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. 2025 Aug 16.
doi: 10.1007/s40291-025-00809-2. Online ahead of print.

Human Papillomavirus Type and Viral Load in Relation to Circulating Cell-Free Tumour HPV DNA Level and Survival in Cervical Cancer

Kristina Hellman  1   2 , Mark Zupancic  1   3 , Cecilia Jylhä  4   5 , Emma Tham  4   5 , Lars Sivars  6   7
Affiliations

Human Papillomavirus Type and Viral Load in Relation to Circulating Cell-Free Tumour HPV DNA Level and Survival in Cervical Cancer

Kristina Hellman et al. Mol Diagn Ther. .

Abstract

Background and objective: Human papillomavirus (HPV) is the cause of most cervical cancers and is released as circulating cell-free tumour HPV DNA (ctHPV DNA) into circulation. Earlier studies have indicated that ctHPV DNA is a promising biomarker for analysing treatment response and for recurrence surveillance. However, factors influencing the release of ctHPV DNA, including HPV type and HPV viral load, have not been extensively studied and additional biomarkers for prognosis are needed. Therefore, here we analysed ctHPV DNA, HPV type and viral load in relation to each other and to progression-free survival in patients with locally advanced or advanced cervical cancer.

Methods: Pre-treatment biopsies and blood samples were collected from patients diagnosed with cervical cancer (Federation of Gynecology and Obstetrics [FIGO] stage IB-IV). One hundred and seventeen patients with HPV-positive tumours were included. Human papillomavirus type-specific, droplet digital polymerase chain reaction (ddPCR) assays were used to analyse previously genotyped biopsies for the viral load. Pre-treatment plasma from 92/117 patients were available and analysed for ctHPV DNA and total cell-free DNA levels. Results were related to patient and tumour characteristics and progression-free survival. Patients were grouped based on HPV species where alpha-9-species (including HPV16) and alpha-7-species (including HPV 18) constituted the majority of cases.

Results: Cell-free tumour HPV DNA was found in 83/92 (90.2%) of pre-treatment plasma samples. Higher biopsy viral load was significantly related to a higher ctHPV DNA level. Higher stage and larger primary tumour size were also associated with higher ctHPV DNA level. Alpha-9 species, including HPV16, had a significantly higher viral load (16×), a higher ctHPV DNA level (17×), and a higher detection rate in plasma than alpha-7 species, including HPV18. Alpha-9 species also had significantly better progression-free survival than alpha-7 species. Additional factors leading to better progression-free survival included a lower stage, a lower total cell-free DNA level, a viral load in the 90th percentile and, in the high-risk cervical cancer group, a higher pre-treatment ctHPV DNA level.

Conclusions: Cell-free tumour HPV DNA, HPV type and viral load are promising biomarkers in cervical cancer. The lower sensitivity for ctHPV DNA detection for alpha-7 species, including HPV18, needs to be considered in future studies on ctHPV DNA, especially if used as a marker for relapse during surveillance when ctHPV DNA levels are very low.

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Conflict of interest statement

Declarations. Funding: This work was supported by grants from Karolinska Institutet Foundations (LS), Magnus Bergvall Foundation (LS), Region Uppsala (LS) and Cancerfonden (ET). The open access fee was sponsored by Uppsala University. Conflict of interest: Kristina Hellman, Mark Zupancic, Cecilia Jylhä, Emma Tham and Lars Sivars have no conflicts of interest that are directly relevant to the content of this article. Ethics approval: The study was approved by the Ethical Review Board at Stockholm county, approval number 2016/2-31/1, with addendums 2016/1689-32, 2018/1472-32/1 and 2019-01222. The study was performed in accordance with the Declaration of Helsinki. Consent to participate: Written informed consent was obtained from all patients. Consent for publication: Not applicable. Availability of data and material: The data that support the findings of this study are not openly available because of reasons of sensitivity and are available from the corresponding author upon reasonable request. Code availability: Not applicable. Author contributions: KH: investigation, conceptualisation, resources, formal analysis, writing (original draft), writing (review and editing). MZ: investigation, writing (review and editing). CJ: investigation, writing (review and editing). ET: conceptualisation, resources, formal analysis, funding acquisition, methodology, writing (review and editing). LS: conceptualisation, data curation, formal analysis, funding acquisition, investigation, visualisation, methodology, writing (original draft), writing (review and editing).

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