Therapy monitoring in plasma DNA of patients with mRCC

Renal cell carcinoma is the most common type of kidney cancer in adults accounting for approximately 3% of adult malignancies and 90-95% of neoplasms arising from the kidney. About 20% to 25% of patients diagnosed have already developed metastases. The five-year survival rates for metastatic cancer renal cell carcinoma (mRCC) are approximately 8%, which indicates that mRCC is a deadly disease. The implementation of targeted therapies changed the therapeutic possibilities in mRCC and led to a dramatically improved survival of 27 months for progression-free survival and 40 months of overall survival. Nevertheless, due to the tremendous heterogeneity of these tumors most patients become resistance to these therapies within a few months. Therefore, sequential therapy is considered an innovative option providing maximal efficacy with a minimum risk of therapeutic failure for mRCC. Monitoring of treatment response in mRCC is mostly based on imaging techniques, i.e. computed tomography or MRI. Stopping of one treatment and changing to an alternative treatment regime is currently solely based on unacceptable toxicity and progressive disease based on clinical parameters, which are often not very accurate. A valuable alternative could be analysis of cell-free circulating tumor DNA in plasma in order to obtain genetic follow-up data in a non-invasive manner. The main aim of the proposed study is to monitor therapy response of mRCC patients under targeted therapy through two lines of treatment in plasma DNA. The project involves a non- invasive establishment of the mutational spectrum of 50 genes that are frequently mutated in RCC and an assessment of copy number aberrations. Results from the molecular genetic analysis will be linked to clinical data in order to investigate whether changes in tumor genomes can be associated with treatment response and tumor progression in plasma DNA of mRCC patients undergoing 1st and 2nd line treatment. Knowledge of underlying resistance mechanisms is a prerequisite to overcome acquired resistance and to guide treatment decisions, therefore a secondary aim is to define resistance mechanisms and to assess the pathways they control using cell culture studies. Results of this study might contribute to a better understanding of renal cancer and might lead to the identification of novel predictive and prognostic biomarkers, which might pave the way for novel strategies to improve the care of patients with renal cancer and represents an important contribution to the realization of personalized medicine.

The so-called liquid biopsy offers a powerful and minimally invasive approach for successive profiling of tumor-specific alterations in blood and other body fluids. In particular, the detection of cell-free circulating tumor DNA (ctDNA) from blood plasma is very promising and has already been used in many solid tumors to monitor the success of treatment during anti-tumor therapy and for the early detection of recurrences. Despite showing great promise in a variety of solid cancers, the utility of liquid biopsy approaches in the management of renal cell carcinoma (RCC), the most common form of malignant kidney tumours with many different subtypes, is largely lagging behind. Therefore, the goal of this study was to provide insights into the ctDNA levels, composition and clinical potential of liquid biopsy approaches in the management of RCC patients. We applied high-resolution sequencing techniques and sophisticated bioinformatic algorithms for the detailed characterization of ctDNA in RCC. The use of genome-wide as well as targeted personalized sequencing techniques enabled the detection of tumor-specific changes in the plasma of renal cancer patients. Furthermore, the sensitivity of existing analytical methods could be improved due to new insights into the biology and composition of ctDNA. In addition, it could be shown that the analysis of ctDNA correlates with the response to so-called targeted therapies and can thus be used for therapy monitoring in RCC. These comprehensive molecular genetic results provide an insight into the biology of metastatic renal cell carcinoma, furthermore, these results make an important contribution to the realization of personalized cancer medicine.