title: A new era of improving progression-free survival with dual blockade in postmenopausal HR(+), HER2(-) advanced breast cancer.
abstract: Disease progression despite existing endocrine therapies remains a major challenge to the effective management of hormone-receptor-positive (HR(+)), human epidermal growth factor receptor-2-negative (HER2(-)), advanced breast cancer. Recent advances in elucidating the molecular mechanisms of disease progression have identified the existence of adaptive "cross-talk" between the estrogen receptor (ER) and various growth factor receptor and intracellular signaling pathways, allowing breast cancer cells to escape the inhibitory effects of endocrine therapy. These findings provide the clinical rationale for enhancing or extending endocrine sensitivity by combining endocrine therapy with a targeted agent against a compensatory pathway. In BOLERO-2, adding the mTOR inhibitor everolimus to endocrine therapy significantly improved progression-free survival (PFS) in patients with HR(+) advanced breast cancer previously treated with nonsteroidal aromatase inhibitor therapy. Notably, PFS benefits were comparable in subgroup analyses of first- and later-line settings. These results contrast with those of the large first-line HORIZON study, wherein adding the mTOR inhibitor temsirolimus to endocrine therapy did not improve PFS. Therefore, it is unclear whether a targeted agent should only be combined with endocrine therapy to restore endocrine sensitivity or whether it may also prevent or delay resistance in hormone-sensitive advanced breast cancer. Numerous additional targeted agents are currently being evaluated in combination with endocrine therapies, including PI3K, cyclin-dependent kinase 4/6, SRC, and histone deacetylase inhibitors. Appropriate patient selection based on prior treatment history will become increasingly important in maximizing the incremental benefit derived from these new agents combined with existing endocrine therapies in HR(+) advanced breast cancer.
authors.affiliation: Centre Hospitalier Universitaire du Sart Tilman Liège and Liège University, Domaine Universitaire du Sart Tilman, B35, 4000 Liège, Belgium. Electronic address: g.jerusalem@chu.ulg.ac.be.
authors.forename: Guy
authors.initials: G
authors.lastname: Jerusalem
authors.affiliation: Centre de Recherche en Cancérologie de Lyon, Inserm U1052 CNRS 5286, Centre Léon Bérard, 28 rue Laënnec, 69373 LYON cedex 08, Lyon, France. Electronic address: thomas.bachelot@lyon.unicancer.fr.
authors.forename: Thomas
authors.initials: T
authors.lastname: Bachelot
authors.affiliation: PUCRS School of Medicine, Padre Chagas 66, 203, Porto Alegre, RS 90 570 080, Brazil. Electronic address: chbe@via-rs.net.
authors.forename: Carlos
authors.initials: C
authors.lastname: Barrios
authors.affiliation: University Hospitals Leuven, Leuven, Belgium. Electronic address: patrick.neven@uzleuven.be.
authors.forename: Patrick
authors.initials: P
authors.lastname: Neven
authors.affiliation: Hospital of Prato, Istituto Toscani Tumori, Prato, Italy. Electronic address: adileo@usl4.toscana.it.
authors.forename: Angelo
authors.initials: A
authors.lastname: Di Leo
authors.affiliation: Women's Hospital, University of Ulm, Prittwitzstr. 43, D-89075 Ulm, Germany. Electronic address: wolfgang.janni@uniklinik-ulm.de.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Janni
authors.affiliation: Royal Melbourne Hospital, Grattan St., Parkville, Melbourne 3050, Australia. Electronic address: Richard.DeBoer@wh.org.au.
authors.forename: Richard
authors.initials: R
authors.lastname: de Boer
mesh_terms: D000077384:Anastrozole; D000730:Androstadienes / Q000008:administration & dosage; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage; D018931:Antineoplastic Agents, Hormonal / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D047072:Aromatase Inhibitors / Q000008:administration & dosage; D000068258:Bevacizumab; D014408:Biomarkers, Tumor / Q000032:analysis*; D001943:Breast Neoplasms / Q000737:chemistry / Q000188:drug therapy* / Q000401:mortality*; D002986:Clinical Trials as Topic; D018572:Disease-Free Survival; D004958:Estradiol / Q000008:administration & dosage / Q000031:analogs & derivatives; D000068338:Everolimus; D005260:Female; D000077267:Fulvestrant; D006801:Humans; D058990:Molecular Targeted Therapy / Q000379:methods*; D009570:Nitriles / Q000008:administration & dosage; D018579:Patient Selection; D017698:Postmenopause; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000032:analysis / Q000037:antagonists & inhibitors*; D011960:Receptors, Estrogen / Q000032:analysis / Q000037:antagonists & inhibitors*; D011980:Receptors, Progesterone / Q000032:analysis / Q000037:antagonists & inhibitors*; D020123:Sirolimus / Q000008:administration & dosage / Q000031:analogs & derivatives; D017211:Treatment Failure; D016896:Treatment Outcome; D014230:Triazoles / Q000008:administration & dosage
chemical_list: D000077384:Anastrozole; D000730:Androstadienes; D061067:Antibodies, Monoclonal, Humanized; D018931:Antineoplastic Agents, Hormonal; D047072:Aromatase Inhibitors; D000068258:Bevacizumab; D014408:Biomarkers, Tumor; D004958:Estradiol; D000068338:Everolimus; D000077267:Fulvestrant; D009570:Nitriles; D018719:Erb-b2 Receptor Tyrosine Kinases; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; D020123:Sirolimus; D014230:Triazoles; C401859:temsirolimus; C508053:ERBB2 protein, human; C056516:exemestane
keywords: Endocrine therapy; Everolimus; Hormone receptor-positive advanced breast cancer; Overall survival; Progression-free survival; mTOR inhibitor