title: The benefit of HER2-targeted therapies on overall survival of patients with metastatic HER2-positive breast cancer--a systematic review.
abstract: BACKGROUND
  This study aimed at evaluating the overall survival (OS) gain associated with human epidermal growth factor receptor 2 (HER2)-directed therapies in patients with metastatic breast cancer (mBC).
  
  
  METHODS
  A bibliographic search was conducted in PubMed and Cochrane databases. Only phase III randomized controlled trials (RCTs) including HER2-positive (HER2+) mBC patients were included in this review. OS was defined as time from randomization until the occurrence of death from any cause. Studies have been grouped according to the line of treatment, i.e., first-line or second-line or beyond.
  
  
  RESULTS
  Nineteen RCTs were eligible for inclusion, of which 12 assessed therapies targeting HER2+ mBC in the first-line setting. OS improved from 20.3 months in the first RCT (standard chemotherapy; Slamon et al. (N Engl J Med 344:783-92, 2001)) evaluating HER2-targeting therapies to 48 months in the study of Swain et al. (Lancet Oncol 14:461-71, 2013), with triple combination of pertuzumab, trastuzumab and docetaxel. Seven RCTs evaluated the OS of HER2-targeting therapies in the second-line setting and beyond. The OS in second-line setting improved from 15.3 months (capecitabine; Cameron et al. (Breast Cancer Res Treat 112:533-43, 2008)) to 30.7 months (trastuzumab emtansine; Verma et al. (N Engl J Med 367:1783-91, 2012)). In the third-line setting, the association of lapatinib and trastuzumab has demonstrated to improve OS to 4.5 months compared with lapatinib alone (14 months vs. 9.5 months; Blackwell et al. (J Clin Oncol 30:2585-92, 2012)).
  
  
  CONCLUSIONS
  HER2-directed therapies had an undeniable beneficial impact on the OS of patients with HER2+ mBC. The triple combination of docetaxel, pertuzumab and trastuzumab is associated with a survival extent of more than 4.5 years, compared with a life expectancy of 1.5 years achieved 14 years ago.
authors.affiliation: CHAD - Centre for Health Technology Assessment and Drug Research, AIBILI - Association for Innovation and Biomedical Research on Light and Image, Azinhaga de Santa Comba, Celas, 3000-548, Coimbra, Portugal. diogomendes26@gmail.com.|Faculty of Pharmacy, University of Coimbra, Azinhaga de Santa Comba, 3000-548, Coimbra, Portugal. diogomendes26@gmail.com.
authors.forename: Diogo
authors.initials: D
authors.lastname: Mendes
authors.affiliation: CHAD - Centre for Health Technology Assessment and Drug Research, AIBILI - Association for Innovation and Biomedical Research on Light and Image, Azinhaga de Santa Comba, Celas, 3000-548, Coimbra, Portugal.|Faculty of Pharmacy, University of Coimbra, Azinhaga de Santa Comba, 3000-548, Coimbra, Portugal.
authors.forename: Carlos
authors.initials: C
authors.lastname: Alves
authors.affiliation: Medical Oncology Service, IPO - Portuguese Institute of Oncology Professor Francisco Gentil, Rua Dr. António Bernardino de Almeida, 4200-072, Oporto, Portugal.
authors.forename: Noémia
authors.initials: N
authors.lastname: Afonso
authors.affiliation: Breast Cancer Unit, Champalimaud Cancer Center, Avenida De Brasília s/n, 1400-038, Lisbon, Portugal.
authors.forename: Fátima
authors.initials: F
authors.lastname: Cardoso
authors.affiliation: Medical Oncology Service, Hospital da Luz, Avenida Lusíada, 100, 1500-650, Lisbon, Portugal.
authors.forename: José Luís
authors.initials: JL
authors.lastname: Passos-Coelho
authors.affiliation: Medical Oncology Service, Santa Maria Hospital, Rua de Santa Marta, 1169-024, Lisbon, Portugal.
authors.forename: Luís
authors.initials: L
authors.lastname: Costa
authors.affiliation: Market Access Department, Roche Pharmaceuticals, Estrada Nacional 249-1, 2720-413, Amadora, Portugal.
authors.forename: Sofia
authors.initials: S
authors.lastname: Andrade
authors.affiliation: CHAD - Centre for Health Technology Assessment and Drug Research, AIBILI - Association for Innovation and Biomedical Research on Light and Image, Azinhaga de Santa Comba, Celas, 3000-548, Coimbra, Portugal.|Faculty of Pharmacy, University of Coimbra, Azinhaga de Santa Comba, 3000-548, Coimbra, Portugal.
authors.forename: Francisco
authors.initials: F
authors.lastname: Batel-Marques
mesh_terms: D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000401:mortality*; D017326:Clinical Trials, Phase III as Topic; D018572:Disease-Free Survival; D000077143:Docetaxel; D005260:Female; D006801:Humans; D000077341:Lapatinib; D058990:Molecular Targeted Therapy / Q000379:methods; D011799:Quinazolines / Q000008:administration & dosage; D016032:Randomized Controlled Trials as Topic; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D043823:Taxoids / Q000008:administration & dosage; D000068878:Trastuzumab / Q000008:administration & dosage
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000077143:Docetaxel; D000077341:Lapatinib; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases; D043823:Taxoids; D000068878:Trastuzumab; C508053:ERBB2 protein, human; C485206:pertuzumab