breast cancer

Abstract
Introduction
Breast cancer remains a significant scientific, clinical and societal challenge. This gap analysis has reviewed and critically assessed enduring issues and new challenges emerging from recent research, and proposes strategies for translating solutions into practice.

Methods
More than 100 internationally recognised specialist breast cancer scientists, clinicians and healthcare professionals collaborated to address nine thematic areas: genetics, epigenetics and epidemiology; molecular pathology and cell biology; hormonal influences and endocrine therapy; imaging, detection and screening; current/novel therapies and biomarkers; drug resistance; metastasis, angiogenesis, circulating tumour cells, cancer ‘stem’ cells; risk and prevention; living with and managing breast cancer and its treatment. The groups developed summary papers through an iterative process which, following further appraisal from experts and patients, were melded into this summary account.

Results
The 10 major gaps identified were: (1) understanding the functions and contextual interactions of genetic and epigenetic changes in normal breast development and during malignant transformation; (2) how to implement sustainable lifestyle changes (diet, exercise and weight) and chemopreventive strategies; (3) the need for tailored screening approaches including clinically actionable tests; (4) enhancing knowledge of molecular drivers behind breast cancer subtypes, progression and metastasis; (5) understanding the molecular mechanisms of tumour heterogeneity, dormancy, de novo or acquired resistance and how to target key nodes in these dynamic processes; (6) developing validated markers for chemosensitivity and radiosensitivity; (7) understanding the optimal duration, sequencing and rational combinations of treatment for improved personalised therapy; (8) validating multimodality imaging biomarkers for minimally invasive diagnosis and monitoring of responses in primary and metastatic disease; (9) developing interventions and support to improve the survivorship experience; (10) a continuing need for clinical material for translational research derived from normal breast, blood, primary, relapsed, metastatic and drug-resistant cancers with expert bioinformatics support to maximise its utility. The proposed infrastructural enablers include enhanced resources to support clinically relevant in vitro and in vivo tumour models; improved access to appropriate, fully annotated clinical samples; extended biomarker discovery, validation and standardisation; and facilitated cross-discipline working.

Conclusions
With resources to conduct further high-quality targeted research focusing on the gaps identified, increased knowledge translating into improved clinical care should be achievable within five years.

Introduction
Globally, breast cancer is the most frequently diagnosed cancer in women, with an estimated 1.38 million new cases per year. Fifty thousand cases in women and 400 in men are recorded each year in the UK alone. There are 458,000 deaths per year from breast cancer worldwide making it the most common cause of female cancer death in both the developed and developing world [1].

In the UK, the age-standardised incidence of breast cancer in women has increased by 6% over the last decade, between 1999 to 2001 and 2008 to 2010 [2]. It is estimated that around 550,000-570,000 people are living with or after a diagnosis of breast cancer in the UK [3] and, based on current projections, this figure is expected to triple by 2040 due to an ageing population and continued improvements in survival [4]. Recent research indicates that the annual cost of breast cancer to the UK economy is £1.5bn, with just over a third of that cost (£0.6bn) from healthcare alone [5]. Yet the annual spend on breast cancer research by partners of the National Cancer Research Institute has reduced in recent years despite the level of cancer research spend being generally maintained [6].

In 2006, the charity Breast Cancer Campaign facilitated a meeting of leading breast cancer experts in the United Kingdom to explore which gaps in research, if filled, would make the most impact on patient benefit. The subsequent paper [7] has helped shape the direction of breast cancer research since that time. One overarching need identified was the ‘lack of access to appropriate and annotated clinical material’, which directly led to the formation of the UK’s first multi-centre, breast-specific tissue bank [8].

This new gap analysis represents an expanded, evidence-based follow-on developed collaboratively by clinicians, scientists and healthcare professionals. The aim is to ensure that the roadmap for breast cancer research remains a relevant, consensual and authoritative resource to signpost future needs. It builds upon the previous gap analysis by briefly reviewing the current status of key areas, critically assessing remaining issues and new challenges emerging from recent research findings and proposes strategies to aid their translation into practice. Whilst a survey of progress during the last five years is not the intention of this article, the preparatory detailed discussions and data analysis could provide the basis for such a retrospective review.

Methods
During 2012, Breast Cancer Campaign facilitated a series of workshops, each covering a specialty area of breast cancer (Figure 1). These working groups covered genetics, epigenetics and epidemiology; molecular pathology and cell biology; hormonal influences and endocrine therapy; imaging, detection and screening; current and novel therapies and associated biomarkers; drug resistance; invasion, metastasis, angiogenesis, circulating tumour cells, cancer ‘stem’ cells; breast cancer risk and prevention; living with and managing breast cancer and its treatment. Working group leaders and their multidisciplinary teams (comprising a representative cross-section of breast cancer clinicians, scientists, and healthcare professionals) participated in iterative cycles of presentation and discussion, offering a subjective consideration of the recent relevant peer-reviewed literature. Summary reports were prepared by each group, collated, condensed and edited into a draft, which was critically appraised by an external Executive Advisory Board of international experts. This position paper highlights the key gaps in breast cancer research that were identified, together with detailed recommendations for action.
Results
Genetics, epigenetics and epidemiology
Current status
Genetic predisposition
Our knowledge of the heritability of breast cancer has increased significantly since 2007. Known breast cancer genes (BRCA1, BRCA2, CHEK2, ATM, PALB2, BRIP1, TP53, PTEN, CDH1 and STK11) make up 25 to 30% of the heritability [9]. Genome-wide association studies (GWAS) and the recent international collaborative analyses have confirmed 77 common polymorphisms individually associated with breast cancer risk, which add a further 14% [9-11]. Evidence from an Illumina collaborative oncological gene-environment study (iCOGS) experiment suggests that further single nucleotide polymorphisms (SNPs) may contribute at least 14% to the heritability, leaving only approximately 50% as ‘missing heritability’ (Figure 2).

thumbnailFigure 2. Familial cancer genetics. The proportion of the familial component of breast cancers that can be ascribed to specific genetic defects. The difference between June 2007 and 2013 shows the impact of genome-wide association studies (GWAS) that have now identified 77 common low-risk SNPs. Courtesy of Professor Douglas Easton (University of Cambridge). Reprinted by permission from Macmillan Publishers Ltd: Nature Genetics (45,345-348), copyright 2013.
If we assume the risk estimates for polygenic markers are log additive, the cumulative risk associated with these SNPs has a median of 9% to age 80 (95% confidence intervals 5 to 15%). In the familial setting, we have learnt that common genetic SNPs can modify the risk associated with BRCA2, which may be relevant when considering risk-reducing surgery [12,13].

BRCA1 and BRCA2
There is improved understanding of the function of BRCA1 and BRCA2 in relation to DNA repair and therapeutic responses. For example, BRCA2 functions in RAD51 loading and BRCA1 in countering 53BP1-mediated blocking of homologous recombinational (HR)-DNA repair; hence poly (ADP-ribose) polymerase (PARP) inhibitors have been developed and trialled against BRCA-driven cancers [14]. Several additional genes associated with breast cancer risk are part of the BRCA network and there is a clear relationship with the Fanconi pathway [9]. Genes in this network point to reduced HR-DNA repair as the mechanism underlying cancer susceptibility, although the precise functions of associated signalling proteins (for example PTEN, CHK2, ATM and N-terminal BRCA1) that relate to cancer development are unknown. Gene interactions of some higher risk alleles are recognised to be sub-multiplicative, whereas low risk alleles are log-additive [15]. Some susceptibility SNPs may function at the level of chromatin remodelling/enhancer activity related to nearby gene expression.

Epigenetics
Epigenetic alterations are frequent and cancer-specific methylation in circulating tumour (ct)DNA in serum can be used as an early detection biomarker, or as a prognostic indicator [16,17]. The recent ENCODE study provided a wide-ranging analysis of epigenetic marks on a small fraction of the genome [18]. The first candidate gene epigenetic risk factor that could usefully be included in breast cancer risk models (once fully validated) has been identified [19]. Epigenetic factors also provide molecular measures of long-term exposure to potentially oncogenic agents. Epigenetic alterations are reversible; preclinical and recent clinical testing of epigenetic-targeted therapies such as etinostat (a DNA methylation inhibitor) and vorinostat (a histone deacetylase inhibitor) indicate that such drugs may prove effective in combination with other therapies [20,21].

Psychosocial considerations
Predictive genetic testing for breast cancer predisposition genes can increase distress in the short term (which reduces over time) for those identified as gene carriers, whilst non-carriers report lower levels of concern following genetic testing [22]. A number of interventions have now been developed and tested to support the genetic testing process and have been shown to reduce distress, improve the accuracy of the perceived risk of breast cancer, and increase knowledge about breast cancer and genetics [23]. Examples introduced since the last gap analysis include education using tailored information technology to prepare women for genetic counselling [24]; interventions to support women’s decisions about whether or not to have genetic testing [25] and support for gene carriers thus identified [12].

What are the key gaps in our knowledge and how might they be filled?
Moderate risk alleles
Remaining ‘moderate risk’ alleles will be found within the short term by exome sequencing and extended GWAS studies will identify additional lower risk alleles. If up to 28% of the risk from known SNPs could be explained, while the median of the risk distribution changes little, confidence limits would change dramatically, such that the women in the top 5% at risk would have >15% lifetime risk, compared with