The Molecular Epidemiology of Non-Small Cell Lung Cancer

Abstract: The aim of this thesis was to explore the role of a spectrum of biomarkers, for disease classification or predictors of treatment outcomes in non-small cell lung cancer (NSCLC).Paper I examined the impact of systemic inflammation on the clinical outcome of NSCLC patients.Paper II evaluated if plasma protein markers are able to predict immunotherapy response and if they are associated with patient survival. Paper III examined outcomes and relapse patterns in NSCLC patients treated with chemoradiotherapy with curative intent.In Paper IV we identified patients with tumors harboring a KRAS G12C mutation and determined the clinical characteristics in comparison to patients with other KRAS mutations and without KRAS mutations. Results in Paper I showed that systemic inflammation is pronounced in NSCLC and has a substantial effect on overall survival in advanced stage NSCLC. In Paper III, inflammation was linked to worse overall survival in patients treated with curative chemoradiotherapy and mOS was drastically higher in patients without signs of systemic inflammation. Moreover, in Paper II, we used a multiplex proteomic assay to investigate expression levels of various proteins involved in immune cell activation and could show an association between T-cell activation markers and response to immunotherapy.In Paper III, relapse patterns were influenced by the presence of driver mutation alterations. This indicates that fundamental biological mechanisms behind local relapse and metastatic dissemination are regulated by early mutational events such as classical lung adenocarcinoma driver mutations. Likewise, in Paper IV, unlike other KRAS variants, patients with the specific KRAS G12C mutation subtype had a large fraction of CNS metastasis at diagnosis, normally with the CNS as the only metastatic site. These findings indicate a need for CNS monitoring as a routine in curative treatment settings and suggests that KRAS G12C patients should be evaluated with CT-scans of the brain during initial diagnostic procedures.In conclusion, available but underutilized parameters from routine diagnostics have prognostic utility and impact on patient stratification. These biomarkers provide guidance for the evaluation of treatment efficacy and disease monitoring and deserve more attention during diagnostic work-up of lung cancer patients.  However, the mechanics behind this impact is less well understood and offers avenues for further research.