AbstractTwo hypotheses underpin this thesis. The first is that exposure to HER2-directed therapies as neo/adjuvant therapies in patients presenting with metastatic breast cancer (MBC), following a prior diagnosis of early breast cancer (EBC), could influence survival outcomes. Clinical real-world data (RWD) could elucidate patterns in treatment responses and survival outcomes which may be indicative of an interplay between dormancy and acquired resistance. The second hypothesis is that HER2-HER3 dimerisation could predict responses to HER2-directed therapies. These findings could find translational value in identifying patient groups that require closer surveillance and highlight considerations when selecting and sequencing HER2-directed therapies.
HER2-positive breast cancer is associated with a poor prognosis. HER2-directed therapies like Trastuzumab and advanced anti-HER2 therapies like monoclonal antibodies (Pertuzumab), antibody-drug conjugates (Trastuzumab-emtansine, Trastuzumab deruxtecan) and tyrosine kinase inhibitors (Lapatinib, Neratinib, Tucatinib) have contributed to improvements in survival outcomes, changing the natural history of this cancer subtype. Resistance to HER2-directed therapies remains a challenge and ~70% of patients receiving Trastuzumab develop resistance to treatment. Several mechanisms of resistance have been described including HER-HER crosstalk. The inability to measure HER-HER interactions to identify and/or target resistance in current clinical practice despite the availability of advanced targeted treatments represents an unmet clinical need.
In this work, RWD analysis indicated poorer progression-free and overall survival outcomes in patients with HER2-positive MBC with prior history of receiving neo/adjuvant therapies. RWD is a powerful tool that can be used to identify patient subgroups that may benefit from further consideration, e.g., the ER-positive HER2-positive breast cancer subtype and the older patient groups in this analysis. This work used Förster resonance energy transfer (FRET) to measure the HER2-HER3 dimer in Formalin-Fixed Paraffin-Embedded (FFPE) tumour tissue. This analysis indicated the HER2-HER3 dimer could be a predictive biomarker with quantitative interaction. This could be of clinical relevance in describing patient groups that may benefit from treatment escalation. Finally, the exploratory assessment of an assay to measure the HER2-HER3 dimer in extracellular vesicles indicated that the approach requires further investigation to assess its utility in patient-derived blood samples.
A pilot clinical study HERdi PREDICT, set up as onward steps from this work is recruiting 40 participants with HER2-positive early and metastatic breast cancer. The study is measuring the HER2-HER3 dimer in tumour tissue and serum-derived exosomes in an iterative manner while participants receive HER2-directed therapies contributing to the translational validation of the HER2-HER3 dimer as a biomarker while clarifying its clinical relevance and context of use.
|Date of Award||2023|
|Supervisor||Chris Pepper (Supervisor), Dr Gargi Patel (Supervisor) & Gregory Weitsman (Supervisor)|