Early-onset lung cancer: etiologic heterogeneity, genomic features, and age-informed clinical management.

Abstract

Early-onset lung cancer, commonly defined as disease diagnosed at or before 50 years of age, represents a growing but insufficiently characterized subset of lung cancer in clinical practice. However, much of the evidence informing current diagnostic and therapeutic practice has been generated from age-unselected or older, smoking-dominant populations and may not fully capture the clinical characteristics of younger patients. Consequently, younger individuals with lung cancer may face delayed risk recognition, incomplete molecular evaluation, and treatment decisions not fully informed by age-associated clinicobiological features. Accumulating evidence indicates that early-onset non-small cell lung cancer (NSCLC) is enriched for actionable oncogenic alterations, particularly gene fusions and selected HER2/ERBB2 alterations, and is frequently associated with lower tumor mutational burden and a less inflamed tumor microenvironment. Although these features do not yet establish early-onset NSCLC as a separate treatment category, they support age-informed refinement of guideline-based management, particularly in initial molecular testing, interpretation of immunotherapy-relevant immune features, treatment transitions, and survivorship planning. In this review, we synthesize current evidence on disease burden, etiologic heterogeneity, age-related genomic features, and treatment-relevant tumor immune context in early-onset lung cancer, with a focus on issues relevant to clinical interpretation and management prioritization. We further outline age-informed clinical management for molecular evaluation, resistance reassessment, and survivorship care, aiming to complement rather than replace established NSCLC guidelines for patients aged ≤50 years.