Elsevier

The Lancet

Volume 364, Issue 9437, 4–10 September 2004, Pages 858-868
The Lancet

Articles
Treatment of lymph-node-negative, oestrogen-receptor-positive breast cancer: long-term findings from National Surgical Adjuvant Breast and Bowel Project randomised clinical trials

https://doi.org/10.1016/S0140-6736(04)16981-XGet rights and content

Summary

Background

Findings from the National Surgical Adjuvant Breast and Bowel Project B-14 and B-20 trials showed that tamoxifen benefited women with oestrogen-receptor-positive tumours and negative axillary nodes, and that chemotherapy plus tamoxifen was more effective than tamoxifen alone. We present long-term findings from those trials and relate them to age, menopausal status, and tumour oestrogen-receptor concentrations. We also discuss the extent of progress made in the treatment of such patients.

Methods

B-14 patients were randomly assigned to placebo (n=1453) or tamoxifen (n=1439); B-20 patients to tamoxifen (n=788) or cyclophosphamide, methotrexate, fluorouracil, and tamoxifen (CMFT, n=789). Primary endpoints were recurrence-free survival and overall survival estimated according to patients' age, menopausal status, and tumour oestrogen-receptor concentration. Smoothed recurrence rates were used to measure patterns of recurrence as a continuous function of age.

Findings

Compared with placebo, tamoxifen benefited women in B-14 through 15 years, irrespective of age, menopausal status, or tumour oestrogen-receptor concentration (hazard ratio [HR] for recurrence-free survival 0·58, 95% CI 0·50–0·67, p<0·0001; HR for overall survival 0·80, 0·71–0·91, p=0·0008). In B-20, the benefit from CMFT over 12 years was greater than that from tamoxifen alone (HR for recurrence-free survival 0·52, 0·39–0·68, p<0·0001; HR for overall survival 0·78, 0·60–1·01, p=0·063). When CMFT was compared with placebo, there were reductions in treatment failure of about 65% in all age-groups.

Interpretation

Much benefit has been achieved in treatment of women with oestrogen-receptor-positive tumours and negative nodes. When planning systemic therapy for such patients of all ages, it should be understood that some have tumours with variable concentrations of oestrogen-receptors, a surrogate for other biomarkers associated with tumour growth and response to treatment. Older women tend to have higher tumour oestrogen-receptor concentrations and are more likely to benefit from tamoxifen than from chemotherapy; in younger women, the converse is true. Consequently, the notion that use of tamoxifen or chemotherapy should be based only on age is too restrictive.

Introduction

In 1982, the National Surgical Adjuvant Breast and Bowel Project (NSABP) initiated the first randomised clinical trial (B-14) designed to assess the efficacy of adjuvant tamoxifen treatment in women with oestrogen-receptor-positive breast cancer and histologically negative axillary lymph nodes. Initial results from that study, from nearly 3000 women, showed that tamoxifen-treated women had a significantly better outcome than did those who received placebo.1 Findings from long-term follow-up continued to lend support to the initial results.2, 3, 4 Before the B-14 results became available, we thought that the degree of benefit achieved with tamoxifen would probably be insufficient to eliminate the need to assess potentially more effective therapeutic regimens in that patient population. Consequently, in 1988, we implemented B-20, a randomised trial designed to test the hypothesis that addition of chemotherapeutic drugs to tamoxifen would result in a greater benefit than that achieved with tamoxifen alone. Findings from more than 2000 women enrolled in the B-20 study showed a significantly better outcome after treatment with chemotherapy and tamoxifen.5

In this report, we present data on recurrence-free survival and overall survival of all women in the B-14 study through 15 years of follow-up, and of all women in the B-20 study through 12 years of follow-up. We also present information about the outcome of women in both studies according to age, menopausal status, and concentrations of tumour oestrogen receptors, and estimate the extent of the progress achieved in the treatment of node-negative patients with oestrogen-receptor-positive tumours.

Section snippets

Patients

Women at NSABP institutions in the USA and Canada who had primary breast cancer and axillary lymph nodes that were negative for cancer on histological examination, were eligible for participation in either the B-14 or the B-20 trial if their tumours were oestrogen-receptor-positive—ie, had 10 or more fmol per mg cytosol protein—and if they fulfilled specific eligibility criteria that were similar in both trials. Written, informed consent was required from patients who entered the study. Both

B-14

On average, women had significantly better outcomes after tamoxifen treatment than after placebo throughout 15 years of follow-up (recurrence-free survival 78% vs 65%, p<0·0001; overall survival 71% vs 65%, p=0·0008, figure 2). When these outcomes were examined in women according to age (table 1), a significant benefit of tamoxifen in women aged 49 years or younger was noted for each of the endpoints. In women aged 50–59 years, a significant benefit of tamoxifen was apparent for recurrence-free

Discussion

In the B-14 study, the benefit from tamoxifen initially reported after 4 years of follow-up1 has continued to increase through 15 years for all patients, irrespective of age. Moreover, the B-14 study has provided the longest prospective natural history information from oestrogen-receptor-positive, node-negative breast cancer patients treated with surgery alone. The rate of nearly 35% for treatment failure and about 35% for overall mortality in women who were assigned to placebo emphasises the

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