title: Incidence of central nervous system metastases in patients with HER2-positive metastatic breast cancer treated with pertuzumab, trastuzumab, and docetaxel: results from the randomized phase III study CLEOPATRA.
abstract: BACKGROUND
  Results from the phase III trial CLEOPATRA in human epidermal growth factor receptor 2-positive first-line metastatic breast cancer demonstrated significant improvements in progression-free and overall survival with pertuzumab, trastuzumab, and docetaxel over placebo, trastuzumab, and docetaxel. We carried out exploratory analyses of the incidence and time to development of central nervous system (CNS) metastases in patients from CLEOPATRA.
  
  
  METHODS
  Patients received pertuzumab/placebo: 840 mg in cycle 1, then 420 mg; trastuzumab: 8 mg/kg in cycle 1, then 6 mg/kg; docetaxel: initiated at 75 mg/m(2). Study drugs were administered i.v. every 3 weeks. The log-rank test was used for between-arm comparisons of time to CNS metastases as first site of disease progression and overall survival in patients with CNS metastases as first site of disease progression. The Kaplan-Meier approach was used to estimate median time to CNS metastases as first site of disease progression and median overall survival.
  
  
  RESULTS
  The incidence of CNS metastases as first site of disease progression was similar between arms; placebo arm: 51 of 406 (12.6%), pertuzumab arm: 55 of 402 (13.7%). Median time to development of CNS metastases as first site of disease progression was 11.9 months in the placebo arm and 15.0 months in the pertuzumab arm; hazard ratio (HR) = 0.58, 95% confidence interval (CI) 0.39-0.85, P = 0.0049. Overall survival in patients who developed CNS metastases as first site of disease progression showed a trend in favor of pertuzumab, trastuzumab, and docetaxel; HR = 0.66, 95% CI 0.39-1.11. Median overall survival was 26.3 versus 34.4 months in the placebo and pertuzumab arms, respectively. Treatment comparison of the survival curves was not statistically significant for the log-rank test (P = 0.1139), but significant for the Wilcoxon test (P = 0.0449).
  
  
  CONCLUSIONS
  While the incidence of CNS metastases was similar between arms, our results suggest that pertuzumab, trastuzumab, and docetaxel delays the onset of CNS disease compared with placebo, trastuzumab, and docetaxel.
  
  
  BACKGROUND
  NCT00567190.
authors.affiliation: Washington Cancer Institute, MedStar Washington Hospital Center, Washington sandra.m.swain@medstar.net.
authors.forename: S M
authors.initials: SM
authors.lastname: Swain
authors.affiliation: Memorial Sloan-Kettering Cancer Center, Memorial Hospital, New York, USA.
authors.forename: J
authors.initials: J
authors.lastname: Baselga
authors.affiliation: Mount Vernon Cancer Centre, Middlesex, UK.
authors.forename: D
authors.initials: D
authors.lastname: Miles
authors.affiliation: Division of Hematology and Medical Oncology, Department of Internal Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea.
authors.forename: Y-H
authors.initials: YH
authors.lastname: Im
authors.affiliation: Genentech, Inc., South San Francisco, USA.
authors.forename: C
authors.initials: C
authors.lastname: Quah
authors.affiliation: Genentech, Inc., South San Francisco, USA.
authors.forename: L F
authors.initials: LF
authors.lastname: Lee
authors.affiliation: Vall d'Hebron University Hospital, Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain.
authors.forename: J
authors.initials: J
authors.lastname: Cortés
mesh_terms: D000328:Adult; D000368:Aged; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy / Q000401:mortality / Q000473:pathology*; D016543:Central Nervous System Neoplasms / Q000453:epidemiology* / Q000556:secondary*; D000077143:Docetaxel; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D015994:Incidence; D053208:Kaplan-Meier Estimate; D008875:Middle Aged; D016016:Proportional Hazards Models; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics; D043823:Taxoids / Q000008:administration & dosage; D000068878:Trastuzumab
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000077143:Docetaxel; D018719:Erb-b2 Receptor Tyrosine Kinases; D043823:Taxoids; D000068878:Trastuzumab; C508053:ERBB2 protein, human; C485206:pertuzumab
keywords: HER2; central nervous system; metastatic breast cancer; pertuzumab; trastuzumab