多中心真实世界研究:基于血浆ctDNA突变的转移性乳腺癌亚型临床分析

2022-07-30 测序中国 测序中国

该研究依据传统的HER2/HR的状态对乳腺癌患者进行分层治疗,但经过多线治疗后,传统基于免疫组化的HER2/HR的状态不能指导转移性乳腺癌的患者治疗。

乳腺癌是女性常见的恶性肿瘤之一,虽然目前乳腺癌总体的5年生存率已高达90%,但是IV期患者的五年生存率仅为27%。癌症发生转移是乳腺癌患者死亡的主要原因,每年大约有50万患者死于转移性乳腺癌(mBC)。传统上mBC患者的治疗是根据HR和HER2的分型进行相关的内分泌治疗,HER2靶向治疗或者化疗。然而mBC患者在经历多线治疗后,没有标准的基于循证医学证据的后线治疗方式。此外考虑到mBC的异质性和基因变异的动态变化,目前临床上急需新的治疗策略。

循环肿瘤DNA(ctDNA)由肿瘤细胞死亡后释放到体循环中,理论上是来自不同转移部位的肿瘤DNA混合物,可以充分体现肿瘤的异质性。因此ctDNA可以作为mBC患者监测临床预后和治疗疗效的指标,并可根据ctDNA特定的变异指导mBC患者的后线治疗。

近日,湖南省肿瘤医院乳腺内科欧阳取长主任团队吉因加合作的一项研究成果发表在Lancet子刊eClinicalMedicine(IF=17.033),文章题为“Subtyping of metastatic breast cancer based on plasma circulating tumor DNA alterations: An observational, multicentre platform study”。该研究使用吉因加1021基因Panel,对223例后线mBC患者治疗过程中的ctDNA进行高深度测序,探索了ctDNA指导后线mBC患者治疗的临床应用价值相较没有ctDNA指导,ctDNA指导下的mBC患者的无疾病生存期(PFS)和疾病控制率显著提高。通过层次聚类的方法,并根据ctDNA的突变基因,该研究将后线转移性乳腺癌患者分为四种亚型:细胞外功能(ECF)、细胞增殖(CP)、核功能(NF)和级联信号通路(CSP)。此外,研究团队在核功能和级联信号通路ctDNA突变的患者中观察到根据ctDNA突变指导的治疗具有显著临床获益
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研究设计

该研究是一项观察性、多中心研究,于2016年12月至2019年6月共纳入223例拟接受后线治疗的mBC患者。研究团队依据基线ctDNA结果和是否具备相应的药物推荐,将患者分成ctDNA指导组(Druggrable ctDNA Alteration-Gudied Treatment, DDAT)和医师决策组(Physician-chosen Treatment, PCT)。 
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图1. 分组临床设计方法

表1. 入组人群的基本特征

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研究结果

1. 转移性乳腺癌ctDNA变异图谱

在参加该试验的223例患者中,190例患者(85%)在基线ctDNA被检出阳性,此外有132例患者(69.5%)检测到了可以提示临床靶向治疗的ctDNA 突变。研究结果显示,频繁突变的基因是TP53PIK3CA、ERBB2、BRCA1ESR1CDK12FGFR。除TP53外,其它基因变异均存在相关药物。(图2) 

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图2. ctDNA变化图谱

如下表所示(表2),具有FGFR/VEGFR突变的患者接受抗VEGFR/FGFR抑制剂单用或者联合化疗治疗,具有影响细胞增殖突变的患者使用细胞周期蛋白依赖性激酶4/6抑制剂(Cyclin-dependent kinase 4/6 inhibitor, CDK4/6i)治疗;具有同源重组修复(homologous recombination repair, HRR)通道突变的患者,接受PAPR抑制剂(PAPRi)治疗;具有PI3K/mTOR通路基因相关突变的患者接受PI3K/mTOR抑制剂治疗。结果显示,该研究发现绝大部分ctDNA阳性患者存在药物相关的基因变异,可用于指导临床用药

表2. 不同突变类型的患者用药方案 

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2. DDAT组有更高的疾病控制率和无病进展生存期

经过两个治疗疗程后,通过影像学的方式对223例患者进行临床疗效评估(图3)。总体而言,45例患者疾病进展(PR), 92例患者疾病稳定(SD), 86例患者部分缓解(PR),疾病控制率(DCR)高达79.8%。在ctDNA指导治疗组(DDAT)中,89.4%的患者肿瘤PR或SD(118例),但是医师决策治疗组(PCT)中仅65.9%的患者PR或SD(60例),DDAT组有显著的临床获益(P<0.0001)。 

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图3. 223名患者临床疗效评估

根据治疗策略进行亚组分析,生存曲线分析结果显示DDAT组的患者相较PCT组的患者具有更长PFS(6.3 vs 4.3 月,P<0.001)(图4)。此外,DDAT组的患者相较PCT组ctDNA阳性但是缺乏可用药物的患者同样具有更长PFS(6.3 vs 4.7月,HR: 0.56, 95%CI: 0.38-0.82, P=0.003)(图5)。COX分析结果也同样表明DDAT组的患者风险比显著低于所有PCT组的患者(HR:0.49, 95%CI: 0.33-0.73, P=0.0004)和PCT组ctDNA阳性但是缺乏可用药物的患者(HR:0.59, 95%CI: 0.39-0.91, P=0.02)(表3)。上述结果均表明,利用ctDNA检测存在药物靶点的患者的临床获益好于PCT组的患者。 

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图4. DDAT组的患者较于PCT组的患者具有更长PFS 

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图5. DDAT组的患者较于PCT组ctDNA阳性但是缺乏可用药物的患者同样具有更长PFS

表3. 所有患者(n=223)和ctDNA改变患者(n=190)的多元COX回归分析
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3. 不同分子亚型的转移性乳腺癌临床获益

为了阐明不同的分子亚型对转移性乳腺癌临床获益的影响,该研究利用层次聚类的方法对223例患者的ctDNA结果进行聚类。研究结果表明,mBC的基因变异可以分成4种亚型,分别是subtype 1(extracellular function,ECF同血管生成相关)subtype 2(cell proliferation, CP, 细胞增殖相关),subtype 3(nuclear function, NF, DNA修复相关)和 subtype 4(cascade signal pathway, CSP, PI3K/mTOR, MAPK等信号代谢通路相关)

为了评估不同的分子亚型对PFS临床获益的影响,该研究采用单因素COX分析的方法,其结果如下图所示。subtype 3亚型(NF)的患者相较于PCT的患者获得了显著获益(HR:0.394, 95% CI 0.238-0.652, P=0.0003),同时,subtype 4亚型(CSP)的患者较于PCT患者获得了更好的临床获益(HR:0.142, 95% CI 0.094-0.215, P<0.0001)(图6)。但subtyple1(ECF)和subtype 2(CP)亚型没有获得显著的临床获益(P>0.05)。上述结果表明,DDAT组中特别是具有能够影响信号通路和DNA修复变异的患者能够获得更好的临床获益。 

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图6. 基于ctDNA亚型的无进展生存风险比亚组分析 

研究结论

综上所述,该研究依据传统的HER2/HR的状态对乳腺癌患者进行分层治疗,但经过多线治疗后,传统基于免疫组化的HER2/HR的状态不能指导转移性乳腺癌的患者治疗。该研究旨在强调ctDNA监测可以作为一种有用的技术手段提供全面的分子信息,指导后线转移性乳腺癌的药物治疗。利用mBC患者高频的突变基因对患者进行分子分型,从而选择不同治疗的策略,该研究结果也表明这种方式相较于医师决策的系统临床获益更大。

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    2022-07-30 ms7000001229951125

    学习

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    2022-07-30 1480a5b2m95暂无昵称

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