title: Breast Cancer Chemoprevention: A Network Meta-Analysis of Randomized Controlled Trials.
abstract: BACKGROUND
  Several agents have been advocated for breast cancer primary prevention. However, few of them appear effective, the associated severe adverse effects limiting their uptake.
  
  
  METHODS
  We performed a comprehensive search for randomized controlled trials (RCTs) reporting on the ability of chemoprevention agents (CPAs) to reduce the incidence of primary breast carcinoma. Using network meta-analysis, we ranked CPAs based simultaneously on efficacy and acceptability (an inverse measure of toxicity). All statistical tests were two-sided.
  
  
  RESULTS
  We found 48 eligible RCTs, enrolling 271 161 women randomly assigned to receive either placebo or one of 21 CPAs. Aromatase inhibitors (anastrozole and exemestane, considered a single CPA class because of the lack of between-study heterogeneity; relative risk [RR] = 0.468, 95% confidence interval [CI] = 0.346 to 0.634), arzoxifene (RR = 0.415, 95% CI = 0.253 to 0.682), lasofoxifene (RR = 0.208, 95% CI = 0.079 to 0.544), raloxifene (RR = 0.572, 95% CI = 0.372 to 0.881), tamoxifen (RR = 0.708, 95% CI = 0.595 to 0.842), and tibolone (RR = 0.317, 95% CI = 0.127 to 0.792) were statistically significantly associated with a therapeutic effect, which was restricted to estrogen receptor-positive tumors of postmenopausal women (except for tamoxifen, which is active also during premenopause). Network meta-analysis ranking showed that the new selective estrogen receptor modulators (SERMs) arzoxifene, lasofoxifene, and raloxifene have the best benefit-risk ratio. Aromatase inhibitors and tamoxifen ranked second and third, respectively.
  
  
  CONCLUSIONS
  These results provide physicians and health care regulatory agencies with RCT-based evidence on efficacy and acceptability of currently available breast cancer CPAs; at the same time, we pinpoint how much work still remains to be done before pharmacological primary prevention becomes a routine option to reduce the burden of this disease.
authors.affiliation: Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy (SM, PP, MB, DN); Istituto Oncologico Veneto, IOV-IRCCS, Padova, Italy (SM); Sant'Antonio Hospital, Padova, Italy (PP). simone.mocellin@unipd.it.
authors.forename: Simone
authors.initials: S
authors.lastname: Mocellin
authors.affiliation: Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy (SM, PP, MB, DN); Istituto Oncologico Veneto, IOV-IRCCS, Padova, Italy (SM); Sant'Antonio Hospital, Padova, Italy (PP).
authors.forename: Pierluigi
authors.initials: P
authors.lastname: Pilati
authors.affiliation: Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy (SM, PP, MB, DN); Istituto Oncologico Veneto, IOV-IRCCS, Padova, Italy (SM); Sant'Antonio Hospital, Padova, Italy (PP).
authors.forename: Marta
authors.initials: M
authors.lastname: Briarava
authors.affiliation: Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, Italy (SM, PP, MB, DN); Istituto Oncologico Veneto, IOV-IRCCS, Padova, Italy (SM); Sant'Antonio Hospital, Padova, Italy (PP).
authors.forename: Donato
authors.initials: D
authors.lastname: Nitti
mesh_terms: D000328:Adult; D000368:Aged; D016588:Anticarcinogenic Agents / Q000008:administration & dosage*; D018931:Antineoplastic Agents, Hormonal / Q000008:administration & dosage*; D047072:Aromatase Inhibitors / Q000008:administration & dosage*; D001943:Breast Neoplasms / Q000517:prevention & control*; D005260:Female; D006801:Humans; D008875:Middle Aged; D009652:Norpregnenes / Q000008:administration & dosage; D010880:Piperidines / Q000008:administration & dosage; D017698:Postmenopause; D011322:Primary Prevention / Q000379:methods*; D011759:Pyrrolidines / Q000008:administration & dosage; D020849:Raloxifene Hydrochloride / Q000008:administration & dosage; D016032:Randomized Controlled Trials as Topic; D018570:Risk Assessment; D020845:Selective Estrogen Receptor Modulators / Q000008:administration & dosage*; D013629:Tamoxifen / Q000008:administration & dosage; D013764:Tetrahydronaphthalenes / Q000008:administration & dosage; D013876:Thiophenes / Q000008:administration & dosage
chemical_list: D016588:Anticarcinogenic Agents; D018931:Antineoplastic Agents, Hormonal; D047072:Aromatase Inhibitors; D009652:Norpregnenes; D010880:Piperidines; D011759:Pyrrolidines; D020845:Selective Estrogen Receptor Modulators; D013764:Tetrahydronaphthalenes; D013876:Thiophenes; D013629:Tamoxifen; C111332:Lasofoxifene; D020849:Raloxifene Hydrochloride; C115121:LY 353381; C027385:tibolone