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Early menopause (menopause before age 45 years) affects up to 80% of premenopausal women with breast cancer. Early menopause is associated with negative impacts on psychological and physical health, both short and long term. The increasing numbers of breast cancer survivors highlights the importance of early menopause as a health issue. There is a lack of understanding of early menopause, it’s health impacts, and treatment options amongst consumers and health professionals, potentially leading to delayed diagnosis and sub-optimal management. This proposal aims to address these gaps in knowledge with best practice research investigating (i) the longer term health impacts of early menopause in the setting of breast cancer, (ii) the quality of evidence based information related to early menopause and treatment options currently available, and (iii) women’s and health professional’s experiences related to early menopause associated with breast cancer. We will then use these findings to develop a comprehensive website and range of resources for consumers and health professionals related to early menopause which will detail women’s and health professionals’ experiences (written, video and audio), provide relevant consumer and health professional information regarding early menopause and treatment options and links to other useful resources. We will also evaluate the impact and reach of this work to ensure it reaches women and their health professionals.
The immune system plays an integral and complex role in breast cancer biology. There is much more that needs to be understood of the role of the immune system in the development of breast cancer in order to harness its potential in the early detection, prevention and treatment of the disease.
A critical part of the immune system is the lymphatic system which is responsible for maintaining fluid levels in the body as well as draining molecules (antigens) shed from bacteria and other microbes from body tissues and delivering them to the lymph nodes. Within the lymph nodes an immune response is generated resulting in killer cells and molecules (antibodies) that are released into the blood stream to kill these invaders. In the same way, cancer cells release antigens that get trapped inside lymph nodes, making it an ideal site for understanding the earliest stages of breast cancer.
It has been established that some molecules are altered in cancer cells and recognised by the immune system as foreign entities – these are called tumour-associated antigens (TAAs). TAAs are expressed by malignant cells during tumour progression, and are recognised by a patient’s immune system, in some cases several years prior to the manifestation of clinical symptoms. They prompt the production of cancer-specific antibodies that are generated in the lymph nodes, before being released into the blood stream.
The antibodies are produced very early during tumour growth, often before a tumour is even visible, making them the most sensitive way to identify cancers at an early stage. Previous attempts, using blood antibodies to identify the critical TAAs for cancer diagnosis, have failed due to the presence of too many other unrelated antibodies in the bloodstream.
The research being led by Associate Professor Elgene Lim from the Garvan Institute, in collaboration with Latrobe University, will provide a better understanding of the role the immune system plays in breast cancer, and could inform more targeted use of immunotherapies for treatment. It’s particularly exciting because for immunotherapy to be successful the tumour needs to be targeted at the earliest stage, before immune evasion strategies evolve.
A/Prof Meeusen has developed a process that captures TAA-specific antibodies directly from the lymph node, before they are released into the blood. They believes this approach will make the breast cancer-specific TAAs visible amongst the other irrelevant matter in the blood and it will be the first time TAAs relevant to early stage breast cancer are identified.
Through this novel approach of harnessing the local immune response, this project aims to identify the TAA profile of different breast cancer subtypes (Estrogen receptor (ER) positive, HER2-amplified and triple negative breast cancer), to enable a better understanding of the immune response of breast cancer, according to subtype. It can also reveal potential new biomarkers for early and sub-types of breast cancer, which could have an important impact on earlier diagnosis and treatment of breast cancer.
The potential applications include the development of a sensitive and subtype-specific blood test for breast cancer diagnosis, for which there are currently no blood-based tests, and a better knowledge of the more effective use of immune-based therapies in breast cancer.
Triple-negative breast cancer accounts for approximately 15 per cent of all breast cancers, and they are challenging to treat because they are typically more aggressive and don’t respond to current treatments.
Much of the underlying biology that increases cancer risk is unknown and as such, reliable biomarkers that would help with diagnosing early stage, high risk triple-negative breast cancer patients have not yet been identified.
One key factor in the fast progression of triple-negative breast cancer is a high level of vascularisation – when the tumour develops blood vessels such as capillaries and veins. This vascularisation process is a precursor to the tumour spreading to other parts of the body (metastasises).
New promising treatment methods are arising that focus on targeting the vascularisation process for many types of breast cancer, however, it is still poorly understood for triple-negative breast cancer. A better understanding of the biological mechanisms involved could result in potential prognostic markers or new therapies for breast cancer patients.
The process for testing our understanding of how cells interact is to culture them in a petri dish. However, experiments on cells in petri dishes do not accurately mimic the natural human tissue environment and cannot represent the progression of breast cancer in the human body.
In order for researchers to obtain useful results from laboratory cell culturing, they need to be able to replicate the breast environment as closely as possible. In this project, to properly understand the cellular interactions in triple-negative breast cancer that control its vascularisation and metastasis, Dr Laura Bray and her team aim to upgrade the existing practice in culturing tumour cells by developing a more sophisticated, three dimensional culture technology to create experimental models that better reflect real breast cancer interactions, and have greater clinical relevance.
The study will also seek to identify key biomarkers that can predict the response to breast cancer therapy, and develop a model system to test patient biopsies which would help determine if the patient’s cancer is likely or unlikely to develop into metastatic form of triple negative breast cancer, and to individualise their treatment program.
Two thirds of the Australian female population are overweight or obese which increases their risk of developing hormone receptor-positive breast cancer after menopause.
The hormone estrogen plays a pivotal role as, in addition to being produced by the ovaries, it is also produced by fat and the majority of obesity-related breast cancers are estrogen-dependent.
Dr Kristy Brown’s research program is wide-ranging in its scope and intends to provide better understanding of the regulation of metabolic pathways in cells of the breast with the aim of identifying new therapy options for the effective treatment and prevention of breast cancer.
She is continuing with research that demonstrated a direct metabolic link between obesity and breast cancer and expanding this research to look at the possible interaction between breast inflammation, the metabolism of cells within the breast and the production of estrogen that drives tumour growth.
Additionally, this program will look further into an appetite stimulating protein produced by the gut, called ghrelin, and its potential to inhibit the body’s ability to synthesise estrogen and the growth of breast tumours, including breast cancers with limited available treatments.
Overall this program will take the next steps in building on previous research into new ways of blocking cancers spreading to other sites, provide hope for treating women with limited options, and look at treatments that have fewer side-effects.
We have known for over 300 years that childbearing protects against breast cancer, but the reasons are not clear.
A woman’s reproductive history is a strong risk factor for breast cancer; women who do not bear children or who have them at an older age are at an increased risk of developing the disease. This is alarming given the global reproductive trend of women bearing fewer children. Societal changes have meant that the age at which women are having their first baby is also increasing.
It’s not possible to dictate when women should have children just to decrease their breast cancer risk, but there is potential to develop therapies aimed to mirror this protection if we understand how pregnancies protect the breast against cancer development.
Currently Tamoxifen is the most frequently prescribed treatment for the treatment of existing breast cancers and has resulted in a 50 per cent fall in the death of breast cancer patients in the last 30 years. Tamoxifen is also used in the preventative setting as it can reduce the risk of estrogen positive benign and invasive breast cancers in high risk women (those with a family history).
However, Tamoxifen has numerous toxicities, including increased risk of thromboembolism, endometrial cancer, hot flushes and vaginal symptoms. It has a low compliance rate, with only 50 per cent of patients adhering by the full treatment, meaning preventative strategies with fewer side effects are needed.
Dr Kara Britt believes that a protein that is increased in the breast tissue of individuals who have borne children may be responsible for the protective effects of pregnancy and childbearing.
The study will focus on testing whether this protein, when given to mice, can inhibit breast cancer development, or slow the growth of tumours. This will allow Dr Britt and her team to determine if it should be considered for clinical use as a preventative for high risk women.
Australian women who have been identified with a high-risk of breast cancer often don’t undergo recommended cancer prevention and screening procedures.
This study will use interviews and surveys to study women enrolled in the kConFab (Kathleen Cunningham Foundation Consortium for Research into Familial Breast Cancer) Follow-Up Study to determine why; from the perspectives of high-risk women and their clinicians.
High-risk women include those who have the BRCA1 and BRCA2 gene mutation, either themselves or in their family, or have a strong family history of breast and/or ovarian cancers.
The range of potential options available to manage cancer risk includes intensified screening such as MRI scans, tablet medications that reduce cancer risk, and surgery such as preventive mastectomies.
Professor Phillips believes reasons for the limited take up of these options could include concerns about side effects, lack of knowledge about available options by both women and their doctors, and perhaps difficulty accessing the full range of options, particularly for women in rural and regional Australia.
However, the study is also expected to discover important barriers to uptake that have not previously been considered.
She says there is an urgent need to more fully understand why high-risk women do not take steps to reduce their chance of developing breast cancer. This information will inform the development of educational materials and changes to health policy that will reduce the national cancer burden by helping women get the best care.
The incidence of breast cancer has historically been lower in Asian countries, but this is changing rapidly with economic development. It is changing more rapidly for Asian women living in developed countries.
We know this because the Multi Ethnic Cohort Study of the Japanese community living in Hawaii has shown that exposure to Western lifestyles had a substantial impact on breast cancer risk. Their breast cancer incidence has increased enormously in the last 50 years and is now at the same level as for the Caucasian population, especially for third and fourth generations of Japanese Americans.
Australia has a growing population of women and families of Vietnamese descent and, given global trends, their incidence of breast cancer is likely to increase rapidly in the next few generations.
This presents not only a major challenge for breast cancer control in Australia, but also an opportunity to study the causes of breast cancer, and in particular, to try to prevent an increase in this disease  Australia’s Vietnamese community. If we can do this, it would have profound implications for the enormous populations of Asian women living in developing and developed countries across the world.
The objective of this study is to establish a cohort of women and families of Vietnamese descent who have been living in Australia for different amounts of time to study the impact environmental factors, such as migration and acculturation, have on risk of developing breast cancer.
This project has the potential to put in place an early warning system and educational program about breast cancer and how to reduce risk and develop opportunities for early detection in this expanding migrant community.
The ovarian hormones, estrogen and progesterone, are critical in normal development of the breast, but are also major drivers of breast cancer risk although the precise details of how remains unclear.
Cancer can be viewed as abnormal development in which regular developmental mechanisms have gone awry. To prevent cancer, a key approach is to define these normal mechanisms and determine how they are corrupted during early cancer formation.
In this project Dr Heidi Hilton will document cell types in the normal breast across the whole of reproductive life, and by identifying the impact of hormones on these cell types, she aims to draw a link between hormone exposure, the presence of hormone receptors for estrogen (ER) and progesterone (PR), and the switching on/off of cellular pathways that may be harmful to these cells. This is important, as the detection of ER and PR in new breast cancers is crucial to decisions about treating these cancers.
Dr Hilton’s recent data shows that ER and PR are found in different cells in the normal breast, but can also be found in cells, called progenitors, that are thought to be susceptible to the first cancer-causing activity. She and her team have shown that progesterone stimulates these progenitor cells to grow and is associated with cancer-stimulating properties.
This project will build on this knowledge and take a new approach to understanding how hormones (particularly progesterone) influence breast cancer risk, by identifying the targets of these hormones in normal breast and pre-invasive cancers (called ductal carcinoma in situ).
Although the hormones progesterone and estrogen are critical in normal breast development, women taking hormone replacement therapy (HRT) that contains synthetic progesterone analogues, called progestins, have an increased breast cancer risk.
The outcome of this study could lead to earlier diagnosis for breast cancer, and also help women who are faced with the difficult decision of deciding between using HRT, or dealing with the uncomfortable and often debilitating symptoms of menopause.
Our DNA is like a blueprint of biological guidelines for staying alive and functional, but it’s up to RNA to carry out these guidelines, and many RNAs play crucial, active roles in the cell.
Some RNA molecules are involved in switching genes on and off, and others called non-coding RNA are not involved in gene changes but can have other important roles. The number of non-coding RNAs in the human genome is unknown and not much is known about many of them.
Professor Gregory Goodall recently identified an abundant form of non-coding RNA, called Circular RNAs (CircRNA), which are likely to be regulators of cell activities associated with cancer invasion and metastasis – i.e. they could play a role in cancer development and progression.
Following on from that initial surprising discovery, he is now conducting one of the first investigations into the role of this novel type of regulatory molecule in breast or any other cancer.
The aim of the study is to substantiate evidence regarding the role of these circular RNA molecules in affecting cancer cell properties, in particular how they influence cancers to progress to an invasive, metastasising form.
This is a new exciting avenue of research that in the long run could lead to discovery of new types of therapeutic target or a diagnostic marker for early stages of metastasis.
More immediately, Professor Goodall hopes his results will stimulate other researchers to join the investigation of cancer roles of these molecules.
Although significant advances have been made in recent years in the diagnosis and treatment of breast cancer, the greatest improvements have been made for tumours with a ‘good’ prognosis, i.e. those that are diagnosed early and express proteins called hormone receptors for estrogen and progesterone. These account for about 70 per cent of all breast cancers.
Hormone receptors pick up hormone signals, which control many aspects of cell behaviour, including increasing the growth of cancer cells. A cancer is called estrogen-receptor-positive (or ER+) if it has receptors for estrogen. ER+ and PR+ cancers can be identified with current biopsy tests and standard treatments for these tumours are generally effective. Around 15-25 per cent of breast cancers have a high number of receptors for the human epidermal growth factor (Her2), which is a protein that affects the growth of some cancer cells, and this type of breast cancer also has effective treatment options.
Tumours that lack all three of the above receptors are called triple negative breast cancers, and account for about 15 per cent of breast cancers. They are part of a diverse group of tumours which are often more aggressive and generally have poor outlook because there are no targeted treatment options available.
This study aims to remedy the critical gap in our understanding of how to treat patients with triple negative breast cancer by identifying a different hormone receptor that can be targeted with an effective therapy.
The two best known breast cancer hormone receptors, ER and PR, are members of a large family of nuclear receptors. Dr Dinny Graham and her team will go beyond ER and PR, to test whether other nuclear receptors can act as specific biomarkers for triple negative breast cancers or may represent new treatment targets in triple negative disease.
Once identified, the research team aims to develop personalised tests that can more accurately predict the outcome of treatment options, and also lead to new more effective treatments that target specific features of triple negative breast cancer. This will not only spare patients from the side effects of untargeted chemotherapy, but will reduce the mortality rate from triple negative breast cancer.