title: Anastrozole versus tamoxifen in postmenopausal women with ductal carcinoma in situ undergoing lumpectomy plus radiotherapy (NSABP B-35): a randomised, double-blind, phase 3 clinical trial.
abstract: BACKGROUND
  Ductal carcinoma in situ is currently managed with excision, radiotherapy, and adjuvant hormone therapy, usually tamoxifen. We postulated that an aromatase inhibitor would be safer and more effective. We therefore undertook this trial to compare anastrozole versus tamoxifen in postmenopausal women with ductal carcinoma in situ undergoing lumpectomy plus radiotherapy.
  
  
  METHODS
  The double-blind, randomised, phase 3 National Surgical Adjuvant Breast and Bowel Project (NSABP) B-35 trial was done in 333 participating NSABP centres in the USA and Canada. Postmenopausal women with hormone-positive ductal carcinoma in situ treated by lumpectomy with clear resection margins and whole-breast irradiation were enrolled and randomly assigned (1:1) to receive either oral tamoxifen 20 mg per day (with matching placebo in place of anastrozole) or oral anastrozole 1 mg per day (with matching placebo in place of tamoxifen) for 5 years. Randomisation was stratified by age (<60 vs ≥60 years) and patients and investigators were masked to treatment allocation. The primary outcome was breast cancer-free interval, defined as time from randomisation to any breast cancer event (local, regional, or distant recurrence, or contralateral breast cancer, invasive disease, or ductal carcinoma in situ), analysed by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00053898, and is complete.
  
  
  RESULTS
  Between Jan 1, 2003, and June 15, 2006, 3104 eligible patients were enrolled and randomly assigned to the two treatment groups (1552 to tamoxifen and 1552 to anastrozole). As of Feb 28, 2015, follow-up information was available for 3083 patients for overall survival and 3077 for all other disease-free endpoints, with median follow-up of 9·0 years (IQR 8·2-10·0). In total, 212 breast cancer-free interval events occurred: 122 in the tamoxifen group and 90 in the anastrozole group (HR 0·73 [95% CI 0·56-0·96], p=0·0234). A significant time-by-treatment interaction (p=0·0410) became evident later in the study. There was also a significant interaction between treatment and age group (p=0·0379), showing that anastrozole is superior only in women younger than 60 years of age. Adverse events did not differ between the groups, except for thrombosis or embolism--a known side-effect of tamoxifen-for which there were 17 grade 4 or worse events in the tamoxifen group versus four in the anastrozole group.
  
  
  CONCLUSIONS
  Compared with tamoxifen, anastrozole treatment provided a significant improvement in breast cancer-free interval, mainly in women younger than 60 years of age. This finding means that women will benefit from having a choice of effective agents for ductal carcinoma in situ.
  
  
  BACKGROUND
  US National Cancer Institute and AstraZeneca Pharmaceuticals LP.
authors.affiliation: NRG Oncology/National Surgical Adjuvant Breast and Bowel Project (NSABP), Pittsburgh, PA, USA; Jewish General Hospital, McGill University, Montreal, QC, Canada. Electronic address: richard.margolese@mcgill.ca.
authors.forename: Richard G
authors.initials: RG
authors.lastname: Margolese
authors.affiliation: NRG Oncology/National Surgical Adjuvant Breast and Bowel Project (NSABP), Pittsburgh, PA, USA; Department of Biostatistics, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: Reena S
authors.initials: RS
authors.lastname: Cecchini
authors.affiliation: NRG Oncology/National Surgical Adjuvant Breast and Bowel Project (NSABP), Pittsburgh, PA, USA; Department of Surgical Oncology, Allegheny Cancer Center at Allegheny General Hospital, Pittsburgh, PA, USA.
authors.forename: Thomas B
authors.initials: TB
authors.lastname: Julian
authors.affiliation: NRG Oncology/National Surgical Adjuvant Breast and Bowel Project (NSABP), Pittsburgh, PA, USA; University of California, Los Angeles, CA, USA.
authors.forename: Patricia A
authors.initials: PA
authors.lastname: Ganz
authors.affiliation: NRG Oncology/National Surgical Adjuvant Breast and Bowel Project (NSABP), Pittsburgh, PA, USA; Department of Biostatistics, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: Joseph P
authors.initials: JP
authors.lastname: Costantino
authors.affiliation: NRG Oncology/National Surgical Adjuvant Breast and Bowel Project (NSABP), Pittsburgh, PA, USA; Department of Radiation Oncology, Mayo Clinic, Jacksonville, FL, USA.
authors.forename: Laura A
authors.initials: LA
authors.lastname: Vallow
authors.affiliation: NRG Oncology/National Surgical Adjuvant Breast and Bowel Project (NSABP), Pittsburgh, PA, USA; SWOG, San Antonio, TX, USA; Department of Medicine, Loyola University Chicago Stritch School of Medicine, Chicago, IL, USA.
authors.forename: Kathy S
authors.initials: KS
authors.lastname: Albain
authors.affiliation: NRG Oncology/National Surgical Adjuvant Breast and Bowel Project (NSABP), Pittsburgh, PA, USA; ALLIANCE/ACOSOG, Chicago, IL, USA; Nashville Breast Center, Nashville, TN, USA.
authors.forename: Patrick W
authors.initials: PW
authors.lastname: Whitworth
authors.affiliation: NRG Oncology/National Surgical Adjuvant Breast and Bowel Project (NSABP), Pittsburgh, PA, USA; SWOG, San Antonio, TX, USA; ECOG/ACRIN, Philadelphia, PA, USA; Department of Hematology/Oncology, Banner MD Anderson Cancer Center, Gilbert, AZ, USA.
authors.forename: Mary E
authors.initials: ME
authors.lastname: Cianfrocca
authors.affiliation: NRG Oncology/National Surgical Adjuvant Breast and Bowel Project (NSABP), Pittsburgh, PA, USA; Department of Hematology/Oncology, Magee Womens Hospital/University of Pittsburgh Department of Hematology/Oncology, Pittsburgh, PA, USA.
authors.forename: Adam M
authors.initials: AM
authors.lastname: Brufsky
authors.affiliation: NRG Oncology/National Surgical Adjuvant Breast and Bowel Project (NSABP), Pittsburgh, PA, USA; Dayton Physicians LLC, Dayton, OH, USA.
authors.forename: Howard M
authors.initials: HM
authors.lastname: Gross
authors.affiliation: NRG Oncology/National Surgical Adjuvant Breast and Bowel Project (NSABP), Pittsburgh, PA, USA; Missouri Valley Cancer Consortium, Omaha, NE, USA.
authors.forename: Gamini S
authors.initials: GS
authors.lastname: Soori
authors.affiliation: NRG Oncology/National Surgical Adjuvant Breast and Bowel Project (NSABP), Pittsburgh, PA, USA; SCOR NCORP, Winston Salem, NC, USA; Department of Hematology/Oncology, Forsyth Regional Cancer Center, Winston Salem, NC, USA.
authors.forename: Judith O
authors.initials: JO
authors.lastname: Hopkins
authors.affiliation: NRG Oncology/National Surgical Adjuvant Breast and Bowel Project (NSABP), Pittsburgh, PA, USA; Department of Medical Oncology, Kaiser Permanente Northern California Vallejo, CA, USA.
authors.forename: Louis
authors.initials: L
authors.lastname: Fehrenbacher
authors.affiliation: NRG Oncology/National Surgical Adjuvant Breast and Bowel Project (NSABP), Pittsburgh, PA, USA; Department of Medical Oncology Colorado Cancer Research Program, Denver, CO, USA.
authors.forename: Keren
authors.initials: K
authors.lastname: Sturtz
authors.affiliation: NRG Oncology/National Surgical Adjuvant Breast and Bowel Project (NSABP), Pittsburgh, PA, USA; CCOP, Christiana Care Health Systems, Newark, DE, USA.
authors.forename: Timothy F
authors.initials: TF
authors.lastname: Wozniak
authors.affiliation: NRG Oncology/National Surgical Adjuvant Breast and Bowel Project (NSABP), Pittsburgh, PA, USA; Atlanta Regional Community Clinical Oncology Program, Atlanta, GA, USA.
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Seay
authors.affiliation: NRG Oncology/National Surgical Adjuvant Breast and Bowel Project (NSABP), Pittsburgh, PA, USA; UF Health Cancer Center at Orlando Health, Orlando, FL, USA.
authors.forename: Eleftherios P
authors.initials: EP
authors.lastname: Mamounas
authors.affiliation: NRG Oncology/National Surgical Adjuvant Breast and Bowel Project (NSABP), Pittsburgh, PA, USA; Department of Surgical Oncology, Allegheny Cancer Center at Allegheny General Hospital, Pittsburgh, PA, USA.
authors.forename: Norman
authors.initials: N
authors.lastname: Wolmark
mesh_terms: D000284:Administration, Oral; D000367:Age Factors; D000077384:Anastrozole; D018931:Antineoplastic Agents, Hormonal / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D047072:Aromatase Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000532:radiotherapy / Q000601:surgery; D018270:Carcinoma, Ductal, Breast / Q000188:drug therapy* / Q000532:radiotherapy / Q000601:surgery; D003131:Combined Modality Therapy; D004311:Double-Blind Method; D004617:Embolism / Q000139:chemically induced; D005260:Female; D006801:Humans; D015412:Mastectomy, Segmental; D008875:Middle Aged; D009570:Nitriles / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D017698:Postmenopause; D013629:Tamoxifen / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D013927:Thrombosis / Q000139:chemically induced; D014230:Triazoles / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*
chemical_list: D018931:Antineoplastic Agents, Hormonal; D047072:Aromatase Inhibitors; D009570:Nitriles; D014230:Triazoles; D013629:Tamoxifen; D000077384:Anastrozole