ctDNA dynamics: a novel indicator to track resistance in metastatic breast cancer treated with anti-HER2 therapy.
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.
Department of Medical Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
Fei
F
Ma
Department of Medical Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
Wenjie
W
Zhu
Geneplus-Beijing, Beijing, China.
Yanfang
Y
Guan
Geneplus-Beijing, Beijing, China.
Ling
L
Yang
Houston Methodist Research Institute, Weill Cornell School of Medicine, Houston, TX, USA.
Xuefeng
X
Xia
Department of Medical Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
Shanshan
S
Chen
Department of Medical Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
Qiao
Q
Li
Department of Medical Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
Xiuwen
X
Guan
Department of Medical Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
Zongbi
Z
Yi
State Key Laboratory of Molecular Oncology, Cancer Institute/Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
Haili
H
Qian
Geneplus-Beijing, Beijing, China.
Xin
X
Yi
Department of Medical Oncology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
Binghe
B
Xu
D000178:Acrylamides / Q000627:therapeutic use*; D000634:Aminoquinolines / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000097:blood* / Q000235:genetics; D001943:Breast Neoplasms / Q000097:blood* / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D016022:Case-Control Studies; D000074141:Circulating Tumor DNA / Q000097:blood / Q000235:genetics*; D058534:Class I Phosphatidylinositol 3-Kinases / Q000235:genetics; D004273:DNA, Neoplasm / Q000097:blood / Q000235:genetics*; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D009154:Mutation; D051059:PTEN Phosphohydrolase / Q000235:genetics; D011379:Prognosis; D011446:Prospective Studies; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors*; D015996:Survival Rate; D058570:TOR Serine-Threonine Kinases / Q000235:genetics
D000178:Acrylamides; D000634:Aminoquinolines; D014408:Biomarkers, Tumor; D000074141:Circulating Tumor DNA; D058534:Class I Phosphatidylinositol 3-Kinases; D004273:DNA, Neoplasm; D051059:PTEN Phosphohydrolase; D018719:Erb-b2 Receptor Tyrosine Kinases; D058570:TOR Serine-Threonine Kinases; C000622954:pyrotinib; C484760:PIK3CA protein, human; C508053:ERBB2 protein, human; C494929:PTEN protein, human
anti-HER2 therapy; circulating tumor DNA; dynamics; metastatic breast cancer; progression