Personalized Monitoring in Breast Cancer
PerMoBreCan is working to establish robust circulating biomarkers (e.g.: circulating tumor cells, cell-free tumor DNA, exosomes, and cytokines from blood) for ultra-early detection of systemic recurrence with a view to providing the possibility of early secondary adjuvant therapy.
About the project
The aim of the PerMoBreCan research project is to investigate the clinical relevance of new circulating tumor biomarkers with respect to predicting and detecting early systemic recurrence in early stage breast cancer patients (stages I and II). The project is organized into several sub-projects and includes investigation of primary tumor and circulating tumor biomarkers in high-risk breast cancer patients (all stages I and II receiving adjuvant chemotherapy, with and without relapse) included in the PBCB project.
Analysis of primary tumor
Total RNA from the primary tumor will be fully sequenced on our Ion Proton (NGS). MicroRNA profiles from tumors sensitive to adjuvant chemotherapy will be compared with profiles from resistant tumors. In addition, samples will be checked for mutations at the DNA level, especially in the estrogen receptor and other known oncogenes. Also, the Ki67-Adjusted Mitotic Score (KAMS), which provides a measure of cell cycle kinetics of the proliferative population of cells, will be considered. Centrosome amplification (as a measure of tumor heterogeneity and chromosome instability) will be analyzed. The work is carried out by researchers at the Department of Pathology, Stavanger University Hospital.
Clinical significance of circulating tumour cells in early breast cancer
Circulating tumour cells in blood have been shown to be prognostic in both metastatic and non-metastatic breast cancer. The conventional method for detecting circulating tumour cells (CellSearch) relies on the surface protein EpCAM, which is downregulated in some circulating tumour cells as a result of an epithelial to mesenchymal cell change. In this study, we will investigate the clinical significance of EpCAM-independent detection of circulating tumour cells in early breast cancer. The tumor cells are enriched using the immunomagnetic method MINDEC, which we have recently developed (Lapin et al. 2016, Scientific Rep), and are detected by quantitative RT-PCR by measurement of a panel of mRNA that is virtually absent in normal blood cells but present in the tumor cells. The panel includes both epithelial and mesenchymal mRNA.Blood samples taken before surgery are examined for prognostic significance. Biannual blood tests after surgery constitute a unique material for evaluating the value of the examinations in relation to disease surveillance. Over 171 blood samples from 133 PBCB patients have been examined so far, with very promising findings. The work is carried out by researchers from the Research Group for Cancer and Medical Physics, Micrometastasis Group, Stavanger University Hospital.
Clinical significance of circulating tumour DNA in early breast cancer
Circulating tumor DNA (ctDNA) is a promising new biomarker for prognosis and disease development in breast cancer. ctDNA originates from dying cells from a primary tumor or any metastases. It can be detected by tumor-specific mutations, whether for point mutations or insertions/deletions. In this study, we will detect and characterize ctDNA using next-generation sequencing. We will then use a breast cancer-specific gene panel and increase sensitivity to detection of rare variants by molecular barcoding.
Plasma from patients in the PBCB study will be analysed, both preoperative samples and semi-annual follow-up samples. The level of ctDNA and any increase in the incidence of specific mutations will be compared with radiological and biochemical monitoring of the disease. In this way, we can both reveal whether measurement of ctDNA has a clinical significance and detect any resistance mutations if patients receive chemotherapy The work is carried out by researchers from the Research Group for Cancer and Medical Physics, Micrometastasis Group, Stavanger University Hospital.
Circulating micro-RNA from exosomes
MicroRNA profiles from primary tumors, which are sensitive to adjuvant chemotherapy, will be compared with profiles from more treatment-resistant tumors. Candidate microRNA, found in analyses of primary tumors, which correlates with treatment response will be analyzed on total RNA isolated from exosomes from high-risk patients. Here we will see whether or not these microRNAs can be used for treatment monitoring, follow-up and early detection of systemic recurrence. The work is carried out by researchers at the Department of Pathology, Stavanger University Hospital.