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When diagnosed with breast cancer women have a lot of things to think about. For younger women, cancer treatment can reduce a woman’s ability to have children in the future. This may add to the worry about the cancer, especially if women have not yet finished their families. Research has shown that some women will make choices based on whether they can have children later. This is why it is very important that women know what the side-effects of cancer treatment are. Since there are steps that women can take to increase their chances of having a child later. To do this, they need to know about their options and they need this information early.

It can be difficult for women to make decisions about which treatment is best for them. If people are not given good-quality information they may regret the choices made. This is why it is important that we give women the information they need to make the best choice for them. This study aims to create and give women in this situation information that is easy to get hold of and to understand. It will test how helpful the information is in helping women to make decisions about what they can do to raise the chances of having a baby at a later date. It is hoped that this will help make these decisions easier. We will also look at how this information can be easily accessed by women as a part of their medical care.

Worldwide, more than one million women are diagnosed with breast cancer every year, making it the most common malignancy of females in the developed world. Approximately one-third of breast cancer patients will have tumours that become resistant to standard chemotherapy, and their tumours may relapse and subsequently metastasise. This is thought to be due to the existence of a small population of drug-resistant cells, which may initiate and maintain the tumour. The cells have been termed ‘breast cancer stem cells’ and may originate from normal breast stem cells. The purpose of this project is to understand how healthy mammary stem cells are maintained in the breast and how this process goes awry in breast cancer. We will do this by studying a group of proteins known as “epigenetic modifiers”, which instruct cell identity and behaviour. This knowledge will aid in the earlier detection of tumours and in design and development of novel therapeutic strategies for patients with advanced and metastatic disease.

In breast cancer surgery, it is vitally important to accurately remove the entire tumour and, also, to minimise removal of normal tissue to preserve cosmesis. Current tools are severely limited in their ability to detect microscopic regions of tumour during the surgery. Consequently, in more than one quarter of breast-conserving surgeries, additional surgery is required because histological analysis after the surgery indicated that small traces of tumour had been missed. This has traumatic consequences for patients and places a significant economic burden on healthcare systems. To reduce the unacceptably high number of re-excisions, new intraoperative techniques are needed.

In this project, we will develop an innovative technique, micro-palpation, which will provide microscopic images indicating how hard or soft tissue is, during the surgery. As tumour is typically stiffer than surrounding healthy tissue, this technology has the potential to provide high resolution images identifying cancerous tissue. Micro-palpation enhances the sense of touch (manual palpation) using optical imaging. In micro-palpation, tissue stiffness is determined by measuring deformation introduced to a silicone layer placed on the tissue surface.

The project will be implemented by a multidisciplinary research team involving engineers, surgeons and pathologists. Within the scope of this project, the team will develop the world’s first micro-palpation system and determine the accuracy of this technology in identifying tumour, validated against gold standard histology. Micro-palpation may enable the surgeon to detect small regions of tumour and has the potential to dramatically improve the accuracy of breast surgery.

Around 15% of breast cancers overexpress the human epidermal growth factor 2 receptor (HER2), and several HER2 targeted therapies are now leading to an improved prognosis for women with HER2 positive disease. The NeoALTTO clinical trial has recently demonstrated the promising role of dual inhibition of HER2 with lapatinib and trastuzumab in the neoadjuvant (preoperative) treatment setting. Neoadjuvant therapy is now becoming standard practice in many patients with high risk early breast cancers, however, accurate monitoring of treatment response to neoadjuvant therapy is challenging. Novel biomarkers are needed to more precisely monitor the effectiveness of treatment in women receiving neoadjuvant therapy and guide treatment decisions. Many breast cancers shed small amounts of DNA (called circulating tumour DNA or ctDNA) into the bloodstream and the measurement of ctDNA has the potential to be used as a highly specific marker of response to therapy in women with breast cancer. Through recent advances in genomic technologies, it is now possible to characterise specific DNA mutations in a patient’s tumour, design tests to identify these mutations, and then apply these tests to accurately measure the amount of ctDNA in blood. This research proposal will investigate the role of ctDNA as a novel tool to measure responses to neoadjuvant therapy in women with HER2 positive breast cancer within the NeoALTTO clinical trial. This research will open up new opportunities for molecular disease monitoring during neoadjuvant therapy, in order to personalise treatment decisions, improve disease outcomes and guide the implementation of new therapeutics in this setting.

Patients with triple negative breast cancers (TNBC) have the poorest survival outcomes of all the breast cancer subtypes and unfortunately, TNBC is far more common in breast cancer diagnosed in younger women. At present we lack understanding of potential therapeutic targets that could be present in TNBC. Hence, research into TNBC is an urgent priority.

My lab was the first to publish that some patients with TNBC have the presence of a marked lymphocytic infiltration or features of inflammation in their breast cancer when they are diagnosed and that this feature is correlated with better survival outcomes. As such, we believe that this marker represents an immune response to the tumour. Currently we do not understand why some patients do or do not develop a good immune response to their tumour. We have preliminary data suggesting that activation of the RAS/MAPK signalling pathway is associated with lower immune responses to a patients’ TNBC. Our proposal aims to understand why this is so, and then test therapies that can enhance or create an immune response. We strongly believe that enhancing immunity will be a way to combat the poor outcomes of TNBC, but we need to first understand the intricacies of the relationship between breast cancer biology and host anti-tumour immunity.

Early-stage detection of breast cancer bone metastases is challenging, and once established, the disease is virtually incurable. This highlights the urgent need to develop new approaches for the clinical management of the disease. Unfortunately, efforts towards this have been hampered by the lack of suitable animal models that recapitulate human bone metastasis. In traditional models, researchers inject human cancer cells into the animal and then they analyse the interactions between human cancer cells and mouse cells. However, it is well-known that there are incompatibilities in these mutual interactions and human cancer cells behave differently when grown in a human or mouse microenvironment. Conclusions drawn from observations of human cancer cells grown in a murine organism can therefore not directly be transferred from bench to bedside.

To address this challenge, Dietmar Hutmacher and colleagues aim to develop a fully humanised mouse model of breast cancer bone metastasis, where human cancer cells grow in humanised breast tissue and metastasise to humanised bone. In this model the human elements will be incorporated into the rat mammary fat pad and skeleton, respectively. This fully humanised model of breast cancer bone metastasis will recapitulate the conditions seen in the clinic to a much greater extent than traditional animal models.

More than 90% of breast cancer-related death is associated with metastatic cancer relapse. Relapse can occur from few months to several years following the treatment of the primary tumour, and is often characterised by tumour growth at multiple locations in the body. Early detection of such growth dramatically increases the effectiveness of further cancer treatment. Since at the early stage of metastasis new tumours are small, their detection is very difficult. Tumour growth is accompanied by release of tumour DNA into the surrounding tissues and blood, and so the ability to detect tumour DNA in blood provides a very attractive avenue for breast cancer diagnostics. However the current methods for detection of tumour DNA require complex equipment and are not suitable for continuous monitoring. Therefore we propose to develop a simple diagnostic test that identifies tumour DNA in the patient’s blood. Conceptually this test is similar to the one used for measuring the blood sugar in diabetic patients. The test is based on semiconductor-like proteins developed in CI Alexandrov’s laboratory. These proteins could be engineered to selectively recognize the tumour DNA and pass this information to a detector connected to a smart phone. Such test will improve the treatment outcome and quality of life of breast cancer patients.

This project aims to identify whether patients can be selected for a certain type of therapy by non-invasively imaging the expression of the glutathione s-transferase enzyme. Another potential application of this project lies in the early detection of treatment response and to monitor this in a non-invasive manner. This is particularly important in breast cancer, since chemotherapy and targeted agents may be used, but can have side effects, and not all patients respond to treatment. Early identification of the molecular signature of a breast cancer may allow selection of a more appropriate treatment, thus improving patient outcome.

Double reading of mammography images, where two radiologists independently read the same patient images is current practice in the Breast Screening service in Australia. Compared with single reads, the double read strategy improves outputs from breast screening programs, e.g. if a woman’s cancer is missed by one radiologist, the second radiologist may pick it up by thus leading to improved cancer detection rates. Unfortunately however double reading only works if paired radiologists complement each other, i.e. they do not make the same type of error, therefore sophisticated matching is required. Such sophisticated matching has never been implemented due to historic reasons: since mammographic films can only be physically stored at one location (often where they are produced), matching of radiologists has been performed out of geographic convenience rather than maximizing diagnostic potential. However in 2014, almost all mammographic images are produced, transmitted and stored electronically (digitally) meaning that a woman’s images can be read by anyone, anywhere (regardless of where they are produced). This means that radiologists can be matched on reading characteristics and individual errors rather than geography.

By bringing together scientists from Australia and the US we will:

Streamlining the double reading strategy, will result in substantial benefits for the 1.6 million Australian women who participate in breast screening over a two-year cycle, as well as the millions who undergo mammography world-wide each year.

In breast cancer patients whose tumour has spread to other parts of the body (metastasised), the presence of cancer cells in the blood (known as circulating tumour cells or CTCs) has been shown to predict for future relapse and death from breast cancer. Whereas current clinical trials are measuring the absence or presence of CTCs, we believe that the individual analysis of specific cancer markers will be more informative. We have developed a set of procedures to capture CTCs from blood and perform simultaneous analysis for multiple markers within each sample (blood) collection. We propose to perform molecular analysis of CTCs throughout the course of treatment in multiple blood collections from each of 15 patients with metastatic breast cancer. For controls, 10 bleeds from normal healthy volunteers (NHV) will be analysed as well. While this is primarily a pilot study to test our technologies, the detailed molecular analysis of CTCs may eventually allow us to better (i) predict whether a patient is likely to respond to a given therapy, (ii) determine already during treatment whether a patient is responding, and (iii) to understand when a therapy stops working.