Gene expression profiles have identified five major molecular breast cancer subtypes (Luminal A, Luminal B, Basal-like, HER2+/estrogen receptor− , and Normal Breast-like) that show significant differences in survival. The cost and complexity of gene expression technology has impeded its clinical implementation. By comparison, immunohistochemistry is an economical technique applicable to the standard formalin-fixed, paraffin-embedded material commonly used in hospital labs, and has the advantage of simultaneously interpretation with histomorphology. In this thesis, I hypothesize that a surrogate panel of immunohistochemical biomarkers can be developed to discriminate the breast cancer biological subtypes. The main study cohort consists of over 4000 primary invasive breast tumors, assembled into tissue microarrays. These patients were referred to the British Columbia Cancer Agency between 1986-1992 and have staging, pathology, treatment and follow-up information. In summary, our results demonstrate that (1) the rabbit monoclonal antibody, SP1, is an improved standard for immunohistochemiscal estrogen receptor assessment in breast cancer; (2) the transcription factor, GATA-3, is almost exclusively expressed among estrogen receptor positive tumors but does not seem to predict for tamoxifen response among estrogen receptor positive patients; (3) the proliferation marker, Ki-67, together with HER2 can segregate Luminal A from Luminal B subtypes, which carry distinct risks for breast cancer relapse and death; and (4) the inclusion of the basal markers EGFR and ck5/6 to “triple negative” breast cancers provides a more specific definition of basal-like breast cancer that better predicts patient survival. These results consistently demonstrate that an immunopanel of six biomarkers (estrogen receptor, progesterone receptor, HER2, Ki-67, epidermal growth factor receptor and cytokeratin 5/6) can be readily applied to standard pathology specimens to subtype breast cancer samples based on their underlying molecular biology. These findings have been considered sufficient to justify application of this panel onto NCIC (MA5, MA12) and CALGB (9341 and 9741) clinical trials specimens. This followup work which is underway and will determine if the six marker immunopanel can guide decisions about which patients need aggressive systemic drug treatment, and thereby ensure patients get the most effective, individualized adjuvant systemic therapy for their breast tumor.

Title page, contents and abstract only. The complete thesis in print form is available from the University of Adelaide Library. / "The present study investigated the expression and function of IGF-1R, CXCR4 and CCR7, in metastatic MDA-MB-231 and non-metastatic MCF-7 cells." / http://proxy.library.adelaide.edu.au/login?url= http://library.adelaide.edu.au/cgi-bin/Pwebrecon.cgi?BBID=1295746 / Thesis (Ph.D.) -- University of Adelaide, School of Molecular and Biomedical Science, 2007

Title page, table of contents and summary only. The complete thesis in print form is available from the University of Adelaide Library. / This thesis describes two studies, one in vitro and one in vivo, which show that Apo2L/TRAIL can prevent breast cancer-induced bone destruction, and highlight the potential of this ligand for the treatment of metastatic breast cancer in bone. They also highlight the complexity of Apo2L/TRAIL signalling, and the need for further studies into this area to fully exploit the potential of Apo2L/TRAIL as an anti-cancer agent for breast and other cancers. / http://proxy.library.adelaide.edu.au/login?url= http://library.adelaide.edu.au/cgi-bin/Pwebrecon.cgi?BBID=1283688 / Thesis (Ph.D.) -- University of Adelaide, School of Medicine, 2007

Title page, table of contents and summary only. The complete thesis in print form is available from the University of Adelaide Library. / This thesis describes two studies, one in vitro and one in vivo, which show that Apo2L/TRAIL can prevent breast cancer-induced bone destruction, and highlight the potential of this ligand for the treatment of metastatic breast cancer in bone. They also highlight the complexity of Apo2L/TRAIL signalling, and the need for further studies into this area to fully exploit the potential of Apo2L/TRAIL as an anti-cancer agent for breast and other cancers. / http://proxy.library.adelaide.edu.au/login?url= http://library.adelaide.edu.au/cgi-bin/Pwebrecon.cgi?BBID=1283688 / Thesis (Ph.D.) -- University of Adelaide, School of Medicine, 2007

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

Thesis (M.S. in exercise science)--Washington State University, December 2007. / Includes bibliographical references.

Thesis (Ph. D.)--University of Texas at Austin, 2002. / Vita. Includes bibliographical references. Available also from UMI Company.

Thesis (Ph. D.)--University of Chicago, Dept. of Organismal Biology and Anatomy, December 2000. / Includes bibliographical references. Also available on the Internet.

Thesis (Ph. D.)--Drexel University, 2007. / Includes abstract and vita. Includes bibliographical references (leaves 93-112).

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