Cell-free DNA mutations as biomarkers in breast cancer patients receiving tamoxifen
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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
Stefan Sleijfer, email: firstname.lastname@example.org
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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