Immune-inflammatory predictors of early and brain recurrence in young patients with resected non-small cell lung cancer

Objectives: Non-small-cell lung cancer (NSCLC) diagnosed before the age of 50 is uncommon and remains poorly characterized from a prognostic perspective. This study aimed to identify clinical, pathological, and inflammatory-immune predictors of recurrence, early recurrence, and brain metastasis after curative resection in young patients. Methods: This multicenter retrospective study included 224 consecutive patients aged <50 years who underwent anatomical lung resection between 2015 and 2024 at five Italian centers. Recurrence-free survival (RFS) was analyzed using Fine-Gray competing-risk regression and overall survival (OS) using Cox proportional hazards models. Early recurrence was defined as occurring within 12 months after surgery. The prognostic value of preoperative neutrophil-to-lymphocyte ratio (NLR), PD-L1 expression, and their combined phenotypes was explored. An exploratory ROC-derived NLR cut-off of 2.35 was used for stratification. Results: During follow-up, 65 patients (29.0%) experienced recurrence, with brain metastases representing the most frequent distant site (10.3% overall). Early recurrence occurred in 11.6% of patients. On multivariable analysis, higher NLR independently predicted recurrence (sHR 1.37, 95% CI 1.09-1.73), mortality (HR 1.82, 95% CI 1.27-2.61), and early recurrence (OR 3.61, 95% CI 1.07-12.21). PD-L1 expression alone was not prognostic; however, when combined with NLR, it identified inflammatory-immunologic phenotypes with different risks of brain metastasis among patients who recurred (p = 0.051). Conclusions: Young-onset NSCLC is characterized by a high burden of early and distant recurrence, particularly involving the brain. Preoperative NLR is a robust predictor of recurrence, early relapse, and mortality. Combined NLR-PD-L1 phenotypes identify a subgroup at increased risk of neurotropic relapse.