Sir Peter MacCallum Department of Oncology - Theses
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ItemIdentifying heterogenous mechanisms of drug resistance in high grade serous ovarian cancer( 2023-05)Ovarian, fallopian tube and primary peritoneal cancer is the sixth most common cause of cancer death for women in Australia. A diagnosis of ovarian cancer is life-altering with a five-year survival of only 45.7%. While clinical factors such as disease stage are important for prognosis and response to therapy, the underlying genomic, transcriptomic and immune characteristics of the tumour are also key determinants of outcome. High grade serous ovarian cancer (HGSC) is the most common epithelial ovarian cancer subtype, and is characterised by frequent germline, somatic and epigenetic aberrations which result in homologous recombination DNA repair (HR) deficiency. Aneuploidy and frequent somatic copy number aberrations (SCNA) are common features of the genomic landscape of HGSC. Despite often initially responding to therapy, acquired resistance is extremely common, arising through a variety of genomic, transcriptomic, adaptive and microenvironmental mechanisms. Owing to the scarcity of biopsies or surgery in relapsed disease, the frequency and distribution of these acquired resistance mechanisms is only partially known. In particular, there is a paucity of information about resistance mechanisms in late-stage disease following the multiple lines of therapy that a typical patient with HGSC receives. This thesis addressed these important gaps in knowledge by examining resistance mechanisms in a cohort of women with HR deficient HGSC who underwent a research autopsy, providing unique insight into the architecture of end stage disease. Importantly, resistance mechanisms were frequently subclonal, often with more than one mechanism detected within a single metastatic site. Evidence of convergent evolution was also observed, including of reversion mutations and BRCA1-specific mechanisms of HR restoration. An increased frequency of whole genome duplication, an important event in cancer evolution, was noted in the end-stage samples compared to what is known in primary tumours. Following this observation, the transcriptomic differences between tumours with and without WGD were assessed. Examination of the transcriptomic differences in whole genome duplication revealed downregulation of CIITA and other MHC-II genes, highlighting a potential means of immune escape and a potential therapeutic vulnerability. This thesis also examined mechanisms of resistance specifically occurring following receipt of poly-ADP ribose polymerase (PARP) inhibitor therapy, and the natural history and evolution of reversion mutations in HR deficient HGSC, showing that they are in fact not frequently present outside of a progressing or resistant cohort. The findings of this thesis add to the current knowledge of resistance to therapy, demonstrate the need for accessible genomic testing in the clinical management of HGSC and indicate that further exploration of resistance should focus on transcriptomics, epigenetics, and the tumour microenvironment.
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ItemEffectiveness and cost-effectiveness of programs for BRCA pathogenic variant carrier cancer risk management( 2019)Background Women who inherit a germline pathogenic variant in the BRCA1 or BRCA2 genes have a significantly elevated lifetime risk of breast and ovarian cancer. Women who are aware of their BRCA carrier status can mitigate their increased risk by undergoing intensive breast cancer screening from a young age for early detection, and risk-reducing surgery for prevention of breast and/or ovarian cancer. The effectiveness of these interventions is dependent on BRCA carriers taking up these risk management strategies at an appropriate time, considering factors such as their age, personal preferences, and life stage. The most effective approach to ensuring carriers adhere to risk management recommendations is unknown. This project evaluates the lifetime health outcomes and cost-effectiveness of long-term clinical management of BRCA carriers in the context of structured clinical programs, using real-world data. Methods This thesis describes the development and outcomes of a discrete-time state-based microsimulation model. The model, named miBRovaCare, simulates the gene-specific natural histories for breast and ovarian cancer in BRCA carriers. Cost-effectiveness and cost-utility analyses were performed to evaluate the lifetime outcomes of different approaches to clinical management of carriers from the perspective of the Australian public healthcare system. The comparator for the base case analysis was the natural history (no cancer risk management). The interventions included: (i) a structured familial cancer service with a multidisciplinary high-risk clinic, and (ii) a formal annual carrier review program. For the intervention arms, BRCA carriers could undergo annual breast imaging, risk-reducing bilateral or contralateral mastectomy, and risk-reducing bilateral salpingo-oophorectomy. Uptake of and adherence to these strategies (patient behaviour) was based on an analysis of 983 BRCA carriers seen through a clinic in Melbourne, Australia. Additional model inputs were obtained from a local hospital database, the literature, government reports, and expert opinion. Costs and health outcomes were discounted by 5%. Results Long-term management of BRCA carriers through a familial cancer service is likely to be cost-effective, with or without an annual review program. A familial cancer service was the preferred strategy if the willingness-to-pay was at least $29,000 per quality-adjusted life-year (QALY) for BRCA1 carriers and $57,000 per QALY for BRCA2 carriers. Inclusion of an annual review program for BRCA1 carriers had a 75% probability of being cost-effective at a willingness-to-pay threshold of $50,000 per QALY. For BRCA2 carriers, a familial cancer service with or without an annual review program had only a 37% probability of being cost-effective at a $50,000 per QALY willingness-to-pay threshold. Discounting of health outcomes had, by far, the greatest impact on cost-effectiveness outcomes. Conclusions This thesis describes a novel microsimulation model for optimising clinical management of BRCA carriers. BRCA carriers are likely to benefit from access to structured clinical programs and regular review, due to fewer cancer diagnoses, improved life expectancy and an increase in QALYs. Genetic testing for hereditary breast and ovarian cancer predisposition syndromes is steadily expanding, and may even be available at a population-based level in the near future. Maximising adherence to evidence-based risk management guidelines along with access to appropriate follow-up services will therefore be increasingly important. The model developed for this thesis can enable faster evaluation of emerging risk management strategies and behavioural interventions, and can be easily adapted to alternative settings and healthcare systems.
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ItemA Genome-wide RNAi screen identifies combinatorial efficacy of CX-5461 with homologous recombination deficiency and Topoisomerase I inhibition in ovarian cancer( 2019)High-grade serous ovarian cancer (HGSC) is common, with poor prognosis. Limited therapeutic options are available, and the development of new therapies is of high priority. The RNA Polymerase I (Pol I) transcription inhibitor CX-5461 has shown efficacy in both chemotherapy-sensitive and -resistant ovarian cancer through its ability to activate the DNA damage checkpoint. Here, we combine a genome-wide RNAi screening approach with a focussed drug screen to identify potential targets whose inhibition can enhance the efficacy of CX-5461. We demonstrate that CX-5461 combined with knockdown of homologous recombination DNA repair genes shows cooperative cell proliferation inhibition in several HGSC cell lines. We also demonstrate combinatorial efficacy between CX-5461 and topoisomerase 1 (TOP1) depletion or the TOP1 poison Topotecan. The combination induces cell death, cell cycle arrest and senescence even after drug withdrawal. The mechanism of their cooperativity relies on a cell cycle-independent, nucleolar DNA damage response (DDR) associated with topological stress at the ribosomal DNA and is independent of the ability to inhibit PoI I transcription or induce global replication stress. Despite dose-limiting toxicities hampering the broad use of Topotecan in the clinic, combined treatment with CX-5461 and low-dose Topotecan exhibits striking therapeutic efficacy in vivo, thus providing evidence for a novel strategy to treat HGSC.