Lung cancer is the leading cause of death due to cancer worldwide. Survival rates of patients with lung cancer and mesothelioma continue to be very low, with 5-year survival rates of 12% and 5%, respectively. Systemic treatment with chemotherapy has reached its plateau. Better survival rates can only be achieved through a better understanding of molecular biology of primary tumors and host characteristics, which will enable us to tailor and individualize therapy for these malignancies in future. The treatment of non- small-cell lung cancer (NSCL) with tyrosine kinase inhibitors (TKIs), targeted against the epidermal growth factor (EGFR), represent the first individualized treatment approach based on the molecular biology of tumor in lung cancer. Patients with activating EGFR mutations (EGFRmu+) in the primary tumor respond especially well to this type of treatment. However, not all the patients with EGFRmu + tumors respond to therapy and almost all of them eventually develop resistance to the treatment. To overcome resistance, additional biomarkers of sensitivity/resistance to TKIs, such as additional EGFR mutations, KRAS mutations and others need to be researched. Platinum-based chemotherapy represents the standard treatment of lung cancer as well as mesothelioma nowadays. It is predicted that in the near future, by means of a better understanding and detection of certain biomarkers, such as ERCC1 and TOPO2, we will be able to select which patients will respond to a particular cytostatic . In addition, host characteristics were found to influence the efficacy of any particular systemic therapy substantially, with various polymorphisms in genes which code for enzymes from the CYP family playing an important role. All of these factors, alongside with new biomarkers such as tumor stem cells, have not yet been researched thoroughly enough in lung cancer and mesothelioma to allow for individualized treatment approaches.

The main goal of our research project is to study the value of various EGFR mutations, KRAS mutations, cMET amplifications and EML4/ALK translocation for response to TKI therapy in lung adenocarcinoma and mesothelioma and by doing that to form a prognostic model which will predict for resistance/sensitivity to TKI treatment. We will also study the predictive value of the expression of ERCC1 and TOPO2 in primary tumors of lung cancer and mesothelioma for response to different cytostatics, such as cisplatin and etoposide. By determining the plasma drug concentrations and by defining polymorphisms of the CYP3A enzyme, our research will look into the pharmacokinetics of per oral and/or intravenous administered etoposide. Additional research focus will be on determining the presence of cancer stem cells in the blood of lung cancer patients. The trial will include 330 patients with lung cancer and mesothelioma, treated with standard systemic therapy at the University Clinic Golnik (UCG) during the next two years. The efficacy of treatment will be determined by using the RECIST method and on the basis of survival rates. Simultaneously the standards for a tissue and blood sample biobank will be formed and institutionalized. Biological markers in the primary tumor tissue and in the blood will be determined by use of the standard methods at histological and molecular biology laboratory at the UCG. Drug concentrations in the plasma will be determined by liquid chromatography. Prognostic models for response to certain systemic therapy, based on the presence of multiple biomarkers will be formed by using standardized statistical tools and artificial intelligence methods. We strongly believe that our findings will have a significant contribution towards improving the overall understanding of the molecular biology of lung cancer and host characteristics on the outcome of systemic therapy, thus enabling us individualize treatment of patients with these types of cancer in everyday clinical practice.