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众所周知，检测血液循环的肿瘤DNA可以取代肿瘤活检，反映肿瘤动态变化，而肿瘤动态变化与转移性乳腺癌治疗结局密切相关。不过，通过检测循环肿瘤DNA检测分析肿瘤动态变化能否预测转移性乳腺癌治疗结局尚不明确。 2019年6月26日，国际抗癌联盟《国际癌症杂志》在线发表中国医学科学院肿瘤医院、国家癌症中心、国家肿瘤临床医学研究中心、北京吉因加基因研究院、上海交通大学系统生物医学研究院、康乃尔大学威尔医学院休斯顿卫理公会研究所、德克萨斯大学MD安德森癌症中心、圣迭戈加利福尼亚大学摩尔斯癌症中心的研究报告，通过循环肿瘤DNA分析肿瘤动态变化，对吡咯替尼治疗转移性乳腺癌的生存结局进行了预测和监测。 该研究对中国医学科学院肿瘤医院吡咯替尼单药或联合卡培他滨治疗37例HER2阳性转移性乳腺癌患者进行分析。
结果，根据治疗前和治疗时的循环肿瘤DNA，肿瘤动态变化较大（突变簇≥3个）与肿瘤动态变化较小（突变簇<3个）患者相比，无进展生存结局显著较差（中位无进展生存：30.0比60.0周），复发或死亡风险高2.9倍（风险比：2.9，P=0.02）。 根据治疗前的循环肿瘤DNA，有主干耐药突变与无主干耐药突变（有分支耐药突变或无任何耐药突变）患者相比，吡咯替尼单药治疗的无进展生存结局显著较差（中位无进展生存：7.8比27.4周），复发或死亡风险高4.5倍（风险比：4.5，P=0.03）。 根据治疗时对21例患者纵向监测，分子肿瘤负荷指数（标本循环肿瘤DNA比例）与根据CT测量的肿瘤大小成正比（P<0.0001，皮尔逊相关系数=0.52）并且检出疾病进展提早8～16周。 因此，该研究结果表明，对于吡咯替尼治疗HER2阳性转移性乳腺癌患者，循环肿瘤DNA可以用于判断肿瘤动态变化和预测治疗结局。此外，分子肿瘤负荷指数与单基因突变相比，能够较好地评定治疗效果，并且可能对现有治疗效果评估系统进行补充。评估治疗效果时，监测循环肿瘤DNA多种基因变异连续变化与单基因突变相比，可能更为敏感，该变化可以比CT提早几周至十几周检出疾病进展。 相关阅读 Int J Cancer. 2019 Jun 26. [Epub ahead of print] Assessing tumor heterogeneity using ctDNA to predict and monitor therapeutic response in metastatic breast cancer. Ma F, Guan Y, Yi Z, Chang L, Li Q, Chen S, Zhu W, Guan X, Li C, Qian H, Xia X, Yang L, Zhang J, Husain H, Liao Z, Futreal A, Huang J, Yi X, Xu B. National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College Beijing China; Geneplus-Beijing Institute Beijing China; Houston Methodist Research Institute Weill Cornell School of Medicine Houston TX USA; University of Texas MD Anderson Cancer Center Houston TX USA; University of California San Diego Moores Cancer Center La Jolla CA USA; Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University Shanghai China. This study provided evidences that tumor heterogeneity present in ctDNA can predict therapeutic outcome. Tracking serial changes of multiple gene variants in ctDNA in evaluating treatment response could be more sensitive than single gene mutation, as such changes could detect disease progression several weeks earlier than radiographic imaging. Our study suggests that ctDNA analysis can serve as a prognostic and predictive factor for treatment in metastatic breast cancer and points toward new avenues of therapeutic management. Tumor heterogeneity was associated with treatment outcome of metastatic cancers but few studies have examined whether tumor heterogeneity in circulating tumor DNA (ctDNA) can be used to predict treatment outcome. ctDNA analysis was performed in 37 HER2-positive metastatic breast cancer patients treated with pyrotinib. Patients with high tumor heterogeneity had significantly worse PFS outcomes, with a median PFS of 30.0 weeks versus 60.0 weeks for patients with low tumor heterogeneity (hazard ratio [HR], 2.9; P = 0.02). Patients with trunk resistance mutations receiving pyrotinib monotherapy had worse outcomes (HR, 4.5; P = 0.03), with a median PFS of 7.8 weeks versus 27.4 weeks for those with branch resistance mutations or without any resistance mutations in baseline ctDNA. Longitudinal monitoring of 21 patients during treatment showed that the molecular tumor burden index ([mTBI] a measure of the percentage of ctDNA in samples) was positively correlated with tumor size as evaluated by computed tomography (P < 0.0001, Pearson r = 0.52) and detected disease progression 8-16 weeks earlier. Our current findings suggested that ctDNA could be used to assess tumor heterogeneity and predict treatment outcomes. Furthermore, the mTBI is better for assessing therapeutic response than single gene mutations and might supplement the current therapeutic response evaluation system. KEYWORDS: cell-free circulating tumor DNA (ctDNA) tumor heterogeneity trunk/branch resistance mutations PFS metastasis breast cancer DOI: 10.1002/ijc.32536 |
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