title: Clinical Implementation of Novel Targeted Therapeutics in Advanced Breast Cancer.
abstract: The majority of advanced breast cancers have genetic alterations that are potentially targetable with drugs. Through initiatives such as The Cancer Genome Atlas (TCGA) and the International Cancer Genome Consortium (ICGC), data can be mined to provide context for next-generation sequencing (NGS) results in the landscape of advanced breast cancer. Therapies for targets other than estrogen receptor alpha (ER) and HER2, such as cyclin-dependent kinases CDK4 and CDK6, were recently approved based on efficacy in patient subpopulations, but no predictive biomarkers have been found, leaving clinicians to continue a trial-and-error approach with each patient. Next-generation sequencing identifies potentially actionable alterations in genes thought to be drivers in the cancerous process including phosphatidylinositol 3-kinase (PI3K), AKT, fibroblast growth factor receptors (FGFRs), and mutant HER2. Epigenetically directed and immunologic therapies have also shown promise for the treatment of breast cancer via histone deacetylases (HDAC) 1 and 3, programmed T cell death 1 (PD-1), and programmed T cell death ligand 1 (PD-L1). Identifying biomarkers to predict primary resistance in breast cancer will ultimately affect clinical decisions regarding adjuvant therapy in the first-line setting. However, the bulk of medical decision-making is currently made in the secondary resistance setting. Herein, we review the clinical potential of PI3K, AKT, FGFRs, mutant HER2, HDAC1/3, PD-1, and PD-L1 as therapeutic targets in breast cancer, focusing on the rationale for therapeutic development and the status of clinical testing. J. Cell. Biochem. 117: 2454-2463, 2016. © 2016 Wiley Periodicals, Inc.
authors.affiliation: Department of Medicine, Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire. Mary.D.Chamberlin@Hitchcock.org.|Department of Hematology-Oncology, One Medical Center Dr., Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire. Mary.D.Chamberlin@Hitchcock.org.|Comprehensive Breast Program, Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire. Mary.D.Chamberlin@Hitchcock.org.
authors.forename: Mary D
authors.initials: MD
authors.lastname: Chamberlin
authors.affiliation: Department of Medicine, Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire.
authors.forename: Erica B
authors.initials: EB
authors.lastname: Bernhardt
authors.affiliation: Comprehensive Breast Program, Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire.|Department of Pharmacology and Toxicology, Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire.
authors.forename: Todd W
authors.initials: TW
authors.lastname: Miller
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000037:antagonists & inhibitors*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D005260:Female; D006801:Humans; D058990:Molecular Targeted Therapy; D009154:Mutation / Q000235:genetics
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor
keywords: AKT; FGFR1; HER2; IMMUNOTHERAPY; PI3K