Controversies in hormonal adjuvant therapy for premenopausal patients

The major controversy concerning adjuvant hormonal therapy for premenopausal patients is the absence of appropriate clinical trial data to indicate the appropriate way to treat patients presenting with oestrogen receptor (ER)-positive operable breast cancer. This is despite the fact that the first randomized trial in breast cancer, begun in 1947, was a comparison of ovarian irradiation versus no further treatment after primary surgery for breast cancer [1] and the availability of recent overviews [2, 3]. The Oxford overview indicates that tamoxifen is as effective in premenopausal women as in postmenopausal women. It also indicates that ovarian ablation is effective alone but not in addition to chemotherapy [3]. Subsequent studies indicate that ovarian suppression is effective in addition to chemotherapy in young women who do not develop chemotherapy-induced amenorrhoea. Multiple randomised studies indicate in patients with ER-positive tumours that ovarian suppression with or without tamoxifen is as effective as chemotherapy. All of these studies have been of poor design since none has had a third arm where both endocrine therapy and chemotherapy are given. It is likely that in the chemotherapy-alone arm there would be additional patients who would have responded to endocrine therapy and vice versa so that, although no differences between endocrine and chemotherapy were seen in these trials, it is not logical to conclude that either treatment alone is optimal without appropriate trial data. Because trials comparing methods of ovarian suppression have relatively few patients, we do not know the most effective method. LHRH agonists are associated with temporary ovarian suppression. The ZEBRA trial demonstrated that 2 years of goserelin was as effective as chemotherapy, but in this and subsequent trials of the use of LHRH agonists we do not have a clear indication of the duration of treatment required. Finally, no adequate trials indicate whether an LHRH agonist adds to the effectiveness of tamoxifen as adjuvant therapy. Given the uncertainties of treatment of premenopausal ER-positive early breast cancer, it is vital that patients are entered into appropriate trials such as SOFT.