Sir Peter MacCallum Department of Oncology - Theses
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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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ItemIdentification and validation of novel breast cancer predisposition genes( 2019)The genetic causes of the majority of hereditary breast cancer families remain unresolved (BRCAx families) and lack of this information compromises primary and secondary cancer prevention for the affected women and their family members. Despite intensive efforts, no major new breast cancer predisposition genes with equivalent impact have been discovered since the identification of BRCA1 and BRCA2 in the 1990s. Research from our laboratory provided direct demonstration that the remaining hereditary causes of breast cancer are not due to a few BRCA1-like genes (high penetrance and high carrier frequency) but instead by numerous moderate penetrance genes, each accounting for only a small fraction of families. This finding highlighted the need for very large case-control studies as the only way of resolving the missing breast cancer heritability. In this thesis I aimed to carry out such a study. Using existing germline whole exome and targeted sequencing data, 162 candidate genes were selected for validation in ~8,000 unrelated BRCAx cases and cancer-free controls. Combined with the existing targeted sequencing data of ~4,000 cases and controls, this analysis represents one of the largest targeted sequencing studies of its kind. A significant association with breast cancer predisposition was confirmed for known breast cancer genes PALB2, CHEK2 and ATM. Among the 162 candidate genes, nearly twice as many had more LoF variants in the cases than the controls, compared to those with more variants in the controls than the cases, demonstrating a high enrichment for genuine breast cancer predisposition genes. Most novel candidate genes appeared to convey only low to moderate risks, with a total of 35 genes identified that had an OR>2. Despite the very large sample size, the number of carriers of LoF variants for any candidate gene was still small, further demonstrating the extreme genetic heterogeneity of BRCAx families, and that case-control data is still insufficient on its own to claim the discovery of a specific new breast cancer gene. Nevertheless, this large-scale case-control data will be a valuable guide for future validation. Many of the candidate genes such as NTHL1, WRN, BAP1, PARP2 and CDK9 play essential roles in DNA damage repair, consistent with the function of all the established breast cancer genes. An intriguing exception is CTH which is involved in the trans-sulfuration pathway, and if confirmed, would be the first moderate penetrance breast cancer predisposition not involved in DNA repair. This study also re-evaluated some contentious genes and provided strong evidence to reject RINT1 and RECQL as breast cancer predisposition genes. On the other hand, by combining both case-control data with tumour sequencing data, RAD51C was identified as a triple-negative breast cancer predisposition gene. This study has shown that because of the high genetic heterogeneity of BRCAx families, future validation studies will require either an extremely large sample size (>10,000 subjects), and/or the inclusion of approaches providing independent evidence, such as tumour sequencing to identify bi-allelic inactivation and specific mutational signatures.