Human epidermal growth factor receptor-2 (HER2) is amplified in approximately 20% of breast cancers (BCs) causing upregulated cell growth and survival. Anti-HER2 targeted therapies, including trastuzumab, significantly improved the poor prognosis conferred by this phenotype. However, de novo and acquired resistance are a consistent feature for patients with advanced disease and represent an unsolved clinical challenge. Acquired resistance suggests the possible rise of a subclonal driver mutation leading to disease progression. One proposed mechanism of trastuzumab resistance is by constitutive activation of the phosphatidylinositol-3-kinase (PI3K) pathway via either PTEN loss or PIK3CA mutation. Activating mutations in the PIK3CA gene are frequent in BC making it an attractive and rational drug target to overcome HER2 therapy resistance.
Copanlisib is a PI3K inhibitor that can reverse acquired resistance to trastuzumab and/or lapatinib in HER2-positive BC cell lines. To validate copanlisib as a new effective therapy option we are conducting a phase Ib/II clinical trial of copanlisib and trastuzumab and a phase Ib trial of copanlisib and T-DM1 in advanced HER2-positive BC resistant to HER2 targeted therapies. The aim of this project is to understand the evolutionary development of metastatic HER2-positive BCs, as patients undergo treatment with copanlisib/trastuzumab or copanlisib/T-DM1, to identify novel, molecular biomarkers of resistance and sensitivity to copanlisib treatment. By comparing molecular/clonal evolution in initially benefitting vs. progressing tumours and those with de novo resistance to treatment, we will identify potential resistance mechanisms, which may be validated as future treatment targets. We will track mutations that are associated with adaption to treatment (secondary mutations) in serial blood samples from each patient, to comprehensively explore the utility of serial liquid biopsies as a strategy to track disease response. Finally, we will establish circulating tumour cell (CTC)-derived cell lines as genomic and molecular surrogates of their matched human HER2-positive BCs.
