Ultrasensitive next‐generation sequencing–based detection of circulating human papillomavirus DNA for cervical cancer recurrence monitoring

BACKGROUND: Circulating cell-free human papillomavirus (ccfHPV) DNA is a promising biomarker for cervical cancer monitoring. This study used next-generation sequencing (NGS) to assess its prognostic and surveillance value. METHODS: The authors included 141 cervical cancer patients (International Federation of Gynecology and Obstetrics IA1-IVB) grouped by treatment: primary surgery (n = 50), primary surgery + adjuvant oncological (n = 22), and primary oncological treatment (n = 69). Plasma was collected pretreatment, at early follow-up (first post-treatment sample [FPS]), and during longer follow-up. ccfHPV DNA was detected using an NGS-based assay, enabling high sensitivity without prior knowledge of human papillomavirus (HPV) genotype. Associations between ccfHPV DNA status and recurrence were assessed using Cox proportional hazards models, and predictive accuracy was evaluated via sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV). RESULTS: Pretreatment ccfHPV DNA positivity was detected in 8.0%, 36.4%, and 82.6% of patients across the groups, and ccfHPV DNA positivity was significantly associated with higher recurrence risk (adjusted hazard ratio [HR], 4.92; 95% confidence interval [CI], 1.29-18.7; p = .02). At FPS, ccfHPV DNA positivity strongly predicted recurrence (adjusted HR, 19.1; 95% CI, 7.27-50.2), with a PPV of 83% and NPV of 90% for recurrence within 50 months. Among patients who developed recurrence, ccfHPV DNA was detectable before clinical evidence of recurrence in 60.9% of cases with a mean lead time of 144 days. CONCLUSION: ccfHPV DNA detected by NGS is a strong prognostic biomarker for residual disease or recurrence. Its strong performance, already at early follow-up, supports its integration into individualized follow-up strategies. Prospective multicenter studies should validate these findings and guide clinical implementation. TRIAL REGISTRATION: The study was registered with ClinicalTrials.gov (identifiers: NCT03749720).