The focus of this research will be on the translational aspects of the Shamrock Study – a single arm phase 2 trial of neoadjuvant trastuzumab deruxtecan (T-DXd) with response-directed definitive therapy in early stage HER2-positive breast cancer: a cytotoxic chemotherapy-sparing approach to curative-intent treatment. The current standard of care in the neoadjuvant setting of HER2-positive breast cancer is to combine chemotherapy with trastuzumab and pertuzumab for a synergistic anti-tumour effect. Chemotherapy-sparing approaches to neoadjuvant therapy have failed to become incorporated into routine practice due to a higher incidence of locoregional progression prior to surgery and the lack of available biomarkers to guide pre-operative therapy by identifying patients in whom chemotherapy can be safely omitted. T-DXd is an antibody-drug conjugate which is highly active in HER2-positive breast cancer. We hypothesise that neoadjuvant T-DXd will have a high pathological complete response (pCR) rate and that this will facilitate identification of clinically useful biomarkers that predict pCR. In this single arm phase 2 trial we will administer T-DXd 5.4mg/kg intravenously every 3 weeks for either 4 or 6 cycles to all patients. The primary endpoint is to determine the percentage of patients who are successfully treated without cytotoxic chemotherapy i.e. with only T-DXd and trastuzumab. Secondary endpoints will include disease free survival, overall survival and identifying molecular biomarkers of treatment response. We will accrue 80 patients in total for this trial. Serial blood samples will be collected from patients to evaluate changes in circulating tumour cells and mutations in circulating tumour DNA and RNA during treatment, with the aim of assessing for predictive biomarkers and to track molecular tumour evolution in response to treatment.
