title: Fulvestrant with or without selumetinib, a MEK 1/2 inhibitor, in breast cancer progressing after aromatase inhibitor therapy: a multicentre randomised placebo-controlled double-blind phase II trial, SAKK 21/08.
abstract: BACKGROUND
  Second line endocrine therapy has limited antitumour activity. Fulvestrant inhibits and downregulates the oestrogen receptor. The mitogen-activated protein kinase (MAPK) pathway is one of the major cascades involved in resistance to endocrine therapy. We assessed the efficacy and safety of fulvestrant with selumetinib, a MEK 1/2 inhibitor, in advanced stage breast cancer progressing after aromatase inhibitor (AI).
  
  
  METHODS
  This randomised phase II trial included postmenopausal patients with endocrine-sensitive breast cancer. They were ramdomised to fulvestrant combined with selumetinib or placebo. The primary endpoint was disease control rate (DCR) in the experimental arm. ClinicalTrials.gov Indentifier: NCT01160718.
  
  
  RESULTS
  Following the planned interim efficacy analysis, recruitment was interrupted after the inclusion of 46 patients (23 in each arm), because the selumetinib-fulvestrant arm did not reach the pre-specified DCR. DCR was 23% (95% confidence interval (CI) 8-45%) in the selumetinib arm and 50% (95% CI 27-75%) in the placebo arm. Median progression-free survival was 3.7months (95% CI 1.9-5.8) in the selumetinib arm and 5.6months (95% CI 3.4-13.6) in the placebo arm. Median time to treatment failure was 5.1 (95% CI 2.3-6.7) and 5.6 (95% CI 3.4-10.2) months, respectively. The most frequent treatment-related adverse events observed in the selumetinib-fulvestrant arm were skin disorders, fatigue, nausea/vomiting, oedema, diarrhoea, mouth disorders and muscle disorders.
  
  
  CONCLUSIONS
  The addition of selumetinib to fulvestrant did not show improving patients' outcome and was poorly tolerated at the recommended monotherapy dose. Selumetinib may have deteriorated the efficacy of the endocrine therapy in some patients.
authors.affiliation: Breast Center Medical Oncology, University Hospital CHUV, Lausanne, Switzerland. Electronic address: Khalil.Zaman@chuv.ch.
authors.forename: Khalil
authors.initials: K
authors.lastname: Zaman
authors.affiliation: Division of Medical Oncology, Luzerner Kantonsspital, Lucerne, Switzerland. Electronic address: ralph.winterhalder@onkologie.ch.
authors.forename: Ralph
authors.initials: R
authors.lastname: Winterhalder
authors.affiliation: Medical Oncology, Kantonsspital Aarau, Aarau, Switzerland. Electronic address: christoph.mamot@ksa.ch.
authors.forename: Christoph
authors.initials: C
authors.lastname: Mamot
authors.affiliation: Breast Center, Kantonsspital, St Gallen, Switzerland. Electronic address: ursula.hasler-strub@kssg.ch.
authors.forename: Ursula
authors.initials: U
authors.lastname: Hasler-Strub
authors.affiliation: Breast Center, Universitätsspital, Basel, Switzerland. Electronic address: crochlitz@uhbs.ch.
authors.forename: Christoph
authors.initials: C
authors.lastname: Rochlitz
authors.affiliation: Medical Oncology and Breast Center, Kantonsspital, Winterthur, Switzerland. Electronic address: andreas.mueller@ksw.ch.
authors.forename: Andreas
authors.initials: A
authors.lastname: Mueller
authors.affiliation: SAKK Coordinating Center, Bern, Switzerland. Electronic address: catherine.berset@sakk.ch.
authors.forename: Catherine
authors.initials: C
authors.lastname: Berset
authors.affiliation: Department of General Medical Oncology, Leuven Cancer Institute, University Hospitals Leuven, KU Leuven, Belgium. Electronic address: hans.wildiers@uz.kuleuven.ac.be.
authors.forename: Hans
authors.initials: H
authors.lastname: Wiliders
authors.affiliation: Medical Oncology, Morges Hospital, Switzerland. Electronic address: lucien.perey@ehc.vd.ch.
authors.forename: Lucien
authors.initials: L
authors.lastname: Perey
authors.affiliation: SAKK Coordinating Center, Bern, Switzerland. Electronic address: Christine.Biaggi@sakk.ch.
authors.forename: Christine Biaggi
authors.initials: CB
authors.lastname: Rudolf
authors.affiliation: SAKK Coordinating Center, Bern, Switzerland. Electronic address: hanne.hawle@sakk.ch.
authors.forename: Hanne
authors.initials: H
authors.lastname: Hawle
authors.affiliation: SAKK Coordinating Center, Bern, Switzerland. Electronic address: stephanie.rondeau@sakk.ch.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Rondeau
authors.affiliation: University Hospital Gasthuisberg, Leuven, Belgium. Electronic address: patrick.neven@uz.kuleuven.ac.be.
authors.forename: Patrick
authors.initials: P
authors.lastname: Neven
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D047072:Aromatase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D001562:Benzimidazoles / Q000008:administration & dosage; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D018450:Disease Progression; D004311:Double-Blind Method; D004958:Estradiol / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000627:therapeutic use; D005260:Female; D000077267:Fulvestrant; D006801:Humans; D048369:MAP Kinase Kinase 1 / Q000037:antagonists & inhibitors; D048370:MAP Kinase Kinase 2 / Q000037:antagonists & inhibitors; D008875:Middle Aged; D010919:Placebos; D017698:Postmenopause; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage
chemical_list: C517975:AZD 6244; D047072:Aromatase Inhibitors; D001562:Benzimidazoles; D010919:Placebos; D047428:Protein Kinase Inhibitors; D000077267:Fulvestrant; D004958:Estradiol; C482128:MAP2K2 protein, human; D048369:MAP Kinase Kinase 1; D048370:MAP Kinase Kinase 2; C482125:MAP2K1 protein, human
keywords: Advanced breast cancer; Endocrine therapy; Fulvestrant; MAPK pathway; MEK 1/2 inhibitor; Selumetinib