解惑:晚期乳腺癌患者早期进展的循环肿瘤 DNA 标志物有何变化?

2021/12/16 820

 循环肿瘤 DNA (ctDNA) 中的基因组标志物是否可以识别在氟维司群治疗中使用或不使用 palbociclib(一种 CDK4/6i)时早期进展风险较高的患者呢?


CDK4/6抑制剂(CDK4/6i)在晚期雌激素受体阳性(ER+)乳腺癌[1]的治疗中发挥关键作用,在一线和二线治疗中与内分泌治疗联合已确立的疗效。[2-8]然而,有相当一部分患者在治疗早期发生进展,临床医生需要识别患者是否有进展风险。


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今天,文章探索了循环肿瘤 DNA (ctDNA) 中的基因组标志物是否可以识别在氟维司群治疗中使用或不使用 palbociclib(一种 CDK4/6i)时早期进展风险较高的患者。


汇聚专业医学学术知识,提供线上线下整体解决方案

循环肿瘤DNA


循环肿瘤DNA (ctDNA)存在于绝大多数晚期癌症患者的血浆中,是肿瘤体细胞遗传特征无创分析的肿瘤DNA来源。此外,循环肿瘤分数,即来自肿瘤的血浆DNA分数,是一种生物学标记物,可同时报告肿瘤体积和肿瘤侵袭性[23],并与三阴性乳腺癌较差的临床结果相关。


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CDK4/6i联合内分泌治疗


CDK4/6i联合内分泌治疗是晚期ER+乳腺癌的标准治疗。目前很少有分子标记物可以用于识别有早期进展风险的患者,增加监测以检测进展可能是适当的,对这些患者的研究工作可以集中于改善结果。PALOMA-3试验研究耐药性进化的工作在此基础上,使用ctDNA多模态测序分析所有基线血浆样本,以评估预测和预后基因组特征,大大扩大了基线基因组改变的范围。


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汇聚专业医学学术知识,提供线上线下整体解决方案

基因表达


在早期ER+乳腺癌中,已经建立了许多与不良预后相关的分子标记,最显著的是基于肿瘤活检中评估的基因表达的风险分类器,它们通常用于增强临床决策与原发疾病预后不良反应[9],除HER2扩增外的基因组标记包括TP53突变,FGFR1扩增[10-11],可能导致内分泌治疗耐药性[12-13]和MYC扩增[14]。对于晚期ER+乳腺癌中常见的基因组变异与临床结果之间的关系,尤其是包括联合CDK4/6i治疗的最新治疗前景中,所知较少。


目前已知一些对CDK4/6i耐药的潜在基因组机制,如CCNE1的扩增、FAT1的突变、CDK6过表达和RB1的丢失[15-16],以及免疫信号和其他致癌信号的新数据。其中[17-18],临床数据支持在少数CDK4/6i进展的癌症中获得RB1突变[19-20],这些肿瘤先前存在功能性RB1缺失,与CDK4/6i治疗预后不良相关。尽管FAT1失活突变在晚期ER+乳腺癌中很少见,但FAT1丢失也与CDK4/6i治疗的不良结果相关。有研究证明,在既往接受内分泌治疗的晚期ER+乳腺癌中,PIK3CA和ESR1突变不能预测palbociclib的反应[22]。


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总结


总的来说,循环肿瘤比例和那些通常被认为是克隆性的突变之间有很强的一致性,例如在PIK3CA和TP53中,尽管这种相关性在低突变等位基因部分较弱,这可能反映了亚克隆性突变和随机效应。在PALOMA-3研究中,两个治疗组的循环肿瘤分数都与不良PFS密切相关,并在多变量分析中成为一个独立的预后因素——这在ER+乳腺癌中首次证明了这种相关性。尽管添加了 CDK4/6 抑制,治疗前 ctDNA 仍确定了临床结果不佳的高危患者。这些患者可能会受益于未来升级治疗的试验,这些治疗在这些基因组背景下有效。


汇聚专业医学学术知识,提供线上线下整体解决方案
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声明:本文为医会宝编辑部原创整理,仅代表作者个人观点,希望大家理性判断,有针对性应用。