Morphological and Molecular Characterization of KRAS G12C-Mutated Lung Adenocarcinomas

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.

Kras G12C Mutated Advanced Non-Small Cell Lung Cancer (NSCLC): Characteristics, Treatment Patterns and Overall Survival from a Danish Nationwide Observational Register Study

“…The higher proportion of females in the KRAS G12C group is in concordance with some recent studies [22][23][24][25][26], but not all identified studies [26][27][28][29][30]. It is well established that KRAS G12C is associated with smoking and that non-squamous cell carcinoma is the most frequent histological subtype [30].…”

Tumor heterogeneity and its impact on sotorasib response in a patient with non-small cell lung cancer

“…Heterogeneity can lead to a decrease in sensitivity to individualized treatment methods. The use of next-generation sequencing techniques greatly facilitates understanding the genetic and epigenetic basis of cancer and its heterogeneity [13]. Intratumoral heterogeneity and different responses to treatment represent a current challenge in the development of targeted therapies in lung cancer patients.…”

Prognostic value ofKRASmutations,TP53mutations and PD-L1 expression among lung adenocarcinomas treated with immunotherapy

“…STK11 mutational inactivation has been associated with a ‘cold’ tumour immune microenvironment with fewer infiltrating T lymphocytes and could represent a major driver to primary resistance to ICI in KRAS -mutated adenocarcinomas 51. Adenocarcinomas with concomitant KRAS p.G12C and STK11 mutations might benefit from the new KRAS G12C inhibitors potentially combined with ICI 52. In contrast, TP53 mutations have been associated with a prominent inflammatory response with increased amount of infiltrating T lymphocytes which could make it susceptible to treatment with ICI 17 26.…”