Cell-free DNA mutations as biomarkers in breast cancer patients receiving tamoxifen.
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.
Department of Medical Oncology and Cancer Genomics, Erasmus MC Cancer Institute, Rotterdam, The Netherlands.
Maurice Phm
MP
Jansen
Department of Medical Oncology and Cancer Genomics, Erasmus MC Cancer Institute, Rotterdam, The Netherlands.
John Wm
JW
Martens
Department of Medical Oncology and Cancer Genomics, Erasmus MC Cancer Institute, Rotterdam, The Netherlands.
Jean Ca
JC
Helmijr
Department of Medical Oncology and Cancer Genomics, Erasmus MC Cancer Institute, Rotterdam, The Netherlands.
Corine M
CM
Beaufort
Department of Pathology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands.
Ronald
R
van Marion
Department of Pathology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands.|Cancer Computational Biology Center, Rotterdam, The Netherlands.
Niels Mg
NM
Krol
Department of Pathology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands.
Kim
K
Monkhorst
Department of Medical Oncology and Cancer Genomics, Erasmus MC Cancer Institute, Rotterdam, The Netherlands.
Anita Mac
AM
Trapman-Jansen
Department of Medical Oncology and Cancer Genomics, Erasmus MC Cancer Institute, Rotterdam, The Netherlands.
Marion E
ME
Meijer-van Gelder
Department of Medical Oncology and Cancer Genomics, Erasmus MC Cancer Institute, Rotterdam, The Netherlands.
Marjolein Ja
MJ
Weerts
Department of Medical Oncology and Cancer Genomics, Erasmus MC Cancer Institute, Rotterdam, The Netherlands.
Diana E
DE
Ramirez-Ardila
Department of Pathology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands.
Hendrikus Jan
HJ
Dubbink
Department of Medical Oncology and Cancer Genomics, Erasmus MC Cancer Institute, Rotterdam, The Netherlands.
John A
JA
Foekens
Department of Medical Oncology and Cancer Genomics, Erasmus MC Cancer Institute, Rotterdam, The Netherlands.
Stefan
S
Sleijfer
Department of Medical Oncology and Cancer Genomics, Erasmus MC Cancer Institute, Rotterdam, The Netherlands.
Els Mjj
EM
Berns
D054758:A Kinase Anchor Proteins / Q000235:genetics; D018931:Antineoplastic Agents, Hormonal / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000097:blood / Q000235:genetics; D001940:Breast / Q000473:pathology; D001943:Breast Neoplasms / Q000097:blood / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D050882:CREB-Binding Protein / Q000235:genetics; D000073888:Cell-Free Nucleic Acids / Q000097:blood / Q000235:genetics* / Q000302:isolation & purification; D058534:Class I Phosphatidylinositol 3-Kinases / Q000235:genetics; D003598:Cytoskeletal Proteins / Q000235:genetics; D004273:DNA, Neoplasm / Q000097:blood / Q000235:genetics* / Q000302:isolation & purification; D018450:Disease Progression; D005091:Exons / Q000235:genetics; D005260:Female; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D017422:Sequence Analysis, DNA; D051901:Smad4 Protein / Q000235:genetics; D013629:Tamoxifen / Q000627:therapeutic use*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics
D054758:A Kinase Anchor Proteins; C119719:AKAP9 protein, human; D018931:Antineoplastic Agents, Hormonal; D014408:Biomarkers, Tumor; D000073888:Cell-Free Nucleic Acids; D003598:Cytoskeletal Proteins; D004273:DNA, Neoplasm; C497796:SMAD4 protein, human; D051901:Smad4 Protein; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D013629:Tamoxifen; D050882:CREB-Binding Protein; C494363:CREBBP protein, human; D058534:Class I Phosphatidylinositol 3-Kinases; C484760:PIK3CA protein, human
breast cancer; cell-free DNA; disease progression; tamoxifen therapy; targeted next generation sequencing