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晚期结直肠癌用药顺序、肿瘤位置与预后关系及分子分型的最新进展

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结直肠癌是恶性肿瘤中死亡率第三高的恶性肿瘤。近20%的患者确诊时即为转移性疾病,25-30%的Ⅱ/Ⅲ期患者接受根治手术后5年内仍会复发。系统治疗是进展期/转移性结直肠癌的有效治疗手段。


现在一线、二线治疗方案主要包括含5-FU的双药化疗(FOLFOX /CAPOX /FOLFIRI /CAPIRI),联合抗血管生成剂或EGFR抑制剂(仅限RAS野生型)。


在一些患者中,序贯治疗也是一种合情合理的选择,其疗效不比联合治疗差。5-FU联合或不联合贝伐珠单抗的维持治疗也在一些谨慎选择的特定患者中改善了患者的生存。


最近,对于结直肠癌患者一、二线的用药顺序、肿瘤位置与基因表达以及分子分型又有了一些新进展,以下是详细内容。


一线与二线治疗应用顺序与肿瘤位置


接受含5-FU双药一线或二线治疗时,奥沙利铂和伊立替康谁先谁后不会影响患者的生存结局。


一般来说,可根据当地的临床习惯、治疗相关毒性、并发症等作出决定。


最近,关于应用Biomarker帮助选择一线化疗“基石”药物的很多尝试都以失败告终。


对于有预后不良因素(例如BRAF突变)或者是需要肿瘤快速消退的患者来说,可能应用FOLFOXIRI联合贝伐珠单抗是较好的选择。对于RAS突变的患者来说,双药或三药联合贝伐珠单抗均可。


最近有研究表明,原发肿瘤位置不仅是预后的预测因子,并且在RAS野生型的mCRC中,其预测作用与的分子学分型有一定的关系。


左半结肠癌与右半结肠癌相比的预后更好,这可能是与右半结肠癌的分子学特征有关。例如右半结肠癌的BRAF突变和MSI患者更多。右半结肠可观测到更多的CMS1患者,他们的MSI率更高,CIMP-H及超变患者更多、免疫浸润与活性增强患者也更多,生存数据也就更差。


最近的回顾性分析也合并分析了不同分子特征mCRC患者接受抗EGFR治疗的不同结果。总的来说,在RAS野生型患者的一线治疗中,左半结肠癌患者接受抗EGFR治疗的中位无进展生存(mPFS)和中位总生存(mOS)均更好。


经过BRAF突变状态的调整后,左右半结肠癌的差异仍为独立的预测因子。


而在右半结肠癌的患者中,可以观测到完全不同的疗效。在CRYSTAL,FIRE-3, PRIME, PEAK,80405,181和NCIC CO.17研究中均可以见到相同的趋势。CRYSTAL,FIRE-3,80405研究中见到了明显的统计学差异。


在NCIC CO. 17研究的三线治疗研究中,左半肿瘤的患者序贯西妥昔单抗与最佳支持治疗相比也见到了生存获益, 而右半结肠却没有观测到相同的趋势。


所以,肿瘤位置对疗效的预测作用具有了更多的循证医学证据支持,而生物学相关的探索也为其提供了理论基础。


结直肠癌的分子分型


二代基因测序(NGS)的快速发展使肿瘤的分子分型具有了更高的敏感性。这允许我们确定了对更多治疗耐药相关通路的探索。


例如抗EGFR治疗后,有多个基因改变可以引起治疗耐药。包括RAS突变、EGFR突变、ERBB2扩增、MET扩增等等。让我们理解了更多的耐药机制,给联合用药提供了可能。


主要的改变之一是NGS可以通过Panel同时测定多个基因了。这也就允许了对精准药物的广泛筛查,并且成本一直在下降中。现在一个NGS panel的多基因检测与单个基因的PCR检测的成本已相差不多。


多RAS基因检测


NGS检测的出现对于RAS检测来说重要性非凡。最初研究表明,KRAS第2外显子被证实可以证明抗EGFR治疗耐药。而根据PRIME研究的结果,K-RAS和NRAS的第2,3,4外显子均可以指导抗EGFR治疗。


通过多RAS基因检测可以筛选出约56%的突变患者。而通过单基因PCR检测只能检测出40-45%的患者。


这些基因突变的患者接受抗EGFR治疗可能均无效,并且RAS突变患者行抗EGFR治疗的毒性可能会增加。


液体活检


评估细胞游离DNA(cfDNA)的液体活检是一种新型的实时测定患者分子学特征的方法。应用几毫升血液,可以应用NGS panels诊断出基因突变,进而指导用药、在进展前确认耐药机制。


这些panels可以在治疗过程中给临床医生提供实时的生物学信息跟踪,调整治疗方案。它也可以让医生了解是否可以重新应用既往应用过的治疗药物。


已经有案例表明,应用实时cfDNA检测后,如果耐药基因改变消失,可以让患者重新接受抗EGFR治疗,达到二次缓解。


共识分子亚型(CMS)


单个基因的突变可以允许我们对特定患者群选择特定的方案。但是最新研究表明,结直肠癌患者可以根据基因表达的CMS进行分组。


在特定的CMS亚组中,某些基因突变率可能比例不同。更重要的是,某些基因突变在不同亚组中的重要性会不同。


根据该分类方式,可将患者分为MSI/免疫组(CMS1)、WNT组(CMS2)、代谢组(CMS3)和间质组(CMS4)。通过这个分子亚型,可以指导精准医疗诊疗实践,提高靶向药物的疗效。


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