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Female cancer prediction using cervical omics to individualise screening and prevention

Periodic Reporting for period 3 - FORECEE (Female cancer prediction using cervical omics to individualise screening and prevention)

Reporting period: 2018-09-01 to 2020-02-29

The FORECEE project is focused on the shared ambition of a group of leading European clinicians and researchers to promote women’s health and prevent female cancers. The radical progression we wish to see is the implementation of omics-based methods into wide scale clinical practice for the stratification and risk prediction of cancers that are hormone-associated and specific to women (breast, ovarian, endometrial and cervical cancers). These represent more than 47% of all cancers in women and amongst them are cancers with a 5-year survival rate of less than 40%. We set out to devise a series of tests, referred to as Women’s cancer risk IDentification tests (WID tests), and based on multi-omics data, that can predict an individual’s risk independently for all women specific cancers from a single sample, i.e. a cervical smear. Specifically, we aim to:
1 Identify women with a high risk genetic mutation (in BRCA1/2 or Lynch syndrome).
2 Increase the specificity of the HPV-test to predict cervical intra-epithelial neoplasia grade 3 or early invasive cervical cancer (CIN3+).
3 Predict the risk for female (breast, ovarian and endometrial) cancers and quantify the impact of environmental exposure, reproductive and lifestyle factors on the epigenome.
4 Validate the risk prediction models established in 1-3 in a large population based cohort.
5 Develop a decision modeling tool with integrated information regarding costs, long-term benefits, harms and cost-effectiveness of WID test implementation.
6 Perform an ethical, legal, regulatory and social impact assessment to explore individual attitudes to risk prediction.
7 Engage with key stakeholders, including influential decision makers from across the EU in government agencies, healthcare procurement, reimbursement and regulation, in key workshops to critique the implementation of the WID tests into health systems.
We successfully recruited ~6,000 women who provided cervical samples across the consortium. We implemented a novel laboratory pipeline for processing and analysis of epigenome wide methylation data from complex multicellular sample mixtures. We developed and successfully validated multiple WID tests as set out at the start of the programme. When assessing cervical smears, these indices demonstrated clinically relevant levels of performance that enable: 1) identification of HPV+ve cytology normal smears [WID-HPV-Index – a test that we have furthermore shown to inform whether an individual has mounted an adequate defensive response to HPV infection], 2) identification of CIN3+ in cervical smears [WID-CIN-Index – a test that can also be used to predict future development of CIN3+ and outperforms current cytology triage pathways], 3) breast cancer diagnosis and determination of BRCA status [WID-BC-Index – a test which outperforms current SNP-based risk prediction models, 5) ovarian cancer diagnosis and risk prediction [WID-OC-Index], and, 6) endometrial cancer diagnosis and risk prediction [WID-EC-Index]. In addition we developed a DNA methylation test [WID-LO Index] that identifies women with an aberrant cervico-vaginal microbiome that is in turn associated with ovarian cancer risk and BRCA1 germline mutation status.

We produced a series of successful sub studies investigating risk perception, knowledge of female cancer risk and current screening programmes, attitudes and beliefs regarding predictive cancer testing and risk-dependent considerations of preventive surgery among European women and leading to several scientific publications. Furthermore, ethical, legal, and regulatory issues for the implementation of omics-based risk prediction of women's cancer have been explored in additional published articles.

We have produced recommendations for personalised screening/prevention based upon WID-test information. We developed several decision-analytic models for each of the female cancers and target groups of interest (cervical cancer, ovarian cancer, breast cancer, BRCA-specific breast and ovarian cancer). We evaluated these models together with systematically assessed model input parameters for different countries. Furthermore, we adapted and applied the developed decision-analytic model to evaluate the cost-effectiveness of WID-test based screening (WID-HPV and CIN3+ Indices) as a primary or triage test for HPV-positivity in cervical cancer screening programmes.

We established a working group (ENVISION team) comprising the coordinators of six EU H2020 funded consortia (FORECEE, BRCA-ERC, B-CAST, BRIDGES, MyPeBS, EU-TOPIA) and organised the joint EU ENVISION (European Collaborative on Early Diagnosis, Personalised Care and Prevention of Breast Cancer) Conference, which took place in June 2019 inclusive in Hall in Tirol, Austria. The conference stakeholders, including policymakers, healthcare professionals, managers, lay public, voluntary organisations and researchers, identified strategies to integrate omics-based screening and prevention into routine clinical practice. A consensus paper is now being published in Nature Reviews Clinical Oncology.

Finally, we ensured dissemination and engagement with the public via the FORECEE website, a multimedia presentation that was produced in August 2018 and linked up with the ENGAGe Executive Committee (which ensured awareness regarding the study and of our early findings), and more recently, a public engagement event “Informationsveranstaltung Brustkrebs – Risiko, Früherkennung, Vorbeugung” (Breast Cancer Information Event - Risk, Early Detection, Prevention) held on 26 June 2019 at ORF (Österreichischer Rundfunk, an Austrian national public service broadcaster), Innsbruck, Austria. A comprehensive strategy for the advancement of the WID tests for use in clinical practice has been defined and is currently being rolled out. The major barriers to commercial implementation of WID tests have been identified and a plan put in place to overcome these.
The FORECEE project has combined several approaches that go beyond the current state-of-the-art in women’s health:
1) We have developed several independent tests, all of which are applied to a single sample type i.e. cervical liquid base cytology, and one test-principle i.e. DNA methylation.
2) We have developed statistical algorithms and pipelines to take into account the heterogeneity of a biological sample that are essential for optimal analysis and interpretation of tissue specific epigenetic signatures.
3) We have shown that we are able to identify HPV+ve women who have or will eventually develop a pre-invasive or an invasive cancer and, moreover show that this test outperforms conventional cytology assessment.
4) We have demonstrated we are able to both diagnose and predict the future risk of endometrial cancer.
5) We have demonstrated we are able to identify women with ovarian cancer in the absence of tumour-DNA in the sample, indicating the indentification of surrogate epigenetic markers in normal cells and their association with OC risk.
6) We have shown that the WID-BC-test is able to identify women with poor prognostic features and this outperforms current risk strategies (i.e. the polygenic risk score).
7) Finally we have shown that a DNA methylation signature is able to identify women with an aberrant vaginal microbiome, which is a strong risk factor for ovarian cancer.