title: Evaluating the pharmacokinetics and pharmacodynamics of everolimus for treating breast cancer.
abstract: BACKGROUND
  The aberrant activation of the phosphoinositide 3-kinase-Akt-mTOR signaling pathway is a common mechanism of resistance to endocrine therapy and human epidermal growth factor receptor 2 (HER2)-targeted treatments in breast cancer. Data from large clinical trials have shown that the combination of everolimus , an orally bioavailable mTOR inhibitor with exemestane improves outcome of metastatic breast cancer resistant to non-steroidal aromatase inhibitors. On the other hand, the addition of everolimus to trastuzumab in order to overcome resistance did not show meaningful clinical benefit in recent reported Phase III clinical trials. Everolimus has a favorable pharmacokinetic (PK) profile in early breast cancer studies. The association of endocrine therapy and HER2-targeted agents did not influence the main PK parameters of the drugs.
  
  
  METHODS
  This review article focuses on the biological rationale of using everolimus in breast cancer and on latest advances in the field of everolimus-based combinations with an emphasis on the PK and pharmacodynamic parameters of the drug throughout different studies.
  
  
  CONCLUSIONS
  Better identification of patients who sustain benefit or who are resistant to everolimus-based combinations in the treatment of advanced breast cancer remains an unmet need. New combination strategies based on the understanding of resistance mechanisms and intracellular feedback loops should be studied further in the future.
authors: Université Libre de Bruxelles, Institut Jules Rue Héger-Bordet 1 , Medical Oncology Clinic , Rue Héger 1, Brussels 1000 , Belgium andrea.gombos@bordet.be.
authors: Andrea
authors: A
authors: Gombos
authors: Philippe
authors: P
authors: Barthélémy
authors: Ahmad
authors: A
authors: Awada
mesh_terms: D000730:Androstadienes / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D019008:Drug Resistance, Neoplasm; D000068338:Everolimus / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000494:pharmacology; D005260:Female; D006801:Humans; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
chemical_list: D000730:Androstadienes; D000068338:Everolimus; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; C056516:exemestane
keywords: breast cancer; everolimus; pharmacodynamics; pharmacokinetics