型乳腺癌、曲妥珠單抗耐藥的HER2陽性乳腺癌及三陰性乳腺癌(triple-negative breast cancer,TNBC)這三類“難治性乳腺癌”的管控仍然十分有限[7-9]。2011年“精準(zhǔn)醫(yī)學(xué)”理念的提出則為更加個(gè)體化的治療乳腺癌提供了新的機(jī)遇。

循證醫(yī)學(xué)時(shí)代的乳腺癌治療David Sackett于20世紀(jì)90年代初提出循證醫(yī)學(xué)(evidence-based medicine ,EBM)的概念,其目的是將臨床及基礎(chǔ)實(shí)驗(yàn)證據(jù)與醫(yī)師的臨床經(jīng)驗(yàn)及患者的體驗(yàn)有機(jī)結(jié)合,最終應(yīng)用于臨床,為患者提供最科學(xué)的治療[10]。循證醫(yī)學(xué)深刻地改變了乳腺癌的臨床實(shí)踐。

手術(shù)治療 乳腺癌的手術(shù)策略經(jīng)歷了由小到大再變小的過程。手術(shù)方式從最初的腫塊切除術(shù)逐漸增大到根治術(shù)甚至擴(kuò)大根治術(shù),再逐漸縮小至保乳手術(shù)及部分患者以前哨淋巴結(jié)活檢術(shù)(sentinel lymph node biopsy,SLNB)替代腋窩淋巴結(jié)清掃術(shù)。循證醫(yī)學(xué)在這一過程中發(fā)揮了重要作用。在乳房手術(shù)方式的選擇上,NSABP B-04臨床試驗(yàn)證實(shí)了對(duì)腋窩淋巴結(jié)陰性患者行乳房單純切除術(shù)可取得與根治術(shù)相似的生存結(jié)局,開啟了乳腺癌手術(shù)縮小化的序幕[11]。此后,NSABP B-06臨床試驗(yàn)進(jìn)一步證實(shí)了保乳手術(shù)在Ⅰ/Ⅱ期患者中的可行性,實(shí)現(xiàn)了乳腺癌手術(shù)范圍的進(jìn)一步縮小[12]。SLNB的引入則是循證醫(yī)學(xué)在乳腺癌外科領(lǐng)域的另一重要進(jìn)展。NSABP B-32臨床試驗(yàn)顯示,為臨床腋窩淋巴結(jié)陰性患者行SLNB以替代腋窩淋巴結(jié)清掃術(shù)成功率高、生存相仿、且并發(fā)癥更少[13-15]。目前SLNB已在臨床廣泛開展。

放療 放療的加入也充分體現(xiàn)了循證醫(yī)學(xué)的智慧。用于探究保乳手術(shù)療效的一系列臨床試驗(yàn)(如NSABP B-06、Milan和EORTC)發(fā)現(xiàn),保乳手術(shù)加術(shù)后放療與僅行保乳相比,可顯著降低局部和區(qū)域淋巴結(jié)復(fù)發(fā)率,且生存結(jié)局與全乳切除術(shù)類似[16-17]。在乳房全切后高危的患者(如腫瘤大于5 cm,陽性腋窩淋巴結(jié)大于3枚)中,DBCG 82b 和82c臨床試驗(yàn)及2005年EBCTCG的Meta分析均提示,全乳切除術(shù)后放療可提高局部控制率及生存率[18]。保乳術(shù)后行放療和全乳切除術(shù)后高?；颊咝蟹暖熅殉蔀镹CCN指南推薦的標(biāo)準(zhǔn)治療方案。

全身治療 “乳腺癌一經(jīng)發(fā)生即是全身性疾病”觀念的提出促進(jìn)了全身輔助治療的發(fā)展。而循證醫(yī)學(xué)在藥物選擇、服藥時(shí)間、藥物劑量等方面均發(fā)揮了巨大作用[19]。

在內(nèi)分泌治療領(lǐng)域,1983年發(fā)布的NATO臨床試驗(yàn)開啟了循證醫(yī)學(xué)在內(nèi)分泌治療領(lǐng)域的探索。對(duì)于絕經(jīng)前激素受體陽性的患者,NSABP B-14臨床試驗(yàn)和1998年EBETCG的Meta分析證實(shí)了服用5年他莫昔芬對(duì)于降低復(fù)發(fā)、延長(zhǎng)生存的作用,2011年EBETCG的Meta分析則進(jìn)一步提出了5年后繼續(xù)用藥的必要性[20-22]。此外,SOFT和TEXT臨床試驗(yàn)的聯(lián)合分析指出,部分高?；颊呒佑寐殉补δ芤种颇苓M(jìn)一步獲益[23]。對(duì)于絕經(jīng)后激素受體陽性的患者,ATAC、MA.17、BIG I-98和ATLAS等臨床試驗(yàn)則對(duì)芳香化酶抑制劑的地位予以肯定,并對(duì)其使用時(shí)長(zhǎng)、與他莫昔芬配合使用時(shí)序予以說明[24-27]。近年來,氟維司群、mTOR抑制劑、CDK4/6抑制劑等藥物在激素受體陽性的復(fù)發(fā)轉(zhuǎn)移性乳腺癌中的作用也相繼被臨床試驗(yàn)證實(shí)[7]。

在靶向治療領(lǐng)域,將曲妥珠單抗用于治療HER2陽性乳腺癌是循證醫(yī)學(xué)領(lǐng)域里程碑式的成果。NSABP B-31和NCCTG N9831臨床試驗(yàn)聯(lián)合分析顯示使用曲妥珠單抗1年可以顯著提高HER2陽性乳腺癌患者的生存率[28-29]。近年來的研究提出曲妥珠單抗與帕妥珠單抗在新輔助治療階段和復(fù)發(fā)轉(zhuǎn)移階段聯(lián)用可以進(jìn)一步提高療效,而TDM-1也經(jīng)由MARIANNE臨床實(shí)驗(yàn)證實(shí)被列入復(fù)發(fā)轉(zhuǎn)移型HER2陽性乳腺癌二線治療方案[8]。

在化療領(lǐng)域,1976年首次證實(shí)CMF方案可以提高乳腺癌患者的生存率,確立了輔助化療在乳腺癌全身治療的地位[30]。此后,NSABP B-15臨床試驗(yàn)和EBCTCG Meta分析證實(shí)含蒽環(huán)類藥物的方案優(yōu)于CMF方案,奠定了蒽環(huán)類藥物的“基石”地位,并進(jìn)一步探索了多柔比星和表柔比星的最佳使用劑量[31-34]。紫杉類藥物的加入則主要?dú)w功于CALGB9344、NSABP B-28和BCIRG 001臨床試驗(yàn)[33,35-36]。近年來,以卡培他濱為代表的抗代謝藥物、以長(zhǎng)春瑞濱為代表的非紫杉醇類微管形成抑制劑在復(fù)發(fā)轉(zhuǎn)移型乳腺癌中的療效也得到臨床試驗(yàn)的印證,其中吉西他濱療效的確認(rèn)是中國專家作出的重要貢獻(xiàn)[37]。此外,在給藥周期的研究中,CALGB 9741證實(shí)對(duì)于淋巴結(jié)陽性患者,在G-CFS的支持治療下,2周方案比3周生存獲益更大,從而動(dòng)搖了3周化療方案的地位[38]。循證醫(yī)學(xué)也為近年來蓬勃發(fā)展的新輔助化療提供了依據(jù)。自NSABP B-18臨床試驗(yàn)首次證實(shí)新輔助化療可以提高保乳率,并達(dá)到與輔助化療相似的生存結(jié)局開始,多項(xiàng)臨床試驗(yàn)探索了蒽環(huán)聯(lián)合紫衫、卡培他濱、卡鉑等方案在新輔助化療中的療效,為臨床治療提供了依據(jù)[39-41]。

循證醫(yī)學(xué)面臨的不足與挑戰(zhàn) 盡管循證醫(yī)學(xué)為乳腺癌的綜合治療帶來了豐碩的成果,但隨著對(duì)個(gè)體化治療的進(jìn)一步強(qiáng)調(diào),其弊端也日益顯現(xiàn)。循證醫(yī)學(xué)往往是基于大型隊(duì)列的研究得到“一刀切”的結(jié)論,過分強(qiáng)調(diào)了方法學(xué)的可靠性,而忽略了證據(jù)本身的可靠性及準(zhǔn)確性。循證醫(yī)學(xué)對(duì)個(gè)體化信息的忽略最終導(dǎo)致部分患者的過度醫(yī)療或治療不足。在強(qiáng)調(diào)個(gè)體化治療的當(dāng)下,循證醫(yī)學(xué)迫切需要注入新的內(nèi)核。

精準(zhǔn)醫(yī)療時(shí)代乳腺癌的研究進(jìn)展精準(zhǔn)醫(yī)學(xué)(precision medicine)的理念最早由美國國家科學(xué)院在2011年提出,旨在通過評(píng)估患者的組學(xué)信息,建立新的知識(shí)網(wǎng)絡(luò),促進(jìn)生物醫(yī)學(xué)研究及其與臨床研究,最終制定個(gè)體化的治療方案[42]。

乳腺癌分子分型的發(fā)展 2000年,Perou等基于8 102個(gè)基因的表達(dá)譜數(shù)據(jù)首次將乳腺癌分為4個(gè)亞型:Luminal型、HER2過表達(dá)型、Basal-like型和Normal-like型[5]。隨后,S?rlie等[43]將Luminal型進(jìn)一步分為L(zhǎng)uminal A型和Luminal B型,并指出每種分子分型與預(yù)后密切相關(guān)。2009年,Parker等構(gòu)建50個(gè)基因組成的陣列來快速區(qū)分5種分子分型,稱為PAM50分型[44]。研究表明Normal-like型可能是測(cè)序樣本中混入較多正常組織導(dǎo)致的誤差,因此目前公認(rèn)的是其余4型,其與免疫組化分型的異同也被深入研究[45-46]。此后國際乳腺癌分子分型聯(lián)盟(Molecular Taxonomy of Breast Cancer International Consortium,METABRIC)則依據(jù)表達(dá)譜和拷貝數(shù)變異譜將乳腺癌分成10類,并深入闡述了每一類別的多組學(xué)特征[47]。盡管METABRIC的分類模式并未被應(yīng)用于臨床,其從多組學(xué)角度探究乳腺癌特征的思路已成為未來研究的方向。

在TNBC的分子分型領(lǐng)域,2011年Lehmann等基于表達(dá)譜信息首先提出6分類模式,分別是基底細(xì)胞樣1(basal-like 1,BL1)、基底細(xì)胞樣2(basal-like 2,BL2)、免疫調(diào)節(jié)型(immunomodulary,IM)、間充質(zhì)型(mesenchymal,M)、間充質(zhì)干細(xì)胞型(mesenchymal stem-like,MSL)和雄激素依賴型(luminal androgen receptor,LAR)[48]。2015年Burstein等則提出了4分類模式,即基底細(xì)胞樣免疫抑制型(basal-like immunosuppressed,BLIS)、基底細(xì)胞樣免疫激活型(basal-like immune-activated,BLIA)、間充質(zhì)型(mesenchymal,M)和雄激素依賴型(luminal androgen receptor,LAR),并從多組學(xué)角度探索各亞型的分子特征[49]。2017年,本中心基于mRNA-lncRNA表達(dá)信息將TNBC劃分為4個(gè)亞群,即基底細(xì)胞樣免疫抑制型(basal-like immunosuppressed,BLIS)、免疫調(diào)節(jié)型(immunomodulary,IM)、間充質(zhì)型(mesenchymal-like,MES)和雄激素依賴型(luminal androgen receptor,LAR)[50]。

針對(duì)Luminal型乳腺癌遠(yuǎn)期復(fù)發(fā)風(fēng)險(xiǎn)和耐藥的探索 Luminal型乳腺癌是一類存在遠(yuǎn)期復(fù)發(fā)的疾病,且復(fù)發(fā)風(fēng)險(xiǎn)在患者間存在明顯異質(zhì)性。因此,挑選出高危人群強(qiáng)化治療,避免對(duì)低危人群進(jìn)行過度醫(yī)療是精準(zhǔn)醫(yī)學(xué)在Luminal型乳腺癌領(lǐng)域的重要研究方向。2002年Agendia等通過表達(dá)譜數(shù)據(jù)構(gòu)建了包含70個(gè)基因的模型——MammaPrint用于預(yù)測(cè)淋巴結(jié)陰性、腫瘤小于5 cm、Ⅰ/Ⅱ期乳腺癌的預(yù)后,已被FDA批準(zhǔn)用于臨床[51]。此后陸續(xù)發(fā)布的76基因陣列和GGI指數(shù)等均在回顧性研究中證實(shí)有預(yù)測(cè)ER陽性患者預(yù)后的作用[52-53]。2004年P(guān)aik等提出的Oncotype DX評(píng)分則是預(yù)測(cè)Luminal型乳腺癌復(fù)發(fā)風(fēng)險(xiǎn)和化療敏感性的突出成果。通過對(duì)ER陽性患者石蠟包埋組織中21個(gè)基因qPCR檢測(cè),Oncotype DX評(píng)分將患者復(fù)發(fā)風(fēng)險(xiǎn)劃分為高、中、低危組,其預(yù)測(cè)效果先后在多項(xiàng)臨床試驗(yàn)中驗(yàn)證,目前已被寫入NCCN指南[54]。盡管如此,由于目前預(yù)測(cè)復(fù)發(fā)風(fēng)險(xiǎn)的評(píng)分系統(tǒng)缺乏前瞻性臨床試驗(yàn)結(jié)論,多為依靠經(jīng)驗(yàn)挑選的、與增殖相關(guān)的基因陣列,對(duì)其臨床應(yīng)用仍需謹(jǐn)慎。此外,內(nèi)分泌耐藥是激素受體陽性乳腺癌治療失敗的首要原因。通過多組學(xué)分析,研究人員相繼揭示了cyclin D-CDK4或 CDK6-RB信號(hào)通路異常、PI3K/AKT1/mTOR信號(hào)通路激活等在Luminal型乳腺原發(fā)或激發(fā)耐藥中的作用,并通過PALOMA-3、TAMRAD和BELLE2等臨床試驗(yàn)對(duì)CDK4/6抑制劑、mTOR抑制劑、PI3K抑制劑的聯(lián)合用藥效果予以證實(shí)[7]。

克服HER2過表達(dá)型乳腺癌耐藥的嘗試 盡管抗HER2治療的臨床應(yīng)用帶來了巨大獲益,其較為嚴(yán)重的耐藥問題也格外值得關(guān)注。目前研究表明,抗HER2治療耐藥的機(jī)制主要可分為以下幾個(gè)方面:首先,HER家族基因及其配體的超高表達(dá)[55]。其次,HER2蛋白本身結(jié)構(gòu)改變降低了與藥物結(jié)合的親和力。如HER2基因翻譯起始位點(diǎn)可以被金屬蛋白酶水解而丟失胞外段,造成無法與曲妥珠單抗結(jié)合和下游通路的持續(xù)激活[56]。而ERBB2基因的突變則通過改變HER2蛋白的結(jié)構(gòu)導(dǎo)致其與藥物親和力的下降引發(fā)耐藥[57]。如本中心的研究發(fā)現(xiàn)ERBB2基因K753E位點(diǎn)突變是導(dǎo)致拉帕替尼耐藥的機(jī)制之一[58]。第三,HER2下游通路的持續(xù)激活及其與其他通路的交互作用影響了抗HER2治療的敏感性。如PI3K/AKT1/mTOR信號(hào)通路的激活、HER2信號(hào)通路與IGF-1R和Src信號(hào)通路的交互影響降低了抗HER2治療的敏感性[57]。多項(xiàng)探索帕妥珠單抗(抑制HER2異源二聚體形成)、T-DM1(靶向結(jié)合后發(fā)揮化療療效)、PI3K抑制劑(抑制PI3K/AKT1/mTOR信號(hào))和來那替尼(另一種酪氨酸激酶抑制劑)等在克服抗HER2治療耐藥中療效的臨床試驗(yàn)已經(jīng)開展[8]。

三陰乳腺癌藥物靶點(diǎn)的尋覓 三陰乳腺癌(triple negative breast cancer,TNBC)是一類惡性程度很高的疾病,高侵襲性、高異質(zhì)性和缺乏藥物靶點(diǎn)是造成其預(yù)后不良的主要因素。TNBC個(gè)體對(duì)傳統(tǒng)化療的敏感性差異很大[59]。在精準(zhǔn)醫(yī)療時(shí)代,以TNBC分子分型為基礎(chǔ)對(duì)其藥物靶點(diǎn)進(jìn)行了探索。含鉑類藥物的新輔助方案已被GeparSixto和CALGB 40603等臨床試驗(yàn)證實(shí)在基因組不穩(wěn)定性較高的TNBC(如基底樣亞型或BRCA1/2突變)中顯著提高pCR[60-61]。此外,針對(duì)BRCA1/2胚系突變的患者聯(lián)用鉑類和PARP抑制劑可抑制腫瘤進(jìn)展[62]。雄激素依賴亞型的TNBC往往伴有PI3K通路的激活,聯(lián)用雄激素受體阻斷劑和PI3K抑制劑可能發(fā)揮更好的療效[9]。而在免疫調(diào)節(jié)亞型的TNBC中,由于免疫抑制基因如PD-1、PD-L1和CTLA-4表達(dá)高,免疫檢查點(diǎn)抑制劑可能具有應(yīng)用前景[63]。針對(duì)VEGF、PIK3CA等的靶向藥物也在TNBC中具有一定聯(lián)合用藥前景[64-65]。此外,在TNBC化療耐藥領(lǐng)域,本中心研究發(fā)現(xiàn)紫杉新輔助化療可使TNBC患者富集TEKT4突變,TEKT4突變可通過降低微管穩(wěn)定性,抵抗紫杉醇穩(wěn)定微管的作用,導(dǎo)致引起紫杉醇耐藥。因此TEKT4突變型TNBC可能對(duì)微管解聚劑(如長(zhǎng)春瑞濱)敏感[66]。該研究的轉(zhuǎn)化臨床試驗(yàn)正在進(jìn)行中,將為TNBC的精準(zhǔn)治療提供新的依據(jù)。

精準(zhǔn)醫(yī)療背景下乳腺癌診療的發(fā)展方向

多組學(xué)分子圖譜的繪制 多組學(xué)研究的發(fā)展提供了從基因組學(xué)角度深入理解乳腺癌進(jìn)展機(jī)制的契機(jī)。2012年是乳腺癌組學(xué)研究史上具有里程碑式意義的一年。美國癌癥基因組圖譜(The Cancer Genome Atlas Network,TCGA)工作組和國際乳腺癌分子分型聯(lián)盟(METABRIC)首次繪制了乳腺癌的多組學(xué)圖譜[67-68]。研究表明乳腺癌是一類突變負(fù)荷較低但以拷貝數(shù)變異為主要特征的腫瘤。ER陽性的Luminal型乳腺癌具有高頻突變多(如PIK3CA、CDH1、MAP3K1和GATA3)、個(gè)體突變負(fù)荷低,FOXA1/ER復(fù)合物通路激活等特征;HER2陽性的乳腺癌ERBB2基因高度擴(kuò)增、高頻突變少、個(gè)體突變負(fù)荷高,并可進(jìn)一步分為L(zhǎng)uminal型和HER2過表達(dá)型;而Basal-like型乳腺癌則以TP53高頻體系突變和富集BRCA1胚系突變?yōu)樘卣鳌Ｔ诖嘶A(chǔ)上,通過原位癌與浸潤(rùn)性癌、原發(fā)灶與轉(zhuǎn)移灶、耐藥個(gè)體與敏感個(gè)體多組學(xué)層面的比較,研究者對(duì)乳腺癌的發(fā)生發(fā)展、腫瘤進(jìn)化、轉(zhuǎn)移機(jī)制和藥物靶點(diǎn)等方面進(jìn)行了探索[50,69-70]。多組學(xué)研究是未來乳腺癌科研重要的研究方向。

循環(huán)腫瘤DNA(ctDNA)的臨床轉(zhuǎn)化 ctDNA是指腫瘤細(xì)胞通過壞死、凋亡或直接分泌的方式向血液中釋放的游離DNA。由于其有創(chuàng)性小、實(shí)時(shí)動(dòng)態(tài)性佳,目前已引起臨床重視[71]。在早期診斷領(lǐng)域,ctDNA比傳統(tǒng)腫瘤標(biāo)志物具有更高的敏感性和特異性[72]。在監(jiān)測(cè)輔助治療療效方面,研究表明治療過程中ctDNA中某些特殊分子(如RASSF1A甲基化)的變化趨勢(shì)與腫瘤負(fù)荷的改變一致,證實(shí)了ctDNA在監(jiān)測(cè)療效方面的能力[73]。此外,ctDNA還可有效地預(yù)測(cè)乳腺癌患者的復(fù)發(fā)風(fēng)險(xiǎn)和提示預(yù)后[71]。而ctDNA中一些特殊基因突變頻率的升高則與耐藥密切相關(guān)。如PIK3CA基因E545K位點(diǎn)突變與紫杉醇耐藥、ESR1基因突變與他莫昔芬耐藥的相關(guān)性均已被研究證實(shí)[74-75]。盡管存在巨大的臨床應(yīng)用潛力,目前ctDNA的相關(guān)研究仍處于起步階段,精確檢測(cè)ctDNA的技術(shù)手段仍不成熟,大樣本前瞻性的臨床研究仍十分匱乏,限制了其臨床轉(zhuǎn)化。解決技術(shù)難點(diǎn)、開展大型前瞻性隊(duì)列研究是未來ctDNA研究的突破點(diǎn)。

腫瘤內(nèi)部異質(zhì)性(intratumour heterogeneity,ITH)的檢測(cè)與管理 隨著高通量測(cè)序的發(fā)展,研究者逐漸意識(shí)到不僅腫瘤間存在顯著差異,同一腫瘤病灶內(nèi)部、原發(fā)灶與轉(zhuǎn)移灶之間均存在異質(zhì)性。ITH包括時(shí)間異質(zhì)性和空間異質(zhì)性,體現(xiàn)了腫瘤在時(shí)間和空間維度的動(dòng)態(tài)進(jìn)化過程[76]。研究ITH的經(jīng)典手段是多點(diǎn)測(cè)序,然而由于其對(duì)樣本要求高、耗時(shí)長(zhǎng)、花費(fèi)大,難以開展大樣本研究。近年來,基于二代測(cè)序數(shù)據(jù)建立數(shù)學(xué)模型用于評(píng)估ITH的生物信息學(xué)技術(shù)快速發(fā)展。基于ASCAT或ABSOLUTE算法的PyClone和改進(jìn)版PyClone均已被用于ITH的評(píng)估[77-79]。評(píng)估ITH對(duì)于理解腫瘤進(jìn)化的機(jī)制、控制治療耐藥和管理ITH以限制腫瘤進(jìn)展等有重要意義[76-80]。對(duì)亞克隆突變數(shù)量、頻率和分布的分析有助于推測(cè)腫瘤進(jìn)化的方式。對(duì)耐藥亞克隆群體基線水平的評(píng)估和治療過程中變化水平的監(jiān)測(cè)(如利用ctDNA)則有助于治療方案的及時(shí)調(diào)整。而對(duì)克隆性事件的尋覓和靶向用藥則可能限制ITH水平,控制腫瘤進(jìn)展。目前ITH和腫瘤進(jìn)化領(lǐng)域的研究均處于起始階段,用于評(píng)估ITH的生物信息學(xué)工具有待優(yōu)化,分析得出的誘發(fā)ITH的驅(qū)動(dòng)分子事件缺乏實(shí)驗(yàn)證據(jù)支持。

腫瘤細(xì)胞與微環(huán)境交互影響的探索 腫瘤與微環(huán)境之間存在密切的交互作用。一方面,腫瘤細(xì)胞改變微環(huán)境以促進(jìn)其浸潤(rùn)和轉(zhuǎn)移;另一方面,微環(huán)境也深刻地改變腫瘤細(xì)胞的特征以適應(yīng)生長(zhǎng)環(huán)境[81]。腫瘤微環(huán)境由免疫細(xì)胞、成纖維細(xì)胞、細(xì)胞外基質(zhì)、肌上皮細(xì)胞等組成。目前研究較多的是免疫細(xì)胞與乳腺癌的相關(guān)性。多項(xiàng)研究表明腫瘤浸潤(rùn)淋巴細(xì)胞(tuomr-infiltrating lymphocytes,TILs)在HER2陽性乳腺癌及TNBC中與新輔助化療療效及預(yù)后密切相關(guān),但具體機(jī)制不明[82-84]。腫瘤浸潤(rùn)性免疫細(xì)胞的具體成分(如CD8+ T細(xì)胞、調(diào)節(jié)性T細(xì)胞、巨噬細(xì)胞等)在乳腺癌侵襲轉(zhuǎn)移及預(yù)測(cè)預(yù)后中的作用也已得到重視[85-87]。此外,乳腺癌病灶的纖維化程度與預(yù)后的相關(guān)性、成纖維細(xì)胞、肌上皮細(xì)胞在乳腺原位癌進(jìn)展和侵襲轉(zhuǎn)移中的作用也都已得到證實(shí)[88-89]。但是,由于腫瘤微環(huán)境的成分多樣,微環(huán)境各成分之間、微環(huán)境與腫瘤細(xì)胞之間的交互作用復(fù)雜,并且很多實(shí)驗(yàn)研究在體外進(jìn)行,目前對(duì)于乳腺癌中腫瘤細(xì)胞與微環(huán)境的交互作用的具體機(jī)制仍缺乏深入理解,對(duì)其交互影響的探索需要“整體觀”的引導(dǎo)。

循證醫(yī)學(xué)開創(chuàng)了一個(gè)以科學(xué)證據(jù)為參考依據(jù),對(duì)乳腺癌患者進(jìn)行治療的時(shí)代,在乳腺癌規(guī)范化治療領(lǐng)域取得了豐碩的成果,但個(gè)體化信息的丟失和“一刀切”的結(jié)論限制了其進(jìn)一步發(fā)展。精準(zhǔn)醫(yī)學(xué)則因其更加個(gè)體化、精細(xì)化的疾病管理方式豐富了循證醫(yī)學(xué)的內(nèi)涵。通過獲取高質(zhì)量研究隊(duì)列和綜合分析多組學(xué)數(shù)據(jù),將獲得更加可靠的預(yù)測(cè)標(biāo)志物和治療靶點(diǎn),從而實(shí)現(xiàn)乳腺癌患者的精準(zhǔn)治療。

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Precisionmedicineinbreastcancerresearch

XIAO Yi1,2, JIANG Yi-zhou1,2, SHAO Zhi-min1,2△

(1DepartmentofBreastSurgery,ShanghaiCancerCenter,FudanUniversity,Shanghai200032,China;2CancerInstituteofFudanUniversity,Shanghai200032,China)

Breast cancer is the most common malignant tumor in women,and its incidence has increased in recent years in China.Evidence-based medicine has made great achievements in systemetic treatment of breast cancer,which laid the foundation for standardized treatment of breast cancer.Additionally,precision medicine provides more refined,individualized treatment for breast cancer patients.Breast cancer research in multiomic analysis,ctDNA,intratumour heterogeneity and interaction between tumor and microenvironment has broad prospects.

breast cancer; precision medicine; multiomics

R737.9

A

10.3969/j.issn.1672-8467.2017.06.013

國家自然科學(xué)基金(81502278,81572583,81372848,81370075),上海市衛(wèi)生系統(tǒng)優(yōu)秀青年人才計(jì)劃(2017YQ038),復(fù)旦大學(xué)附屬腫瘤醫(yī)院院級(jí)優(yōu)秀人才計(jì)劃(YJYQ201602)

△Corresponding author E-mail:zhimingshao@yahoo.com

*ThisworkwassupportedbytheNationalNaturalScienceFoundationofChina(81502278,81572583,81372848,81370075),YouthTalentsProgramforShanghaiMunicipalCommissionofHealthandFamilyPlanning(2017YQ038),andTalentsProgramforFudanUniversityShanghaiCancerCenter(YJYQ201602).

2017-09-18;編輯:張秀峰)