title: Emerging treatment combinations: integrating therapy into clinical practice.
abstract: OBJECTIVE
  To review data supporting the effectiveness of emerging treatment options for metastatic breast cancer.
  
  
  CONCLUSIONS
  Recent research has focused on several signal-transduction pathways important in the pathogenesis of breast cancer. Mammalian target of rapamycin (mTOR) is a serine-threonine protein kinase that is involved in cell growth and survival. Everolimus, an orally active inhibitor of mTOR, has demonstrated promising efficacy results and a favorable safety profile in initial studies. Epidermal growth factor receptor (EGFR), a cell-surface molecule that has been implicated in the pathogenesis of breast cancer, may also be important in the emergence of resistance to endocrine therapy. Initial clinical studies have suggested that EGFR inhibitors such as gefitinib may delay the development of resistance to endocrine therapy in patients with breast cancer when given concurrently with tamoxifen or an aromatase inhibitor. Finally, considerable recent research has examined the role of epigenetic gene silencing, in which acetylation or deacetylation of DNA modifies the expression of tumor-suppressing genes. The enzyme histone deacetylase (HDAC) suppresses gene transcription by modifying chromatin into a more compact form. HDAC inhibitors have emerged as a potential new treatment option for several cancer types, including breast cancer. The HDAC inhibitor vorinostat has recently been examined in combination with other treatments, including cytotoxic agents and bevacizumab, for the treatment of breast cancer. In one small Phase I and II study, first-line treatment with the combination of vorinostat, paclitaxel, and bevacizumab produced objective responses (partial or complete) in more than 50% of patients with recurrent or metastatic breast cancer.
  
  
  CONCLUSIONS
  Although the results of the described studies are promising, randomized controlled clinical trials are needed to better understand the efficacy and safety of emerging treatment options for patients with metastatic breast cancer.
authors.affiliation: The Cancer Institute of New Jersey, University of Medicine and Dentistry of New Jersey, New Brunswick, NJ 08903-2681, USA. wongse@umdnj.edu
authors.forename: Serena T
authors.initials: ST
authors.lastname: Wong
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy*; D016503:Drug Delivery Systems; D015507:Drugs, Investigational / Q000008:administration & dosage / Q000494:pharmacology; D066246:ErbB Receptors / Q000037:antagonists & inhibitors; D000068338:Everolimus; D005260:Female; D000077156:Gefitinib; D056572:Histone Deacetylase Inhibitors / Q000008:administration & dosage; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors; D008954:Models, Biological; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D011799:Quinazolines / Q000008:administration & dosage / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects*; D020123:Sirolimus / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases
chemical_list: D015507:Drugs, Investigational; D056572:Histone Deacetylase Inhibitors; D047908:Intracellular Signaling Peptides and Proteins; D011799:Quinazolines; D000068338:Everolimus; C546842:MTOR protein, human; D066246:ErbB Receptors; D017346:Protein Serine-Threonine Kinases; D058570:TOR Serine-Threonine Kinases; D000077156:Gefitinib; D020123:Sirolimus