Abstract: We identified 14 randomised trials that involved over 13,000 premenopausal women with operable breast cancer, most of whom were ER+. The numbers of trials making the different comparisons were: (A) i. LHRH versus tamoxifen (three trials), ii. LHRH versus chemotherapy (four trials); (B) i. LHRH + tamoxifen versus tamoxifen (two trials), ii. LHRH + tamoxifen versus LHRH (three trials), iii. LHRH + tamoxifen versus chemotherapy (two trials), iv. LHRH + aromatase inhibitor versus LHRH + tamoxifen (one trial); (C) i. LHRH + chemotherapy versus LHRH (one trial), ii. LHRH + chemotherapy versus chemotherapy (five trials); (D) LHRH + tamoxifen + chemotherapy versus chemotherapy (three trials). The LHRH agonist in most of these trials was goserelin. For most of the treatment comparisons there are too few trials, too few randomised patients, or too little follow up to draw reliable estimates of the relative effects of different treatments. (A) LHRH monotherapy: results suggest that adjuvant LHRH agonist monotherapy is similar to older chemotherapy protocols (eg. CMF) in terms of recurrence-free and overall survival in ER+ patients. There are insufficient data to compare LHRH agonist monotherapy to tamoxifen alone, but available results suggest that these treatments are comparable in terms of recurrence-free survival. (B) LHRH + anti-oestrogen therapy: there are insufficient data to compare the combination of an LHRH agonist plus tamoxifen to tamoxifen alone. Results suggest that the LHRH agonist plus tamoxifen combination may be superior to an LHRH agonist alone or to chemotherapy alone, but the chemotherapy protocols tested are outdated. The data comparing LHRH agonists plus aromatase inhibitors to LHRH agonists plus tamoxifen are currently inconclusive. (C) LHRH + chemotherapy: there are insufficient data to compare the LHRH + chemotherapy combination to an LHRH agonist alone, although results from a single study suggest comparable efficacy in ER+ patients. There is a trend towards improved recurrence-free and overall survival in patients who received an LHRH agonist plus chemotherapy combination in comparison to chemotherapy alone. (D) LHRH agonist + chemotherapy + tamoxifen: there is a trend towards improved recurrence-free and overall survival in patients who received an LHRH agonist plus tamoxifen plus chemotherapy in comparison to chemotherapy alone. There are insufficient data to assess the effect of the addition of LHRH agonists to the current standard treatment of chemotherapy plus tamoxifen. Endocrine therapy with LHRH agonists appears to have fewer side-effects than the forms of chemotherapy assessed. The optimal duration of LHRH therapy in the adjuvant setting is unclear. Overall, the data from currently published clinical trials of LHRH agonists in the adjuvant setting for premenopausal women with endocrine-sensitive breast cancer are supportive of clinical benefit. Nonetheless, definitive comparisons against current clinical standards of care that include third generation chemotherapy regimens and tamoxifen are required before their place in the adjuvant setting can be properly defined. The authors conclude that the current data strongly support the continuation of current trials that definitively compare a variety of combinations of LHRH agonists and anti-oestrogenic strategies to the current standard of five years of tamoxifen.

Plain-language summary: We found seven trials comparing LHRH agonist therapy (alone) to other treatments. There is not enough evidence to compare LHRH agonists directly to tamoxifen. Four of the trials compared an LHRH agonist to a now superseded chemotherapy regimen. For ER+ women, these trials showed no significant differences between LHRH agonists and chemotherapy on recurrence and death, but LHRH agonists had fewer side effects. Six trials compared LHRH agonists in combination with tamoxifen to other treatments. There is currently insufficient information to reliably compare this combination with tamoxifen alone. The LHRH agonist plus tamoxifen combination may reduce the risk of breast cancer recurrence, but not death, when compared to an LHRH agonist alone or chemotherapy alone. There is insufficient evidence to know whether an LHRH agonist plus an aromatase inhibitor is better or worse than an LHRH agonist plus tamoxifen. Three trials compared combining an LHRH agonist plus chemotherapy plus tamoxifen to chemotherapy alone. There was a reduction in the risk of breast cancer recurrence, and possibly death, with the combination treatment. It is important to note that the current standard of care for premenopausal women with ER+ breast cancer is five years of tamoxifen, often with chemotherapy. We found no trials of LHRH agonist-containing regimens versus this standard. The women in the trials in this review need to continue to be followed up so that the longer-term effects can be investigated, to 10 and more years after diagnosis. More research is also needed to help choose between different types of LHRH agonist, and to find out if the length of time that the drug is used makes a difference. It is also unknown whether there are important differences between the effects of LHRH agonists and ovarian ablation by surgery or radiotherapy.