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CIN2+-specific methylation markers in the triage of hrHPV-positive self-samples will improve efficacy of population-based cervical cancer screening

Projectomschrijving

Verbetering van het bevolkingsonderzoek baarmoederhalskanker bij gebruik van de zelfafnameset

Vraagstuk

Het doel van het bevolkingsonderzoek is om baarmoederhalskanker in een vroeg stadium op te sporen. Vrouwen met HPV hebben kans om baarmoederhalskanker te krijgen. In het vernieuwde bevolkingsonderzoek wordt eerst op HPV getest op het gebruikelijke uitstrijkje of met een zelfafnameset. Echter, als de zelfnameset positief is voor HPV, moet de vrouw alsnog naar de huisarts voor een uitstrijkje om te bepalen of doorverwijzing naar een gynaecoloog nodig is. Dit leidt tot vertraging en verminderde deelname aan het bevolkingsonderzoek, waardoor minder afwijkingen vroeg worden gevonden.

Onderzoek

Het materiaal van de zelfnameset wordt bij HPV-positieve vrouwen geanalyseerd op DNA afwijkingen met een nieuwe test, zodat de vrouw niet naar de huisarts hoeft voor een uitstrijkje.

Verwachte uitkomst

Dit onderzoek zal resulteren in een efficiëntere screening, met minder kanker, meer gemak voor de vrouw en minder kosten voor de gezondheidszorg.

Verslagen


Samenvatting van de aanvraag

INTRODUCTION 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)[3] - 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.[3] Thus, number of GP-visits involves much more women than anticipated earlier. AIM 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.[3] 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)[8] 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.[26] 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).[27] 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[3] - 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+.

Kenmerken

Projectnummer:
531002021
Looptijd: 100%
Looptijd: 100 %
2019
2024
Onderdeel van programma:
Gerelateerde subsidieronde:
Projectleider en penvoerder:
Wisman
Verantwoordelijke organisatie:
Universitair Medisch Centrum Groningen