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Breast Cancer Risk after Diagnostic Gene Sequencing (BRIDGES)

Periodic Reporting for period 4 - BRIDGES (Breast Cancer Risk after Diagnostic Gene Sequencing (BRIDGES))

Reporting period: 2020-03-01 to 2021-08-31

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. The precise identification of significantly elevated risk is a crucial determinant to empower women to make better informed decisions about primary and secondary prevention. The BRIDGES project will define which genes on multigene panels are truly associated with breast cancer risk and assess the breast cancer risk with the highest possible accuracy. Moreover, BRIDGES 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 testing, hormonal, lifestyle, and breast density risk factors into a single score.
BRIDGES has completed the analysis of multigene panel sequencing of a very large case-control cohort with >110,000 individuals, the largest case-control study to date. The results identified nine genes as clinically most useful for inclusion on panels for breast cancer risk prediction. The study-size allowed us 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 breast 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 (subsets of) missense variants are associated with risk for some genes.

The BOADICEA breast cancer prediction model, realised by the joint efforts of BRIDGES and B-CAST EU-programs, was externally validated and prospectively calibrated. The online web-interface for BOADICEA was developed into a user-friendly version called CanRisk and successfully launched (https://canrisk.org/). The tool received CE marking from the EU in December 2019.

We have surveyed the use of the CanRisk webtool by healthcare providers, mostly clinical geneticists, early and late in the BRIDGES project. The results show that uptake has increased, not only in number of users, but also in the number of countries where MDs are using it.

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 have examined rare missense variants and potential splice-variants revealed by BRIDGES. An encyclopaedia of ex vivo validated alternative mRNA-splice products has been generated for all DNA repair genes in the BRIDGES gene-set. In addition, a novel in silico tool for variant classification was developed with improved accuracy relative to other publicly available tools.

We prepared validated questionnaire instruments for the identification of patients with psychological distress after genetic counselling for familial breast cancer, as well as a template for psychological intervention. These were used in a prospective cohort of 450 counselees from France, Germany, Netherlands. The results revealed the psychosocial impact on women from breast cancer families upon being given a personalised risk estimate based on CanRisk, as well as how their medical counsellors perceive this.

An evidence-based patient decision aid for the uptake of preventive measures was designed for BRCA1 and BRCA2 carriers in the German language. For women at moderate risk of breast cancer, information leaflets were conceived, as the evidence-base for these genes was still too weak to define optimal clinical management decisions.

Finally, an e-learning tool for health care providers, based on the concept of shared decision-making, was designed to train MDs how to use CanRisk (in German language).
RESULTS
BRIDGES has achieved nearly all the innovations described in the original project proposal.

The list of well-established BC genes with immediate clinical impact has been extended from 5 to 9, while estimates of the breast cancer risks conferred by each of them were refined, including estimates for morphological subtypes. All the variants detected by BRIDGES in the assayed 34 genes have been made publicly available through the LOVD platform and BCAC websites. A new version of the commercial software tool Alamut® Visual used by diagnostic laboratories around the world, will provide hotlinks to the BRIDGES data.

The discriminatory power of the BOADICEA model (an AUC of 0.70) is the highest of all known breast cancer prediction models. The CE marking will expedite its utility in the Cancer Family Clinic and beyond to empower women to manage their breast cancer risk with unprecedented accuracy.

The results of our VUS analyses have been contributed to relevant ENIGMA working groups to aid variant classification by the ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel according to the ACMG/AMP guidelines, which will ultimately be disseminated into the public domain through ClinVar, LOVD and ENIGMA websites.

The preparatory work for the e-learning tool for the clinical implementation of CanRisk for genetic counsellors and oncogeneticists will serve as a framework for other EU-countries to develop similar training curricula.

The questionnaires that collect relevant medical and socio-economical information addressing risk perception, level of medical information received, important live events and the experience of medical and psychological counselling, can be used to define psychological needs in a patient cohort receiving counselling using the CanRisk prediction tool.

Finally, BRIDGES helped designing and publishing two position reports on how personalised risk prediction might change the practice of population screening programs for breast cancer in the EU.

POTENTIAL IMPACTS
Healthy women with or without a family history of breast cancer now have access to the most comprehensive breast cancer risk prediction, although this access requires proper genetic counselling by a healthcare provider. The CanRisk tool does not necessitate new guidelines on how to clinically manage the various breast cancer risk-levels, but will facilitate more accurate assignment of individual women in these risk classes. Implementation of CanRisk in the clinical routine of the Cancer Family Clinic is currently ongoing or under investigation in many countries across the EU.

CanRisk might also facilitate the transition from age-based to risk-based participation of women in breast cancer population screening programmes in the EU, with the potential to improve cost-benefit. This was acknowledged by stakeholders in two international meetings, co-organised by BRIDGES and B-CAST in 2019 and published in two position papers. These can serve as starting points for programs in the new Horizon Europe program to design roadmaps to achieve this.

Finally, commercial companies looking for opportunities to develop better genetic testing kits can now inform customers more accurately about genetic breast cancer risks using BRIDGES’ published results.
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