中国学者发现转移性乳腺癌抗HER2疗法耐药性监测新指标
大多数研究利用循环肿瘤DNA（ctDNA）仅监测肿瘤的一个或几个基因，而且未能制定可操作的临床实践标准。
2016年9月1日，美国《肿瘤标靶》在线发表中国医学科学院北京协和医学院附属肿瘤医院肿瘤研究所、国家癌症中心、分子肿瘤学国家重点实验室、北京吉因加、美国康奈尔大学医学院休斯敦卫理公会医院研究所的研究报告，评估了通过连续ctDNA测序检测抗HER2疗法耐药性的可行性。
该研究（NCT01937689）前瞻性收集了18例口服抗HER1/HER2酪氨酸激酶抑制剂（吡咯替尼）HER2阳性转移性乳腺癌患者的52份血浆标本，通过基因测序连续检测其ctDNA。
结果在14例疾病进展患者中确定原发性治疗耐药6例。对该亚组进行治疗前后ctDNA比较，结果发现4例（66.7%）HER2扩增且疾病进展。TP53突变检出3例（50.0%），PI3K/mTOR通路相关基因突变检出3例（50.0%），这两种基因突变也与耐药有显著相关性。治疗期间如有下列情况，应考虑HER2抑制剂耐药：ctDNA首次或持续检出HER2扩增；包括TP53/PIK3CA/mTOR/PTEN的任一耐药相关基因突变出现或频率增加≥20%。
与CT扫描相比，利用预定义标准分析动态ctDNA对于识别药物耐药较敏感（敏感度85.7%，特异度55.0%），一致性高达82.1%。此外，ctDNA标准还具有判断HER2阳性转移性乳腺癌预后的作用。
因此，动态的ctDNA测序可被用于确定耐药，以及指导抗HER2靶向疗法在转移性乳腺癌患者中的精准实施。
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Oncotarget. 2016 Sep 1. [Epub ahead of print]
ctDNA dynamics: a novel indicator to track resistance in metastatic breast cancer treated with anti-HER2 therapy.
Ma F, Zhu W, Guan Y, Yang L, Xia X, Chen S, Li Q, Guan X, Yi Z, Qian H, Yi X, Xu B.
Department of Medical Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China; Geneplus-Beijing, Beijing, China; Houston Methodist Research Institute, Weill Cornell School of Medicine, Houston, TX, USA; State Key Laboratory of Molecular Oncology, Cancer Institute/Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
BACKGROUND: Most studies utilizing circulating tumor DNA (ctDNA) to monitor disease interrogated only one or a few genes and failed to develop workable criteria to inform clinical practice. We evaluated the feasibility of detecting resistance to anti-HER2 therapy by serial gene-panel ctDNA sequencing.
METHODS: 52 plasma samples were prospectively collected from 18 patients with HER2-positive metastatic breast cancer who were treated with an oral anti-HER1/HER2 tyrosine kinase inhibitor (ClinicalTrials.gov NCT01937689). ctDNA was assayed by gene-panel target-capture next-generation sequencing.
RESULTS: Primary therapeutic resistance was identified in 6 out of 14 patients with events of progressive disease. For this subset comparison of pre- and post-treatment ctDNA assay results revealed that HER2 amplification concurred with disease progression (4/6, 66.7%). Mutations in TP53 (3/6, 50.0%) and genes implicated in the PI3K/mTOR pathway (3/6, 50.0%) were also dominant markers of resistance. Together, resistance to HER2 blockade should be indicated during treatment if any of the following situations applies: 1) recurrence or persistence of HER2 amplification in the blood; 2) emergence or ≥20% increase in the fraction of mutations in any of these resistance-related genes including TP53/PIK3CA/MTOR/PTEN. Compared with CT scans, dynamic ctDNA profiling utilizing pre-defined criteria was sensitive in identifying drug resistance (sensitivity 85.7%, specificity 55.0%), with a concordance rate up to 82.1%. Besides, the ctDNA criteria had a discriminating role in the prognosis of HER2-positive metastatic breast cancer.
CONCLUSIONS: Longitudinal gene-panel ctDNA sequencing could be exploited to determine resistance and guide the precise administration of anti-HER2 targeted therapy in the metastatic setting.
KEYWORDS: anti-HER2 therapy; circulating tumor DNA; dynamics; metastatic breast cancer; progression
PMID: 27602761
DOI: 10.18632/oncotarget.11791