Τίτλος:
ESR1 methylation: A Liquid biopsy-based epigenetic assay for the follow up of patients with metastatic breast cancer receiving endocrine treatment: Short running title: Liquid biopsy: ESR1 methylation in CTCs and paired ctDNA
Γλώσσες Τεκμηρίου:
Αγγλικά
Περίληψη:
Purpose: Liquid biopsy provides real-time monitoring of tumor evolution and response to therapy through analysis of CTCs and plasma-ctDNA. ESR1 epigenetic silencing potentially affects response to endocrine treatment. We evaluated ESR1 methylation in CTCs and paired plasma-ctDNA. We evaluated ESR1 methylation in CTCs and paired plasma-ctDNA as a potential biomarker for response to everolimus/exemestane treatment. Experimental Design: A highly sensitive and specific real-time MSP assay for ESR1 methylation was developed and validated in: a) 65 primary breast tumors (FFPEs), b) EpCAM+ CTC-fractions (122 patients and 30 healthy donors; HD), c) plasma-ctDNA (108 patients and 30HD), d) in CTCs (CellSearch®) and in paired plasma-ctDNA for 58 BrCa patients. ESR1 methylation status was investigated in CTCs isolated from serial peripheral blood samples of 19 patients with ER+/HER2-advanced BrCa receiving everolimus/exemestane. Results: ESR1 methylation was detected in: a) 25/65(38.5%) FFPEs, b) EpCAM+ CTC-fractions: 26/112(23.3%) patients and 1/30(3.3%) HD, c) plasma-ctDNA: 8/108(7.4%) patients and 1/30(3.3%) HD. ESR1 methylation was highly concordant in 58 paired DNA samples, isolated from CTCs (CellSearch®) and corresponding plasma. In serial peripheral blood samples of patients treated with everolimus/exemestane, ESR1 methylation was observed in 10/36(27.8%) CTC-positive samples, and was associated with lack of response to treatment (p=0.023 Fisher's Exact Test). Conclusions: We report for the first time the detection of ESR1 methylation in CTCs and a high concordance with paired plasma-ctDNA. ESR1 methylation in CTCs was associated with lack of response to everolimus/exemestane regimen. ESR1 methylation should be further evaluated as a potential liquid biopsy-based biomarker. © 2017 American Association for Cancer Research.
Συγγραφείς:
Mastoraki, S.
Strati, A.
Tzanikou, E.
Chimonidou, M.
Politaki, E.
Voutsina, A.
Psyrri, A.
Georgoulias, V.
Lianidou, E.
Περιοδικό:
Clinical Cancer Research
Εκδότης:
American Association for Cancer Research Inc.
Λέξεις-κλειδιά:
chloroplast DNA; epithelial cell adhesion molecule; everolimus; exemestane; androstane derivative; antineoplastic agent; circulating tumor DNA; estrogen receptor alpha; everolimus; exemestane; tamoxifen; tumor marker, Article; cancer hormone therapy; circulating tumor cell; controlled study; DNA methylation; epigenetics; ESR1 gene; follow up; gene; human; human cell; liquid biopsy; major clinical study; metastatic breast cancer; priority journal; treatment response; blood; breast tumor; female; genetic epigenesis; genetics; Kaplan Meier method; liquid biopsy; MCF-7 cell line; metabolism; metastasis; pathology; tumor cell line; tumor embolism, Androstadienes; Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Breast Neoplasms; Cell Line, Tumor; Circulating Tumor DNA; DNA Methylation; Epigenesis, Genetic; Estrogen Receptor alpha; Everolimus; Female; Humans; Kaplan-Meier Estimate; Liquid Biopsy; MCF-7 Cells; Neoplasm Metastasis; Neoplastic Cells, Circulating; Tamoxifen
DOI:
10.1158/1078-0432.CCR-17-1181
