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Breast Cancer Risk after Diagnostic Gene Sequencing (BRIDGES)

Periodic Reporting for period 3 - BRIDGES (Breast Cancer Risk after Diagnostic Gene Sequencing (BRIDGES))

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

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 (or early detection) of breast cancer is practiced in most EU countries at the population level, in the form of mammographic screening programs, which is off-set by false-negative and false-positive results, but most importantly, by over-diagnosis (it detects breast cancers that would not have been detected in a woman's lifetime had she not undergone mammography).
A crucial determinant of the uptake, and hence effectiveness of primary prevention is the identification of women at high risk. A major outcome of the BRIDGES project will be to redefine and significantly increase the number of women in this category. Current genetic testing can identify <0.5% of the population at these risk levels; we estimate that BRIDGES will identify approximately 4% of women at high risk, accounting for ~19% of the total breast cancer burden. Moreover, many women currently considered at high risk will be given lower risk estimates, potentially sparing them unnecessary interventions.
The BRIDGES program will develop an online tool, termed BOADICEA, 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.
At 54 months into the project, BRIDGES has completed the analysis of multigene panel sequencing of a very large case-control cohort with >110,000 individuals. We have performed variant-calls for 34 genes, quality-checks of the data and statistical analyses of the curated dataset; we have collected pedigree structures with cancer incidence data for >95% of sequenced individuals, totalling to approximately 1 million subjects. We estimated odds ratios for overall breast cancer and tumour subtypes, separately for protein-truncating and rare missense variants. We evaluated missense variant associations by protein-domain and clinical classification of pathogenicity.
The results define more precisely the genes most clinically useful for inclusion on panels for breast cancer risk prediction and their associated risks. The risks will be used to further refine the statistical model underlying the BOADICEA risk prediction tool (the overarching major deliverable of BRIDGES). Because the BRIDGES dataset represents the largest case-control study to date, we were able to provide the narrowest confidence intervals on risk estimates so far, further reducing uncertainty during risk counselling in the clinic. In addition, we were able to improve insights into tumour subtype-specificity of the risks conferred by some genes. Since it is known that some subtypes have a poor prognosis (such as oestrogen receptor-negative breast cancer) and require other treatments, this information could become relevant when considering preventive options. Finally, we were able to demonstrate that missense variants are associated with risk for some genes.
Laboratory assays to support the pathogenic classification of variants of uncertain clinical significance (VUS) have been developed for all genes with good evidence for being associated with breast cancer. These assays were applied to large numbers of the DNA variants identified by BRIDGES, both at the protein- and the mRNA-level. In addition, a novel in silico tool was developed with improved accuracy of variant classification relative to other publicly available tools.
The online web-interface for BOADICEA was further developed into a more user-friendly version and successfully launched (https://canrisk.org/). The tool received CE marking from the EU in December 2019 under the Medical Device Regulation.
Surveys have been conducted on the use of the BOADICEA webtool by healthcare providers, mostly clinical geneticists, both in its previous version (before BRIDGES started) and its most recent version. The results show that uptake has increased, not only in number of users, but also in number of countries where MDs are using it.
Data from a first prospective cohort of counselees were used to prepare validated instruments for the identification of patients with psychological distress, as well as a template for psychological intervention. These are now being used for a second prospective cohort, which at M54 had accrued >60% of the targeted 400 women from France and Germany. This study will teach us what the psychosocial impact is on unaffected women from breast cancer families upon being given a personalised risk estimate based on genetic and non-genetic risk factors.
At M54, BRIDGES still expects to achieve all the innovations as described in the original project proposal.
All variants detected by the sequencing effort will be disseminated to publicly available databases such as LOVD, BRCA Exchange and ClinVar, to facilitate patient counselling and further research worldwide.
BRIDGES will combine data with other, similar projects being conducted elsewhere to arrive at an even stronger dataset and further improve confidence intervals of risk estimates.
To guide the adoption of BOADICEA into the Cancer Family Clinic, work on an e-learning tool for clinicians and an information leaflet on moderate risk genes for patients is nearing completion.
Changing the practice of breast cancer screening and prevention will require a long-term effort to achieve broad consensus among the entire spectrum of stakeholders. To begin building towards this, BRIDGES, together with several other EU Horizon 2020 programs, organised the European Collaborative on Personalised Early Detection and Prevention of Breast Cancer (ENVISION) Network to bring together the international research consortia working on different aspects of personalised early detection and prevention of breast cancer. A consensus conference in 2019, held in Innsbruck, Austria, ENVISION identified priority areas for development to enable evidence-based personalised interventions that could improve the benefits and reduce the harms of existing screening and prevention programmes.
In parallel, the Cologne Centre for Ethics, Rights, Economics and Social Sciences of Health, with several BRIDGES partners and funded by the German Ministry of Health, gathered an international interdisciplinary expert group to produce a report on how to deal with the medical, ethical and legal challenges of genetic testing in the context of breast cancer prevention. It developed a conceptual framework and set international standards to address the manifold challenges in the field of early detection of prevention of breast cancer. It was presented to representatives of civil society, policy makers, industry, health insurance and scientists, on November 6, 2019, in Berlin, during a full-day workshop.
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