title: Phosphatidylinositol 3-kinase/AKT/mammalian target of rapamycin pathway inhibition:  a breakthrough in the management of luminal (ER+/HER2-) breast cancers?
abstract: OBJECTIVE
  Recent data from clinical trials evaluating mammalian target of rapamycin (mTOR) inhibitors in the setting of endocrine resistance in luminal (estrogen receptor-positive, human epidermal growth factor receptor 2-negative) breast cancers have validated this pathway as a bona-fide therapeutic target in this setting. There are currently many agents under clinical investigation that inhibit the phosphatidylinositol 3-kinase (PI3K) pathway. We review these findings in the context of the preclinical data and the current status of biomarker development in this field.
  
  
  RESULTS
  Clinical trials in the neoadjuvant (RAD2222) and metastatic setting (TAMRAD, BOLERO-2) have reported improved clinical outcome of patients with unselected luminal breast cancer through the addition of mTOR inhibitors to standard endocrine treatment. PI3K molecular aberrations are frequently found in luminal breast cancer, yet the role of these in defining patients' prognosis and response to PI3K/AKT/mTOR inhibitors remains to be determined.
  
  
  CONCLUSIONS
  Therapeutic targeting of the PI3K pathway promises improved clinical outcome for patients with luminal breast cancer. Correspondingly, agents that target this pathway are entering the clinic at an unprecedented rate. Future clinical trials that incorporate correlative translational research will help us decipher important information critical for successful development of these agents in breast cancer: which part of the pathway should be targeted and in which clinical scenario; and which patients are more likely to benefit from these drugs, particularly in the adjuvant setting.
authors.affiliation: BrEAST Data Center, Institut Jules Bordet, Brussels, Belgium.
authors.forename: Dimitrios
authors.initials: D
authors.lastname: Zardavas
authors.forename: Debora
authors.initials: D
authors.lastname: Fumagalli
authors.forename: Sherene
authors.initials: S
authors.lastname: Loi
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D002986:Clinical Trials as Topic; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D011960:Receptors, Estrogen / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D020123:Sirolimus / Q000494:pharmacology / Q000627:therapeutic use; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D018719:Erb-b2 Receptor Tyrosine Kinases; D011960:Receptors, Estrogen; D020123:Sirolimus; D058570:TOR Serine-Threonine Kinases; C546842:MTOR protein, human; C508053:ERBB2 protein, human