Research activities
CLINICAL FOCUS AREAS AND NATIONAL INFRASTRUCTURES
The research activities at the center are organized into 5 Clinical Focus Areas (CFA) that concentrate on detecting and treating cancer, and 5 National Infrastructures (NI) that cover everything from biopsy collection to the implmentation in the clinical setting.
Covering cancer treatment from discovery to final outcome
CLINICAL FOCUS AREA (CFA)
The center has five Clinical Focus Areas (CFA) including screening and diagnosis, treatment decisions, treatment monitoring, residual disease detection, and relapse surveillance. All the projects under the center are covered by one or more of the CFA's.
Each CFA is headed by two leaders, each with international capacities within the field of the CFA. The role of the leaders are to facilitate initiation of national ctDNA studies and trials, through organization of CFA workshops and meetings, where knowledge transfer and collaborations can flourish.
The Clinical Focus Areas (CFA) ensure national collaborations and cover clinical protocols. They aim to improve understanding of cancer biology and document how measuring ctDNA can enhance cancer diagnostics and treatment. The knowledge and information generated from the CFA's will ultimately lead to better treatment of cancer patients in Danish cancer clinics.
Below you can find more information about each of the CFAs.
OBJECTIVE ...
... To investigate the potential roles for minimal-invasive ctDNA detection in early detection of cancer in asymptomatic individuals
We will investigate the potential of using ctDNA as a primary cancer screening tool, and as a tool to supplement ongoing screening. In some screening programs only 60% of invitees take the offered test, potentially participation can be increased if non-responders are offered a blood-based test, after refusing the standard test.
LEADERS
Claus Lindbjerg Andersen
Department of Molecular Medicine
Aarhus University Hospital
Christina Therkildsen
The Gastro Unit
Hvidovre Hospital
OBJECTIVE ...
... To investigate if postoperative ctDNA analysis is a better tool for identifying the patient population likely to benefit from adjuvant therapy, than the risk markers used today.
We will initiate interventional trials aimed at investigating, if postoperative ctDNA-stratification can be used to personalize the adjuvant therapy decision and thereby reduce the fraction of patients receiving futile treatment. In the clinic today it is impossible to define which patients are disease-free after surgery (cured) and who has minimal residual disease and will develop recurrence if no further treatment is given.
For most cancer types it is estimated that more than 60% of patients treated with adjuvant therapy are already cured by surgery alone. Postoperative ctDNA detection is an effective method for distinguishing patients with and without postoperative residual disease, and its implementation in decision making could potentially spare cured patients from undergoing toxic adjuvant chemotherapy while at the same time identify those patients who are most likely to benefit from adjuvant therapy.
LEADERS
Karen-Lise Garm Spindler
Department of Oncology
Aarhus University Hospital
Morten Mau-Sørensen
Department of Oncology
Rigshospitalet
OBJECTIVE ...
... To investigate the benefit of ctDNA guided postoperative surveillance compared to the current “one-size fits all” imaging-based surveillance strategies.
Disease recurrence is a major problem for nearly all cancer types. With current imaging-based surveillance programs, less than 20% of the recurrence events are detected sufficiently early to enable curatively intended intervention. ctDNA analysis enables detection of microscopic residual disease after end of definitive treatment, and moreover detects recurrence up to 16 months before standard radiological surveillance. Hence, ctDNA analysis represents a promising new approach for pinpointing the patients likely to benefit from high-intensity surveillance or to identify patients likely to benefit from early treatment of micro-metastatic disease before detectable by standard imaging methods.
Within the frame of this CFA we will initiate and conduct several clinical studies comparing personalized radiological surveillance, guided by longitudinal ctDNA analysis, to the current “one-size-fits all” surveillance strategies. With a paradigm shift to ctDNA stratified surveillance, we aim for 1) early detection of recurrence, 2) increasing the fraction of patients receiving curative treatment of the recurrence, and 3) improving survival. In essence, a re-allocation of surveillance resources without compromising patient quality of life.
LEADERS
Lars Dyrskjøt Andersen
Department of Molecular Medicine
Aarhus University Hospital
Kåre Gotschalck
Department of Surgery
Horsens Regional Hospital
OBJECTIVE ...
... To investigate if monitoring of ctDNA levels during treatment (including neo-adjuvant and palliative chemo-, targeted-, and immunotherapy) is a better measure of treatment efficacy compared to standard imaging methods.
We will design and initiate interventional trials to compare ctDNA based monitoring approaches to standard imaging strategies performed during neo-adjuvant and palliative treatment. Monitoring of response to treatment in the metastatic setting is performed by standard computed tomography (CT), and while imaging techniques offer an assessment of the tumor burden, the monitoring potential is restricted by a suboptimal detection limit and inherent variability in measurements. Evaluation of treatment efficacy is therefore a major
clinical challenge.
It would be beneficial to only continue therapeutic treatment in patients that show a clear response, and change treatment when possible. Changes in ctDNA levels during treatment are correlated with tumor burden and outcome. ctDNA analysis may provide predictive information regarding treatment efficacy.
LEADERS
Julia S. Johansen
Deptartment of Oncology
Herlev and Gentofte Hospital
OBJECTIVE ...
... To investigate if liquid biopsy analysis can replace or supplement tissue biopsies in the metastatic setting for identification of therapeutically actionable targets and for screening of resistance-causing variants.
With the hypothesis that ctDNA is better suited than biopsies to detect intratumoral subclones and clonal evolution during treatment, we will initiate interventional trials to investigate the clinical benefit of using ctDNA analysis for identification of new therapeutic targets arising during metastatic progression and for tracking the rise of specific variants associated with treatment resistance during disease progression.
LEADERS
Iben Spanggaard
Department of Oncology
Rigshospitalet
Karin Birkenkamp-Demtröder
Department of Molecular Medicine
Aarhus University Hospital
Quality work from biopsy collection to clinical implementation
NATIONAL INFRASTRUCTURES (NI)
To support the projects in the different CFAs, the ctDNA center also consist of five National Infrastructures (NI). The NIs support the research in the different projects across Denmark by offering their expertise, knowledge, and facilities. Further the NIs will ensure a high scientific and clinical standard.
OBJECTIVE ...
... To establish best practice guidelines for collection and pre-analytical processing of liquid biopsies.
Standardized pre-analytical conditions are of utmost importance in national protocols where samples are collected locally but analyzed centrally. By bringing together information from literature and guidelines/recommendations from national and international workgroups we will investigate which sample type (e.g. plasma, urine, feces, and breath exhale), sample collection time point (e.g. in relation to surgery and treatment), type of collection container and sample storage, is best suited for various clinical situations.
In addition, the influence on ctDNA analyses of pre-analytical processing parameters will be investigated, such as time from sampling until start of processing, DNA purification and centrifugation procedures, endogenous and exogenous specific inhibitors affecting analytical accuracy, and pre-amplification of DNA prior to the ctDNA detection.
LEADERS
Rikke Fredslund Andersen
Department of Clinical Immunology and Biochemstry
Sygehus Lillebælt, Vejle
Estrid Høgdall
The Molecular Unit, Department of Pathology
Herlev Hospital
SOP
OBJECTIVE ...
... To coordinate a national assessment of ctDNA analytical methods with the aim of increasing diagnostic efficacy of current ctDNA practices as well as facilitating optimization of existing methods and the development and implementation of novel methods.
New methods and technologies for ctDNA profiling are being continuously developed, mainly focusing on increased detection of minute amounts of ctDNA e.g. by mutation detection using ultra-deep panel sequencing, MassArray and ddPCR or by cell free DNA fragmentation analysis using shallow Whole Genome Sequencing.
We will make several efforts to standardize and optimize these methods. First, an overview of the available assays, capture panels, platforms, and expertise will be collected in a database. The database will include information about analysis work-flows, analytical performance (limit of detection, precision, conformity) and validity of the application for clinical purposes. All participants in DCCC can access this curated database and contribute with analyses or look for relevant cancer-specific assays and sequencing protocols. Secondly, a national quality control program will be developed including traceable national calibrators, national quality control guidelines and sample exchange programs. A number of processes in relation to the methods will be sought optimized, including, the conversion rate of cell free DNA fragments to sequence library and robustness of cell-free DNA pre-amplification.
LEADERS
Mads Heilskov Rasmussen
Department of Molecular Medicine
Aarhus University Hospital
Niels Pallisgaard
Department of Pathology
Zealand University Hospital
OBJECTIVE ...
... We will 1) establish a national bioinformatics infrastructure that ensures the use of consistent, reliable, state-of-the-art bioinformatic ctDNA analyses across Denmark and 2) develop and deploy new computational methods to improve the detection of clinically relevant signals from ctDNA-seq data.
We will set up a national ctDNA-bioinformatics repository containing data, software, workflows and documentation. The repository will be populated with standardised, validated and well-documented software and analysis workflows as well as datasets from the CPs to ensure rapid and consistent quality assessment of both new pipelines and computational methods. We further propose a number of new computational methods that we expect to greatly improve our ability to extract clinically relevant signals from ctDNA-seq data.
LEADERS
Søren Besenbacher
Department of Molecular Medicine
Aarhus University Hospital
OBJECTIVE ...
... To 1) ensure that cost-effectiveness analysis (CEA) is an integrated part of all trials in the ctDNA Research Centre, accompanied by health technology assessment (HTA), business plans and other decision making tools, and 2) planning and supporting data collection for the hospitals and regions to inform and enable clinical implementation of the interventions.
To maintain a preparedness for CEA of ctDNA guided cancer management by ensuring staff with a comprehensive skill set to conduct CEA of ctDNA are part of the Research Centre specialist team. These staff members will help establish economic data collection procedures and employ state-of-the art methodologies to conduct CEA of ctDNA trials and related studies.
LEADERS
Liza Sopina
DaCHE SDU
University of Southern Denmark
Jes Søgaard
DaCHE SDU
University of Southern Denmark
OBJECTIVE ...
... A central element in the philosophy of the cnter is dissemination of knowledge and results within the Research Center, to the scientific community, to the patients, and to the clinical and political decision makers.
Education and knowledge dissemination will take place on several levels:
- Workshops and PhD courses. These will be conducted in collaboration with the DCCC ctDNA network and the Graduate Schools at the Universities of Copenhagen, Aarhus, Aalborg, and Southern Denmark
- Annual meetings for ctDNA Research Center network. Results, progress and new ideas of the Research Center will be presented and discussed at the annual meetings
- Dissemination at national and international meetings and symposiums with participation of international experts. Dissemination at meetings organized in collaboration with patient advocacy groups and aimed at providing the public with information of the results and progress of the Research Center
- Following documentation of clinical benefit and cost-effectiveness of ctDNA guided cancer care we will generate and disseminate business analyses and other decision and implementation supporting information to the hospitals and health regions
- Dissemination to public awareness portals (radio, television, and social media). In close collaboration with the communication departments of the participating institutions, to target key Health Care Media to provide national media coverage of major events in the Research Center e.g. opening of the center, funding, publication of major findings.
LEADERS
Claus Lindbjerg Andersen
Department of Molecular Medicine
Aarhus University Hospital
Morten Mau-Sørensen
Department of Oncology
Rigshospitalet