LANTERN 2: Association Between Gene Molecular Profile and STAS in Lung Adenocarcinoma: A Comparative Analysis in a Prospective Real-World Population

Introduction: Lung cancer, the leading cause of cancer-related mortality worldwide, is a heterogeneous malignancy comprising distinct histological and molecular subtypes, with non-small cell lung cancer (NSCLC) accounting for approximately 85% of cases and adenocarcinoma (ADC) representing the most prevalent histotype. An emerging pathological feature of NSCLC, spread through air spaces (STAS)—defined as the extension of tumor cells into the lung parenchyma beyond the main tumor margin—has been associated with worse disease-free and overall survival and has been proposed as a possible predictor of recurrence to guide surgical extent. Concurrently, recent comprehensive genomic profiling of early-stage NSCLC has highlighted the need to interpret multi-omics data and their relationship with pathological variables, including IASLC histological subtypes, to better personalize treatment strategies. In this context, we investigated the overall distribution of STAS and its association with tumor mutational profiles and IASLC histological subtypes in a large real-world cohort of lung adenocarcinoma patients from the LANTERN project. Materials and Methods: In a prospective, multicenter observational study (March 2023–December 2024), 271 NSCLC patients were enrolled, and clinicopathological, immunohistochemical, and genomic data were collected; comprehensive genomic profiling was performed using the TruSight Oncology 500 assay to analyze 523 cancer-related genes, tumor mutational burden (TMB), and microsatellite instability; and STAS was assessed according to IASLC criteria. Adenocarcinoma accounted for roughly 90% of the cases, with a median age of 69 years and a predominance of stage IV disease (49.5%). STAS was evaluable in 162 cases and was detected in 17.9% of tumors. Results: STAS-positive tumors showed a higher trend towards locally advanced and advanced disease; no differences were observed in sex, age, smoking status, tumor mutational burden, or PD-L1 expression. Additionally, STAS-positive tumors showed a higher association with micropapillary, mucinous, and papillary patterns, whereas the acinar pattern was more frequent in STAS-negative tumors. The most frequently mutated genes were TP53, KRAS, EGFR, and STK11, with no significant differences between groups; ROS1 alterations were absent in STAS-negative tumors but detected more frequently in STAS-positive cases. Conclusions: Overall, these findings indicate that STAS positivity is associated with high-risk histological subtypes and advanced disease, suggesting its importance as a marker of tumor aggressiveness and emphasizing the need for its systematic evaluation in lung adenocarcinoma to better guide surgical planning and patient risk assessment.