Cell-free human papillomavirus (HPV) DNA is a sensitive biomarker for prognosis and for early detection of relapse in locally advanced cervical cancer

Abstract Purpose: Human papillomavirus (HPV) is the cause of the majority of cervical cancers and has been showed to be released as cell-free tumour DNA (ctHPV DNA) into the circulation. We here analyse if ctHPV DNA could be used as a prognostic biomarker and/or to detect relapse earlier than traditional methods in locally advanced cervical cancer (LACC). Experimental Design: 74 patients with LACC were included, 66/74 were positive for 13 high-risk HPV-types using a bead-based assay on tumour biopsies. HPV-type-specific droplet digital PCR (ddPCR) assays were developed. Longitudinal plasma samples were then analysed for the biopsy-verified HPV-type for each patient. 418 plasma samples were analysed. Patients were followed for a median of 37 months. Results were correlated to tumour- and clinical characteristics. Results: 92.4% of pre-treatment plasma samples were positive for ctHPV DNA. Persistent ctHPV DNA in end-of-treatment, early follow-up (1-2 months after end-of-treatment) or tumour evaluation (3-4 months after end-of-treatment) plasma was correlated with worse progression-free survival (p < 0.001) compared to if ctHPV DNA was not found. The positive predictive value of ctHPV-status at early follow-up for predicting disease progression was 87.5% and the negative predictive value was 89.3%. ctHPV DNA was found in plasma before relapse was diagnosed on radiology in all patients (n=10) who experienced relapse after complete clinical response to treatment with a median 315 days lead time. Conclusions: ctHPV DNA in follow-up plasma is a promising prognostic biomarker in patients with LACC, useful for analysis of response to therapy and for early detection of relapse.