title: Therapeutic implications of estrogen receptor signaling in HER2-positive breast cancers.
abstract: There is considerable pre-clinical and clinical evidence demonstrating that HER2-positive breast cancers that express estrogen receptor (ER) exhibit intrinsic resistance to endocrine therapy. Therefore, in general, chemotherapy in combination with HER2-directed agents is recommended for all but the smallest HER2-positive early stage breast cancers regardless of ER status. This paradigm has recently come into question when responses to neo-adjuvant HER2-directed regimens were noted to vary based on ER expression, and pathologic complete response was noted not to be prognostic for ER-positive, HER2-positive breast cancers. These and other data suggest the possibility that a subset of HER2-positive, ER-positive breast cancers are driven primarily by ER, and biologically behave more like HER2-negative, ER-positive breast cancers. Identification of this subset of HER2-positive breast cancers is essential to avoid over-treatment of patients with small HER2-positive, ER-positive breast cancers, who may be optimally treated with endocrine therapy alone, or in combination with a HER2-directed agent, thereby avoiding the use of chemotherapy. Crosstalk between the ER and HER2 pathways has been established as playing a role in both intrinsic and acquired resistance to endocrine agents. Emerging data suggests that crosstalk between these pathways is also involved in resistance to HER2-directed agents. Unraveling the role of the ER pathway in resistance to HER2-directed agents could potentially result in therapeutic approaches that can improve outcome for patients with ER-positive, HER2-positive breast cancer.
authors.affiliation: Department of Pharmacology, Emory University, Atlanta, GA, USA.
authors.forename: Rita
authors.initials: R
authors.lastname: Nahta
authors.forename: Ruth M
authors.initials: RM
authors.lastname: O'Regan
mesh_terms: D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology / Q000627:therapeutic use*; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism*; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D011960:Receptors, Estrogen / Q000378:metabolism*; D015398:Signal Transduction; D000068878:Trastuzumab; D016896:Treatment Outcome
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D018931:Antineoplastic Agents, Hormonal; D018719:Erb-b2 Receptor Tyrosine Kinases; D011960:Receptors, Estrogen; D000068878:Trastuzumab; C508053:ERBB2 protein, human