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With 53 Australians being diagnosed with breast cancer every day and over 3,000 dying from the disease each year, there is an urgent need to reduce the numbers of women developing breast cancer in the first place.

There are many ways that women can reduce their risk of developing breast cancer and it’s important that these options are known and available across the entire population, regardless of geographical or socio-economic situation.

As an NBCF-funded fellow, Professor Kelly-Anne Phillips has developed a web-based tool called iPrevent which is designed to help all Australian women to know and appropriately manage their personal breast cancer risk.

Professor Kelly-Anne Phillips

Professor Kelly-Anne Phillips

NBCF has now provided additional fellowship funding to complete the testing and roll out of iPrevent so that women and their doctors can work together to try to  prevent breast cancer.

Professor Phillips will also seek information directly from women and their clinicians about why some women do not utilise breast cancer prevention and screening options. Understanding these barriers is the first step to breaking them down and will enable more women to access the benefits of 21st century breast cancer prevention knowledge.

In addition, this far-reaching research fellowship includes studies of medications that might prevent cancer or stop it returning in women who have increased breast cancer risk because they have abnormalities in the BRCA1 or BRCA2 gene. Two of these studies will help work out whether tamoxifen and aspirin respectively can prevent cancer in women with these gene abnormalities. Another study will see if the drug olaparib can help stop breast cancer returning if it does occur in these women.

Professor Phillips will also continue to lead the Australian arm of a huge international study looking at lifestyle risk factors for breast cancer risk and aimed at further refining current methods of assessing a woman’s risk of developing the disease.

This broadly collaborative, multidisciplinary research program builds on almost 20 years of clinical and research contributions by Professor Phillips who is dedicated to helping women to reduce their risk of developing breast cancer.

Genetic services and familial cancer centres across Australia investigate women and their families when there is an evident inherited predisposition to breast cancer, due to a family history of cancer for instance.

Primarily the doctor is looking to see if these women have mutations in the BRCA1 and/or BRCA2 genes – genes that have been specifically linked to breast cancer risk. However, most of these women do not have mutations in either of these genes.

Mutations in other genes having been recognised as playing a role, especially in cases where breast cancer is diagnosed at an early age. Until recently however, tests have been conducted one gene at a time, at very high cost. The testing process is slow and laborious, and most test results remain uninformative, despite great advances in research into breast cancer predisposition.

The revolution in our capacity to conduct genetic analyses in very recent years has had a profound impact on how genetic testing services can be applied. New technology is enabling multiple genes to be screened for mutations in a single test, at considerably reduced cost

However, the choice of genes to include in panel testing needs careful consideration. Around 20 genes are currently included in commercial panel tests.There is very little known about these additional genes or whether they are actually associated with breast cancer risk. Essentially the information in the report beyond BRCA1 and BRCA2 is not useful to either the patient or the doctor and is ignored.

There is an opportunity to make genetic tests an even more powerful tool in determining women’s genetic risk of developing breast cancer by ensuring the cutting-edge technology is providing only clinically useful information.

Dr Tu Nguyen-Dumont

Dr Tu Nguyen-Dumont

NBCF is funding a research project aimed at better understanding the genes used in genetic tests to maximise the potential of genetic testing and ensure better outcomes for women.
In this project, Dr Tu Nguyen-Dumont will analyse vast libraries of genes to determine whether the genes that are on the test are connected to breast cancer, and whether newly discovered genes should be added to the test.

The aim is to make genetic testing more comprehensive with the ability to identify genes beyond BCRA1 and BRCA 2 that also point to a woman having a higher risk of developing breast cancer.

With more information these women and their families can be better informed about their situation and make choices that could prevent them ever having to deal with predictable breast cancer.

This year breast cancer became the most commonly diagnosed cancer in Australia. Although it has one of the highest survival rates, thanks largely to research, 10 per cent of those diagnosed with breast cancer still die from the disease within five years. NBCF has commissioned an Australian-first research project to better understand and predict who makes up that 10 per cent.

David Roder

Professor David Roder

Professor David Roder, Chair of Cancer Epidemiology and Population Health at the University of Adelaide will undertake a project that will provide valuable information on pockets of risk among the breast cancer population.

This information will allow a substantial leap forward in understanding which women have worse health outcomes compared to others, the detailed reasons for the disparity and what that means for the women affected. NBCF will use the information to make data-driven decisions in setting research priority areas for breast cancer research funding. It will also provide a platform for NBCF to advocate changes in public health policy and service delivery that could help close the gap and stop deaths from breast cancer.

 

 

Women with a mutation in the BRCA1 gene have a high lifetime risk of developing breast (and ovarian) cancer, often at an early age. While regular screening can detect breast cancer at an early stage, this does not by itself prevent cancer.

Although mastectomy (breast removal) can be highly effective at preventing breast cancer, most women choose not to pursue this surgical option. Apart from a mastectomy, currently available prevention strategies for BRCA1 mutation carriers include taking the drug tamoxifen and/or removal of the ovaries (the latter primarily to reduce ovarian cancer risk).

There is good evidence that tamoxifen reduces the incidence of estrogen receptor (ER) positive tumours, but its role in BRCA1 mutation carriers is unclear. Moreover, there has been poor uptake of tamoxifen as a preventative treatment for breast cancer, even when prescribed by clinicians. For this reason a suitable prevention therapy is needed that is both safe and effective, so that women with a BRCA1 mutation never face breast cancer.

Professor Geoff Lindeman

Professor Geoff Lindeman

Professor Geoff Lindeman and his team recently identified a protein, called RANKL, as a potential target for breast cancer prevention for BRCA1 mutation carriers (and possibly other high-risk women). A currently available inhibitor of RANKL, called denosumab, is used to treat osteoporosis and breast cancer spread to bone. Professor Lindeman believes denosumab has potential to be ‘repurposed’ as a prevention agent for breast cancer.

In this NBCF-funded study he will compare the relative effectiveness of tamoxifen, removal of the ovaries and RANKL inhibition in mice, and also determine whether RANKL has any relevance to BRCA1-associated ovarian cancer.

These findings will provide pilot data to support an international clinical trial aimed at preventing breast cancer in women at high genetic risk for developing breast cancer with the long-term goal of improving the lives of BRCA1 mutation carriers and their families.

Up to now the emphasis has been on identifying individuals with a family history of breast cancer. Our approach to understanding non-familial breast cancer risk is based on the emerging field of epigenetics which is the study of how our genetic machinery is programmed.

Mutations in the BRCA1 gene, which is involved in the repair of DNA damage, underlie much of familial breast and ovarian cancer. Our previous studies indicate that the epigenetic modification called DNA methylation, which can inactivate the BRCA1 gene, might be a novel mechanism of breast cancer predisposition. DNA methylation of the BRCA1 gene is known to occur in breast cancer (and was first reported by us) but it has been unclear as to how much this DNA methylation might be an initiating event in the cancer.

The novelty of our approach is to examine normal tissues for evidence of DNA methylation of the BRCA1 cancer gene to identify individuals that may be at increased risk of developing breast cancer. Using very sensitive methodologies developed by us, it was shown that BRCA1 methylation in the normal tissues was much more common in some breast cancer patients.

Studies of methylation as a mechanism of cancer predisposition represent a frontier area in cancer research. Once it is understood how such methylation arises, it may be possible to for dietary or other environmental interventions to reduce this methylation, and thereby decrease the risk of developing cancer.

There are currently few management options that reduce breast cancer risk for BRCA1 and BRCA2 mutation carriers. Safe and effective prevention strategies beyond prophylactic mastectomy are urgently required.

We previously discovered an abnormal population of ‘progenitor’ cells (the descendants of stem cells) in breast tissue from BRCA1 mutation carriers, suggesting they are the culprits that give rise to breast cancer. Recently, we discovered a key messenger, called RANKL, which activates progenitors and demonstrated that inhibition of RANKL switches them off. Notably, we also found that RANK (the target of RANKL) is present much more frequently (4-fold) in BRCA1 tumours. These findings raise the very real prospect that targeting RANKL might represent a novel breast cancer prevention strategy for BRCA1 mutation carriers, and possibly other high-risk women. Denosumab is an anti-RANKL drug approved in the clinic to treat bone metastases. Our findings suggest that it might have a ‘repurpose use’ for breast cancer prevention.

Our goal is to pilot denosumab therapy in healthy BRCA1 and BRCA2 gene carriers, to determine whether RANKL inhibition switches off proliferative activity in breast tissue and modifies breast density (a marker of risk), as determined by MRI, and to ensure it is tolerable and safe. The BRCA-D study will recruit women planning prophylactic mastectomy (or who agree to undergo paired biopsies). Women will receive 4 doses of denosumab over 3 months.

This study will provide proof-of-principle findings essential for enabling progression to an international randomised phase 3 prevention study, with long-term ramifications for improving clinical outcome.

The best way of beating breast cancer is to prevent it from developing in the first place. For women at high risk of developing breast cancer, such as those with a family history of the disease or those who have previously had breast cancer, options to prevent breast cancer are limited to either surgery to remove the breasts or long-term use of existing drugs such as tamoxifen. Both of these strategies can cause significant physical and psychological side effects such as endometrial cancer, blood clotting and depression. In this pilot study we will test whether a new drug called enobosarm, which works by selectively activating beneficial androgen hormone action, is effective at preventing breast cancer in experimental models of the disease. Recently enobosarm was reported to provide beneficial effects in women with advanced breast cancer, with minimal side effects. Therefore this drug has excellent potential as a breast cancer prevention drug. Demonstrating that enobosarm can prevent tumour development in experimental models, and providing evidence for no apparent long term deleterious effects on normal tissues and their function, is essential before this drug can be tested for the ability to prevent breast cancer in women. Our aim is to provide women at high risk of breast cancer with new alternatives to prevention that would reduce their risk of disease and improve their quality of life.

Breast density is a strong risk factor for breast cancer(1) where women with very dense breasts for their age are more likely to develop breast cancer than women with non-dense (fatty) breasts. Based on what we know thus far, we think that breast density is established when the breasts form, largely due to genetic factors, and then environmental factors modify breast density over time. However, all of this evidence has been derived from mammography which is not recommended for younger women (<40 years) due to low absolute risk and radiation exposure. There is almost no data from younger women. New methods of measuring breast density are therefore needed to bridge large gaps in knowledge regarding breast density in young women and its relation to later-life breast cancer risk. Members of our team have developed Transillumination Breast Spectroscopy (TiBS) which uses light to estimate breast density and is safe and easy to use.

We are proposing a pilot study to test the feasibility and acceptability of this novel method, TiBS, to measure breast density in young adult women participating in the Western Australian Pregnancy Cohort (the Raine Study) who have been followed from prenatal life and are now aged 24. We will also use the extensive data collected by the Raine Study to help validate TiBS as a measure of breast density in young women. This study will lay the groundwork for future follow-up studies needed to understand the life course of breast density and its relation to breast cancer risk.

This request for infrastructure support will enable lifepool to maintain operation and expand to recruit women from other states in Australia. The national lifepool cohort will provide data and biospecimens to enable laboratory based, clinical and psychosocial research into better understanding breast cancer. A key strength of lifepool is the capacity to support research aimed at understanding breast cancer risk factors; in particular through supporting research which gathers an evidence base for design of breast cancer screening strategies tailored to personal risk factors. Lifepool can provide DNA and tumour samples with extensive clinical and outcome information in a group of women gathered from across the Australian population. Lifepool engages with women across the spectrum of breast cancer risk: Those who have not been diagnosed and are at ‘population’ risk, women recently diagnosed through the BreastScreen program and women from high risk families with and without a breast cancer diagnosis. Close collaboration across medical research institutes, breast cancer clinicians, BreastScreen services, epidemiologists and other experts in public health as well as active and committed representation from breast cancer advocacy groups has produced a resource of enormous potential in the shared aim of reducing the burden on breast cancer on the community.

Exercise can reduce the risk of developing breast cancer, and improve survival amongst women diagnosed with the disease. Despite this knowledge, the majority of Australian women do not participate in sufficient exercise. Further, how the eight or nine hours of daily sitting time accumulated by Australian women affects their breast cancer risk is unknown. Given what we know about the biology of breast cancer, it is likely that sitting time also contributes to risk.

The proposed research will address two themes: breast cancer prevention, and breast cancer survivorship. Using data collected by existing studies I will examine how the type, duration, intensity and frequency of exercise and sitting time relate to breast cancer. A new study (part of a much larger project being undertaken by Cancer Council Victoria – the ABC Study) will collect accurate information on the exercise and sitting time patterns of approximately 1,000 postmenopausal women, by using small devices called accelerometers. This will help us to understand how exercise and sitting time affect breast cancer risk. Another new study will investigate whether the use of wearable activity monitors (such as the Fitbit®) can increase breast cancer survivors’ exercise and reduce their sitting time.

The proposed research will enable us to provide more specific advice to women about how much, and what type of, exercise they should be doing to prevent breast cancer, or to improve their survival after diagnosis. It will also allow us to give guidance on how much sitting is can be safely done each day.