Proteogenomics of Breast Cancer
NCI's Center for Cancer Research (CCR) Grand Rounds Dr. Matthew Ellis ’ s clinical and basic research focuses on breast cancer. He has developed neoadjuvant endocrine therapy as an alternative to chemotherapy for promoting breast-conserving therapy in postmenopausal women with ER+ HER2- stage 2 and 3 disease. He developed and validated the Ki67 proliferation marker-based Preoperative Endocrine Prognostic Index which is now undergoing a large validation study (the ALTERNATE study). These clinical studies have provided the clinical context and tumor specimens for seminal investigations into the ER+ breast cancer somatic genome, with insights into massive clonal heterogeneity, new tumor suppressor gene discovery specific to ER+ disease and new therapeutic targets. These include activating mutations in the HER2 gene that Dr. Ellis has shown respond to HER2 kinase inhibition in clinical trials. He also pioneered patient-derived xenograft research (PDX). A PDX study in triple negative breast cancer revealed clonal remodeling during brain metastasis. PDX analysis also revealed that acquired resistance to endocrine therapy is a consequence of ESR1 ligand-binding mutation; ESR1 amplification and most uniquely chromosomal translocation causing fusions between the N terminus of ESR1 and the C-terminus of genes that can confer constitutive transcriptional activity. The ability to understand the complex somatic genomes was enhanced though Dr. Ellis ’ s work with the Clinical P...
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