Prof. Christoph Klein, University of Regensburg and Fraunhofer ITEM-R; Dr Sebastian Scheitler, Fraunhofer ITEM-R; Dr Melanie Werner-Klein, University of Regensburg; Dr Martin Hoffmann, Fraunhofer ITEM-R
Cancer staging determines the extent to which a cancer has developed by spreading and takes into account tumor size, invasion in adjacent organs, spread into lymph nodes (if any), and whether it metastasized to distant organs. The stage of a cancer is generally used to find a suitable strategy for its therapy. The time-window after primary surgery and before manifestation of metastasis, i.e. during clinically undetectable minimal residual disease (MRD), defined by disseminated cancer cells (DCCs) left behind after primary tumor (PT) surgery, may be particularly suitable to prevent lethal metastasis (Polzer and Klein 2013). Circulating tumor cells (CTCs) are found in blood and inform about the molecular characteristics of a large tumor mass, either non-resected PT or metastasis, which are targeted by the current therapy decision. In contrast, DCCs inform about MRD after resection of the tumor mass, about the cells that may give rise to metastasis in the future - months or years after periods of evolution and progression. Currently only circumstantial knowledge is available about MRD. Consequently (neo-)adjuvant therapies, i.e. the administration of systemic drugs before or after surgery, improve outcome in only about 20% of patients (Gianni et al. 2011). Moreover, when targeted therapies with documented efficacy in patients with manifested metastasis were applied in the adjuvant therapy setting, success was low (Polzer and Klein 2013). Recent data suggests that DCCs acquire alterations critical for metastatic progression outside of the PT, e.g. in the lymph node. In consequence this indicates that therapeutic target selection for treatment of MRD should not be based on molecular characteristics of the PT, but on cells that have successfully left the PT, entered and survive in a new organ, possibly hostile environment, i.e. on DCCs (Werner-Klein et al. 2018). The underlying technical problem is the provision of accurate methods for the early determination of MRD and corresponding improved strategies for treating MRD.
The presented technology provides a highly sensitive method for early metastatic disease detection, prognosis, staging and selection of (neo-)adjuvant therapies based on molecular characterization of DCCs in the context of minimal residual disease. Upon isolation of DCCs from single cell suspensions of lymph nodes and/or bone marrow their genetic, epigenetic and transcriptomic signatures can be analyzed. These signatures provide prognosis value for identification of patients at risk to develop metastasis as well as patient stratification and precision therapy in adjuvant treatment setting (Ulmer et al. 2014, Ulmer et al. 2018, Werner-Klein et al. 2018).
- Development of diagnostic tests to be used for staging, patient stratification, personalized adjuvant cancer therapy
- Development of laboratory automation for detection and isolation of DCCs from tissues for routine pathology
The technology has been already accredited for detection and isolation of DCCs for molecular identification of somatic alterations (DIN EN IS0/IEC 17020). In order for the technology to be implemented into routine pathology and/or diagnostic laboratories, further development into a commercial diagnostic kit as well the automation of the entire workflow is necessary.
Patent pending. European Patent Application: EP 3 199 641 A1
Ulmer et al. (2014) PLoS medicine 11, e1001604
Werner-Klein et al (2018) Nat Commun 9, 595
Ulmer et al. (2018). EurJCancer 91, 1-10.
Polzer and Klein (2013) Nature Med. 19(3)
Gianni et al. (2011) Lancet Oncol. 12:236-244