Breast cancer is a heterogeneous disease, and can be classified according to histological subtypes based on cellular morphology. Invasive ductal carcinoma (IDC) and invasive lobular carcinoma (ILC) are the most common histological subtypes, accounting for approximately 80% and 12% of cases respectively. ILC exhibits a number of distinct clinico-pathological features in comparison with IDC, and is understudied as a breast cancer subtype. ILC tumours are typically oestrogen receptor positive, HER2 negative, and frequently demonstrate early loss of Ecadherin expression, which is a hallmark of the lobular phenotype. ILC is presently treated in a similar manner to IDC, with treatment generally directed against hormone receptors. Upon acquisition of hormone resistance, limited secondary options are available; patients are rarely candidates for agents targeting HER2, and are recognised to be poorly responsive to chemotherapeutics. We therefore need to advance our understanding of lobular tumour biology, in order to identify suitable biomarkers that will guide the development of targeted therapies for ILC patients. As protein expression levels determine cellular phenotype, a protein-based approach has the potential to provide biologically relevant insight into the mechanisms driving ILC. A range of protein analysis platforms, including reverse phase protein array, label-free mass spectrometry and immunohistochemistry, were therefore used to elucidate biological mechanisms active in the ILC subtype. Such experiments led to the identification of activated PI3K-Akt signalling in mouse and human ILC, suggesting that inhibition of this pathway may be an effective treatment strategy in lobular breast cancer. Preliminary evidence of differences in cytoskeletal and extracellular matrix (ECM) proteins was also acquired, providing an interesting basis for future research. A further major strand of this project was the development of in vitro and in vivo tools, to facilitate further interrogation of lobular biology. This included determination of a representative mouse model of ILC, and generation of primary cancer cells and cancer-associated fibroblasts (CAFs) from patient-derived material. Analysis of CAFS showed differential expression of ECM-associated genes, consistent with proteomic analyses. In addition, a tissue micro-array (TMA) comprising primary ILC and IDC tumours, with associated clinical data, was developed. Immunohistochemical staining of the TMA identified a potential role for IGF-1 pathway signalling in ILC, with increased expression of IGF-1 ligand associating with increased tumour size and metastasis in ILC patients. Taken together, the generation and validation of a range of useful tools in the course of this work has provided useful insight into the unique biology of ILC.

The problem investigated Four studies investigated the phenomenon of cancer-related fatigue (CRF) in women who had received adjuvant treatment for early-stage breast cancer, with a view to reducing the diagnostic uncertainty surrounding the syndrome and thus facilitating progress in both clinical management and aetiological research. Procedures and results A cross-sectional study of 109 women compared a ???cancer-specific??? self-report questionnaire (FACT-F) (canvassing fatigue symptoms) and a more generic questionnaire (SPHERE) (identifying depression and fatigue). Thirty-seven percent of women reported fatigue. Overall in 20%, fatigue was associated with psychological distress. Seventeen percent of women had fatigue but no depression. A qualitative study utilised focus groups to identify and compare the distinctive features of CRF with those of women with chronic fatigue syndrome (CFS). A similar set of symptoms was found in both groups, including overwhelming fatigue, un-refreshing sleep and subjective concentration problems. However, women with CFS also reported myalgia and arthralgia. Using the Structured Clinical Interview for Neurasthenia- SCIN, the third study compared the symptoms of three groups of women with fatigue: those with CRF, CFS or major depression. The detailed ???interviewer guide??? provided explicit directions for evaluating and classifying symptoms. This study confirmed the core symptom of ???profound fatigue unrelieved by rest???, and additional features that distinguished between the clinical diagnoses. The fourth study compared features of the evolution of clinically-identified fatigue syndromes in women from two prospective cohort studies; women with post-cancer fatigue (PCF) and women with post-infective fatigue syndrome (PIFS). Major conclusions A syndrome of PCF, present at least six months following adjuvant treatment and unexplained by medical or psychiatric disorder was investigated. The characteristics of PCF and those of CFS are very similar, with the fatigue state having indistinguishable descriptors. Longitudinal evaluation of the symptom complexes of PCF and PIFS suggests divergent pathways may be relevant. Co-morbid features like sleep disturbance; physical deconditioning and mood disturbance may be implicated as factors in the evolution and prolongation of PCF. These studies provide a basis for a more uniform and rigorous classification system - a necessary first step towards advancing the field both in investigating aetiology and new intervention strategies.

Typescript (photocopy) / 163 leaves, [8] leaves of plates : / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / Thesis (M.D.)--Dept. of Surgery, University of Adelaide, 1981

Background: Axillary lymph node dissection as routine part of breast cancer treatment has been questioned in relation to the balance between benefits and morbidity. The purpose of this study is to determine the association of tumor size, age and histological grade with axillary lymph node metastasis, to determine if some patients could be exempted from axillary dissection. Methods: The data are derived from BreastScreen NSW, the government sponsored population-based breast screening program. In New South Wales (NSW) Australia between 1995 and 2002, 7,221 patients with invasive breast carcinoma were diagnosed and 5,290 patients were eligible for this study. The relationship between incidence of positive axillary lymph nodes and three study factors (tumor size, age and histological grade) was investigated by univariate and multivariate analysis. Logistic regression models were used to predict probability of axillary metastases. Results: The incidence of axillary lymph node metastases was 28.6% (95% CI: 27.4%- 29.8%). Univariate analysis showed that age, tumor size and histological grade were significant predictors of axillary lymph node metastases (p<0.0001). Multivariate analysis identified age, tumor size and histological grade remained as independent predictors (p<0.0001). From multivariate analysis, patients with T1a (Less than or equal to 5mm) and grade I tumors regardless of age had 5.2% (95% CI: 1.2%- 9.3%) frequency of node metastases. Patients 70 years or older with grade I, T1a and T1b (6-10mm) tumors had 4.9% (95% CI: 3.2%- 7.5%) and 6.6% (95% CI: 5.3%-8.3%) predicted frequency of node metastases. Conclusions: Tumor size, age and histological grade are predictors of axillary lymph node metastases. Routine axillary lymph node dissection could be avoided in some patient groups with a low frequency of involved lymph nodes if the benefits are considered to exceed the risks.

"October 2003" / Bibliography: leaves 223-271. / xiii, 271 leaves : ill. (some col.), plates (col.) ; 30 cm. / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / 1. Hormonal control of human breast cancer -- 2. General materials and methods -- 3. Proliferative effects of androgens -- 4. Cross-talk between androgen and estrogen signalling pathways -- 5. Androgen receptor function in the MDA-MB-453 cell line -- 6. Gene expression profiles in breast cancer cells: identification of androgen regulated genes -- 7. Regulation of BRCA1 expression -- 8. Regulation of prostate specific antigen expression -- 9. General discussion. / Thesis (Ph.D.)--University of Adelaide, Dept. of Medicine, 2004

The problem investigated Four studies investigated the phenomenon of cancer-related fatigue (CRF) in women who had received adjuvant treatment for early-stage breast cancer, with a view to reducing the diagnostic uncertainty surrounding the syndrome and thus facilitating progress in both clinical management and aetiological research. Procedures and results A cross-sectional study of 109 women compared a ???cancer-specific??? self-report questionnaire (FACT-F) (canvassing fatigue symptoms) and a more generic questionnaire (SPHERE) (identifying depression and fatigue). Thirty-seven percent of women reported fatigue. Overall in 20%, fatigue was associated with psychological distress. Seventeen percent of women had fatigue but no depression. A qualitative study utilised focus groups to identify and compare the distinctive features of CRF with those of women with chronic fatigue syndrome (CFS). A similar set of symptoms was found in both groups, including overwhelming fatigue, un-refreshing sleep and subjective concentration problems. However, women with CFS also reported myalgia and arthralgia. Using the Structured Clinical Interview for Neurasthenia- SCIN, the third study compared the symptoms of three groups of women with fatigue: those with CRF, CFS or major depression. The detailed ???interviewer guide??? provided explicit directions for evaluating and classifying symptoms. This study confirmed the core symptom of ???profound fatigue unrelieved by rest???, and additional features that distinguished between the clinical diagnoses. The fourth study compared features of the evolution of clinically-identified fatigue syndromes in women from two prospective cohort studies; women with post-cancer fatigue (PCF) and women with post-infective fatigue syndrome (PIFS). Major conclusions A syndrome of PCF, present at least six months following adjuvant treatment and unexplained by medical or psychiatric disorder was investigated. The characteristics of PCF and those of CFS are very similar, with the fatigue state having indistinguishable descriptors. Longitudinal evaluation of the symptom complexes of PCF and PIFS suggests divergent pathways may be relevant. Co-morbid features like sleep disturbance; physical deconditioning and mood disturbance may be implicated as factors in the evolution and prolongation of PCF. These studies provide a basis for a more uniform and rigorous classification system - a necessary first step towards advancing the field both in investigating aetiology and new intervention strategies.

The problem investigated Four studies investigated the phenomenon of cancer-related fatigue (CRF) in women who had received adjuvant treatment for early-stage breast cancer, with a view to reducing the diagnostic uncertainty surrounding the syndrome and thus facilitating progress in both clinical management and aetiological research. Procedures and results A cross-sectional study of 109 women compared a ???cancer-specific??? self-report questionnaire (FACT-F) (canvassing fatigue symptoms) and a more generic questionnaire (SPHERE) (identifying depression and fatigue). Thirty-seven percent of women reported fatigue. Overall in 20%, fatigue was associated with psychological distress. Seventeen percent of women had fatigue but no depression. A qualitative study utilised focus groups to identify and compare the distinctive features of CRF with those of women with chronic fatigue syndrome (CFS). A similar set of symptoms was found in both groups, including overwhelming fatigue, un-refreshing sleep and subjective concentration problems. However, women with CFS also reported myalgia and arthralgia. Using the Structured Clinical Interview for Neurasthenia- SCIN, the third study compared the symptoms of three groups of women with fatigue: those with CRF, CFS or major depression. The detailed ???interviewer guide??? provided explicit directions for evaluating and classifying symptoms. This study confirmed the core symptom of ???profound fatigue unrelieved by rest???, and additional features that distinguished between the clinical diagnoses. The fourth study compared features of the evolution of clinically-identified fatigue syndromes in women from two prospective cohort studies; women with post-cancer fatigue (PCF) and women with post-infective fatigue syndrome (PIFS). Major conclusions A syndrome of PCF, present at least six months following adjuvant treatment and unexplained by medical or psychiatric disorder was investigated. The characteristics of PCF and those of CFS are very similar, with the fatigue state having indistinguishable descriptors. Longitudinal evaluation of the symptom complexes of PCF and PIFS suggests divergent pathways may be relevant. Co-morbid features like sleep disturbance; physical deconditioning and mood disturbance may be implicated as factors in the evolution and prolongation of PCF. These studies provide a basis for a more uniform and rigorous classification system - a necessary first step towards advancing the field both in investigating aetiology and new intervention strategies.

A growing body of work implicates chemokines and their receptors in the progression of various types of cancer, including breast cancer. However, as potent chemotactic factors for leukocytes, chemokines also have the potential to enhance anti-cancer immunity. Evidence suggests that the chemokine CXCL12 and its receptors may be important in a number of aspects of breast cancer progression and site-specific metastasis. Another chemokine, CXCL16, has been identified as a specific chemotactic factor for Type Ipolarised T lymphocytes, which are major effectors of cell-mediated immunity and hence efficacious anti-tumour immune responses. The aim of this study, therefore, was to further elucidate the roles of CXCL12 and CXCL16 in breast cancer development and metastasis. To achieve this, wild-type CXCL12 and CXCL16 and antagonists of CXCL12 and CXCL16 activity, CXCL12[subscript](P2G) and CXCL16[subscript](9-220) respectively, were overexpressed in the 4T1.2 mouse model of breast carcinoma. Overexpression of wild-type CXCL12 potently inhibited both primary tumour growth and metastasis in this model. This was attributed to the induction of an anti-tumour response dependent, in part, on T cells, interferon-g and the cytotoxic mediators perforin and TRAIL. This response was characterised by increased numbers of CD11c⁺ cells in the tumour-draining lymph nodes and enhanced cytolytic activity of lymph node-derived effector cells against tumour cells. Unexpectedly, CXCL12[subscript](P2G) inhibited metastasis of tumour cells to the lungs of tumour-bearing mice, without affecting primary tumour growth. Intravenous injection of tumour cells revealed that CXCL12[subscript](P2G) expression could block metastatic steps occurring post tumour cell escape from the primary tumour, though a role for CXCL12([subscript](P2G) at earlier metastatic steps could not be ruled out. Further work is needed to clarify the precise stages of metastasis at which CXCL12[subscript](P2G) exerts its effects. No obvious effects on primary breast tumour growth were observed when CXCL16 or CXCL16([subscript](9-220) were overexpressed in tumour cells. Interestingly, CXCL16[subscript](9-220) expression inhibited experimental metastasis but not spontaneous metastasis. The findings of this study begin to shed light on the roles of CXCL12 and CXCL16 in breast cancer progression and also highlight the potential therapeutic applications of CXCL12, CXCL16 and/or their antagonists in the treatment of breast cancer and breast cancer metastasis. / http://proxy.library.adelaide.edu.au/login?url= http://library.adelaide.edu.au/cgi-bin/Pwebrecon.cgi?BBID=1297662 / Thesis (Ph.D.) -- University of Adelaide, School of Molecular and Biomedical Science, 2007

Ethnodrama has been identified as an effective and innovative qualitative research method and dissemination tool which aims to improve and inform society through theatrical performances. Researchers are increasingly utilizing ethnodrama in their work; however it is relatively new and remains unexplored. The lived experiences of this method have not been extensively documented in prior research.<p> Specifically, I focus on a project which involved ethnodrama workshops for women experiencing arm problems after breast cancer. The ethnodrama workshops revealed that women were feeling: 1) there is a lack of support, 2) a sense of isolation, and 3) a need to heal after breast cancer. The workshops began to break that isolation, provide support, and start a journey of healing. They also provided an unexpected finding that yoga is an effective and sought after method of healing for women after breast cancer. This finding moved the workshops into the creation of healing yoga program for women after breast cancer, instead of a research based theatrical performance (ethnodrama). <p> Phenomenological interviews took place with a yoga teacher, dramatists, and researchers who had lived experiences of ethnodrama. The researchers spoke of the challenges involved in ethnodrama creation including time, funding, participant recruitment, and data collection. I also focus on the themes of emotional connectivity, building trust, healing, breaking isolation, and social change as they were found to resonate across all their experiences with the method.<p> I also use the methodology of autoethnography to connect the common themes across the experiences of ethnodrama with my own experience. My participation in an ethnodrama project allows me to connect my participant and researcher involvement with this method.<p> Ethnodrama is an effective knowledge translation strategy for audiences; however I have found that it is also a method which emotionally connects researchers and participants. There are challenges to this method, but I learned they did not outweigh the benefits. The themes of healing, breaking isolation, building trust, and social change show that ethnodrama is a method which positively impacts researchers and participants involved.

Background: Breast cancer is a diverse disease. Over the past 3 decades it has been increasingly appreciated that therapy should be targeted to specific patient and tumour characteristics. In recent years the evaluation of tailored therapy has been dominated by the development of new drug therapy which when successful has been marketed at a high price. There have been few successful attempts to optimize currently available therapies. This thesis explores the optimization of currently available therapies in three domains: efficacy, toxicity and supportive care. Methods: Three independent studies were undertaken. First, a prospective cohort study was conducted to assess the impact of re-biopsy of recurrent breast cancer on physician choice of therapy and on patient satisfaction. The second study comprised a systematic review and meta-analysis of randomized trials exploring toxicities associated with different endocrine therapy options for early breast cancer with the aim of identification of patients who may be harmed by certain drugs. Finally, a randomized feasibility study was conducted to evaluate de-escalated intravenous bisphosphonates in women with low-risk metastatic breast cancer to bone. Results: All studies met their objectives in showing that the tailored use of available therapies can be optimized. The prospective study of the impact of re-biopsy showed that treatment decisions were modified in 14% of women. Patient satisfaction with the process of re-biopsy was high. The meta-analysis of toxicities of endocrine therapy identified cardiovascular disease as a statistically significant toxicity of aromatase inhibitors, thereby suggesting that those with established cardiovascular disease or risk factors thereof should reduce their exposure to these drugs. Finally, the randomized feasibility study showed that it is possible to conduct randomized trials of de-escalated bisphosphonates in women with low-risk breast cancer and there was no signal that reducing the frequency of treatment was associated with untoward outcomes. Conclusions: It is possible to optimize the tailored therapy of breast cancer using currently available treatments. This may lead to improved patient outcome while using existing resources. Further studies assessing the optimization of other treatments are warranted.