Clinicopathologic features, concurrent genomic alterations, and clinical outcomes of patients with KRAS G12D mutations in resected lung adenocarcinoma

Background: In light of the ongoing clinical development of KRAS G12D-specific inhibitors, we sought to investigate the clinicopathologic, co-occurring genomic features and outcomes of patients with KRAS G12Dmutant lung adenocarcinoma. Methods: 3828 patients with completely resected primary lung adenocarcinomas were examined for KRAS mutations between 2008 and 2020. The association between KRAS G12D and clinicopathologic features, molecular profiles, and outcomes was investigated. Results: 65 patients (1.7%) with KRAS G12D-mutant lung adenocarcinoma were identified. KRAS G12D mutation was more frequent in males, former/current smokers, radiologic solid tumors, and invasive mucinous adenocarcinoma. TP53 and STK11 were the two most frequent concomitant mutations in the KRAS G12D group. KRAS G12D mutation did not appear to be a prognostic factor in resected stage I-III lung adenocarcinomas, while KRAS non-G12D mutation was related to worse survival, especially in stage I tumors. KRAS G12D mutations were associated with positive but low (1-49%) PD-L1 expression compared to negative (<1%), while KRAS non-G12D mutation was associated with high PD-L1 expression (>= 50%). TP53 co-mutation indicated higher PD-L1 expression, while STK11 co-mutation had a negligible impact on PD-L1 expression. Furthermore, data mining of MSK datasets from cBioPortal revealed that KRAS G12D and SKT11 co-mutation were associated with a diminished response to immunotherapy. Conclusions: KRAS G12D-mutant lung adenocarcinoma harbored unique clinicopathologic and genomic characteristics. Despite not being prognostic in resected lung adenocarcinoma, KRAS G12D might be a valuable biomarker in combination with certain co-mutations for identifying relevant subgroups of patients that could eventually influence treatment regimens