Identification of biomarkers to predict differential response to therapeutic agents in advanced triple negative breast cancer

Abstract

Patients with triple negative breast cancer (TNBC) tend to have poor outcomes compared to other subtypes, and this is historically due to a lack of targeted therapies for these patients. PARP inhibitors have recently been approved in TNBC but only for patients with germline BRCA1/2 mutations. Similarly, platinum-based therapies have also proved effective in some subgroups. It is hypothesised that a wider cohort of patients may benefit from these agents due to other DNA damage repair deficiencies. To date however, no additional biomarkers have successfully identified these patients and been approved for use in clinical practice. Several studies have also identified that markers of high immune infiltration are associated with improved response to chemotherapy, but little data exists to dissect this response by chemotherapies with different mechanisms of action. This thesis aims to address these issues by exploring published gene expression-based signatures as differential predictors of response to therapies in advanced TNBC. Integrative analyses have also been applied to combine effective multi-omics markers to identify novel subgroups of TNBC. The results demonstrate that high immune infiltration is associated with preferential response to docetaxel and that combining multi-omics markers related to DNA damage repair processes and immune profiles leads to the identification of novel subgroups with differential response to carboplatin and docetaxel in advanced TNBC. Analysis has also uncovered changes in tumour biology from the primary to metastatic setting with implications for the use of transcriptional signatures related to DNA damage repair biology derived from primary tumours for use at the point of recurrent disease. In summary, through transcriptional profiling and integrative analyses, I aim to better differentiate responders to different therapies in advanced TNBC. This could improve outcomes for these patients through better therapy selection and spare others toxicities from treatments they are unlikely to benefit from.