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EPI-FEM-CARE Résumé de rapport

Project ID: 305428
Financé au titre de: FP7-HEALTH
Pays: United Kingdom


Project Context and Objectives:
Every year in the EU ~45,300 and 330,000 women are diagnosed with ovarian and breast cancer respectively & 28,800 and 90,000 of these two groups of women will die as a consequence of these diseases. Late stage diagnosis coupled with a “one fits all” approach to adjuvant treatment, frequently leads to mutilating surgery, a plethora of adverse effects, and a huge financial burden. Progress in personalised cancer medicine will only be possible with the development of bioassays involving the analysis of easy accessible biomaterials that contain stable target molecules reflective of disease. The EpiFemCare project aims to devise a set of bioassays – or liquid biopsies – based on analysis of the methylation status of tumour DNA found in serum.

The project will establish and clinically validate a series of blood tests based upon DNA methylation technology that will facilitate both early detection and prediction of therapeutic outcome in breast and ovarian cancer. These tests will enable:
• Screening and early detection of breast and ovarian cancer;
• Diagnosis of ovarian cancers through discrimination of benign and cancerous growths within the pelvis; and
• Personalised care through monitoring the efficacy of treatment and determining the right drug regimen for each woman.

DNA methylation is a chemical modification of DNA known to respond to the environment and consequentially capable of modifying gene expression. Selection of DNA methylation as the basis for the EpiFemCare blood tests offers key advantages over other potential biomarkers, including genetic mutation, proteins, lipids and RNA. DNA methylation is: (1) biologically and technically stable, (2) has the capacity to be amplified, and (3) demonstrates cancer specificity when compared to normal or benign tissues. Technology platforms for the analysis of DNA methylation have evolved rapidly over the past few years to the point where epigenome-wide analysis can now be performed with relative ease. We will apply technology capable of the sensitive detection of cell free DNA methylation in serum against an excess background of normal contaminating DNA – a feature that is crucial for the development and clinical success of blood based DNA methylation tests.

Project Results:
Important progress has been made during the second period of the EpiFemCare project. Clinical partners within the EpiFemCare consortium in London, Prague and Munich have completed a collection of serum samples, with matched tissue where possible, from breast and ovarian cancer patients and those with benign conditions attending their clinics. In addition, serum samples have been collected at regular intervals from patients with ovarian cancer undergoing neoadjuvant treatment. Large numbers of samples have been stored in appropriate biobanks and have either been used, or will be used in the final project period, for the discovery and validation of DNA methylation biomarkers for breast and ovarian cancers.

Two complementary approaches to discovery of differentially methylated regions (DMRs) were to be implemented based on either the Illumina Human Methylation450 Beadchip array or reduced representation bisulfite sequencing (RRBS). In the first project period, DMRs for both ovarian and breast cancers were identified from Illumina array data. In this period, following extensive development of the test itself, ovarian cancer DMRs from this approach were tested in two independent sets of prospectively collected serum samples from patients with high grade serous ovarian cancer, benign conditions or from healthy women.

We also established that RRBS can be performed directly from the serum samples. However, technical and financial constraints did not allow analysis of 450 serum samples. Therefore, a novel sequencing approach to maximise specificity was developed and implemented to identify tumour specific methylation within tumour tissue samples. Methylation patterns were subsequently identified for breast and ovarian cancers.

The EpiFemCare project was designed with commercial application in mind. Two possible approaches for a commercial application of the test were included in the project plan – Digital MethyLight and targeted bisulfite sequencing – and have been evaluated in detail during the project to date. Work undertaken during this project period has led to the conclusion that the sensitivity of Digital MethyLight is inferior to qPCR and a decision was taken to stop all digital PCR work up and use qPCR in its place. Subsequently, all activities are now transferred to the targeted bisulfite sequencing approach. Following development of this sequencing method, breast cancer markers were validated in two sets of serum samples. Two DMRs were then selected for validation in UKCTOCS samples and data will be reported at the end of the project. Validation of markers for ovarian cancer is ongoing.

Potential Impact:
Cervical cancer serves as a shining example of the potential of an early detection strategy: the lifetime risk of dying from cervical cancer has fallen by more than 80% for women who attend cervical cancer screening programmes. Mammography screening for breast cancer is able to save some lives, but treatment outcome is improved for only 3-13% of women attending screening; the large majority do not receive a clear treatment benefit. No effective population-based ovarian cancer screening is available. In both cases, therefore, the availability of a simple, non-invasive test that would identify women with early stage cancer would be beneficial; the EpiFemCare project aims to reduce the presentation of late stage cancers.

A cancer screening programme is only considered to be effective if >75% of the population participates. Current screening programs face problems with uptake mainly due to the inconvenience, pain and embarrassment a screening test imposes on women and the fact that multiple different strategies are needed for different cancers. The EpiFemCare project has clear potential to provide screening programmes with a serum based alternative that would be less invasive and imposing than current methodologies.

Beside individualised early detection, monitoring adjuvant treatment is likewise important. Breast cancer is a heterogeneous disease with diverse morphologies, molecular characteristics, clinical behaviour, and response to therapeutics. As we delve more into the complex nature of this disease, it becomes imperative to determine appropriate prognostic and predictive markers that can be used by physicians and patients for informed decision making. The EpiFemCare project will determine whether cancer-specifically methylated DNA in serum is able to act as a surrogate for active cancer and will facilitate future clinical studies immensely. We aim to reduce the requirement for breast cancer patients to undergo adjuvant chemotherapy, antiendocrine and other therapies (including Herceptin or zoledronic acid) by 50%, and to only administer additional therapies upon detection of a positive test result indicative of minimal residual disease.

Treatment of breast cancer in the EU costs about €6.73 billion every year and the majority of this goes into systemic treatment. A test which (i) is able to reduce the need (due to early detection) and (ii) allows the monitoring of adjuvant treatment reduces the costs of treatment as well as the costs associated with treatment-related side effects.

List of Websites:


Greta Borg-Carbott, (European Contracts Executive)
Tél.: +44 20 3108 3033
Fax: +44 20 783 2849
Numéro d'enregistrement: 182398 / Dernière mise à jour le: 2016-05-20
Source d'information: SESAM