Preventing overtreatment of CIN using methylation markers

Current cytology-based cervical screening programmes serve to detect and treat high-grade precursor lesions (CIN2/3) to prevent cervical cancer. However, the diagnostic-treatment trajectory is associated with considerable overtreatment since CIN2/3 lesions, particularly in young women, have a high spontaneous regression rate. Pathologists are unable to differentiate between CIN2/3 lesions with a low short-term progression risk to cervical cancer (productive lesions), not in need of immediate treatment, and those with a high short-term progression risk (transforming lesions) that need immediate treatment. Individual cancer risk prediction of CIN2/3 is therefore essential to reduce overtreatment. Recently, it has been shown that DNA methylation markers can differentiate between productive and transforming CIN2/3. Here, we aim to validate prospectively that testing for the methylation status of a CIN2/3 predicts (non-) regression leading to prevention of overtreatment.

Analysis of methylation status can predict which CIN2/3 lesions will regress and which not, determining the need of immediate treatment versus active surveillance.

Baseline, 6, 12, 18, 24 months

Standard therapy for CIN2/3 lesions consists of excision of the lesion by either LLETZ or cold knife conisation. In this study, treatment consists of a watchful waiting policy. Participants will be monitored by an intense follow-up schedule consisting of 6-monthly visits to the colposcopy clinic for 2 years. During these visits, cervical cytology, hrHPV testing, methylation marker analysis and colposcopic evaluation of the cervix will be performed.

Control:
Women not included in the study population and who will receive standard excisional therapy for
their CIN2/3 lesion will be asked to participate in a reference group. This standard therapy consists of
a LLETZ or cold knife conisation and will be performed according to national guidelines. By including a
reference population in our study, we aim to assess the clinical ‘cutoff’ for lesion size that
gynaecologists use in their decision to treat patients and not to include them in the study protocol. One
hundred subjects will be included in this group.
Women participating in the reference group will be asked to use the Evalyn brush to self-collect a
cervico-vaginal specimen. Furthermore, a cervical scrape will be collected by the gynaecologist.
Sample collection will be done prior to treatment, so that no extra visits or gynaecological
examinations will be needed.