In 2017 the Dutch population-based screening (PBS) program implemented primary high risk human papilloma virus (hrHPV) testing with cytology as triage test on routine cervical scrapings collected during a general practitioner (GP) visit to screen for the presence of high-grade cervical intraepithelial neoplasia and cervical carcinoma (CIN2+). Women also have the option to use a self-sampling device. The self-samples are evaluated for the presence of hrHPV, but cannot be evaluated with cytology.[1,2] So, in case of hrHPV positivity, women are invited to collect a cervical scraping by a GP-visit to determine which women need referral for colposcopy. Despite the main advantage of using self-sampling versus GP-visits, the following drawbacks are related with the use of self-samplers in the new PBS:
- Women with hrHPV-positive self-sample still need a subsequent GP-visit (~2750 women/year)
- This extra GP-visit might be experienced as unwelcome
- The extra GP-visit results in delay before decision for referral to gynecologist can be made
- Self-sampling leads to less compliance to the program (~2-10%)[4-7] as hrHPV-positive women might still not visit the GP including women with a CIN2+ lesion (fig. 1)
- Costs of self-sampling will be higher compared to routine GP-screening.
These drawbacks may be circumvented by direct molecular triage on hrHPV-positive self-samples, provided that molecular testing has a sensitivity and specificity comparable to cytology for the detection of CIN2+ lesions. In contrast to the expected 4% in the first year of new PBS, 7% of all women used self-sampling. Thus, number of GP-visits involves much more women than anticipated earlier.
Introduction of a methylation-based triage test performed on the same self-samples used for hrHPV-testing to avoid the extra GP-visit in the new cervical cancer PBS program. We will evaluate a diagnostic strategy to apply methylation markers on hrHPV-positive self-samples and the cost-effectiveness when including methylation analysis in the program.
PLAN OF INVESTIGATION
WP1: Construction of database
All hrHPV-positive self-samples and their matched scrapings collected by extra GP-visit for the necessary cytomorphological examination, tested in our screenings center (UMCG) will be stored in our local Biobank according local regulations. Registration also includes hrHPV-status, cytology classification, colposcopy results, histology and age. Based on 1 year primary hrHPV-PBS screening, the accrual is estimated at ~2750 hrHPV-positive self-samplers/year.
WP2: Evaluation of methylation analysis as triage test on self-sampled material
Our best methylation panel to identify CIN2+ in cytology-based cohorts (ANKRD18CP/C13ORF18/JAM3) will be validated on a concise (test) series of hrHPV-positive self-samples (205 normal and 155 with CIN2+). To determine whether other markers have an improved sensitivity and specificity, we will analyze 13 additional CIN2+-specific methylation markers with specificity >70% and sensitivity >70% identified by us[8-14] and others[15-25]. All assays for all markers are up and running in our lab.
To validate diagnostic test performance of the most optimal methylation marker panel, 2415 hrHPV-positive self-samples (validation set) (90% power significant non-inferiority to show similar sensitivity and specificity as cytology) will be analyzed. This marker panel will be analyzed on paired GP-collected scrapings of the same women that used self-sampling (n=1355 with 95% power, p<0.05) to directly compare accuracy of methylation test in self-samples and GP-collected scrapings in relation to the currently used cytological triage test.
WP3: Potential cost-effectiveness of methylation analysis
Cost-effectiveness of the new methylation test compared to the current practice (GP-visits and associated cytological examination) will be calculated, taking also into account the assumed higher number of identified CIN2+ lesions. Incremental Cost Effectiveness Ratio (ICER) will be calculated, expressing additional costs or savings per additional identified CIN2+ woman. Screening costs, will be based on literature. Patient and non-medical costs will be collected with an adjusted version of the iMTA Medical Consumption Questionnaire (iMCQ) and the iMTA Productivity Cost Questionnaire (iMCQ/iPCQ).
WP4: implementation of the methylation test
As diagnostic assay multiplex quantitative methylation specific PCR (mQMSP) including the most optimal markers will be developed, ready to be CE-marked, applicable on the Abbott m2000 system.
The expected outcome of the implementation of the methylation-based triage test on self-sampled material will
- avoid ~2750 extra GP-visits per year
- shorten time to referral
- significantly reduce costs for the health-care system
- be more convenient for women
- improve compliance
- result in earlier detection of women with CIN2+.