Optimising colorectal cancer therapies using clinical registries
Document TypePhD thesis
Access StatusOpen Access
© 2020 Siavash Foroughi
Colorectal cancer (CRC) remains one of the leading causes of cancer deaths worldwide. Advances in therapy have resulted in significant gains in survival, particularly in the metastatic setting. While the discovery of biomarkers, such as RAS mutations, have helped refine treatment selection to some degree, more accurate biomarkers are urgently needed. Comparison of existing treatments, as well as the evaluation of the efficacy of new therapies, are informed by randomised controlled trials (RCTs), which form the evidentiary backbone of clinical practice guidelines and represent the gold standard of assessment. Despite their high internal validity, they can lack generalisability due to their highly selective inclusion criteria. Prospective, registry-based, randomised controlled trials (RRCTs) have the potential to bridge the gap between RCTs and real-world clinical practice in oncology. The objective of this thesis is to explore how clinical registries can help to advance biomarker research. This thesis applies real-world data to examine the clinical utility and validity of emerging CRC biomarkers, and explores the feasibility of RRCTs in the oncology setting. In a cohort of 99 metastatic colorectal cancer (mCRC) patients, the role of the epidermal growth factor receptor (EGFR) and its ligands, amphiregulin and epiregulin, as potential prognostic and predictive biomarkers for mCRC patients is explored (Chapter 5). This study examines protein expression by immunohistochemistry and includes patients who were not treated with EGFR inhibitors, representing the largest such cohort reported to date. The real-world validity of biomarker trials is explored in Chapter 6, where the characteristics of patients enrolled in these studies are compared to real-world patients. Using an established multi-centre CRC registry as the reference real-world cohort, clinical data was analysed for participants in three types of biomarker trials (retrospective, prospective observational and prospective interventional). This study provides novel insights into recruitment to, and potential validity of, biomarker trials. Finally, Chapter 7 examines the feasibility of an Australian-first RRCT in oncology. This ongoing study is exploring chemotherapy sequencing in first-line treatment of mCRC and leverages an established multi-centre registry as the data collection platform. This study demonstrates the potential of RRCTs to accelerate progress in optimising patient treatments and outcomes. This thesis demonstrates the power of high-quality clinical registries to facilitate prospective randomised trials, while providing opportunities to investigate and validate biomarkers in real-world settings.
KeywordsColorectal cancer; Real-world data; Registry-based trials; Biomarkers; Epidermal growth factor receptor; Amphiregulin; Epiregulin
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