title: Improving Response to Hormone Therapy in Breast Cancer: New Targets, New Therapeutic Options.
abstract: The majority of breast cancer expresses the estrogen and or progesterone receptors (ER and PR). In tumors without concomitant HER2 amplification, hormone therapy is a major treatment option for all disease stages. Resistance to hormonal therapy is associated with disease recurrence and progression. Recent studies have identified a number of resistance mechanisms leading to estrogen-independent growth of hormone receptor-positive (HR+) breast cancer as a result of genetic and epigenetic alterations, which could be exploited as novel therapeutic targets. These include acquired mutations in ER-alpha (ESR1) in response to endocrine deprivation; constitutive activation of cyclin-dependent kinases (CDK) 4 and 6; cross talk between ER and growth factor receptor signaling such as HER family members, fibroblast growth factor receptor (FGFR) pathways, intracellular growth, and survival signals PI3K/Akt/mTOR; and epigenetic modifications by histone deacetylase (HDAC) as well as interactions with tumor microenvironment and host immune response. Inhibitors of these pathways are being developed to improve efficacy of hormonal therapy for treatment of both metastatic and early-stage disease. Two agents are currently approved in the United States for the treatment of metastatic HR+ breast cancer, including the mTOR inhibitor everolimus and the CDK4/6 inhibitor palbociclib. Management of toxicity is a critical aspect of treatment; the primary toxicity of everolimus is stomatitis (treated with topical steroids) and of palbociclib is neutropenia (treated with dose reduction/delay). Many agents are in clinical trials, primarily in combination with hormone therapy; novel combinations are under active investigation.
authors.affiliation: From the UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, CA; University of San Francisco School of Medicine, San Francisco, CA; Department of Medicine, Washington University School of Medicine in St. Louis, St. Louis, MO.
authors.forename: Hope S
authors.initials: HS
authors.lastname: Rugo
authors.affiliation: From the UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, CA; University of San Francisco School of Medicine, San Francisco, CA; Department of Medicine, Washington University School of Medicine in St. Louis, St. Louis, MO.
authors.forename: Neelima
authors.initials: N
authors.lastname: Vidula
authors.affiliation: From the UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, CA; University of San Francisco School of Medicine, San Francisco, CA; Department of Medicine, Washington University School of Medicine in St. Louis, St. Louis, MO.
authors.forename: Cynthia
authors.initials: C
authors.lastname: Ma
mesh_terms: D047072:Aromatase Inhibitors / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D015914:Estrogen Replacement Therapy; D000068338:Everolimus / Q000627:therapeutic use; D005260:Female; D020249:Hormone Replacement Therapy; D006801:Humans; D058990:Molecular Targeted Therapy; D010879:Piperazines / Q000627:therapeutic use; D011725:Pyridines / Q000627:therapeutic use; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000627:therapeutic use; D011960:Receptors, Estrogen / Q000235:genetics / Q000627:therapeutic use; D011980:Receptors, Progesterone / Q000235:genetics / Q000627:therapeutic use
chemical_list: D047072:Aromatase Inhibitors; D000068338:Everolimus; D010879:Piperazines; D011725:Pyridines; D018719:Erb-b2 Receptor Tyrosine Kinases; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; C500026:palbociclib