Evaluation of the Prognostic and Predictive Significance of EGFR, Kirsten Rat Sarcoma (KRAS), Anaplastic Lymphoma Kinase , Programmed Death-Ligand 1 (PD-L1) Protein and Microsatellite Instability (MSI) in Lung Cancer

Research hypothesis The research hypothesis for this study is that the expression/status of various molecular biomarkers (mainly including EGFR, KRAS, ALK, PD-L1 and MSI) may confer additional prognostic ( in terms of disease outcome i.e. PFS and OS) and/or predictive ( in terms of treatment response) information for lung cancer patients.

The research hypothesis is reflected in the primary objective of this study, which is to further evaluate the prognostic and predictive significance of currently existing molecular markers (EGFR, KRAS, ALK, PD-L1 and MSI), as well as of future biomarkers that may evolve. Secondary objectives include the evaluation of the differential expression/status of the examined biomarkers (EGFR, KRAS, ALK, PD-L1 and MSI) and standard clinicopathologic parameters including: PFS, OS and treatment response as well as age, gender, smoking history/status, performance status (PS), serum lactate dehydrogenase (LDH) and albumin levels, disease stage, tumor size, histology and grade, presence or absence of brain metastases, presence or absence of liver metastases and number of metastatic sites (all at diagnosis), and treatment data (type of treatment(s) received and treatment response. Potential correlations/interactions between the examined biomarkers will also be explored.

Rationale for conducting this study Rationale for biomarker selection The primary aim of this study is to further clarify the differential expression/status and frequency of EGFR and KRAS mutations, ALK rearrangements, PD-L1 protein and MSI, as well as their association with various clinicopathologic parameters, including treatment response, progression-free survival (PFS) and overall survival (OS), in a large and heterogeneous cohort of patients with lung cancer (including both NSCLC and SCLC).

EGFR, KRAS and ALK are among the most clinically important biomarkers of treatment response in NSCLC; EGFR and ALK represent major therapeutic targets in NSCLC. However, relatively little is known as regards their expression and potential clinical significance in SCLC.

PD-L1 protein represents a candidate biomarker of prognosis as well as therapeutic target. Previous experimental and clinical research data have strongly suggested that immune check point inhibitors, including anti-PD-1 and anti-PD-L1 agents, may increase tumor cell vulnerability to immune destruction and potentially improve survival of patients with lung cancer. The MSI phenotype may also affect prognosis of NSCLC patients and response to treatment, including immune checkpoint blockade with PD-1 inhibitors.