Overall aims

The overall aim of the research Center is to open up for stronger collaboration between its clinical and basic scientists, and to motivate exchange of ideas on how to best utilize the huge collection of patient materials and data generated for the benefit of the patients. By such synergism we have been able to explore genes/pathways/networks involved in basic processes like cell cycle, DNA repair, apoptosis, and immune response and their impact on breast cancer (BC) development, progression and response to therapy. By performing longitudinal studies of samples at different stages of the disease and characterize such patient materials in full molecular details, we are moving towards a more individual treatment protocols.

The specific aims of the Center are to:

Develop validated stratification criteria based on phenotypic/genotypic profiling of breast tumors.
Use validated phenotypic and genotypic stratification criteria for assessing individual response and prognosis in patients with breast cancer
Identify molecular pathways and biomarkers predicting treatment response and/or resistance using cell lines and orthotopic xenograft models representing the various subgroups of breast cancer
Translate and validate molecular and imaging biomarkers from preclinical models into clinical trials

The research project utilizes a number of previously and newly collected clinical cohorts and consists of several well integrated activities: 1) High throughput molecular characterisation of primary tumors; 2) Detection and characterization of occult tumor cells in bone marrow (BM) (DTC), blood (CTC) and sentinel lymph nodes (SLN) as well as detection of cell free tumor DNA (ctDNA) in blood as a new development; 3) Functional studies in experimental model systems; 4) Metabolic and physiological characterization and 5) Data integration.
The following results are highlighted:

In primary tumors data of miRNA, mRNA and copy number variation (CNV) were generated and are in the process of being integrated with the clinical data for the first set of 450 cases of Oslo2 and all included patients in the Oslo3 (NeoAva) study. Deep sequencing of selected samples have identified new genes involved in breast cancer, and novel mutational processes that evolve across the lifespan of a tumor, with cancer-specific signatures of point mutations and chromosomal instability often emerging late but contributing extensive genetic variation. A new cohort (OsloVal) with long term follow up was analysed and the data used as the main validation cohort in a worldwide computational competition to predict outcome.
Single DTCs from two breast cancer patients were analysed by single-cell array comparative genomic hybridization and next-generation sequencing following whole-genome amplification based on methods developed in this project. Comparing copy-number profiles of the DTCs and the corresponding primary tumor generated from sequencing and SNP-comparative genomic hybridization data revealed tumor clonality and DTC cell diversity, respectively.
Our current results support the potential use of DTC analysis for monitoring purposes during follow up for selection of patients to secondary treatment intervention within clinical trials.
A method for in-situ RNA expression in DTCs (by Quantigene ViewRNA) is established.
Within the Oslo2 early breast cancer observational study, approximately 1000 patients have been analysed for DTCs/CTCs. The results of these analyses compared to primary tumor characteristics and outcome are pending.
Heterogeneity in primary tumors is studied by an advanced in-situ technique for detection of molecular alterations down to the single cell levels using specific probes for tumor specific DNA rearrangements, transcripts (RNA) and proteins, making it possible to visualize molecular abnormalities with regard to tissue architecture. Novel software was developed and applied to a series of HER2 positive tumors neoadjuvantly treated with HER2 targeted therapy.
A proof of principle detection of cell-free tumor DNA (ctDNA) in blood has been performed using several sensitive methods including targeted massive parallel sequencing and digital PCR.
Orthotopic xenograft models have been established and tumor physiology, molecular and metabolic parameters have been characterized. The xenografts have been utilized for assessment of therapeutic effects and for identification of biomarkers predicting response to anti-angiogenic treatment in combination with cytotoxic therapy.
Drug screens have been performed in order to study whether identified miRNAs modulate the response to HER2-targeted therapy and to identify drugs that can sensitize resistant cells to HER2-targeted therapy, - and miRNAs targeting HER2, B7-H3 and S100A4 have been identified
More than 300 tumor tissue samples from the Oslo 2 study have been subjected to HR MAS MRS and four distinct metabolic subgroups were identified. The data have been combined with transcriptomic and proteomic data from the same patients to statistically evaluate relationships between metabolic profiles and molecular subtypes of BC.
Combined analyses of the molecular data generated (CNV, mRNA and protein expression, metabolic profiles and imaging) point to biological functions and molecular pathways being deregulated in multiple cancers, and will be used to identify novel patient subgroups for tailored therapy and monitoring.

In the period 2011-2014 there have been 13 PhD students who have defended or delivered their thesis, 10 PhD student projects are ongoing, 4 of which are directly funded by the Center.
More than 150 Scientific publications have been published from the Center.