Centre for Cancer Research - Theses

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    Tumour immune microenvironment, genomewide copy number aberrations and their interactions in malignant pleural mesothelioma
    Thapa, Bibhusal ( 2017)
    Malignant pleural mesothelioma (MPM) is a rare but deadly malignancy. Despite predictions, worldwide incidences have not significantly diminished and available therapeutic modalities have failed to improve outcomes. There are some indications that immune based therapies and targeted therapies may hold promise but suitable phenotypes have been hard to identify. This thesis describes investigations we conducted into the tumour immune microenvironment, the copy number aberrations (CNAs) and the interaction between the two in MPM. The findings presented in this thesis elucidate the complexity of the tumour immune microenvironment in MPM. We establish MPM to be immunogenic but also demonstrate that the immune characteristics vary amongst tumours mostly with tumour histological subtype. We reveal sarcomatoid MPMs to be associated with high lymphocytic infiltration but also greater expression of immune checkpoint receptors and their ligands. In addition, we also exhibit the prognostic implications associated with some of these markers. The genome wide copy number analyses described in this thesis disclose that although copy number aberrations are the commoner of genomic alterations in MPM, their extent and pattern vary amongst tumours. We describe their clinical and pathological associations. We confirm most previously described prominent CNAs but more importantly uncover new ones which may be important in MPM prognostication and therapeutics. We find that greater degree of genomic instability confers a worse prognosis in MPM independent of histology but neither degree of genomic instability nor any specific CNA correlates with the immunological milieu. Our findings contribute towards the understanding and development of potential prognostic and predictive markers for immunotherapy in MPM. Further, they also reveal potential targets for development of targeted therapies in this disease where none was thought feasible.
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    Reducing outcome disparities for rural Victorians with colorectal cancer: understanding pathways to treatment and informing policy.
    Bergin, Rebecca ( 2017)
    In Victoria, rural patients with colorectal cancer have poorer outcomes than urban counterparts. To date, research and policy initiatives have focused on addressing potential variation in cancer treatment. However, pre-treatment delays may also be important. Policy change is required to reduce disparities for rural patients with cancer. Determining potential models of rural cancer care and understanding the policymaking process could enhance the success of future policies to address geographic cancer disparities. The overarching aim of the research program was to develop evidence to inform potential health system policies to reduce outcome disparities for colorectal cancer patients in rural Victoria. There were three research objectives: 1. Compare rural and urban patient pathways and experiences to diagnosis and treatment for those with colorectal and breast cancer in Victoria; 2. Identify potential models of rural cancer care that could inform future policies; and 3. Understand how large-scale health service policies in cancer care develop and are implemented. The research used a multi-phase, mixed methods design in five studies. The first phase examined rural and urban patient pathways to colorectal or breast cancer diagnosis and treatment in two studies. Breast cancer patients were included as a comparison group since outcomes are equivalent for women across Victoria. In the first study, interviews with 43 patients showed that rural and urban patients with either cancer experienced relatively similar pathways, though some had difficulty accessing GPs and longer time to specialist referral. Qualitative results informed hypotheses tested in a quantitative study of time intervals to treatment. Survey data from 922 patients with colorectal (n=433) and breast cancer (n=489), 621 GPs and 370 specialists were supplemented with cancer registry data. In quantile regression analyses, the time from first symptom or screening test to treatment was significantly longer for rural than urban patients with colorectal cancer, but not breast cancer. This was likely driven by longer diagnostic intervals for rural patients with colorectal cancer. In the second phase, patient interview data were re-analysed to explore experiences of choice of cancer treatment provider. Although most patients had limited involvement in choosing a provider, decision-making considerations were more complex for rural than urban patients. Studies in the final phase were a scoping review of rural cancer models of care and an interview study with 13 local and international key informants regarding the policymaking process. Across 47 reviewed articles, telehealth models were most common. Navigator and alternative provider models were identified for the pre-treatment period, but very few studies measured time to cancer care, and none assessed clinical cancer outcomes. Developing and implementing cancer policies at national or state-level was found to involve specific change mechanisms, such as stakeholder collaboration and evidence-use, influenced by the physical, political and temporal context. Based on these results, it is recommended that policies to address rural–urban inequities in colorectal cancer patient outcomes in Victoria focus on the diagnostic interval. Initiatives such as GP endoscopy, waiting time reporting or diagnostic centres should be investigated, acknowledging the potential impact of context in policy-change. The current research provides a baseline to assess the impact of future policies, and a starting-point for further research to understand policy development and implementation in cancer care.