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Report

Teaser, summary, work performed and final results

Periodic Reporting for period 1 - B-CAST (Breast CAncer STratification: understanding the determinants of risk and prognosis of molecular subtypes)

Teaser

Summary

Breast CAncer STratification: understanding the determinants of risk and prognosis of molecular subtypes

Breast cancer is not one entity, but different subtypes have different aetiologies and very different prognosis, ranging from highly fatal to fully curable cancers. In B-CAST tools will be developed to allow precise identification of the individual risk of breast cancer, the subtype of cancer that is most likely to develop and the prognosis of that particular subtype. Different molecular subtypes of breast cancer may have distinct risk factor profiles; these risk factors can be genetic, for example the high prevalence of triple negative breast tumours in BRCA1 mutation carriers, but also environmental, for example the influence of reproductive factors on the hormonal status of the breast tumour. Breast cancer subtypes also lead to a differential survival. This project will be the first to try to reach subtype specific risk prediction. Subtype prediction should, for instance, identify more precisely those women that benefit from screening because of an elevated risk of tumours more likely to be screen detected; or through the identification of women more likely to benefit from preventive endocrine therapy because of increased risk for endocrine-responsive tumours. For prognostication tools, our work will add to and go beyond the tumour expression profiles used already in clinical practice for prognosis, by evaluating key markers on a much larger sample size than has previously been possible. To reach above goals, the B-CAST project exploits existing resources, infrastructure and collaborations, established through the Breast Cancer Association Consortium (BCAC). Specifically, clinical information from ~80,000 breast cancer patients with risk factor information will be collated and new data on molecular characterisation of a subset of ~20,000 tumours from a unique worldwide collection from large-scale epidemiological studies, clinical studies and biobanks will be generated. Generating new genomic information based on IHC/ISH panels on ~20,000 tumours and targeted sequencing on a subset of ~10,000 tumours will inform risk and prognosis modelling of breast cancer. User-friendly online tools will be made that implement the risk and prognostication models which can be used to obtain personalized estimates of risk and prognosis.

Project objectives
To define the influence of risk factors, including reproductive history, lifestyle, mammographic breast density and germline genetic variation, on breast cancer overall and by subtypes characterized by clinical and molecular markers.
To define the influence of risk factors and tumour subtypes on clinical prognosis.
To develop and validate breast cancer risk and prognostication models for breast cancer, overall and by subtypes, informed by knowledge acquired under above objectives
To implement these models into online tools for risk prediction and prognostication; and make them available in multiple countries/languages.
To raise awareness, i.e. promote the development and integration of personalized breast cancer prevention within national public health programmes.

Work performed

The project started with a kick-off meeting together with the BRIDGES project in September 2015. For dissemination of the project and its results, and for internal and external communication a website has been published: www.b-cast.eu.

Current and new studies in BCAC and B-CAST have submitted new clinico-pathological, treatment and follow-up data and updates; a new freeze of the BCAC database will be available in October 2016. A software package called PathXL, with specific features for B-CAST build in, was purchased for collation and scoring of the TMAs. PathXL will also function as a repository for all digital TMA images. Currently we are in the process of including all the TMA images and scoring data that is gathered through the BCAC consortium in PathXL. A proposal for staining of new markers has been circulated among all potentially contributing studies.

A panel for targeted DNA sequencing has been developed. Significant breast cancer driver genes were identified by collecting and processing all published whole-exome sequencing data on breast tumours (large-scale tumour profiling studies; revision of available literature; and other previous large-scale sequencing studies). Gene selection for inclusion in the B-CAST targeted sequencing panel have been done based on prioritization using mutation frequency and relevance. The final B-CAST panel includes 107 genes. In addition to these genes, homozygous deleted and amplified genes are added as well as hotspot promotor regions. All studies available in the BCAC consortium were invited to participate in the tumour sequencing of the B-CAST project. So far, 46 studies (with in total >10.000 breast cancer cases) were eligible, and agreed to participate.

To ship the samples from the 50 different studies to Spain for DNA isolation and sequencing, a framework for the sample flow has been established. Standard operating procedures have been developed and a specific B-CAST (SQL-)database has been built to track the samples. It was decided to include RNA isolation from the tumour samples as well, to set up a resource for B-CAST follow-up projects. For the isolation of tumour DNA and RNA a specific kit (AllPrep DNA/RNA FFPE Kit (QIAGEN, 80234)) has been selected and optimized for the use in the B-CAST project. The receipt of samples and tumour DNA/RNA isolations are ongoing.

A survey has been send out to all studies in the BCAC consortium to ask them whether they have data available about risk factors that were not yet gathered trough BCAC, and then specifically on availability of mammograms. Breast density measures can be read from these mammograms, using the STRATUS software, which is now tested for its use in studies in the BCAC consortium. Current and new studies in BCAC and B-CAST have submitted new risk (lifestyle, environmental) data and updates.

Final results

B-CAST will collate clinical data from ~80,000 breast cancer patients with risk factor information and follow-up, and generate data on molecular characterisation of a subset of tumours from a unique worldwide collection. Molecular profiling of breast cancers on this scale, and integrating somatic genetic characteristics with germline genetics and environmental factors has not previously been attempted. With this data, B-CAST will provide validated, easy to use online tools to identify women at different risk of developing, not just breast cancer overall, but specific breast cancer subtypes of public health and clinical relevance, such as fatal cancers (~25% of all breast cancers) and interval cancers (~20-30% of cancers detected in women undergoing screening) that tend to have more aggressive behaviour. Translating these findings to the clinical practice could enable tailoring screening programmes based on individual characteristics, which could in turn improve the effectiveness and cost-effectiveness of screening programs aimed at reducing mortality from breast cancer. Additionally, B-CAST will perform a large-scale evaluation of germline genetic variation, tumour genetic variants and CNAs, IHC/ISH tumour markers, and environmental exposures in relation to prognosis. This information may lead to new models for breast cancer prognosis in specific tumour subgroups.