Methylation-specific epigenetic and ctDNA biomarkers in prognosis of advanced NSCLC.

e20554 Background: Methylation specific epigenetic biomarkers and circulating tumor DNA (ctDNA) are emerging as important prognostic biomarkers in the advanced non-small cell lung cancer (NSCLC). These biomarkers indicate tumor progression, treatment response and patient prognosis. This study evaluated key methylation specific biomarkers in NSCLC and assessed their clinical utility. Methods: This review follows PRISMA guidelines and synthesizes findings of studies published from 2016 to 2024. It examines methylation biomarkers targeted with advanced techniques such as methylation specific PCR, droplet digital PCR and next generation sequencing. The Populations included early stage and operable, advanced, and metastatic cases of NSCLC. Endpoints assessed included Overall survival (OS), progression free survival (PFS), disease free interval and therapeutic response. Results: This systematic review included eight studies examining epigenetic and ctDNA biomarkers in advanced NSCLC using methods such as MSP, ddPCR, and NGS. Methylation of HOXA9, SOX17, and KMT2C was associated with significantly worse overall survival, with HOXA9 also showing a strong correlation with KRAS mutations (p < 0.001). Hypermethylation of NALCN promoter was associated with shorter disease-free interval and higher metastatic potential, suggesting a role of NALCN promoter methylation in disease progression. NALCN promoter methylation was identified as a predictor of metastasis and correlated with shorter disease-free intervals (p = 0.017). Similarly, SNORD3F hypermethylation, poorly promoted EGFR-TKIs were associated with reduced progression free survival in advanced NSCLC patients which could guide to targeted therapies. Circulating tumor DNA (ctDNA) are becoming important prognosticators in advanced non-small cell lung cancer (NSCLC) with implications for patient survivability, therapeutic response and tumor behavior, and are recognized as key in personalized medicine. Conclusions: Prognostication of advanced NSCLC based on epigenetic and ctDNA methylation biomarkers holds immense potential to improve the prognosis. Clinical use of these biomarkers lies in their ability to predict the patient's survival outcome and therapeutic response. Although they showed promise in further validating the role of GWAS loci in routine clinical practice and optimizing treatment of NSCLC patients, further research in larger, more diverse cohorts is needed.