Preventing overtreatment of CIN2/3 lesions: the role of methylation markers in predicting (non-)regression

Current cytology-based cervical screening programs serve to detect and treat high-grade precursor lesions (cervical intraepithelial neoplasia grades 2 and 3; 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 (i.e. productive CIN lesions, representing clinical manifestations of productive high-risk human papillomavirus (hrHPV) infections or early transforming lesions), not in need of immediate treatment, and those with a high short-term progression risk (advanced transforming lesions) that need immediate treatment. Overtreatment of productive or early transforming lesions is a problem because excisional treatment of cervical lesions is associated with increased risk of pregnancy-related morbidity. Individual cancer risk prediction of CIN2/3 is therefore essential. Recently, it has been shown that DNA methylation markers can distinguish advanced transforming CIN2/3 from productive or early transforming CIN2/3. The primary objective of this study is to validate prospectively that testing for the DNA methylation status of some tumor suppressor genes predicts (non-)regression of a CIN2/3 lesion, and therefore can lead to prevention of overtreatment. This study is designed as an observational longitudinal study with a follow-up of 24 months. All women, referred from the population-based cervical screening program with an abnormal cervical smear to one of the participating clinics for colposcopy and who have been diagnosed on a cervical punch biopsy with a CIN2 lesion (covering <= 50% of visible cervix) or small volume CIN3 lesions (covering <= 25% of visible cervix) will be asked to participate in this study. At baseline, a hrHPV-test and methylation marker test on a cervical brush sample will be performed. Participants will be monitored by an intense follow-up schedule with 6-monthly visits for 2 years to the colposcopy clinic. The primary study endpoint is (non-)regression at the end of the study based on histology of the cervical exit biopsy. Regression is defined as <=CIN1 on the exit biopsy based on morphology. Non-regression is defined as CIN2 or worse (CIN2+) on the exit biopsy based on morphology. The secondary study endpoint is defined as HPV clearance (double negative hrHPV test at two consecutive time points). A patient will exit the study before reaching the primary endpoint if she is in need of treatment (clinical progression), or when the transformation zone is not visible during colposcopy. For baseline CIN2 lesions, progression is defined as an increase in lesion volume (>50% of the visible cervix), a histological diagnosis of CIN3+ on a biopsy, or both. For baseline small volume CIN3 lesions, progression is defined as either an increase in lesion volume (>25% of the visible cervix), and/or a histological diagnosis of cervical carcinoma on a biopsy. The results of this study will answer the question whether methylation markers can individually predict (non-)regression of CIN2/3 lesions. This will create the opportunity to optimize management of women with CIN2/3 lesions and prevent overtreatment.