title: NatHER: protocol for systematic evaluation of trends in survival among patients with HER2-positive advanced breast cancer.
abstract: BACKGROUND
  Human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC) is an aggressive form of breast cancer and is historically associated with poor outcomes compared with HER2-negative MBC. Since 1998, four drugs have been globally approved for the targeted treatment of HER2-positive MBC. Additional advances in patient care-such as improved breast cancer screening, HER2 testing, and supportive care-have also occurred. The objective of this systematic review and meta-analysis is to determine whether there has been a cumulative change in survival over time in patients with HER2-positive advanced breast cancer based on results from interventional clinical trials (ICTs) and observational studies and to compare outcomes across these types of studies.
  
  
  METHODS
  A systematic search of Medline, EMBASE, and the Cochrane Central Register of Controlled Trials will be performed. Two investigators will independently assess each abstract for inclusion. English language reports of ICTs and observational studies that include patients with HER2-positive advanced breast cancer from 1987 onwards will be considered. The primary outcome of interest is overall survival; secondary outcomes include progression-free survival and safety. Data on clinical outcomes, as well as on study design, study population, treatment/intervention, methodological quality, and outcomes, will be extracted using a structured codebook developed by the authors for this study. Standard and cumulative random effects meta-analysis will be performed to derive pooled risk estimates, both overall and by study design, controlling for covariates such as aggregate demographic and clinical characteristics of patients, treatment/intervention, and study characteristics. Heterogeneity of studies will be evaluated using the I(2) statistic. Differences in risk estimates by quality characteristics will be performed using meta-regression.
  
  
  CONCLUSIONS
  This study will evaluate current and evolving trends in survival associated with HER2-positive advanced breast cancer over nearly 30 years and will build upon prior, less comprehensive, systematic analyses. This information is important to patients, healthcare providers, and researchers, particularly in the advanced disease setting, in which new therapies have been recently approved. Including observational studies allows us to evaluate real-world effectiveness; useful information will be gained by comparing findings from observational studies with those from ICTs.
  
  
  BACKGROUND
  PROSPERO CRD42014014345.
authors.affiliation: Genentech, Inc., 1 DNA Way, South San Francisco, CA, 94080, USA. korner.eli@gene.com.
authors.forename: Eli J
authors.initials: EJ
authors.lastname: Korner
authors.affiliation: PRO Unlimited, Inc., 1350 Old Bayshore Hwy Suite 350, Burlingame, CA, 94010, USA. morris.anne@gene.com.|College of Social and Behavioral Sciences, School of Psychology, Walden University, 155 5th Avenue South, Minneapolis, MN, 55401, USA. morris.anne@gene.com.
authors.forename: Anne
authors.initials: A
authors.lastname: Morris
authors.affiliation: Department of Epidemiology and Biostatistics, University of California, San Francisco School of Medicine, 550 16th Street, 2nd Floor, San Francisco, CA, 94158, USA. Isabel.allen@ucsf.edu.
authors.forename: Isabel Elaine
authors.initials: IE
authors.lastname: Allen
authors.affiliation: UCLA Jonsson Comprehensive Cancer Center, 2020 Santa Monica Blvd., Suite 580, Santa Monica, CA, 90404, USA. SHurvitz@mednet.ucla.edu.
authors.forename: Sara
authors.initials: S
authors.lastname: Hurvitz
authors.affiliation: Genentech, Inc., 1 DNA Way, South San Francisco, CA, 94080, USA. beattiem@gene.com.
authors.forename: Mary S
authors.initials: MS
authors.lastname: Beattie
authors.affiliation: Department of Epidemiology, Columbia University, 722 W 168th Street, New York, NY, 10032, USA. Bindu.Kalesan@ppdi.com.|Pharmaceutical Product Development, 980 Harvest Drive #130, Blue Bell, PA, 19422, USA. Bindu.Kalesan@ppdi.com.
authors.forename: Bindu
authors.initials: B
authors.lastname: Kalesan
mesh_terms: D001943:Breast Neoplasms / Q000737:chemistry* / Q000401:mortality* / Q000473:pathology / Q000628:therapy*; D002986:Clinical Trials as Topic; D005260:Female; D006801:Humans; D009362:Neoplasm Metastasis; D064887:Observational Studies as Topic; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000032:analysis*; D012107:Research Design; D000078202:Systematic Reviews as Topic; D015201:Meta-Analysis as Topic
chemical_list: D018719:Erb-b2 Receptor Tyrosine Kinases; C508053:ERBB2 protein, human