title: Targeted agents to reverse resistance to endocrine therapy in metastatic breast cancer: where are we now and where are we going?
abstract: Endocrine therapy is the most important systemic therapy for hormone receptor positive breast cancer; however, some patients with ER+ breast cancer show intrinsic resistance to endocrine therapy, whereas others develop acquired resistance. Preclinical models have shown that endocrine resistance is associated with enhanced expression of membrane growth factor pathways or activation of various intracellular pathways involved in signal transduction and cell survival. Despite encouraging preclinical data, clinical trials investigating the combination of endocrine therapy with trastuzumab or the TKIs gefitinib, erlotinib and lapatinib have yielded varied results. This may be related to some limitations in the studies conducted so far: lack of appropriate patient selection and stratification based on previous endocrine exposure and/or sensitivity; lack of identification of a molecular biomarker; lack of appropriate clinical endpoints in the trial design. More promising results come from clinical studies which have focused on novel agents such as the mTOR inhibitor everolimus. The two randomized trials (BOLERO-2 and TAMRAD) evaluating everolimus±endocrine therapy in a selected subgroup of HR-positive metastatic breast cancer patients have demonstrated a significant improvement in progression free survival for the combination compared to the endocrine therapy alone. The data reported so far show that the combination of target agents with endocrine therapy is effective in overcoming acquired resistance in patients with hormone receptor positive metastatic breast cancer. However, this therapeutic strategy is not yet a standard treatment for this patients. Application of more rigorous trial design, tumor and patient selection criteria will be important to better understand the complexity of endocrine resistance.
authors.affiliation: Medical Oncology & Breast Unit, A. Perrino Hospital, Brindisi, Italy. minafedele@hotmail.com
authors.forename: Palma
authors.initials: P
authors.lastname: Fedele
authors.forename: Nicola
authors.initials: N
authors.lastname: Calvani
authors.forename: Antonella
authors.initials: A
authors.lastname: Marino
authors.forename: Laura
authors.initials: L
authors.lastname: Orlando
authors.forename: Paola
authors.initials: P
authors.lastname: Schiavone
authors.forename: Annamaria
authors.initials: A
authors.lastname: Quaranta
authors.forename: Saverio
authors.initials: S
authors.lastname: Cinieri
mesh_terms: D018931:Antineoplastic Agents, Hormonal / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology*; D019008:Drug Resistance, Neoplasm; D066246:ErbB Receptors / Q000037:antagonists & inhibitors; D005260:Female; D056572:Histone Deacetylase Inhibitors / Q000627:therapeutic use; D006801:Humans; D058990:Molecular Targeted Therapy; D009362:Neoplasm Metastasis; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors
chemical_list: D018931:Antineoplastic Agents, Hormonal; D056572:Histone Deacetylase Inhibitors; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D066246:ErbB Receptors; D058570:TOR Serine-Threonine Kinases