KRAS4A, KRAS4B and PD-L1 circulating mRNA analysis and association with progression free survival in a population of metastatic NSCLC patients treated with Pembrolizumab or chemotherapy plus Pembrolizumab by Liquid Biopsy

In the present PhD thesis, the results of a prospective translational research project will be presented. This study was conducted with the final main aim to investigate by liquid biopsy approach if there was a possible correlation between the expression levels of KRAS4A, KRAS4B and PD-L1 cmRNA (circulating mRNA) in plasma of patients affected by metastatic NSCLC (Non-Small Cell Lung Cancer), treated with Pembrolizumab or a combination of chemotherapy plus Pembrolizumab, and if these cmRNA could eventually be used as biomarkers for predicting patients outcomes in terms of PFS (Progression Free Survival). Moreover, having available the genomic DNA from the same patients, an exploratory ancillary project was conducted with the secondary aim to investigate if also some genomic germline variants, or SNPs (Single Nucleotide Polymorphisms), present in the patients’ genome could have an impact on the response to the immunotherapy and, in general, on their outcomes. Firstly, it was confirmed that the KRAS4A, KRAS4B and PD-L1 cmRNA expression levels can be assessed by using the liquid biopsy method. Secondly, it was found out that these expression levels are significantly correlated one with each other. Nonetheless, only KRAS4A showed to have a possible role as a biomarker of patients' PFS. At the same time, it was also preliminary observed that a SNP in particular, the rs10204525, was associated with patients PFS, either when analysed alone and in group with the other SNPs that were selected. Both the main and the secondary aims of this thesis find their roots in the context of Precision oncology and in the current need to implement the use of liquid biopsy, to find and exploit easily accessible biomarkers that may help clinicians in monitoring tumour evolution. In fact, the “one-fit all” approaches used for a long time in the management of cancer patients have been overcome in the recent years. Therefore, the ultimate goal of the current translational cancer research is to define new strategic approaches for tailoring the best therapeutic intervention available for each patients on the basis of their peculiar characteristic, keeping in mind that tumours are highly inter- and intra- heterogeneous pathologies.