title: Trastuzumab containing regimens for early breast cancer.
abstract: BACKGROUND
  Approximately one-fifth of women who develop early breast cancer have HER2-positive tumours, which if untreated, have a worse prognosis than HER2-negative tumours. Trastuzumab is a selective treatment targeting the HER2 pathway. Although the results on efficacy seem to support its use, there are potential cardiac toxicities which need to be considered, especially for women at lower risk of recurrence, or those at increased cardiovascular risk.
  
  
  OBJECTIVE
  To assess the evidence on the efficacy and safety of therapy with trastuzumab, overall and in relation to its duration, concurrent or sequential administration with the standard chemotherapy regimen in patients with HER2-positive early breast cancer.
  
  
  METHODS
  We searched the Cochrane Breast Cancer Group's (CBCGs) Specialised Trials Register, and used the search strategy developed by the CBCG to search for randomised controlled trials (RCTs) in CENTRAL, MEDLINE, EMBASE, BIOSIS, TOXNET, and the WHO ICTRP search portal (up to February 2010).
  
  
  METHODS
  RCTs comparing the efficacy and safety of trastuzumab alone, or in combination with chemotherapy, or no treatment, or standard chemotherapy alone, in women with HER2-positive early breast cancer including women with locally advanced breast cancer.
  
  
  METHODS
  We collected data from published and unpublished trials. We used hazard ratios (HRs) for time-to-event outcomes and risk ratio (RRs) for binary outcomes. Subgroup analyses included duration (less or greater than six months) and concurrent or sequential trastuzumab administration.
  
  
  RESULTS
  We included eight studies involving 11,991 patients. The combined HRs for overall survival (OS) and disease-free survival (DFS) significantly favoured the trastuzumab-containing regimens (HR 0.66; 95% confidence interval (CI) 0.57 to 0.77, P < 0.00001; and HR 0.60; 95% CI 0.50 to 0.71, P < 0.00001, respectively). Trastuzumab significantly increased the risk of congestive heart failure (CHF: RR 5.11; 90% CI 3.00 to 8.72, P < 0.00001); and left ventricular ejection fraction decline (LVEF: RR 1.83; 90% CI 1.36 to 2.47, P = 0.0008). For haematological toxicities, risks did not differ. The two small trials that administered trastuzumab for less than six months did not differ in efficacy from longer studies, but found fewer cardiac toxicities. Studies with concurrent administration gave similar efficacy and toxicity results to sequential studies.
  
  
  CONCLUSIONS
  Trastuzumab significantly improves OS and DFS in HER2-positive women with early and locally advanced breast cancer, although it also significantly increases the risk of CHF and LVEF decline. The available subgroup analyses are limited by the small number of studies. Studies that administered trastuzumab concurrently or sequentially did not differ significantly in efficacy. Shorter duration of therapy may reduce cardiotoxicity and maintain efficacy, however there is insufficient evidence at present to conclude this due to small numbers of patients in these trials.
authors.affiliation: Department of Public Health, Microbiology and Virology, University of Milan, Milan, Italy. moja@marionegri.it.
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Moja
authors.forename: Ludovica
authors.initials: L
authors.lastname: Tagliabue
authors.forename: Sara
authors.initials: S
authors.lastname: Balduzzi
authors.forename: Elena
authors.initials: E
authors.lastname: Parmelli
authors.forename: Vanna
authors.initials: V
authors.lastname: Pistotti
authors.forename: Valentina
authors.initials: V
authors.lastname: Guarneri
authors.forename: Roberto
authors.initials: R
authors.lastname: D'Amico
mesh_terms: D061067:Antibodies, Monoclonal, Humanized / Q000009:adverse effects / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000737:chemistry / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D018572:Disease-Free Survival; D005260:Female; D006333:Heart Failure / Q000139:chemically induced; D006801:Humans; D009364:Neoplasm Recurrence, Local / Q000517:prevention & control; D018719:Erb-b2 Receptor Tyrosine Kinases; D013318:Stroke Volume / Q000187:drug effects / Q000502:physiology; D013997:Time Factors; D000068878:Trastuzumab; D018487:Ventricular Dysfunction, Left / Q000139:chemically induced
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab