Establishment of c-MET as a biomarker in brain metastasis secondary to breast cancer and the identification of additional molecular drivers of brain metastasis
Breast Cancer (BC) is a heterogeneous disease classified by gene expression profiles or immunohistochemical biomarkers. Two key subtypes are HER2-positive BC, defined by overexpression of the HER2 oncogene and triple-negative BC (TNBC) that lack expression of the estrogen, progesterone and HER2 receptors. These account for approximately 25% of all BC. Despite the improvements in current treatments, recurrence and metastasis remains a major clinical problem both for these subtypes, and in particular brain metastasis (BM). One mechanism of resistance to therapy in both HER2-positive and TNBC is via the c-MET pathway. Activated c-MET leads to activation of downstream signalling pathways affecting proliferation, survival, angiogenesis and migration. While, activation of the tyrosine kinase receptor, ALK, via mutations/gene amplification/copy number variations (CNV) is implicated in the initiation and progression of several cancers including neuroblastoma, non-small-cell lung cancer and BC. While several alterations (CNVs/mutations) in genes associated with sensitivity to PI3K/AKT/mTOR and HER2/EGFR inhibitors were identified by analysing matched primary tumours, BM and normal tissue. Furthermore, circulating-tumour DNA isolated from cerebrospinal fluid (CSF) may serve as a tool to help define treatments as well as treatment-response in BM secondary to BC.
The targeting of specific genomic aberrations in BC is key to personalized therapy.
Aim: The project aims to investigate c-MET as a biomarker for development and progression of brain metastasis in HER2-positive and TNBC. c-MET activation leads to activation of PI3K/AKT/mTOR and MAPK pathways. As these pathways are druggable there is a clear interest in identifying molecular alterations which may lead to resistance and to stratify patients based on these alterations for specific targeted therapies.
A study to determine the prevalence of c-MET overexpression/amplification in HER2 positive early breast cancer treated with trastuzumab in the neoadjuvant setting and the establishment of a non-invasive assay for determining c-MET status in metastatic HER2 positive breast cancer.
The cMET digital PCR assay as well as one for HER2 is being used for the identification and early detection of c-MET genetic alterations in HER2 positive breast cancer. This project will determine the prevalence of c-MET amplification/mutations in HER2 positive early breast cancer treated with trastuzumab in the neoadjuvant setting, changes in c-MET status during treatment and the relationship to response will be determined. This project will establish the role of c-MET as a resistance mechanism in early HER2 positive breast cancer and will enable the development of studies with a view to monitor for the emergence of recurrent disease and treatment resistance, as well as identifying novel targets which could lead to the development of new therapeutic strategies, with the ultimate purpose to improve the survival of breast cancer patients.
miRNA in brain metastasis
Several studies using cell lines, mouse models and clinical samples have identified miRNAs differentially expressed in primary tumours and linked them to the metastatic process. Up to date, we are not aware of any study that has compared miRNA expression between matched primary breast cancer and brain metastasis tissues and how the differential miRNA expression affects the targeted mRNAs in the primary and metastatic sites. Screening matched tumour biopsies from HER2-positive primary BC and BM will allow the identification of common and/or differentially expressed miRNAs-mRNAs and their correlation with pathways in the brain metastatic process. This could potentially provide information about the tumour microenvironment niche at distant sites and identify useful biomarkers or therapeutic targets, facilitating personalized breast cancer treatments.