Two years of adjuvant tamoxifen in premenopausal patients with breast cancer: a randomised, controlled trial with long-term follow-up

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Abstract

Adjuvant tamoxifen treatment increases recurrence-free survival (RFS) and overall survival (OS) in early breast cancer, although in premenopausal patients the number of studies comparing tamoxifen vs no treatment are limited. We report herein the effect on RFS of adjuvant tamoxifen treatment in a multicentre trial of premenopausal patients with stage II breast cancer patients randomised between 1986 and 1991 to 2 years of tamoxifen treatment (n = 276) or no treatment (n = 288). The receptor status of the tumour was known for 541 (96%) of the patients included. Tamoxifen treatment significantly increased RFS in patients with hormone receptor-positive (oestrogen receptor-positive (ER+) and/or progesterone receptor-positive (PR+)) tumours (Relative Risk (RR) 0.65; 95% Confidence Interval (CI): 0.48–0.89, P = 0.006), and the beneficial effect of tamoxifen was extended to patients with indicators of poor prognosis, such as young age and nodal-positivity. PR status was a significant predictor of response to tamoxifen in multivariate models with testing of interactions of hormone receptor status and adjuvant therapy.

Introduction

Adjuvant tamoxifen treatment increases recurrence-free survival (RFS) and overall survival (OS) in breast cancer patients with hormone receptor-positive tumours irrespective of their nodal status, menopausal status or age [1]. The tamoxifen effect is best established in postmenopausal patients, where data from our group and others supports the beneficial effect of prolonged tamoxifen treatment (5 years) compared with 2 years [1], [2], [3], [4], [5]. In premenopausal patients, 5 years of adjuvant tamoxifen reduces the risk of recurrence and death, irrespective of whether chemotherapy has been given [1]. An overview analysis suggests that a shorter duration (1 or 2 years of tamoxifen) of treatment in premenopausal patients has less clinical effect and no effect of tamoxifen treatment has been reported from individual studies [1], [6]. Only a few trials investigated tamoxifen as monotherapy in this group of patients, while several studies compared chemotherapy and/or oophorectomy vs tamoxifen [7], [8], [9].

Oestrogen receptor content (ER) is the best recognised predictive marker for adjuvant tamoxifen treatment [1], [10]. Progesterone receptor content (PR) has been proposed to add information and serve as an alternative predictor [11], [12], [13]. Increased proliferation in tumour cells may further predict the patient’s response to adjuvant tamoxifen, which is of interest since a high S-phase rate correlates with an increased risk of relapse and death [14]. The response to tamoxifen in relation to the patient’s histological grade (Nottingham measure) has been explored in retrospective materials, and a positive effect of tamoxifen in hormone-responsive disease has been reported for tumours of all histological grades [15]. New markers to predict response to tamoxifen are continuously being evaluated retrospectively, and HER2 is the most widely studied [16], [17], [18], [19]. HER2 positivity indicates response to trastuzumab and helps to explain biologically resistance to tamoxifen in ER-positive disease.

This is the first report from a Swedish randomised study of 2 years of adjuvant tamoxifen vs no treatment including only premenopausal patients with stage II invasive breast cancer. The main purpose of the trial was to investigate the effect of tamoxifen on RFS in relation to the patient’s ER and PR status. Data regarding OS are also presented.

Section snippets

Study design

The aim of the study was to compare the effect of tamoxifen treatment vs no treatment (control) in relation to RFS (primary outcome) and OS (secondary outcome) in premenopausal patients. RFS included local, regional, distant recurrences and breast cancer-specific death, but not contralateral breast cancer, as the primary event. Premenopausal patients or patients under 50 years with stage II (pT2 N0 M0, pT1 N1 M0 and pT2, N1 M0) invasive breast cancer were included. Stratification for tumour

All patients

There were 262 primary breast cancer events among the included patients – 116 in the tamoxifen group and 146 in the control group. Two years of tamoxifen treatment significantly increased the RFS, (Relative Risk (RR) 0.77; 95% Confidence Interval (CI): 0.60–0.98, P = 0.033), and the 10-year RFS was 60.3% in the tamoxifen-treated arm and 52.7% in the control arm. Death from any cause was recorded in 237 patients (108 in the tamoxifen-treated arm and 129 in the control arm), but tamoxifen treatment

Discussion

The present study demonstrates a positive effect for 2 years treatment of adjuvant tamoxifen as monotherapy vs control with regard to RFS. The tamoxifen effect was only observed for patients with hormone receptor-positive tumours (ER+ and/or PR+) and seems to have no effect in patients with ER− and PR− tumours. In hormone receptor-positive disease, the beneficial effect of 2 years of tamoxifen was extended to patients at high risk of recurrence, including young patients (<40 years) and those

Conflict of interest

None declared.

Acknowledgements

The study was supported by grants from the Swedish Cancer Society, the Stig and Ragna Gorthon Foundation, the Gunnar Nilsson Foundation and Kristianstad College of Higher Education.

The following investigators at the hospitals in the two participating centres.

South Sweden: Bengt Börjesson (Halmstad), Stefan Rydén (Ängelholm), Per-Ebbe Jönsson, Martin Malmberg (Helsingborg), Anders Alwmark, Dick Killander, Christian Ingvar, Per Malmström (Landskrona-Lund), Knut Aspegren, Göran Balldin, Lennart

References (26)

  • S. Gundersen et al.

    Adjuvant tamoxifen for pre- and postmenopausal women with estrogen receptor positive, node positive breast cancer: a randomized study

    Breast Cancer Res. Treat.

    (1995)
  • G. Ribeiro et al.

    The Christie hospital adjuvant tamoxifen trial

    J. Natl. Cancer Inst. Monogr.

    (1992)
  • L.A. Emens et al.

    Adjuvant hormonal therapy for premenopausal women with breast cancer

    Clin. Cancer Res.

    (2003)
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