Research Papers:

Cell-free DNA mutations as biomarkers in breast cancer patients receiving tamoxifen

Maurice P.H.M. Jansen, John W.M. Martens, Jean C.A. Helmijr, Corine M. Beaufort, Ronald van Marion, Niels M.G. Krol, Kim Monkhorst, Anita M.A.C. Trapman- Jansen, Marion E. Meijer-van Gelder, Marjolein J.A. Weerts, Diana E. Ramirez- Ardila, Hendrikus Jan Dubbink, John A. Foekens, Stefan Sleijfer _ and Els M.J.J. Berns

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Oncotarget. 2016; 7:43412-43418. https://doi.org/10.18632/oncotarget.9727

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Maurice P.H.M. Jansen1, John W.M. Martens1, Jean C.A. Helmijr1, Corine M. Beaufort1, Ronald van Marion2, Niels M.G. Krol2,3, Kim Monkhorst2, Anita M.A.C. Trapman-Jansen1, Marion E. Meijer-van Gelder1, Marjolein J.A. Weerts1, Diana E. Ramirez-Ardila1, Hendrikus Jan Dubbink2, John A. Foekens1, Stefan Sleijfer1, Els M.J.J. Berns1

1Department of Medical Oncology and Cancer Genomics, Erasmus MC Cancer Institute, Rotterdam, The Netherlands

2Department of Pathology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands

3Cancer Computational Biology Center, Rotterdam, The Netherlands

Correspondence to:

Stefan Sleijfer, email: [email protected]

Keywords: breast cancer, tamoxifen therapy, targeted next generation sequencing, cell-free DNA, disease progression

Received: February 12, 2016     Accepted: May 08, 2016     Published: May 30, 2016


The aim was to identify mutations in serum cell-free DNA (cfDNA) associated with disease progression on tamoxifen treatment in metastatic breast cancer (MBC). Sera available at start of therapy, during therapy and at disease progression were selected from 10 estrogen receptor (ER)-positive breast cancer patients. DNA from primary tumor and normal tissue and cfDNA from minute amounts of sera were analyzed by targeted next generation sequencing (NGS) of 45 genes (1,242 exons). At disease progression, stop-gain single nucleotide variants (SNVs) for CREBBP (1 patient) and SMAD4 (1 patient) and non-synonymous SNVs for AKAP9 (1 patient), PIK3CA (2 patients) and TP53 (2 patients) were found. Mutations in CREBBP and SMAD4 have only been occasionally reported in breast cancer. All mutations, except for AKAP9, were also present in the primary tumor but not detected in all blood specimens preceding progression. More sensitive detection by deeper re-sequencing and digital PCR confirmed the occurrence of circulating tumor DNA (ctDNA) and these biomarkers in blood specimens.

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