Abstract
BackgroundCirculating tumor cells (CTCs) represent a temporal “snapshot” of a patient’s cancer and changes that occur during disease evolution. There is an extensive literature studying CTCs in breast cancer patients, and particularly in those with metastatic disease. In parallel, there is an increasing use of patient-derived models in preclinical investigations of human cancers. Yet studies are still limited demonstrating CTC shedding and metastasis formation in patient-derived models of breast cancer.MethodsWe used seven patient-derived orthotopic xenograft (PDOX) models generated from triple-negative breast cancer (TNBC) patients to study CTCs and distant metastases. Tumor fragments from PDOX tissue from each of the seven models were implanted into 57 NOD scid gamma (NSG) mice, and tumor growth and volume were monitored. Human CTC capture from mouse blood was first optimized on the marker-agnostic Vortex CTC isolation platform, and whole blood was processed from 37 PDOX tumor-bearing mice.ResultsStaining and imaging revealed the presence of CTCs in 32/37 (86%). The total number of CTCs varied between different PDOX tumor models and between individual mice bearing the same PDOX tumors. CTCs were heterogeneous and showed cytokeratin (CK) positive, vimentin (VIM) positive, and mixed CK/VIM phenotypes. Metastases were detected in the lung (20/57, 35%), liver (7/57, 12%), and brain (1/57, less than 2%). The seven different PDOX tumor models displayed varying degrees of metastatic potential, including one TNBC PDOX tumor model that failed to generate any detectable metastases (0/8 mice) despite having CTCs present in the blood of 5/5 tested, suggesting that CTCs from this particular PDOX tumor model may typify metastatic inefficiency.ConclusionPDOX tumor models that shed CTCs and develop distant metastases represent an important tool for investigating TNBC.
Highlights
Circulating tumor cells (CTCs) represent a temporal “snapshot” of a patient’s cancer and changes that occur during disease evolution
Newer therapies and combinations of therapies for triple-negative breast cancer (TNBC) are under active investigation and hold future promise, including the use of poly (ADP-ribose) polymerase (PARP) inhibitors for TNBC patients with homologous recombination DNA repairdeficient cancers associated with BRCA1 mutations, the use of immune checkpoint inhibitors, approaches that target other signaling pathways, or combination therapies, responses are still only observed in a small fraction of patients with advanced TNBC [24,25,26,27,28,29,30]
Metastases were detected in the lung (20/57, 35%), liver (7/57, 12%), and brain (1/57, 2%), with different TNBC patient-derived orthotopic xenograft (PDOX) models displaying varying sites and frequencies of metastases (Table 1)
Summary
Circulating tumor cells (CTCs) represent a temporal “snapshot” of a patient’s cancer and changes that occur during disease evolution. The intertumoral and intratumoral molecular heterogeneity of breast cancer challenges its diagnosis and effective treatment [2,3,4,5,6,7,8,9]. Tailored therapies, such as hormone therapies (e.g., tamoxifen and inhibitors of the enzyme aromatase, involved in estrogen synthesis) for ER-positive disease and trastuzumab (Herceptin®) for HER2-overexpressing breast cancer have led to considerable success in treating some subtypes of breast cancer. Newer therapies and combinations of therapies for TNBC are under active investigation and hold future promise, including the use of poly (ADP-ribose) polymerase (PARP) inhibitors for TNBC patients with homologous recombination DNA repairdeficient cancers associated with BRCA1 mutations, the use of immune checkpoint inhibitors, approaches that target other signaling pathways, or combination therapies, responses are still only observed in a small fraction of patients with advanced TNBC [24,25,26,27,28,29,30]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
