Morphological and Molecular Characterization of KRAS G12C-Mutated Lung Adenocarcinomas

SIMPLE SUMMARY: Lung adenocarcinoma is currently the main histological subtype of lung cancer, accounting for more than 60% of diagnosed cases. The most frequent genomic alteration in these tumors is the mutation of the Kirsten rat sarcoma viral oncogene homolog (KRAS) gene, which until recently was not accessible to targeted therapy. New phase I, II, and III clinical trials using targeted inhibitors for the specific glycine-to-cysteine mutation at codon 12 (KRAS c.34G>T/KRAS G12C) of the KRAS gene showed promising results in approximately 30% of lung adenocarcinomas harboring a KRAS G12C mutation. In our study, we analyzed the genomic landscape of these tumors using next-generation sequencing technology and characterized new molecular subtypes that could be more susceptible to the new class of KRAS G12C inhibitors. ABSTRACT: Lung adenocarcinoma (LUAD) is the major subtype of non-small cell lung cancer, accounting for approximately 60% of cases. Molecular analysis of LUADs showed that the KRAS gene is mutated in up to 30% of cases; such cases were previously considered “undruggable”. The KRAS G12C mutation has become a hot topic of research after initial, promising, phase I and II trials with targeted inhibitors. We analyzed the morphological and genomic landscape of 202 KRAS G12C mutated LUADs using next-generation sequencing, and identified a specific subtype of patients that could show an improved response to KRAS G12C inhibitors. The main histological subtype was acinar in 29.7% of cases. Tumor-infiltrating lymphocytes (TILs) were highly or moderately abundant in more than 60% of cases. The immunohistochemical profile showed TTF1 positivity in 78.7% of cases and PD-L1 positivity in 44.1% of cases. The molecular profile showed an association between KRAS G12C and STK11 mutations in 25.2% of cases. This subgroup was associated with a statistically significant lower TTF1 (p = 0.0092) and PD-L1 (p < 0.0001) positivity. This type of combined morphological and molecular analysis can improve our understanding of tumor biology, and help us to identify specific patient subgroups that can achieve the best treatment response.