EGFR-TKI治療S768I突變非小細(xì)胞肺癌的研究進(jìn)展*

段樺 綜述 崔慧娟 審校

·綜 述·

EGFR-TKI治療S768I突變非小細(xì)胞肺癌的研究進(jìn)展*

段樺①②綜述 崔慧娟①審校

肺癌是死亡率較高的惡性腫瘤之一，近年來非小細(xì)胞肺癌（non-small cell lung cancer，NSCLC）的治療進(jìn)展迅速，尤其是表皮生長(zhǎng)因子受體絡(luò)氨酸激酶抑制劑（epidermal growth factor receptor-tyrosine kinase inhibitor，EGFR-TKI）的問世，使得攜帶EGFR基因敏感突變患者的中位無進(jìn)展生存期（median progression free survival，mPFS）達(dá)到27.7個(gè)月，但部分不常見的EGFR突變對(duì)TKI的應(yīng)答效果尚不十分明確。S768I突變是EGFR20外顯子攜帶的不常見突變之一，發(fā)生率為1%～2%。本文對(duì)不同代EGFR-TKI治療S768I單一或復(fù)合突變的研究進(jìn)行綜述，旨在為臨床決策提供思路。

EGFR-TKI20外顯子 S768I突變 治療進(jìn)展

根據(jù)2012年全球腫瘤流行病統(tǒng)計(jì)數(shù)據(jù)（Globocan 2012）統(tǒng)計(jì)［1］，2012年全球新發(fā)和死亡癌癥患者分別為1 410萬、820萬例，其中肺癌患者分別為124萬、109萬例，并且無論是發(fā)達(dá)國(guó)家或欠發(fā)達(dá)國(guó)家，肺癌均為男性死亡的主要原因。2015年來自中國(guó)的數(shù)據(jù)同樣表明肺癌是癌癥死亡的主要原因［2］。肺癌按照病理類型可以分為非小細(xì)胞肺癌（non-small cell lung cancer，NSCLC）和小細(xì)胞肺癌（small cell lung cancer，SCLC）。近年來，NSCLC治療進(jìn)展迅速，尤其是分子靶向藥物的應(yīng)用使其療效大幅提高，其中表皮生長(zhǎng)因子受體絡(luò)氨酸激酶抑制劑（epidermal growth factor receptor-tyrosine kinase inhibitor，EGFR-TKI）為代表性藥物。歐洲和北美國(guó)家約10%～20%的NSCLC患者攜帶EGFR突變，東亞國(guó)家的發(fā)生率更高，達(dá)到50%～60%［3-4］。表皮生長(zhǎng)因子受體（epidermal growth factor receptor，EGFR）敏感突變包括19外顯子缺失突變和21外顯子L858R錯(cuò)義突變。有研究顯示［5］，攜帶EGFR敏感突變的NSCLC患者接受吉非替尼一線治療后中位無進(jìn)展生存期（median progression free survival，mPFS）達(dá)到27.7個(gè)月。EGFR不敏感突變主要包括G719X、S768I、L861Q和20外顯子插入［6］，據(jù)統(tǒng)計(jì)發(fā)生率為4%～13%［7］。2015年LUX-LUNG系列研究發(fā)現(xiàn)［8］，8例攜帶S768I突變的患者服用二代絡(luò)氨酸激酶抑制劑（tyrosine kinase inhibitor，TKI）阿法替尼后均達(dá)到部分緩解（partial remission，PR），再次引起學(xué)術(shù)界對(duì)S768I突變的關(guān)注。

EGFR20外顯子的氨基酸位點(diǎn)為762～823，插入突變的發(fā)生人群與經(jīng)典EGFR突變類似，以女性、非吸煙者、腺癌者多見，約占所有EGFR突變的5%［9］，點(diǎn)突變主要包括T790M突變和S768I突變，其中S768I突變的發(fā)生率僅為1%～2%［10-11］。S768I在基因序列上，第768號(hào)密碼子由疏水的異亮氨酸代替親水的絲氨酸，因異亮氨酸的空間阻力比絲氨酸大，從而使得周圍臨近結(jié)構(gòu)發(fā)生改變，且S768I突變還會(huì)影響S768與N700及Y764之間的氫鍵作用，導(dǎo)致間距增加，從而使TKI對(duì)EGFR的親和力部分改變，造成療效的差異［12］。從2006年開始，陸續(xù)有EGFR-TKI治療S768I突變的個(gè)案報(bào)道和臨床研究，但治療效果存在差異，目前尚無明確結(jié)論。本文從第一、二、三代TKI治療S768I突變的角度對(duì)臨床研究進(jìn)行綜述，旨在對(duì)臨床決策有所啟迪。

1 第一代EGFR-TKI治療S768I突變NSCLC

1.1 單一S768I突變

EGFR-TKI對(duì)于敏感突變?nèi)巳嚎陀^緩解率（objective response rate，ORR）高達(dá)70%～80%，一線無進(jìn)展生存期（progression-free survival，PFS）可達(dá)9～14個(gè)月［13］。但對(duì)于S768I突變，目前的研究結(jié)果并不一致。Pallan 等［14］、Weber等［15］、Lund-Iversen 等［16］和Leventakos等［17］分別報(bào)道1例或2例攜帶單一S768I突變的病例，服用厄洛替尼或吉非替尼后均疾病進(jìn)展（progression of disease，PD），部分患者甚至死亡，提示S768I突變對(duì)一代TKI不敏感。2017年Longo等［18］報(bào)道1例初發(fā)L858R突變后繼發(fā)S768I突變的病例，該患者一線口服吉非替尼有效，當(dāng)出現(xiàn)PD時(shí)繼續(xù)服用吉非替尼則無效，說明S768I突變對(duì)吉非替尼應(yīng)答差，并由此推測(cè)S768I突變可能是肺腺癌EGFR耐藥的新機(jī)制。以上研究均說明一代TKI對(duì)S768I突變敏感性差，并且多為原發(fā)耐藥。但同時(shí)有研究顯示出良好的應(yīng)答效果，如2010年Masago等［19］報(bào)道1例S768I突變對(duì)一代TKI應(yīng)答良好的病例，該患者二線口服吉非替尼評(píng)效PR，截止報(bào)道日期PFS為461 d，已經(jīng)接近敏感突變，說明S768I突變對(duì)一代TKI可能存在一定敏感性。另一項(xiàng)報(bào)道［20］也表達(dá)類似觀點(diǎn)，1例分別于2001年和2003年行肺部病灶切除的患者，兩次病理均為單一S768I突變，2005年肺部出現(xiàn)新轉(zhuǎn)移病灶，未重新檢測(cè)病理的情況下口服厄洛替尼并取得療效，2013年病情再次出現(xiàn)進(jìn)展后行肺部病灶切除，基因檢測(cè)示S768I和T790M突變，因?yàn)門790M為最常見的一代TKI耐藥突變，說明厄洛替尼取得療效是因?yàn)檫x擇性抑制S768I的結(jié)果。另外兩項(xiàng)研究中，患者PFS分別達(dá)到8.6［21］、8.8個(gè)月［22］，接近敏感突變，Zhang等［23］報(bào)道1例患者獲得31個(gè)月PFS，遠(yuǎn)超敏感突變。另外，F(xiàn)ASTACT-2研究中1例患者服用厄洛替尼后生存期達(dá)到近5年［24］。可見一代TKI對(duì)S768I突變可以取得良好的治療效果，并且維持時(shí)間較長(zhǎng)。另外，Chiu等［25］研究共納入6例攜帶S768I單一突變的患者，分別口服吉非替尼或厄洛替尼，結(jié)果2例出現(xiàn)PD，該研究說明S768I突變對(duì)一代TKI治療效果存在不穩(wěn)定性。

上述研究共涉及18例攜帶單一突變的患者，服用一代TKI后評(píng)效PR或疾病穩(wěn)定（stable disease，SD）的患者為10例，PD為8例，疾病控制率（disease control rate，DCR）為55.56%，說明S768I突變對(duì)于一代TKI具有一定敏感性，但是整體疾病緩解率仍低于敏感突變，說明S768I較敏感突變對(duì)一代TKI應(yīng)答差。

1.2 S768I合并其他突變

1.2.1 合并19、21外顯子敏感突變 S768I為不敏感突變，當(dāng)與敏感突變合并時(shí)是否影響TKI療效值得研究，部分研究者進(jìn)行了臨床觀察，Yang等［26］、Wu等［27］、Leventakos等［17］、Beau-Faller等［28］均觀察1 例 S768I+L858R突變的患者，服用吉非替尼或厄洛替尼后均評(píng)效為PR或SD。Zhu等［22］觀察2例患者，1例S768I+L858R患者為SD，但1例S768I+19DEL患者為PD。

以上6例合并敏感突變患者中5例有效，ORR為50%～66.7%，DCR達(dá)到83.3%，與敏感突變相近，說明S768I突變不影響敏感突變的應(yīng)答效果。

另外，Zhang等［23］的研究發(fā)現(xiàn)11例攜帶S768I突變患者（4例單一突變，5例為S768I+G719X，2例為S768I+L858R）口服一代TKI藥物后，DCR達(dá)到90.0%，ORR達(dá)到27.3%，mPFS為8.0個(gè)月。Cheng等［21］收集10例攜帶S768I突變的病例（單一突變3例，合并19DEL突變3例，合并L858R突變4例），結(jié)果發(fā)現(xiàn)2例PR，5例SD，3例PD，ORR為20%，DCR為70%，mPFS為2.7個(gè)月，以上兩項(xiàng)研究均納入單一S768I突變的患者，所以O(shè)RR和PFS均低于敏感突變，進(jìn)一步說明S768I突變對(duì)一代TKI的應(yīng)答較差。

1.2.2 合并18外顯子突變 S768I突變除了聯(lián)合敏感突變外，也常和其他突變同時(shí)出現(xiàn)，并且發(fā)生雙突變的概率較單突變的概率高，文獻(xiàn)報(bào)道常與G719、E709、T790M、L861R位點(diǎn)突變聯(lián)合［29］，G719突變位于EGFR18外顯子，主要包括G719A、G719X、G719S突變，約占97%［30］。Svaton 等［31］和Lund-Iversen等［16］均報(bào)道1例攜帶S768I+G719X突變的患者，服用吉非替尼后病灶縮小，PFS分別達(dá)到8、14個(gè)月。Chiu等［25］研究中發(fā)現(xiàn)5例攜帶該突變的患者同樣評(píng)效為PR。Kobayashi等［32］、Leventakos等［17］、Zhu 等［22］均觀察2例攜帶S768I+G719突變的患者，均達(dá)到PR。但是并非多數(shù)研究均為陽性結(jié)果，Wu等［27］研究發(fā)現(xiàn)1例攜帶S768I+G719A的患者服藥5周后即迅速病情進(jìn)展。既往研究表明［30，33］，單一G719突變對(duì)一代TKI的ORR達(dá)到35%～40%，低于敏感突變，但上述合并G719突變病例共12例，僅1例PD，ORR高達(dá)92.8%，甚至高于敏感突變，說明S768I突變與G719突變合并對(duì)一代TKI的應(yīng)答效果好，可能與二者相互作用有關(guān)，但目前尚缺乏深入的機(jī)制研究。

1.2.3 合并其他不常見突變 2006年Asahina等［34］報(bào)道1例S768I+V769L雙突變的患者，該患者一線口服吉非替尼6周后PD，后改為雙藥化療PR，因?yàn)槟壳吧腥狈769L突變的體內(nèi)研究數(shù)據(jù)，說明S768I突變對(duì)吉非替尼為原發(fā)耐藥。Cheng等［35］研究中1例攜帶S768I+G724S突變的患者，二線服用厄洛替尼后SD，PFS達(dá)到24.2個(gè)月。G724突變是EGFR致癌突變，有研究表明其與經(jīng)典的肺癌EGFR突變不同，其對(duì)西妥昔單抗敏感，但對(duì)小分子激酶抑制劑不敏感［36］，說明厄洛替尼通過選擇性抑制S768I發(fā)揮療效。Klughammer等［24］研究發(fā)現(xiàn) TRUST 研究中 1例攜帶S768I+V774M的亞裔女性生存期達(dá)到1 106 d。V774M突變?yōu)槿橄侔┲锌赡芎喜⒌闹掳┗颍伟┲胁⒉怀Ｒ姡?7］。以上研究S768I合并的突變與TKI療效不確切，即TKI主要是作用于S768I突變，但應(yīng)答效果不一致。

2 第二代TKI治療S768I突變NSCLC

2.1 單一S768I突變

由Yang等［8］研究的LUX-LUNG引起廣泛關(guān)注，該研究中僅1例單一突變患者，服用阿法替尼后有效。Heigener等［20］和Yang等［38］研究中同樣僅1例攜帶單一S768I突變，均評(píng)效SD。Kobayashi等［39］報(bào)道1例攜帶S768I突變的肺癌患者，因腹膜轉(zhuǎn)移引起腸梗阻，阿法替尼作為11線治療后癥狀消失，復(fù)查CT腫塊減小，隨訪1年未復(fù)發(fā)。Russo等［40］報(bào)道1例S768I繼發(fā)T790M突變的個(gè)案，該患者一線阿法替尼治療同樣有效，但3個(gè)月后迅速發(fā)生耐藥，并于循環(huán)DNA中查到T790M突變，但具體機(jī)制尚不明確。上述共5例單一突變患者，均治療有效，DCR高達(dá)100%，甚至高于一代TKI，說明S768I突變可能對(duì)二代TKI更敏感，缺點(diǎn)是樣本量較小，亟需后續(xù)研究證實(shí)。

2.2 S768I合并19、21外顯子敏感突變

經(jīng)典的LUX-LUNG研究［8］除1例單一突變，2例S768I+L858R突變患者同樣獲得PR。Zhu等［22］研究中，1例患者攜帶S768I合并L858R突變，服用阿法替尼后，評(píng)效SD。以上3例患者的ORR為67%，DCR達(dá)到100%，說明S768I對(duì)二代TKI應(yīng)答良好，同時(shí)不影響敏感突變的應(yīng)答。

2.3 S768I合并18外顯子突變

2016年Tanizaki等［41］報(bào)道1例S768I+G719C突變以及KRAS基因E49K突變的患者，經(jīng)阿法替尼治療后血清腫標(biāo)明顯下降，復(fù)查PET-CT顯示骨轉(zhuǎn)移灶明顯縮小。上述LUX-LUNG研究有5例攜帶S768I+G719X突變的患者，均評(píng)效為PR，上述6例患者ORR、DCR達(dá)到100%。說明S768I合并G719突變對(duì)二代TKI也有很好的敏感性。

3 第三代TKI治療S768I突變NSCLC

第三代TKI是治療T790M突變的藥物，目前針對(duì)S768I突變的研究?jī)H限于體外實(shí)驗(yàn)，2016年Tanizaki等［41］開展了細(xì)胞實(shí)驗(yàn)，2組Ba/F3細(xì)胞分別表達(dá)L858R和S768I突變，均給予7種不同的EGFRTKI（2種一代TKI，3種二代TKI，2種三代TKI），通過觀察藥物的IC50及IC50比值（L858R/S768I）判定療效，結(jié)果發(fā)現(xiàn)表達(dá)S768I和L858R突變的細(xì)胞組對(duì)于阿法替尼治療的IC50分別為0.82和0.25，結(jié)果相近并遠(yuǎn)小于第一、三代TKI，說明S768I突變對(duì)阿法替尼最敏感，并且敏感性等同于L858R突變，但是對(duì)一代TKI（厄洛替尼、吉非替尼）、三代TKI（奧希替尼）均不敏感。同年Banno等［42］開展了類似的實(shí)驗(yàn)，3組Ba/F3細(xì)胞分別表達(dá)L861Q、S768I和L858R突變，均給予第一、二、三代TKI（厄洛替尼、阿法替尼、奧希替尼），結(jié)果提示S768I突變對(duì)二代（阿法替尼）敏感，對(duì)一代（厄洛替尼）和三代（奧希替尼）均不敏感。

此外，僅針對(duì)第一、二代TKI也有部分體外研究，早期實(shí)驗(yàn)［43］結(jié)果發(fā)現(xiàn)表達(dá)S768I突變的細(xì)胞與野生型細(xì)胞相比，對(duì)吉非替尼的耐藥現(xiàn)象更明顯。2009年Kancha等［44］利用Ba/F3細(xì)胞進(jìn)行藥敏實(shí)驗(yàn)，發(fā)現(xiàn)S768I突變對(duì)吉非替尼和厄洛替尼不敏感，均表明S768I突變對(duì)一代TKI敏感性差。此外，Kobayashi等［11］實(shí)驗(yàn)再次證實(shí)與一代TKI相比，S768I對(duì)阿法替尼最敏感。

4 結(jié)語

S768I突變屬于EGFR20外顯子不常見突變之一，從上述的研究來看，單一S768I突變對(duì)于二代TKI的應(yīng)答效果優(yōu)于第一、三代，提示臨床可以首選以阿法替尼為代表的二代藥物。同時(shí)S768I突變常與其他突變同時(shí)存在，在DCR方面，復(fù)合復(fù)變優(yōu)于單一突變，并且當(dāng)S768I突變與敏感突變同時(shí)出現(xiàn)時(shí)，并不影響敏感突變的應(yīng)答率，這與既往研究［28，45］相符，但具體機(jī)制尚不明確，可能與突變基因的相互作用有關(guān)。值得注意的是，當(dāng)S768I突變與G719突變同時(shí)出現(xiàn)時(shí)，第一、二代TKI均可以取得良好的DCR，阿法替尼的皮疹發(fā)生率和程度比一代TKI重，所以為避免不可耐受的皮膚不良反應(yīng)，臨床可以推薦同時(shí)攜帶S768I和G719突變的患者選用一代TKI。鑒于目前尚無EGFR-TKI治療S768I突變的大樣本臨床研究，同時(shí)本綜述的樣本量較小，后續(xù)亟需開展大樣本量的前瞻性或回顧性研究，進(jìn)一步明確EGFR-TKI對(duì)S768I突變的治療效果以及明確不同突變之間的作用機(jī)制。

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Progress on EGFR-TKI in treatment of non-small cell lung cancer with S768I mutation

Hua DUAN1,2,Huijuan CUI1

1Department of Oncology of Integrative Medicine,China-Japan Friendship Hospital,Beijing 100029,China;2Beijing University of Chinese Medicine,Beijing 100029,China

Huijuan CUI;E-mail:cuihj1963@sina.com

Lung cancer is one of the malignant tumors with high mortality rates.In recent years,considerable progress on the treatment of non-small cell lung cancer has been achieved.Epidermal growth factor receptor-tyrosine kinase inhibitor(EGFR-TKI)improves the median progression free survival of patients with sensitive mutations to 27.7 months.However,the therapeutic effect of EGFR-TKI on uncommon mutations remains unknown.S768I mutation is an insensitive mutation in the EGFR20 exon,and its incidence rate ranges from 1%to 2%.In this review,the effect of different generation EGFR-TKI on single or complex S768I mutation during treatment is discussed.

epidermal growth factor receptor-tyrosine kinase inhibitor,exon,S768I mutation,advances

10.3969/j.issn.1000-8179.2017.22.824

①中日友好醫(yī)院中西醫(yī)結(jié)合腫瘤內(nèi)科（北京市100029）；②北京中醫(yī)藥大學(xué)

*本文課題受北京市科委首都特色應(yīng)用研究項(xiàng)目（編號(hào)：Z151100004015168）資助

崔慧娟 cuihj1963@sina.com

This work was supported by the Capital Application Research of Beijing Municipal Science and Technology Commission(No.Z151100004015168)

（2017-07-20收稿）

（2017-09-08修回）

（編輯：孫喜佳 校對(duì)：鄭莉）

段樺 專業(yè)方向?yàn)橹形麽t(yī)結(jié)合治療肺癌。

E-mail：duanhua1992@bucm.edu.cn