Discrepancies in the Molecular Epidemiology of Druggable Genetic Alterations in Non-Small Cell Lung Cancer

Non-small cell lung cancer (NSCLC) represents most lung cancer diagnoses worldwide and remains a leading cause of cancer-related mortality. The advent of precision oncology has transformed the therapeutic landscape of NSCLC through the identification of druggable genetic alterations, enabling the use of targeted therapies with significant clinical benefit. However, the reported prevalence of these alterations varies widely across studies and populations, raising important questions about the underlying determinants of such discrepancies. In this context, molecular epidemiology provides a framework to understand the distribution of genomic alterations and their interplay with demographic, clinical, and methodological factors. This narrative review examines the spectrum of druggable genetic alterations in NSCLC and critically analyzes the sources of variability in their reported frequencies. We discuss geographic and ethnic differences, particularly between East Asian, European, and North American populations, as well as the influence of smoking status, environmental exposures, histologic subtypes, and sex-related factors. Furthermore, we explore how disease stage and sample type source may contribute to heterogeneity in molecular profiles. A substantial focus is placed on methodological sources of discrepancy, including differences in molecular testing platforms, analytical sensitivity and limits of detection, tissue versus liquid biopsy approaches, tumor heterogeneity, and gene panel design. Finally, emerging trends in the field, such as the use of ultra-large genomic datasets, real-world evidence, multi-omics integration, and artificial intelligence, alongside ongoing efforts toward standardization of molecular testing, are discussed.