Integrated HPV-DNA as individualized biomarker for the detection of recurrent CIN2/3 during post-treatment surveillance

Objective Follow-up after CIN3-surgery is mandatory. Standard follow-up based on hrHPV-DNA and cytology (co-testing) has high sensitivity but limited specificity resulting in overtreatment. Aim of the study was to show that an individualized viral-cellular-junction test (vcj-PCR) combined with cytology has superior specificity compared to standard co-testing for the detection of recurrent CIN2/3.

Methods HPV-INT-CX is a German prospective multicenter observational study adhering to the guidelines for post-conisation monitoring. A cervical sample taken pre-surgically served for the identification of HPV16/18 integration sites by next-generation-sequencing (NGS). Three follow-up exams including cervical sampling were performed at 6, 12 and 24 months or up to the time point of recurrence. All samples were evaluated by cytology, hrHPV-DNA and the patients´ individual HPV-integration sites (vcj-PCR based on NGS data).

Results In 48 of 445 patients HPV integration sites could be identified by sequencing and individualized vcj-PCR assays were established. Thirty-nine of these 48 patients could be followed over 2 years (median). In 33 patients without recurrence the false positive detection rate was 18.2% (95%CI:8.6-34.4%) for standard hrHPV/cytology at 6 months compared to 12.1% (95%CI:4.8-27.3%) for vcj-PCR/cytology, respectively (McNemar p=0.5). Six patients developed histologically confirmed recurrences (≥CIN2) during follow-up. Standard co-testing was positive in all and vcj-PCR/cytology in five patients with recurrence. Vcj-PCR alone discovered three recurrences and was negative for all 33 cases without recurrence.

Summary Although highly specific on its own our individualized biomarker test for the detection of recurrent CIN lacks sensitivity. Possible reasons may be multifocal lesions, incident CIN and/or intratumoral heterogeneity.

Publication History

Article published online:
07 October 2020