Sir Peter MacCallum Department of Oncology - Theses
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ItemClinical implications of genomic driver alterations in hormone receptor-positive, human epidermal growth factor receptor (HER) 2-negative early breast cancer( 2021)Global initiatives applying next generation sequencing to thousands of primary and metastatic tumour samples have detailed the genomic landscape of breast cancer. These unique insights have transformed our understanding of the biological processes underlying these tumours. Despite this, the clinical relevance of these findings remains poorly understood. This is because these datasets are frequently heterogeneous, include patients that may not have received contemporary treatments, often have limited clinical annotation, and commonly lack long-term follow-up for patient survival outcomes. In order to better assess the clinical relevance of genomic driver alterations in breast cancer, this research project performed genomic sequencing using primary tumour samples from patients enrolled in two pivotal phase 3 clinical trials – the Breast International Group 1-98 (BIG 1-98) study and the Suppression of Ovarian Function Trial (SOFT). This provided a well-defined population with hormone receptor-positive, human epidermal growth factor receptor (HER) 2-negative early breast cancer in both postmenopausal and premenopausal populations, as well as long-term survival outcome data collection. Crucially, this allowed for further investigation of late distant recurrence, a unique feature of hormone receptor-positive, HER2-negative breast cancers, as well as the ability to focus on distinct high-risk subpopulations, such as breast cancer arising in young women. In the postmenopausal BIG 1-98 study, comprehensive panel sequencing was performed using 538 tumour samples from patients with hormone receptor-positive, HER2-negative early breast cancer. PIK3CA mutations were the most common driver (49%) and were associated with a reduction in the risk of distant recurrence. Contrastingly, TP53 mutations, amplifications on 11q13 and 8p11, and increasing number of driver alterations were associated with an increase in the risk of distant recurrence. Additionally, PIK3CA mutations were predictive of a greater magnitude of benefit from letrozole compared with tamoxifen. Using the same dataset, we further investigated the association of oncogenic drivers with late distant recurrence (5 years or greater from the time of randomisation). PIK3CA mutations were associated with reduced risk of late distant recurrence, whereas amplifications on 8p11 and BRCA2 mutations were associated with increased risk of late distant recurrence. In the premenopausal SOFT study, comprehensive panel sequencing was performed using 1258 tumour samples from the entire study cohort, and whole exome sequencing was performed using 82 tumour samples from very young patients with high-risk, hormone receptor-positive, HER2-negative early breast cancers. Subgroups of tumours with distinct copy number-amplifications had a higher risk of distant recurrence than tumours that were amplification-devoid, validating previously reported data. Importantly, the study further defined unique molecular characteristics that were enriched in very young women and may explain their poor prognosis. This includes subgroups of tumours with homologous recombination deficiency, a high-risk PIK3CA mutated subgroup, amplification-enriched subsets, and a low estrogen receptor expressing subtype with immune infiltration. Taken together, these results highlight the clinical relevance of genomic sequencing of hormone receptor-positive, HER2-negative early breast cancers. They provide a new prognostic framework using genomic stratification, and highlight molecular targets that should be prioritised for future clinical trial research.