Research Papers:

ctDNA dynamics: a novel indicator to track resistance in metastatic breast cancer treated with anti-HER2 therapy

Fei Ma, Wenjie Zhu, Yanfang Guan, Ling Yang, Xuefeng Xia, Shanshan Chen, Qiao Li, Xiuwen Guan, Zongbi Yi, Haili Qian, Xin Yi and Binghe Xu _

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Oncotarget. 2016; 7:66020-66031. https://doi.org/10.18632/oncotarget.11791

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Fei Ma1,*, Wenjie Zhu1,*, Yanfang Guan2, Ling Yang2, Xuefeng Xia3, Shanshan Chen1, Qiao Li1, Xiuwen Guan1, Zongbi Yi1, Haili Qian4, Xin Yi2, Binghe Xu1

1Department of Medical Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China

2Geneplus-Beijing, Beijing, China

3Houston Methodist Research Institute, Weill Cornell School of Medicine, Houston, TX, USA

4State Key Laboratory of Molecular Oncology, Cancer Institute/Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China

*These authors have contributed equally to this work

Correspondence to:

Binghe Xu, email: [email protected]

Keywords: circulating tumor DNA, dynamics, progression, metastatic breast cancer, anti-HER2 therapy

Received: May 11, 2016     Accepted: August 25, 2016     Published: September 1, 2016


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.

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.

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.

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.

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