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Report

Teaser, summary, work performed and final results

Periodic Reporting for period 1 - BRIDGES (Breast Cancer Risk after Diagnostic Gene Sequencing (BRIDGES))

Teaser

Summary

A central focus of BRIDGES is to establish the validity and utility of personalised risk-based breast cancer prevention, and specifically of gene panel testing, within the clinical routine of high-risk Family Cancer Centres. Options for primary prevention include prophylactic surgery, chemoprevention and lifestyle interventions, all of which are associated with high morbidity and/or low social acceptability. Secondary prevention of breast cancer is practiced in most EU countries at the population level, in the form of mammographic screening programs. The purpose is to detect the development of breast cancer in its earliest stages, for which available treatment options are more effective, leading to a decrease in mortality from breast cancer in the screened population.
A crucial determinant of the uptake, and hence effectiveness of primary prevention is the identification of women at high risk (defined as >3-fold above population average). A major outcome of the BRIDGES project will be to redefine and significantly increase the number of women in this category; we estimate that we will identify approximately 4% of women at high risk, accounting for ~19% of breast cancer cases. Conversely, many women currently considered at high risk will be given lower risk estimates, potentially sparing them unnecessary interventions.
The effectiveness of secondary prevention at the population-level is off-set by false-negative findings, false-positive results, which can cause anxiety, while some detected breast cancers will still have poor prognosis. But most importantly, mammography results in â€œover diagnosisâ€ of breast cancer: it detects breast cancers that would not have been detected in a woman\'s lifetime had she not undergone mammography. This has led to proposals that mammographic screening programmes would be more effective if personalised to the level of individual risk. Such an approach might also lead to a more rational use of MRI screening, which is more sensitive than mammography, but is too expensive and has too high a false-positive rate for use in the general population.
The BRIDGES program will develop an online tool that will allow health care providers to compute an individualised risk for any woman to develop breast cancer during her lifetime. The algorithm will combine genetic, hormonal, lifestyle and breast density risk factors into a single score. While the immediate application of comprehensive risk prediction, as developed by BRIDGES, will be in the context of cancer family clinics, BRIDGES will provide data that will inform on the feasibility of extending the application of preventive measures to the population level. In this process we will establish which gene variants can be reliably associated with risk, improving the counselling process. By prospective evaluation of risk stratification in the clinic, we will examine the clinical utility of this approach. Currently, the large majority of women testing for BRCA1/2 test negative (no mutation found), or uninformative (VUS found) and receive more or less the same risk estimate on the basis of their family history. The new tool, termed BOADICEAPLUS, will allow this to be personalised into more distinct risk classes.
The BOADICEAPLUS risk prediction tool of BRIDGES will benefit women throughout the EU and beyond, in that they will have access to much better services for risk prediction. Consequently, many more women will be able to benefit from preventive options, of the kind that suits their needs best. In short term, the benefit will lie in improved personalised risk prediction; in the long term, the societal benefit will be fewer deaths from breast cancer.

Work performed

At 18 months into the project, BRIDGES has advanced significantly towards achieving these goals. It has completed, or started, the accrual of case-control cohorts to perform the proposed epidemiological analyses. The technology to analyse the first panel of 35 breast cancer genes by DNA sequencing was set up, tested and validated. Sequence data on over 60,000 individuals were delivered. It has created the necessary structures for data storage, maintenance and statistical analysis. A preliminary version of the online web-interface, which will provide the interface for the BOADICEAPLUS risk prediction tool, was developed. It has made good progress with activities to predict and assess the pathogenic classification of variants of uncertain clinical significance (VUS) in the genes under study. Preparations to guide the adoption of BOADICEAPLUS into the Cancer Family Clinic have been made.
The development of the risk prediction tool is executed in close coordination with the B-CAST programme running under Horizon 2020 (Breast CAncer STratification: understanding the determinants of risk and prognosis of molecular subtypes; Project ID 633784), the emphasis of which will lie in the second half of the program. Accordingly, for this reporting period, this interaction has manifested itself in the organisation of concurrent and joint General Assembly meetings.

Final results

The most conspicuous achievement of BRIDGES beyond the original Description of the Action (DoA) is that it has collected over 50% more DNA samples from case-control cohorts than originally projected. The original target was 60,000 samples, but BRIDGES partners and collaborators were able to collect DNA samples from over 90,000 cases and controls. Because the costs for sequencing had meanwhile significantly dropped, BRIDGES can now deliver a much more powerful analysis of one of its primary objectives, i.e., to establish precisely which genes, and which variants therein, are associated with breast cancer risk, and the level of that risk, at no additional costs.
A second development beyond the state of the art is the application of CRIPR/Cas9 genome editing technology to the design of an in vitro assay for the assessment of missense changes in a set of breast cancer genes. This will lead to a better design of the cell line used in the assay, while a much â€œcleanerâ€ read-out is expected in the planned final high-throughput pipeline.

Given the current state of progress of BRIDGES, we expect to deliver all the results described in the original DoA by month 60. The single-most important end-result is a ready-to-use personalised risk assessment tool for breast cancer. The project is also making good progress with exploring how this new tool could best be introduced into the Family Cancer Clinic, and how it could change clinical practice there, as well as impact womenâ€™s risk perception and decision-making. In doing so, the project will generate an evidence-based list of breast cancer genes, with estimates of the breast cancer risks conferred by each of them. Catalogues and assays will have been developed to allow a more efficient pathogenic classification of variants of uncertain clinical significance in these genes.

Likewise, at this stage, we expect no major changes in the potential scientific and societal impact of BRIDGES, relative to what was described in the original DoA. Most importantly, we will provide evidence to indicate the potential impact of the risk assessment tool on current breast cancer population screening programmes.