Morphological and Molecular Characterization of KRAS G12C-Mutated Lung Adenocarcinomas

Radu Pirlog,Florian Guisier,Aude Lamy,Jean-Christophe Sabourin,Ioana Berindan-Neagoe,Florent Marguet,Nicolas Piton

doi:10.3390/cancers14041030

Abstract

Simple SummaryLung 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.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.

Highlights

Lung cancer is the second most common cancer and is responsible for more than 2.2 million cases and almost 1.8 million deaths per year worldwide [1]
We present a retrospective analysis of 202 Kirsten rat sarcoma viral oncogene homolog (KRAS) G12C mutated Lung adenocarcinoma (LUAD) diagnosed in our Department of Pathology
Immunohistochemical, and molecular study presents a cohort of 202 cases of KRAS G12C-mutated LUADs

Summary

Introduction

Lung cancer is the second most common cancer and is responsible for more than 2.2 million cases and almost 1.8 million deaths per year worldwide [1]. Since the approval of targeted therapies against EGFR mutated lung adenocarcinomas (LUADs) by the US Food and Drug Administration (FDA), a dramatic increase in survival has been seen for these patients [4]. The most common activating EGFR mutations are the point mutation L858R and deletions in exon 19 [5] These mutations, together with rearrangements in ALK and ROS genes, can be successfully targeted by tyrosine kinase inhibitors [6]. Additional functional mutations are found in RET, MET, and BRAF genes, which increase the number of actionable mutations for LUAD patients. These targeted therapies have led to major advances in LUAD therapy. New therapies and new actionable mutations are under investigation [7]

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