Blood-based Biomarkers in Cervical Cancer: The Emerging Role of Circulating Human Papillomavirus and Tumor Deoxyribonucleic Acid.

Cervical cancer (CC) remains a major global health burden, particularly in low- and middle-income countries (LMICs), where access to timely diagnosis and surveillance is limited. Circulating tumor deoxyribonucleic acid (ctDNA), including virus-derived human papillomavirus (HPV) ctDNA, offers a promising, noninvasive biomarker for diagnosis, prognosis, and treatment monitoring in CC. A comprehensive literature review of clinical studies, meta-analyses, and ongoing trials evaluating the role of ctDNA in CC. The key aspects analyzed included cell-free HPV (ctHPV) DNA detection, mutation and methylation profiling, correlation with tumor burden and treatment response, technical limitations, and emerging applications. ctHPV DNA is detectable in 60%-95% of patients with CC, particularly in advanced-stage disease. It correlates with tumor size, FIGO stage, lymph node involvement, and treatment efficacy. Serial ctDNA monitoring has demonstrated prognostic value, with persistent ctDNA posttreatment predicting early relapse. In addition, ctDNA-based mutation (e.g. PIK3CA and TP53) and methylation profiling (e.g. CADM1 and PAX1) show utility for molecular characterization and resistance tracking. However, limitations include low sensitivity in early-stage disease, assay variability, lack of standardization, and limited accessibility in LMICs. ctDNA represents a transformative tool in CC care, enabling real-time, tumor-specific insights with broad diagnostic and prognostic implications. Future efforts should focus on prospective validation, integration with imaging and artificial intelligence, and development of cost-effective ctHPV DNA screening panels, particularly for underserved populations.