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Female cancer prediction using cervical omics to individualise screening and prevention

Periodic Reporting for period 2 - FORECEE (Female cancer prediction using cervical omics to individualise screening and prevention)

Reporting period: 2017-03-01 to 2018-08-31

Women-specific cancers (i.e. breast, ovarian, endometrial and cervical cancers) represent more than 47% of all cancers in women and amongst them are cancers with a 5-year survival rate of less than 40%.
The FORECEE programme is seeking to develop a multi-omics enabled risk prediction tool and to translate the tool’s output into recommendations for new clinical pathways for individualised screening and prevention (Figure 1).
The FORECEE Consortium will develop these tests by examining cervical cells and looking at:
• Epigenetic factors (i.e. the cell’s ‘software’) which captures environmental and lifestyle risk factors.
• Genetic factors (i.e. the cell’s ‘hardware’).
• Microbial factors (the viruses and bacteria present in the vagina) that contribute to the development of female genital tract cancers.
FORECEE is in the process of establishing these tests by analysing women with and without a cancer and will then validate these tests using an existing population-based set of cervical epithelial cells to validate whether the tests accurately predict cancer risk in women who went on to develop female cancers years after they donated the samples. FORECEE will also assess whether implementing these tests at a population level is cost effective and whether it offers a positive balance between long-term benefits and the risk of harm to women. In addition, the project will explore women’s attitudes to individualised predictive risk modelling. It also includes an ethical, legal, regulatory and social impact assessment.
In analogy to the smear test which uses cervical cytology (i.e. microscopic assessment of morphological changes of the cervical cells) to predict the cervical cancer risk, we aim to develop the Women’s cancer risk IDentification test (WID test) based on multi-omics data.
For pre-menopausal women the tests aim to (i) identify women with BRCA1/2 mutations or Lynch syndrome (indicating a higher risk of developing breast, ovarian or endometrial cancer at a young age) and (ii) improve on the specificity of existing tests for HPV (human papilloma virus) and indicate which women are at high risk of developing pre-invasive cervical cancer within the next 2-3 years.
For postmenopausal women we will predict the future risk for breast, ovarian, cervical and endometrial cancers.

See Figure 1. The FORECEE Vision – the collection and analysis of cervical cells to predict the risk of all four main women specific cancers in order to tailor preventive and early diagnostic measures.
The FORECEE Consortium has prospectively collected 16,500 samples form 5,300 women with cancer and cancer-free controls. In addition, we have accessed 1,400 samples from a population based cohort.

To date, we have analysed the epigenome (i.e. DNA methylation at 850,000 sites in each sample) in almost 5,000 samples and have analysed the microbiome (i.e. cervical bacteria) in > 600 cervical samples and the genome (i.e. Single Nucleotide Polymorphisms at 600,000 sites in each sample) in > 1,200 samples. We have also successfully applied an algorithm which allows us to quantify the proportion of different subtypes of cells (i.e. mainly the proportion of epithelial and immune cells) in a given sample solely using epigenetic information; this is important due to the tissue specificity of the epigenome. By analysing blood, buccal swabs and cervical smears from women with and without a BRCA mutation we have found that epithelial cells (compared to blood) are a far better surrogate tissue with which to predict an epithelial disease such as cancer.
Importantly, based on data analysed thus far, it appears that DNA methylation based tests outperform risk prediction of any of the previously published tests.

Based on focus group studies and an online survey (in 5 European countries), we studied the risk perception of women’s female cancer risk and knowledge of current screening programmes, attitudes and beliefs regarding predictive cancer testing and risk-dependent considerations of preventive surgery and discovered that the knowledge concerning these issues is surprisingly low and that simple information leaflets substantially improve this.

In order to assess whether the tests being developed are also viable form a health economic perspective, we have started to develop decision-analytic models and the assessment of necessary model input parameters. We developed standardised databases for model input parameters, assessed the necessary (country-specific) data (i.e. clinical practice, epidemiology and costs), transformed data for the implementation in decision models, validated data and prepared documentation. Several decision-analytic models simulating the natural history of single cancer types (e.g. cervical, breast, ovarian or endometrial cancer) were programmed. In addition, a decision-analytic model simulating ovarian and breast cancer development in BRCA-mutation carriers was developed.

Together with Canadian collaborators, we worked on ethical, legal and regulatory issues regarding predictive cancer testing – work which has led to a joint publication.

As a Consortium we worked on a large review on epigenetic risk prediction which was recently published in Nature Rev Clin Oncol.

Finally, we are currently in the process of organising a summit (ENVISION) on risk-stratified screening and prevention of breast cancer by bringing together all 6 consortia funded by the EU H2020 initiative and stakeholders (e.g. policy makers, healthcare professionals, lay public). The outcome of the summit will be a European position statement to set the research agenda and implementation strategies for risk-stratified screening and prevention in the EU.
Female cancers place a high burden on society and healthcare systems. Far more than 500,000 new cases of breast, ovarian, endometrial and cervical cancers are diagnosed in the EU each year. An additional 400,000 women receive treatment for cervical cancer precursors identified following cervical screening. Almost half of all cancers in women are female specific hormone-related cancers. In addition to the personal suffering caused, these cancers represent a significant economic burden. The clinical situation for each of the cancers is different, but in all cases redefining the clinical pathway through tailored screening and prevention programmes will offer significant advantages to female health promotion. Based on the data we have accumulated so far, FORECEE will enable the introduction of risk-based screening strategies that are better than those proposed on the basis of current evidence.