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, Binghe Xu _

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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: bhxu@hotmail.com

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.

Author Information

Fei Ma

Wenjie Zhu

Yanfang Guan

Ling Yang

Xuefeng Xia

Shanshan Chen

Qiao Li

Xiuwen Guan

Zongbi Yi

Haili Qian

Xin Yi

Binghe Xu
Primary Contact  _

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