Evaluation of integrated hpv dna as individualized biomarkers for the detection of recurrent cin2/3 during post-treatment surveillance

Heike Hoyer, Grit Mehlhorn, Cornelia Scheungraber, Ingke Hagemann, Christine Hirchenhain, Linn Woelber, Claudia Stolte, Monika Hampl, Sarah Scherbring, Agnieszka Denecke, Janina Bartels, Andreas D. Ebert, Sabina Meneder, Annett Petzold, Tabitha Heller, Karsten R. Heidtke, Elisabeth Schwarz, Frederik Stübs, Stefanie Schütze, Eva Lena StangeAnna Jaeger, Franca Martignoni, Ansgar Dellmann, Achim Rody, Peter Hillemanns, Tanja Fehm, Karl Ulrich Petry, Gerd Böhmer, Barbara Schmalfeldt, Pauline Wimberger, Matthias W. Beckmann, Ingo B. Runnebaum, Matthias Dürst*

*Corresponding author for this work


Purpose: Post-treatment follow-up in women with cervical pre-cancers (CIN3) is mandatory due to relapse in up to 10% of patients. Standard follow-up based on hrHPV-DNA/cytology co-testing has high sensitivity but limited specificity. The aim of our prospective, multicenter, observational study was to test the hypothesis that an individualized viral-cellular-junction test (vcj-PCR) combined with cytology has a lower false positive rate for the prediction of recurrence compared to standard co-testing. Methods: Pre-surgical cervical swabs served for the identification of HPV16/18 DNA integration sites by next-generation-sequencing (NGS). Samples taken at 6, 12 and 24 months post-surgery were evaluated by cytology, hrHPV-DNA and the patients’ individual HPV-integration sites (vcj-PCR on the basis of NGS). Results: Integration sites were detected in 48 of 445 patients (10.8%), 39 of them had valid follow-up data. The false positive rate was 18.2% (95% CI 8.6–34.4%) for standard hrHPV/cytology at six months compared to 12.1% (95% CI 4.8–27.3%) for vcj-PCR/cytology, respectively (McNemar p = 0.50). Six patients developed recurrences (1 CIN2, 5 CIN3) during follow-up. Standard co-testing detected all, whereas vcj-PCR/cytology detected only five patients with recurrences. Data of 269 patients without evidence of HPV16/18 integration were subject to post-hoc analyses. Standard co-testing revealed a false positive rate of 15.7% (95% CI 11.7–20.7%) and predicted ten of fourteen recurrences at six months. Conclusions: Although highly specific on its own vcj-PCR could not detect all recurrent CIN2/3. Possible reasons for this unexpected result may be multifocal lesions, intratumoral heterogeneity with respect to HPV integration and/or incident CIN.

Original languageEnglish
Article number3309
Issue number13
Publication statusPublished - 01.07.2021

Research Areas and Centers

  • Research Area: Luebeck Integrated Oncology Network (LION)
  • Centers: University Cancer Center Schleswig-Holstein (UCCSH)


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