Evaluation of Integrated HPV DNA as Individualized Biomarkers for the Detection of Recurrent CIN2/3 during Post-Treatment Surveillance

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Titel: Evaluation of Integrated HPV DNA as Individualized Biomarkers for the Detection of Recurrent CIN2/3 during Post-Treatment Surveillance

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

Erschienen: 1 July 2021

Sprache: Englisch

DOI: 10.3390/cancers13133309

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Beschreibung: Abstract: 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. Keywords: HPV DNA integration; CIN3; recurrence; post treatment surveillance; individualized molecular biomarker

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