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RISK-BASED SCREENING FOR CERVICAL CANCER

Periodic Reporting for period 4 - RISCC (RISK-BASED SCREENING FOR CERVICAL CANCER)

Reporting period: 2024-07-01 to 2024-12-31

Cervical cancer (CC) is preventable through vaccination or screening, but still the fourth most common cancer in women worldwide. In Europe alone, 61,000 new cases and 25,000 deaths were reported in 2018. 70% of the EU citizens have access to organized CC screening which has reduced the incidence and mortality rate up to 70%. Still, CC is common and even increasing in several European countries.
Most screening programs report a high proportion of unnecessary colposcopy referrals. Also, the number of screening invitations varies between European countries from 7 to >40, but is not clearly associated with the country-specific CC incidence. This suggests considerable overuse in some regions. To eliminate CC as a public health problem, the effectiveness and efficiency of screening programs and resources should be directed to those most at risk. Current protocols can be dramatically improved. RISCC aims to develop and evaluate the first risk-based screening program for CC, provide open-source implementation tools and contribute to the elimination of CC in Europe.
The aim of WP2 was to develop cervical cancer (CC) risk profiles for screen-eligible women based on their screening history. A database of 225,000 women with 10-20 years of follow-up, including 40,000 women with an HPV self-test result, was established. The database includes trials from the Netherlands, Italy, Slovenia, and Sweden. Data analyses showed that HPV results from previous rounds of screening strongly predict precancer (CIN3+) risk and can be used to determine the screening interval, genotyping strongly predicts CIN3+ risk in HPV-positive women and can be used to optimally stratify HPV-positive women, and that the lifetime residual risk of CIN3+ is low for non-vaccine genotypes, supporting de-intensification of screening programs after vaccination. Another aim of WP2 was to examine the performance of screening tools in screening trials and registry studies. Three main results were that 1) different HPV tests have very similar 9-year CIN3+ risks after a negative result, 2) HPV self-testing is non-inferior to HPV testing on clinician-collected specimens, and 3) DNA methylation analysis can be used to manage HPV-positive self-samples and HPV-positive clinician-collected samples. The statistical models developed to estimate genotype-specific risks of CIN3+ and cancer are available as open source via GitHub.

The aim of WP3 was to evaluate screening strategies after vaccination using randomized controlled trials (RCTs) and observational linkage studies. The RCTs compared infrequent and frequent screening in vaccinated women and unvaccinated women who were indirectly protected through herd effects. The main RCT included 20,514 women and showed that infrequent screening is not inferior to frequent screening, paving the way for infrequent or even once-in-a-lifetime screening after vaccination. In addition, the study showed that methylation analysis should be performed on high-grade lesions in vaccinated women to guide further management. The linkage studies in five European countries were consistent in finding a significant reduction of cervical lesions in vaccinated women.
The objectives of WP4 were to define the risk of pre-cancer and cervical cancer as a function of other risk factors and to assess harms associated with screening and management of screen-positive women. To guide decisions about screening, triage and management of women referred for colposcopy, post-test risks were assessed from diagnostic meta-analyses that provided information on sensitivity and specificity for detecting CIN3+, combined with pre-test risks. In addition, an international data collection was set up to assess the cumulative risk of CIN3+ in HPV-positive women by HPV genotype in order to evaluate the performance of extended genotyping which could not be derived from meta-analyses. Data were obtained and analyzed from three sources. Finally, a review was conducted of key literature on the risk of cervical (pre-) cancer associated with non-HPV factors (smoking, hormonal contraception, obesity, diet, …).
In WP5, microsimulation and open-source models were developed to compare the effects and costs of different cervical cancer screening algorithms adapted to specific risk profiles. The models describe the progression of multiple oncogenic HPV infections to cervical cancer and are able to provide predictions for any European country with sufficient data to inform the natural history model. The models provide estimates of the amount of resources required to implement risk-based screening algorithms and provide an assessment of the optimal balance between effectiveness and screening-related harms of risk-based screening algorithms.
In WP6, eHealth/mHealth platforms have been developed for collecting and analyzing information from screening program participants. These platforms have been used in a registry-based risk-based screening trial in Sweden where women at high risk of cancer were offered self-sampling. The trial targeted nearly 29,000 women. The transferability of the risk-based approach was explored by launching a pilot risk-based screening project in Hungary. In addition, concomitant HPV vaccination and risk-based screening was implemented in the cervical screening program of Sweden to further mitigate the cancer risk of women. The software platform developed for the screening program in Sweden was customised for reuse by designing a multilanguage version. The software is available as Open Source via GitHub, so that simple, efficient and effective cancer-preventive strategies can be launched in any EU country using the open-source support from RISCC.
In WP7, the dissemination and communication plan was developed, the RISCC website, a twitter account, a project leaflet, newsletters and a free online course on CC screening (Spanish and English), targeting healthcare providers and managers. Local ambassadors were identified in different European countries. Development of the end-of-project communication materials for patient advocacy groups, patients and lay public (training materials, brochure and social media posts in different European languages) and a guidance document for policy makers, a RISCC-specific webinar, participation in a roundtable at the European parliament and a monograph in HPV World.

WP8 concerns all ethical issues in the project, all deliverables were submitted.
RISCC has developed risk-based screening strategies that are expected to be acceptable, more effective and more affordable than traditional one-size-fits-all strategies. Implementing these strategies will improve health outcomes and equity across Europe. Important steps have been taken in developing risk profiles based on age, screening history, vaccination status, and individual risk factors. A registry-based pilot study using m-health/e-health solutions to facilitate risk-based screening has been conducted in Sweden and is ongoing in Hungary. In addition to dissemination and communication activities for researchers and other stakeholders, strong efforts have been made to engage women and ensure proper communication to lay people through local ambassadors.
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