Abstract IA03: Mutations, drugs, and breast cancer: How are we going to figure it out?

Abstract

Abstract Massively parallel DNA and RNA sequencing approaches have generated high dimensional data on thousands of breast cancer genomes. Broad-based conclusions include challenges to the multistep model of breast carcinogenesis and the monoclonality of cancer, a link between leukemogenesis and luminal breast cancer and the discovery of new mutagenesis mechanisms. Unfortunately novel and immediately applicable therapeutic insights have been somewhat sparse. Many of the processes that are disrupted by newly discovered somatic mutations include genes with roles in splicing, histone methylation and long non-coding RNA function. Drugs targeting these processes are in the earliest stages of development, emphasizing a pressing unmet need to move drug discovery efforts beyond our current intense focus on kinase inhibitors. Despite the evident complexity, promising examples are emerging including new efforts to target mutations in two well-established drivers in breast cancer: HER2 in HER2 mutant breast cancer and mutant ESR1 in ESR1 endocrine refractory luminal-type breast cancer. A case for the importance of genome-annotated patient-derived breast cancer xenografts (PDX) will also be made. PDX models are potentially more reliable preclinical setting than cell lines and are a setting in which the biological rules for genome driven therapeutic planning could be developed. A call is also made for a new generation of prospective clinical trials that are fully focused on exploring interactions between cancer genomics and drug outcomes as a primary objective. Finally the integration of DNA and RNA based sequencing studies with mass-spectrometry-based peptide sequencing promises a more complete view of the biochemistry of breast cancer cells and represents a new discovery horizon in efforts to drug the pathophysiology of complex epithelial malignancies. Citation Format: Matthew J. Ellis. Mutations, drugs, and breast cancer: How are we going to figure it out? [abstract]. In: Proceedings of the AACR Precision Medicine Series: Drug Sensitivity and Resistance: Improving Cancer Therapy; Jun 18-21, 2014; Orlando, FL. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(4 Suppl): Abstract nr IA03.