Title page, table of contents and summary only. The complete thesis in print form is available from the University of Adelaide Library. / I hereby submit a body of original research for consideration of the award of Doctor of Medicine from the University of Adelaide. This is a collection of published original research that has made substantial contributions to the modern diagnosis and management of breast cancer. The publications have been presented in three clusters, each of which represents one facet of the modern approach to the diagnosis and management of breast cancer. The first section presents my publications on the theme of population based mammographic screening for the early detection of breast cancer. Broadly, the research focus in these publications is on the evaluation of existing methods of assessment of screen-detected breast lesions in order to improve diagnostic accuracy and limit the morbidity associated with mammographic screening. The clinical value of these contributions has been demonstrated independently since this body of work has informed many of the algorithms and protocols used by the South Australian breast cancer screening program. In addition, the protocols have been adopted for use outside of the screening setting into the wider diagnostic arena. The clinical endorsement of my research contributions is a significant acknowledgement of their practical value. The middle group of publications describe my contributions towards the evolving role of sentinel node biopsy as an alternative to axillary clearance for the staging of breast cancer. This area is of particular cogent to our setting, since a large proportion of screen-detected breast cancers, approximately 80%, are node negative. Thus, avoidance of the morbidity of axillary clearance while still achieving accurate axillary staging is of enormous appeal to our patients. My pioneering work in devising and evaluating protocols for the pathologic examination of sentinel nodes has informed the recommendations of the NHMRC sponsored SNAC (Sentinel Node versus Axillary Clearance) randomised trial. Consequently, these protocols have been used extensively and even outside of the trial setting, most pathology laboratories utilise similar assessment protocols as was recommended in SNAC. Furthermore, the United Kingdom's recommendations for the pathology examination of sentinel nodes have drawn on our research. After validating the concept of SNs in breast cancer, many of the clinically important questions emerging in this field have been addressed by our team. For example, my work on intra-operative imprint cytology was a conclusive demonstration of the value and limitations of this technique for one stage axillary surgery. In the light of our findings intra-operative assessment of sentinel nodes has been expanded to many centres and is endorsed by the SNAC trial. In the third section of this thesis, my contributions to the rapidly evolving field of molecular and genetics of breast cancer are highlighted . Through the Australian HER2 Advisory Board, we have led the evaluation and roll out of alternative platforms for HER2 testing and in developing algorithms for the efficient use of resources. We have devised national testing algorithms in both settings of metastatic and early breast cancer. These algorithms have since been utilised by the international HER2 testing bodies. In a further bold initiative, our group pioneered the move to the national adoption of bright field In situ hybridization as the first line testing platform for all newly diagnosed breast cancers throughout Australia. This ambitious undertaking entailed design and implementation of a nation-wide program of training, certification, quality assurance and evaluation. It has been deployed successfully and under my leadership, our laboratory was one of only four laboratories in Australia to commence this test in October 2006. Similarly, in the area of the genetics of breast cancer, my interest in this field and membership of the pathology subcommittee of KCONFAB has provided opportunities to contribute to significant new knowledge that illustrate the role of pathology in identification of mutation associated breast cancers. Under my leadership, our multi-centre studies have provided cogent arguments in favour of the inclusion of the histopathologic and immunophenotypic characteristics of breast cancers in the triage of patients for genetic testing. These results were published in pre-eminent pathology journals and have been referred to at major scientific conferences. Plans are afoot for the future extensions of this work. I am committed to utilising my expertise for the provision of high quality diagnostic services as part of a multi-disciplinary team involved in the treatment of women with breast diseases. I believe an evidence-based approach is central to achieving continuous improvements in these efforts. I am persuaded that there is substantial evidence demonstrating the value of population based mammographic screening in interrupting the natural history of breast cancer and reducing mortality from this disease. I am grateful to have the opportunity to contribute to the provision of this care. / http://proxy.library.adelaide.edu.au/login?url= http://library.adelaide.edu.au/cgi-bin/Pwebrecon.cgi?BBID=1473394 / Thesis (M.D.) -- University of Adelaide, School of Medical Sciences, 2010

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Background: Mammographic density (MD) for age and BMI is a strong risk factor (up to a 6 fold increase across extreme quantiles) for breast cancer. More than 60% of MD variation is estimated to be due to heritable (genetic) factors. Taking two different approaches, this work aimed to determine some of these genetic factors. The recently identified common genetic variants associated with small gradients in breast cancer risk and candidate common genetic variants identified using a genome wide association study (GWAS) of MD extremes were tested for an association with MD. / Methods: Germline DNA extracted from peripheral blood samples from 497 monozygotic (MZ) and 330 dizygotic (DZ) twin pairs, and 634 of their sisters from 903 families were genotyped for 22 independent variants (12 from associations with breast cancer and 10 from GWAS of MD extremes). Mammographic dense area, percent dense area and non-dense area were measured by three observers using a computer thresholding technique. Associations with MD measures adjusted for age, BMI and other determinants were estimated: (a) cross-sectionally using a multivariate normal model for pedigree analysis (P-values reported by Px), and (b) between-sibships and (c) within-sibships using orthogonal transformations of outcomes and exposures. A combined test of association (P-values reported by Pc) was derived using the independent estimates from (b) and (c). The distributions of P-values across variants were tested for a deviation from the uniform distribution (P-values reported by Pu). / Results: For the breast cancer associated common genetic variants tested, for dense area and percent dense area, the distributions of Pc-values deviated from the uniform distribution (both Pu<0.007), providing strong evidence that at least one genetic variant is associated with these MD measures. Consistent with their breast cancer associations, rs3817198 (LSP1) and rs13281615 (8q) were associated with dense area and percent dense area (all Px and Pc<0.05), and rs889312 (MAP3K1), rs2107425 (H19) and rs17468277 (CASP8) were marginally associated with dense area (some Px or Pc <0.05). For the candidate genetic variants from the GWAS of MD extremes the distributions of Pc-values deviated from the uniform distribution for dense area and percent dense area (Pu=0.07 and 0.009). One variant, rs10827227 (NRP1) showed strong evidence for an association with both dense area and percent dense area (Pc<0.009). For both approach, all associations were independent of menopausal status. / Conclusion: At least two common breast cancer susceptibility variants and one common variant identified through a GWAS for MD extremes were associated with MD measures that predict breast cancer. Together these variants explain about 1% of the variation in MD.

Mammographic density (MD), created predominantly by increased stromal tissue, is a major breast cancer risk factor, though little is known about the biological mechanisms mediating it. Tamoxifen prevents breast cancer in a subset of high risk women via mechanisms that appear dependent on reduction of MD. Animal models suggest tamoxifen remodels the mammary stroma to a tumour-inhibitory phenotype. This study aims to analyse the effect of tamoxifen on human breast fibroblast function and identify pro-tumourigenic pathways contributing to density-associated risk. Methods Primary human breast fibroblasts from normal, high risk or breast cancer patients were treated with hydroxytamoxifen (100nM-5μM). Fibroblast function was analysed by measuring: proliferation, expression of stromal proteins fibronectin and collagen 1; effects on TGF-β signalling and up-regulation of myofibroblast marker SMA. Genome wide analysis was performed using RNA-Seq. Significantly deregulated pathways were validated by PCR, western blotting and mass spectrometry. Results Fibroblasts from 23 patients were treated with hydroxytamoxifen. All patients showed reduced proliferation with treatment. 62% of patients showed reduced fibronectin expression. TGF- β-mediated up-regulation of SMA and fibronectin were consistently inhibited by tamoxifen. RNA-Seq analysis revealed down-regulation of Wnt signalling, an established profibrogenic and pro-tumourigenic pathway. In addition, there was significant modulation of many metabolic pathways, including components of the microsomal anti-oestrogen binding site (AEBS). Binding of tamoxifen to the AEBS inhibits cholesterol epoxide hydrolase (ChEH) enzyme activity, promoting an anti-tumourigenic phenotype. The effects of tamoxifen on fibroblasts could be partly replicated using tesmilifene, a commercially available 5 inhibitor of ChEH. Mass spectrometry analysis confirmed an altered cholesterol metabolite profile in tamoxifen treated fibroblasts. Conclusion These data indicate that tamoxifen can directly remodel the mammary stromal microenvironment, generating a less 'reactive' stroma. Thus, tamoxifen impacts on multiple pathways, many independent of the oestrogen receptor, to create a tumourinhibitory microenvironment. This offers exciting potential for patient monitoring and alternative breast cancer prevention strategies.

The older woman's body is an example of the discontinuous nature of those beings who come under the rubric of woman and, as such, demontrates the impossibility of a unitary representation of woman. This thesis explores the social construction of the older woman's body both as abject and as 'docile/useful' and proposes how this abjectification can be re-inscribed as transgressive through a de-territorialization of the older woman's body.This thesis positions the older woman's body as (un)becoming because it lacks cultural intelligibility as representative of the feminine on the one hand and, on the other, because it disrupts normative ideals of femininity and eludes disciplinary practices. Sexuality is used as a resource to conjure, construct, reinforce and validate the 'ideal' woman, a model against which the older woman is redefined as asexual. I argue that the particular technologies employed in the production of the older woman's 'docile/useful' body are those of the health sciences. A 'docile/useful' body transforms the older woman into a knowable, treatable and profitable body through discourses of health. Mass mammographic screening is analysed in order to illustrate how the biomedical sciences are employed in the regulation of the older woman's body through the co-option of health promotion strategy as a disciplinary practice. / Doctor of Philosophy (PhD)

Background: Vitamin D may be important in the causal pathway to breast cancer (BC) by influencing mammographic breast density (MD). However, previous study results in postmenopausal women are inconsistent. Study objectives were to prospectively examine the relationship between biomarkers of vitamin D (25-OH-D) and percent MD in postmenopausal women at northern latitudes. Potential effect modification by exemestane therapy, calcium or genetic polymorphisms in the vitamin D pathway was also examined. Methods: This study evaluated a sub-cohort of postmenopausal women at elevated BC risk who participated in the NCIC Clinical Trials Group placebo-controlled MAP.3 trial with exemestane. Levels of 25-OH-D were measured using LC-MS/MS from serum samples collected at baseline and year 1, averaged and adjusted for month of collection. Baseline and follow-up (≥ 3 year) percent MD was centrally assessed from film and digital mammograms with Cumulus software. Multivariable linear regression was used to estimate the effect of 25-OH-D on log transformed percent MD at follow-up and on the change in percent MD from baseline. Percent MD was also dichotomized and multivariable logistic regression was used to evaluate 25-OH-D levels between 1) women with lower (<25%) compared with higher (≥25%) percent MD and 2) women with a decrease compared with no change or an increase in percent MD over time. Results: Percent MD was measured for 568 participants with a follow-up mammogram and for 388 participants with a baseline mammogram in the same format as the follow-up. The geometric mean percent MD of the follow-up mammograms was 4.3% and few women (13.4%) had percent MD ≥ 25%. The unadjusted mean 25-OH-D concentration was 36.5 ng/mL (SD=10.6) based on pooled baseline and year one samples. After controlling for age, month of sampling and potential confounders, 25-OH-D was not predictive of log transformed percent MD at follow-up (p=0.36) or with annual mean changes from baseline (p=0.33). Similarly, results from the logistic regression analyses were not statistically significant and no interactions with exemestane, calcium or genetic polymorphisms were detected. Conclusion: No association was observed between vitamin D levels and percent MD at ≥3 year follow-up or change in percent MD from baseline. / Thesis (Ph.D, Community Health & Epidemiology) -- Queen's University, 2014-03-31 11:20:23.963

The topic of health is currently very up-to-date and the need for population health promotion and disease prevention is becoming increasingly important. The consequences of neglecting prevention and health promotion on the state's economy are clear, whether it is about increasing public spendings on health care or indirect effects on the level of human capital. The aim of this work is to analyze health promotion in the Czech Republic with a focus on mammographic screening programme introduced in 2002. The study demonstrates a decrease in breast cancer mortality following the screening examination and an increase in the number of tumor findings in earlier stages of the disease. It also analyzes the effect on costs of health care and the impact of screening on them. It also proposes to extend preventive screening examinations to other areas where their implementation could be useful in the future.

Neste trabalho, propõe-se a utilização da técnica Enhanced ICA Misture Model (EICAMM) para a segmentação automática de nódulos mamários em imagens mamográficas digitais. Com o objetivo de compará-la com outros métodos de segmentação encontrados na literatura correlata, como as técnicas Watershed, Self-Organizing Map (SOM), K-Means e Fuzzy C-Means, utiliza-se a métrica Area Overlap Measure (AOM) ou medida de similaridade de Jaccard, para medir a semelhança entre o resultado obtido na segmentação e o recorte efetuado por um especialista (ground truth). Os resultados obtidos mostram um bom desempenho do modelo EICAMM, que foi a única técnica capaz de detectar massas em regiões de interesse de mama densa. Resultados mais precisos produzidos por tal modelo foram aplicados na elaboração de um módulo classificador de nódulos para um esquema CADx (de Computer-aided Diagnosis) em mamografia digital. O módulo utiliza técnicas de extração e seleção de características e técnicas inteligentes, como Redes Neurais Artificiais, para indicar a existência ou não de nódulos em regiões de interesse, bem como avalia seu contorno/margem, forma e densidade, a fim de indicar a pertinência do achado a um caso maligno ou benigno. Para isso, utiliza-se uma base de regras, criada com o auxílio de um especialista e da combinação de diferentes classificações, conhecida como ensemble, para gerar uma única saída. Testes utilizando várias regiões de interesse selecionadas de duas bases de imagens mamográficas disponíveis resultaram numa precisão média de 46,71% na segmentação dos nódulos pela EICAMM (20,72% melhor que a média das demais técnicas comparadas) e um nível de acerto médio de 80,5% na classificação dos nódulos, o que permite considerar o módulo desenvolvido como uma útil ferramenta para auxílio ao diagnóstico desse tipo de estrutura em esquemas CADx. / This work describes the use of a technique called Enhanced ICA Misture Model (EICAMM) for automated segmentation of breast nodules in digital mammography images. Aiming to compare it with other segmentation methods, like Watershed transformation, Self-organizing Map (SOM), K-Means and Fuzzy C-Means, metrics such as Area Overlap Map (AOM) or Jaccard similarity measure are used in order to measure the similarity between the result from the segmentation and the profile determined by a spectialist (ground truth). Results show a good performance for the EICAMM method, the unique able to detect masses in regions of interest from dense breasts. More accurate results from such a model were applied to the development of a nodules classifier module for a CADx scheme in digital mammography. This module uses techniques for features extraction and selection, and intelligent techniques, as artificial neural networks, to determine the existence or not of a nodule, as well as to evaluate its contour/border, shape and radiographic density, in order to point out its pertinency to a malignant or benign case. With this purpose, a rules database known as ensemble, created with help of a specialist and different classifications combination, is used in order to produce only one output. Tests with several regions of interest selected from two available mammographic images databases have resulted in an average accuracy of 46.71% for nodules segmentation by EICAMM (20.72% better than the average of the other compared techniques), as well as an average accuracy of 80.5% in nodules classification, which allows to consider the developed module as an useful tool in aiding the diagnosis of such a structure in CADx schemes.

Neste trabalho, propõe-se a utilização da técnica Enhanced ICA Misture Model (EICAMM) para a segmentação automática de nódulos mamários em imagens mamográficas digitais. Com o objetivo de compará-la com outros métodos de segmentação encontrados na literatura correlata, como as técnicas Watershed, Self-Organizing Map (SOM), K-Means e Fuzzy C-Means, utiliza-se a métrica Area Overlap Measure (AOM) ou medida de similaridade de Jaccard, para medir a semelhança entre o resultado obtido na segmentação e o recorte efetuado por um especialista (ground truth). Os resultados obtidos mostram um bom desempenho do modelo EICAMM, que foi a única técnica capaz de detectar massas em regiões de interesse de mama densa. Resultados mais precisos produzidos por tal modelo foram aplicados na elaboração de um módulo classificador de nódulos para um esquema CADx (de Computer-aided Diagnosis) em mamografia digital. O módulo utiliza técnicas de extração e seleção de características e técnicas inteligentes, como Redes Neurais Artificiais, para indicar a existência ou não de nódulos em regiões de interesse, bem como avalia seu contorno/margem, forma e densidade, a fim de indicar a pertinência do achado a um caso maligno ou benigno. Para isso, utiliza-se uma base de regras, criada com o auxílio de um especialista e da combinação de diferentes classificações, conhecida como ensemble, para gerar uma única saída. Testes utilizando várias regiões de interesse selecionadas de duas bases de imagens mamográficas disponíveis resultaram numa precisão média de 46,71% na segmentação dos nódulos pela EICAMM (20,72% melhor que a média das demais técnicas comparadas) e um nível de acerto médio de 80,5% na classificação dos nódulos, o que permite considerar o módulo desenvolvido como uma útil ferramenta para auxílio ao diagnóstico desse tipo de estrutura em esquemas CADx. / This work describes the use of a technique called Enhanced ICA Misture Model (EICAMM) for automated segmentation of breast nodules in digital mammography images. Aiming to compare it with other segmentation methods, like Watershed transformation, Self-organizing Map (SOM), K-Means and Fuzzy C-Means, metrics such as Area Overlap Map (AOM) or Jaccard similarity measure are used in order to measure the similarity between the result from the segmentation and the profile determined by a spectialist (ground truth). Results show a good performance for the EICAMM method, the unique able to detect masses in regions of interest from dense breasts. More accurate results from such a model were applied to the development of a nodules classifier module for a CADx scheme in digital mammography. This module uses techniques for features extraction and selection, and intelligent techniques, as artificial neural networks, to determine the existence or not of a nodule, as well as to evaluate its contour/border, shape and radiographic density, in order to point out its pertinency to a malignant or benign case. With this purpose, a rules database known as ensemble, created with help of a specialist and different classifications combination, is used in order to produce only one output. Tests with several regions of interest selected from two available mammographic images databases have resulted in an average accuracy of 46.71% for nodules segmentation by EICAMM (20.72% better than the average of the other compared techniques), as well as an average accuracy of 80.5% in nodules classification, which allows to consider the developed module as an useful tool in aiding the diagnosis of such a structure in CADx schemes.

Background and objectives Evidence suggests that circulating IGF-I levels increase mammographic density (a breast cancer risk factor) and breast cancer risk in premenopausal women. The objective of this thesis was to examine the association of genetic variation at the IGF1 gene with IGF-I concentration, mammographic density, breast cancer risk, and related anthropometric measures in premenopausal women. Methods Three IGF1 CA repeat polymorphisms (at the 5′ and 3′ ends, and in intron 2) were genotyped. A cross-sectional design was used to investigate their associations with IGF-I levels, mammographic density, BMI, weight, and height. Families from registries in Ontario and Australia were used to investigate associations with breast cancer risk and also BMI, weight and height. Results In the cross-sectional study, greater number of copies of the 5′ 19 allele were associated with lower circulating IGF-I levels. Greater number of 3′ 185 alleles were associated with greater percentage breast density, smaller amount of non-dense tissue, and lower BMI. Including BMI in regression models removed the association of the 3′ 185 allele with percentage breast density. In the family based study, nominally significant associations (5′ 21 allele, intron 2 212 allele, intron 2 216 allele) with breast cancer risk were observed, but significance was lost after multiple comparison adjustment. There was a stronger association between the intron 2 216 allele and risk under a recessive model, and 5′ allele groupings of length 18 to 20 and 20 or more repeats produced significant positive and negative associations respectively. These associations were not strongly supported in analyses stratified by registry. Results from the family based study did not support an association between genetic variation at IGF1 with BMI, weight or height. Conclusions No specific IGF1 variant influenced each of circulating IGF-I levels, mammographic density, and breast cancer risk. The failure to replicate the association of the 3′ 185 allele with BMI in the family based study suggests that the association of the 3′ 185 allele with percentage breast density is spurious, since this association was mediated through the relationship with BMI (suggesting IGF-I action on body fat). Evidence for an association between IGF1 and breast cancer risk was limited.