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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.

FINDINGS:

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.

INTERPRETATION:

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.

Author information

Margolese RG1, Cecchini RS2, Julian TB3, Ganz PA4, Costantino JP2, Vallow LA5, Albain KS6, Whitworth PW7, Cianfrocca ME8, Brufsky AM9, Gross HM10, Soori GS11, Hopkins JO12, Fehrenbacher L13, Sturtz K14, Wozniak TF15, Seay TE16, Mamounas EP17, Wolmark N3.​

1NRG 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.

2NRG Oncology/National Surgical Adjuvant Breast and Bowel Project (NSABP), Pittsburgh, PA, USA; Department of Biostatistics, University of Pittsburgh, Pittsburgh, PA, USA.

3NRG 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.

4NRG Oncology/National Surgical Adjuvant Breast and Bowel Project (NSABP), Pittsburgh, PA, USA; University of California, Los Angeles, CA, USA.

5NRG Oncology/National Surgical Adjuvant Breast and Bowel Project (NSABP), Pittsburgh, PA, USA; Department of Radiation Oncology, Mayo Clinic, Jacksonville, FL, USA.

6NRG 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.

7NRG Oncology/National Surgical Adjuvant Breast and Bowel Project (NSABP), Pittsburgh, PA, USA; ALLIANCE/ACOSOG, Chicago, IL, USA; Nashville Breast Center, Nashville, TN, USA.

8NRG 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.

9NRG 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.

10NRG Oncology/National Surgical Adjuvant Breast and Bowel Project (NSABP), Pittsburgh, PA, USA; Dayton Physicians LLC, Dayton, OH, USA.

11NRG Oncology/National Surgical Adjuvant Breast and Bowel Project (NSABP), Pittsburgh, PA, USA; Missouri Valley Cancer Consortium, Omaha, NE, USA.

12NRG 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.

13NRG Oncology/National Surgical Adjuvant Breast and Bowel Project (NSABP), Pittsburgh, PA, USA; Department of Medical Oncology, Kaiser Permanente Northern California Vallejo, CA, USA.

14NRG Oncology/National Surgical Adjuvant Breast and Bowel Project (NSABP), Pittsburgh, PA, USA; Department of Medical Oncology Colorado Cancer Research Program, Denver, CO, USA.

15NRG Oncology/National Surgical Adjuvant Breast and Bowel Project (NSABP), Pittsburgh, PA, USA; CCOP, Christiana Care Health Systems, Newark, DE, USA.

16NRG Oncology/National Surgical Adjuvant Breast and Bowel Project (NSABP), Pittsburgh, PA, USA; Atlanta Regional Community Clinical Oncology Program, Atlanta, GA, USA.

17NRG Oncology/National Surgical Adjuvant Breast and Bowel Project (NSABP), Pittsburgh, PA, USA; UF Health Cancer Center at Orlando Health, Orlando, FL, USA.