胃癌是最常见的消化道肿瘤之一。WHO国际癌症研究机构(IARC)于2020年发布的全球癌症数据报告[1]显示,每年胃癌新发患者约109万,在恶性肿瘤中排名第5位;每年胃癌死亡人数约77万,居恶性肿瘤第4位。在我国,胃癌的年发病人数和死亡人数分别为48万和37万,发病率和死亡率分别占恶性肿瘤的第2位和第3位。多数胃癌患者就诊时已是晚期,5年总体生存率仅为35.1%,预后较差[1-2]。
2014年,癌症基因组图谱(TCGA)具有里程碑意义地将胃癌分为4个分子亚型:EB病毒(EBV)阳性型、微卫星不稳定(MSI)型、基因组稳定(GS)型和染色体不稳定(CIN)型[3]。后续研究[4]表明,EBV亚型胃癌患者预后最佳,MSI和CIN亚型患者的总生存期(OS)低于EBV亚型,GS亚型患者预后最差。接受辅助化疗者中,CIN亚型患者获益最大,GS亚型患者获益最小。在ARTIST临床研究[5]中,MSI胃癌患者预后优于微卫星稳定(MSS)型患者。亚洲癌症研究组织(ACRG)将胃癌分为MSI和MSS两大类型,同样发现MSI胃癌患者表现出更好的生存趋势[6]。一项meta分析[7]显示:MSI胃癌患者未从围手术期化疗中获益,甚至生存期缩短。同时,MSI肿瘤由于其固有的突变负荷、炎症加剧和免疫检查点表达增加,表现出对免疫治疗的潜在敏感性[8-9]。随着免疫治疗的发展,胃癌治疗方法也正在发生改变[10]。
1 MSI的发生机制微卫星是一种短串联重复序列(1~6个核苷酸),分布在整个基因组中,容易发生突变。其中,MSI被定义为当DNA错配修复(MMR)机制存在缺陷时,发生于基因组微卫星的高突变表型[11]。错配修复系统主要包括MLH1、MSH2、MSH6和PMS2。在正常的DNA复制过程中,异二聚体复合体MSH2/MSH6检测并结合微小的错配碱基,而MLH1/PMS2杂二聚体负责错配位点上正确DNA碱基的切除和重新合成。在肿瘤细胞中,MMR蛋白功能异常时无法修复DNA复制过程中发生的错误,导致MSI现象的发生。
2 MSI的检测方法目前常用的MSI检测方法主要有两大类:(1)免疫组化,检测MMR蛋白MLH1、MSH2、MSH6和PMS2缺失与否。肿瘤样本中4个MMR蛋白均存在时为错配修复功能完整(proficient mismatch repair,pMMR);任一MMR蛋白缺失即为错配修复缺陷(deficient mismatch repair,dMMR)。一般情况下,dMMR为高度MSI(MSI-H)型,pMMR为低度MSI(MSI-L)或MSS型。MMR蛋白中MLH1与PMS2协同,MSH2与MSH6协同;4个MMR蛋白的表达取决于与伴侣蛋白的结合程度。(2)多重荧光PCR,PCR扩增后通过电泳测量和比较同一患者的正常样本和肿瘤样本扩增的DNA片段大小来检测MSI。多重荧光PCR目前为MSI检测的“金标准”。
3 MSI在胃癌中的流行现状、病理学特征及预后MSI胃癌的总体发病率较低,占胃癌患者总数的8%~25%[3]。MSI胃癌发病率差异与所分析队列的地域、肿瘤分期以及MSI检测方法有关。6%~24%的可切除胃/胃食管结合部癌为MSI-H型[12-15];在85岁以上MSI胃癌患者中,这一比例高达48%[16];在有转移的胃癌患者中,MSI-H型低于10%[17];在接受二线治疗以上的胃癌患者中,MSI-H型不足5%[18]。
此外,MSI胃癌可能与女性、高龄(≥65岁)、肿瘤位于中下部、无淋巴结转移和TNM分期较早(Ⅰ/Ⅱ期)有关[19-20]。纳入34项研究荟萃分析[19]显示,在Lauren’s分型中,MSI表型在肠型胃癌患者中占比最高,约占10.7%,混合型与弥漫型分别仅占0.9%和2.9%。MSI表型可能出现在某些遗传性肿瘤(如Lynch综合征)患者中,但没有证据表明MSI表型可用于区分散发性肿瘤与家族性肿瘤[21]。
近年来研究[22]发现,胃癌患者的预后和治疗反应不仅取决于肿瘤分期,还取决于特定的肿瘤基因型和表型特征。多项研究[7, 22]认为,MSI可作为胃癌患者良好预后的标志特征。Cristescu等[6]通过合并独立队列研究评估了按ACRG分型胃癌患者的生存情况,发现MSI亚型在单队列和多队列研究中均显示生存优势。Polom等[19]发现仅接受手术治疗的MSI胃癌患者的OS优于MSS患者。随机对照试验[9, 12, 23]也表明,单纯接受根治性手术的MSI-H胃癌患者预后更好。然而,MSI表型仍无法作为胃癌的预后生物学标志,主要原因:(1)现有队列的回顾性和异质性;(2)MSI-H胃癌患者数量相对较少;(3)围手术期过度化疗可能造成不良影响[9]。
4 MSI对胃癌治疗的影响 4.1 MSI对化疗的预测作用鉴于目前国内外指南推荐将围手术期化疗作为进展期胃癌的标准治疗方法,相关研究多重点评估MSI对胃癌化疗反应的预测作用。一项针对Ⅱ/Ⅲ期胃癌患者的大规模研究[24]发现,基于5-氟尿嘧啶(5-FU)的辅助化疗延长了MSS/MSI-L患者无病生存期(DFS),但MSI-H型患者从中获益。另一项研究[14]中,285例患者中有28例(9.8%)为MLH1阴性,而大多数MLH1阴性肿瘤(85.7%)为MSI-H表型。MLH1阴性患者对新辅助化疗的反应明显低于阳性患者,未给予新辅助化疗时,MLH1阴性患者的PFS明显长于阳性组;在术前接受化疗的患者中,2组的PFS无明显差异sup>[14]。
一项多中心Ⅲ期临床研究[25]证实,D2根治术联合辅助化疗(卡培他滨联合奥沙利铂)可改善Ⅱ/Ⅲ期胃癌患者预后。事后分析[12]发现,MSI胃癌患者接受辅助化疗后5年DFS为83.9%,单纯手术者为85.7%(P=0.931),提示化疗未改善患者的预后。此外,单病例分层分析[26]发现,MSI-H患者对化疗并不敏感。MAGIC研究[27]将可切除胃癌患者随机分为单纯手术组和手术联合化疗(表阿霉素联合5-FU和顺铂)组,拓展性研究发现,单纯手术MSI-H/dMMR患者中位OS未达到,非MSI-H/dMMR患者中位OS为20.5个月;手术联合化疗MSI-H/dMMR组患者的中位OS为9.6个月,非MSI-H/dMMR患者的中位OS为19.5个月。由此可见,辅助化疗对患者的生存获益有限。Pietrantonio等[7]将国际上4个大型有关胃癌围手术期治疗的临床试验(CLASSIC、MAGIC、ARTIST和ITACA-S)的数据进行了荟萃分析,探讨MSI、OS、DFS及放化疗效果之间的相关性发现,与MSS胃癌患者相比,MSI胃癌患者的5年OS和DFS均优于MSI-L/MSS患者,但MSI-L/MSS胃癌患者可以从手术联合化疗中获益。韩国延世大学的一项回顾性队列研究[28]发现,MSI-H胃癌患者行单纯手术治疗后可获得相对较好的预后,而化疗可能削弱了患者的生存获益。
然而,上述研究中MSI胃癌患者病例数较少,均为拓展性回顾分析。尽管研究结果均提示MSI为胃癌预后良好的预测因素之一,但MSI是否能作为围手术期化疗敏感性的评估因素仍需进一步的前瞻性研究。
4.2 MSI对免疫治疗敏感性胃癌免疫治疗从无到有,从三线治疗到一线治疗,从Ⅲ级推荐到Ⅰ级推荐,逐步改变晚期胃癌患者的预后。在KEYNOTE-012试验[29]中,帕博利珠单抗对PD-L1阳性胃癌患者的疗效首次得到了证实,22%的PD-L1阳性胃癌患者在单用帕博利珠单抗治疗后出现部分缓解(PR);基因组分析显示,约17%的胃癌患者为MSI表型,其中半数患者对帕博利珠单抗有临床反应。Ⅱ期临床试验KEYNOTE-059研究[18]评估了帕博利珠单抗治疗胃/胃食管结合部癌患者的安全性和有效性,发现MSI-H组患者的客观缓解率(ORR)为57.1%、疾病控制率(DCR)为71.4%,非MSI-H组的ORR及DCR仅为9.0%和22.2%,2组间差异有统计学意义。KEYNOTE-061试验[30]研究了帕博利珠单抗二线治疗PD-L1阳性进展期胃/胃食管结合部癌患者的情况,事后分析发现,在MSI-H患者中,帕博利珠单抗组和紫杉醇组患者的ORR分别为46.7%和16.7%。KEYNOTE-062试验[31]中,针对不可手术切除晚期胃癌患者一线使用帕博利珠单抗或帕博利珠单抗联合化疗对比单纯化疗的随机对照研究,其中帕博利珠单抗对比单纯化疗显示非劣效,达到研究终点,联合组OS及PFS亦不优于化疗组,未达到研究终点;但在MSI-H亚组分析中,帕博利珠单抗组及联合组的ORR分别为57.1%和64.7%,高于单纯化疗组的36.8%。此外,KEYNOTE-158的多队列Ⅱ期试验[32]中,24例MSI-H/dMMR胃癌患者的ORR为46%,PFS为11个月,证明帕博利珠单抗在对化疗无效的胃癌患者中有优质。
针对亚洲人群的前瞻性临床研究ATTRACTION-2[33]试验表明,与安慰剂相比,使用纳武利尤单抗治疗复发性或转移性胃/胃食管结合部癌患者的死亡风险降低,2组1年OS分别为10.9%和26.2%。美国临床肿瘤学会胃肠道肿瘤研讨会(ASCO-GI)[34]在2020年更新了纳武利尤单抗治疗胃癌患者3年随访数据,显示纳武利尤单抗组3年OS及PFS仍高于安慰剂组,2组OS分别为5.6%、1.9%,PFS分别为2.4%、0。ATTRACTION-4研究[35]进一步肯定了免疫治疗联合化疗在胃癌一线治疗中的作用。另一项全球多中心Ⅲ期临床研究CheckMate 649[36]证实,一线免疫治疗联合化疗较单纯化疗能提高胃癌患者生存获益:与单纯化疗组相比,纳武利尤单抗联合化疗组MSI-H和MSS患者中位OS更长,MSI-H患者获益大于MSS患者。CheckMate-032临床研究[23]探讨了纳武利尤单抗治疗转移性胃癌患者的安全性和有效性,亚组分析表明,MSI患者较MSS和微卫星状态未知的患者获得更长的OS(约15个月)。一项荟萃分析通过KEYNOTE-061、KEYNOTE-062、CheckMate 649以及JAVELIN Gastric 100[37]评估了MSI-H状态的预测效果,结果表明,接受抗PD-1治疗方案后,胃癌MSI-H患者与MMS患者OS获益的风险比(HR)分别为0.34和0.85(P=0.003)。上述临床研究逐步肯定了免疫治疗在晚期胃癌治疗中的作用。
鉴于上述回顾性分析研究提示围术期化疗无法使MSI-H胃癌患者生存获益,将免疫治疗作为术后辅助治疗能否进一步改善进展期胃癌患者的预后值得关注。2021版中国临床肿瘤学会(CSCO)胃癌诊疗指南[38]Ⅱ级推荐(ⅠB类证据),对于进展期胃癌术后可采取免疫治疗以进行临床研究。海军军医大学第一附属医院近期正开展一项前瞻性、单臂、单中心Ⅱ期临床试验(ChiCTR 2100050575),旨在探讨对于Ⅲ期MSI-H型胃/胃食管结合部癌患者,D2手术切除后采用抗PD-1抗体进行辅助治疗的安全性和有效性。
综上所述,MSI对胃癌免疫治疗效果有一定预测作用,其中MSI-H胃癌患者在免疫治疗中显示明显的生存获益。国内外多个指南建议对晚期实体瘤患者在免疫治疗前检测MSI。最新的NCCN胃癌指南(2022.V2)[39]也明确推荐,所有新诊断胃癌患者都应进行MSI的PCR检测或MMR的免疫组化检测(前版本仅推荐疑似转移胃癌患者进行MSI/MMR)。但是,现有临床研究中MSI-H患者总体数量较少,且多为回顾性分析,目前尚不能明确将MSI用于预测胃癌预后和治疗敏感性,需要更多的前瞻性研究。
利益冲突:所有作者声明不存在利益冲突。
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