Molecular characterization of early-stage lung adenocarcinoma presenting as subsolid nodules in a real-life European cohort

Objectives: Subsolid nodules emerged as frequent radiological variants of lung adenocarcinoma. Radiological features including solid-component prevalence and larger tumour dimensions prompt tumoral invasiveness guiding prognosis and management. Thus, we aimed to clarify the molecular grounds that dictate these radiological appearances and clinical behaviour in a real-life European-cohort. Additionally, following the growing interest toward targeted-therapies in early-stage diseases, we aimed to present real-life epidemiological data of actionable mutations in these patients. Methods: In this retrospective single-centre study, targeted next-generation sequencing was performed continuatively in all the resected subsolid lung adenocarcinomas in the period between May 2016 and December 2023. Clinico-radiological data were collected. The genetic landscape of our real-life European subsolid adenocarcinoma population is defined. Common and actionable mutations (frequency > 5%) relation to key clinico-radiological features are evaluated. Results: Overall, 156 subsolid adenocarcinomas were analysed. KRAS-mutations, mostly KRAS p.G12C, were the most prevalent followed by EGFR, including 25% uncommon EGFR-mutations, TP53 and MET mutations. Amongst the clinico-radiological variables, KRAS-mutations and KRAS p.G12C-mutation were associated to smoking history (≥ 20 pack/years), aggressive histologic subtype and higher consolidation-to-tumor ratio (CTR). Moreover, KRAS-mutated nodules had faster tumour-doubling-time. Conversely, EGFR-mutations were associated to female sex and lower CTR. The latter not being confirmed in common EGFR-mutations. Additionally, in common EGFR-mutated nodules, aggressive histological components were rarer. Conclusion: Our study presents the molecular profile of subsolid lung adenocarcinoma in a real-life European-cohort. KRAS-mutations were the most prevalent, and were related to smoking history, higher CTR and faster growth. Conversely, common EGFR-mutations were rarer than expected and unrelated to smoking history and radiological features.