Elsevier

The Lancet

Volume 387, Issue 10021, 27 February–4 March 2016, Pages 849-856
The Lancet

Articles
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

https://doi.org/10.1016/S0140-6736(15)01168-XGet rights and content

Summary

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.

Funding

US National Cancer Institute and AstraZeneca Pharmaceuticals LP.

Introduction

With continuous improvements in screening mammography and diagnostic breast imaging during the past three to four decades, ductal carcinoma in situ is now identified more frequently and its management has become an increasingly challenging problem. Originally called early or minimal breast cancer, ductal carcinoma in situ is now classified as stage 0 breast cancer and is regarded by some experts as a precancerous entity. As a result, debate is ongoing as to whether ductal carcinoma in situ should be treated as a malignancy or as a precursor of cancer.

Randomised clinical trials of invasive breast cancer have established that breast-conserving surgery and whole-breast irradiation provide the same long-term survival rates as total mastectomy.1, 2 This shift in surgical management has also been adopted for ductal carcinoma in situ, following publication of National Surgical Adjuvant Breast and Bowel Project (NSABP) B-17,1 a randomised prospective clinical trial of lumpectomy versus lumpectomy and radiotherapy for ductal carcinoma in situ. However, breast-conserving therapy leaves open the chance for a local recurrence, which can manifest itself as another ductal carcinoma in situ or as invasive recurrence.

Research in Context

Evidence before this study

We did a thorough review of relevant studies of adjuvant endocrine therapy for breast cancer and ductal carcinoma in situ. We searched the MEDLINE database, using the terms “DCIS”, “adjuvant treatment”, and “hormone therapy” for articles published after the year 2000 in English language only. B-35 was based on previous National Surgical Adjuvant Breast and Bowel Project (NSABP) studies B-06, B-17, and B-24. This sequence of studies showed that lumpectomy and radiotherapy was appropriate for the management of ductal carcinoma in situ, and that adjuvant tamoxifen improved outcomes. In addition to the review of published clinical trials assessing tamoxifen in breast cancer and ductal carcinoma in situ, we did literature surveys annually throughout the duration of this study. These results were interpreted and assessed by the senior authors and incorporated into our annual reports.

Added value of this study

Along with IBIS-II DCIS, this study is one of the the first prospective randomised trials to show that anastrozole has additional efficacy for treating ductal carcinoma compared with tamoxifen. Comprehensive quality-of-life analyses were also done because of the high likelihood that participants in both groups of the study would do well and that assessment of adverse effects would be important.

Implications of all the available evidence

Anastrozole is more effective than tamoxifen in reducing the incidence of invasive cancer. Severe adverse reactions were less frequent with anastrozole. Both drugs have now been shown to be effective, and women with ductal carcinoma in situ who desire adjuvant therapy now have a choice of medication. This decision can be helped by the integration of the efficacy and adverse effect information.

With the aim to minimise these events, adjuvant treatments were tested. The NSABP B-24 trial3 was based on previous reports that adjuvant tamoxifen decreased the incidence of tumour recurrence in the affected breast of patients with invasive breast cancer and reduced the rate of new primary tumours in the contralateral breast. This finding suggested that tamoxifen can interfere with the development of primary invasive breast cancer or with the progression from ductal carcinoma in situ to invasive breast cancer.

In the NSABP B-24 trial, 1804 women with ductal carcinoma in situ were randomly assigned to receive 5 years of adjuvant tamoxifen or placebo following breast-conserving therapy and whole-breast irradiation. At 83 months' follow-up, women in the tamoxifen group had fewer breast cancer events than those in the placebo group (10·3% vs 16·9%, p=0·0003). The cumulative incidence of all breast cancers in the tamoxifen group was 4·8% at 7 years: 2·6% in the ipsilateral breast, 1·8% in the contralateral breast, and 0·4% at regional and distant sites.3

In 2011, Wapnir and colleagues4 assessed long-term outcomes for ipsilateral breast tumour recurrences in the NSABP B-17 and B-24 studies. Of 490 events, 263 (54%) were invasive. The addition of whole-breast irradiation reduced the risk of recurrence compared with lumpectomy alone (hazard ratio [HR] 0·48 [95% CI 0·33–0·69]). Invasive ipsilateral breast tumour recurrence was associated with increased mortality risk (HR 1·75 [95% CI 1·45–2·96]), but recurrence of ductal carcinoma in situ was not (0·81 [0·51–1·27]). In NSABP B-24, lumpectomy and radiotherapy plus tamoxifen reduced invasive ipsilateral breast tumour recurrence by 32% compared with lumpectomy and radiotherapy plus placebo.

Despite these benefits, some women still relapsed or had serious side-effects, such as endometrial cancer, vascular complications, and troublesome menopausal symptoms, which affect compliance to treatment. We postulated that the partial agonist properties of tamoxifen and the absence of complete suppression of oestrogen receptor signalling might limit the benefits of such treatment. The advent of third-generation aromatase inhibitors provided the possibility to reduce or eliminate signalling through the oestrogen receptor pathway with treatments that do not have oestrogen agonist effects.

In the treatment of oestrogen receptor-positive postmenopausal patients with metastatic disease, the aromatase inhibitor anastrozole has been shown to be superior to tamoxifen in overall response rates and time to progression.5 Side-effects and toxicities were similar, but anastrozole was associated with fewer thromboembolic events than tamoxifen.

Results of the ATAC6 trial for women with early-stage invasive breast cancer also showed superiority for anastrozole over tamoxifen. This multicentre, randomised, double-blind study involved 9366 postmenopausal women randomly assigned to receive anastrozole or tamoxifen, or a combination of both drugs. The results showed a 17% reduction in relative risk of disease recurrence with anastrozole (p=0·0129), and an absolute risk reduction of 2%. In women with confirmed oestrogen receptor-positive tumours, the reduction in risk of recurrence was 22%. No additional benefit was recorded in the combination therapy group. Anastrozole was associated with significantly fewer reports of endometrial cancer, deep-vein thrombosis, stroke, and hot flushes, but with more fractures, mainly of the wrist, when compared with tamoxifen. Additionally, anastrozole significantly reduced the risk of developing contralateral breast cancer (odds ratio 0·42 [95% CI 0·22–0·79], p=0·007).

Based on this rationale, we undertook a double-blind randomised trial in postmenopausal patients with oestrogen receptor-positive ductal carcinoma in situ. The primary aim of this trial was to compare the effectiveness of 5 years of treatment with anastrozole versus tamoxifen in preventing subsequent occurrence of breast cancer (local, regional, and distant recurrences, and contralateral breast cancer) following lumpectomy and radiotherapy.

Section snippets

Study design and participants

NSABP B-35 was a randomised, double-blind, phase 3 study, which was undertaken in 333 participating NSABP centres in the USA and Canada. Postmenopausal women with ductal carcinoma in situ or mixed ductal carcinoma in situ and lobular carcinoma in situ who were oestrogen receptor positive or progesterone receptor positive, with no invasive component, were eligible for inclusion. Participants had to have undergone a lumpectomy with clear margins and negative nodes (if biopsied), followed by

Results

Between Jan 6, 2003, and June 15, 2006, 3104 patients were enrolled into the trial and randomly assigned to tamoxifen (n=1552) or anastrozole (n=1552; figure 1 and appendix p 1). The present analysis used data collected up to Feb 28, 2015. A total of 3083 (99%) of 3104 patients had follow-up information available for survival, with 3077 (99%) also having follow-up information for all other disease-free endpoints. Median duration of follow-up was 9·0 years (IQR 8·2–10·0). All baseline patient

Discussion

This trial can be viewed as part of a stepwise evaluation by the NSABP of new treatments for patients with ductal carcinoma in situ. The NSABP B-171, 2 trial established that lumpectomy and whole-breast irradiation was an appropriate, optional treatment for ductal carcinoma in situ. The NSABP B-24 trial3 subsequently showed that the addition of adjuvant tamoxifen following lumpectomy and whole-breast irradiation resulted in fewer recurrences of cancer (invasive or non-invasive), in either

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