Morphological and Molecular Characterization of KRAS G12C-Mutated Lung Adenocarcinomas
Radu Pirlog1,2, Nicolas Piton1, Aude Lamy1
1Pathology Department and INSERM U1245, Rouen University Hospital, Normandy University, 76000 Rouen, France.
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.
Insights
Researchers identified a specific subtype of lung adenocarcinoma (LUAD) with KRAS G12C and STK11 mutations. This subgroup shows lower TTF1 and PD-L1 positivity, potentially improving response to KRAS G12C inhibitors.
Area of Science:
- Oncology
- Genomics
- Molecular Biology
Background:
- Lung adenocarcinoma (LUAD) is a major non-small cell lung cancer subtype.
- KRAS mutations, particularly KRAS G12C, are common in LUAD and historically challenging to treat.
- Targeted KRAS G12C inhibitors show promise in early clinical trials.
Purpose of the Study:
- To analyze the morphological and genomic landscape of KRAS G12C-mutated LUAD.
- To identify patient subgroups with potential for improved response to KRAS G12C inhibitors.
Main Methods:
- Next-generation sequencing of 202 KRAS G12C-mutated LUAD cases.
- Analysis of histological subtypes, tumor-infiltrating lymphocytes (TILs), TTF1, and PD-L1 expression.
- Genomic profiling to identify co-occurring mutations.
Main Results:
- Acinar subtype was most common (29.7%).
- High TILs observed in over 60% of cases.
- KRAS G12C and STK11 co-mutation found in 25.2% of cases.
- This subgroup exhibited significantly lower TTF1 and PD-L1 positivity (p=0.0092 and p<0.0001, respectively).
Conclusions:
- Combined morphological and genomic analysis aids understanding of LUAD biology.
- Identification of the KRAS G12C/STK11 co-mutated subgroup may guide targeted therapy selection.
- This subgroup might benefit from specific KRAS G12C inhibitor treatment strategies.
