Combined endocrine therapy for breast cancer--new life for an old idea?

Endocrine therapy has been a mainstay of breast cancer treatment for more than 100 years. The first interventions, oophorectomy for premenopausal women and pharmacologic doses of estrogen for postmenopausal women, have been supplanted by targeted therapy, including selective estrogen receptor modulators (SERMs) like tamoxifen, luteinizing hormone-releasing hormone (LHRH) agonists, and aromatase inhibitors. The initial attempts to combine hormonal therapies generally led to the finding of increased response rates but at the expense of higher toxicity and without an obvious survival advantage when compared with the survival with sequential monotherapy. These results have led to the current practice of serial hormonal manipulation in advanced breast cancer—i.e., the use of one endocrine therapy until disease progression, followed by a second intervention until its failure and so on. In practice, this means that a strategy of tamoxifen followed by ovarian ablation or the reverse has been the norm for premenopausal women with metastatic breast cancer who are believed to be candidates for endocrine therapy (1). This practice dogma is challenged by the findings of Klijn et al. (2) reported in this issue of the Journal. In this European Organization for Research and Treatment of Cancer (EORTC) study, 161 premenopausal women with potentially hormoneresponsive metastatic breast cancer were randomly assigned to tamoxifen, buserelin (an LHRH agonist that effects a chemical castration), or the combination. Not surprisingly, the effects of tamoxifen or buserelin alone on a number of clinical end points were similar. However, contrary to prevailing views, the combination of tamoxifen and buserelin led to a superior response rate and to improved median progression-free and overall survivals, as well as a doubling of 5-year survival from 15%–18% for the single agents to 34% for the combined therapy. For comparison, a contemporaneous U.S. trial of surgical oophorectomy versus goserelin (another LHRH agonist) in premenopausal women with steroid receptor-positive metastatic breast cancer (3) gave intermediate results. A response rate of 31%, a median failure-free survival of 6 months, a median overall survival of 37 months, and an estimated 5-year survival of 25% were noted for the 69 patients assigned to goserelin. The major strengths of the trial conducted by Klijn et al. (2) are its maturity and its design, which permits direct comparison of the three interventions, a rare opportunity in breast cancer. In addition, the definition of the premenopausal state was rigorous, and registration was limited to women with steroid receptor-positive tumor or receptor-unknown tumor with a long disease-free interval. Thus, this trial, unlike many trials of ovarian ablation, was targeted toward the population of women most likely to benefit from this approach. The results are biologically plausible because ovarian ablation and tamoxifen could potentially function in part via different pathways (those of estrogen withdrawal and estrogen receptor blockade, respectively) and might, therefore, target different cell populations. The ancillary laboratory study measuring serial estrogen levels is congruent with other studies showing that tamoxifen can increase circulating 17b-estradiol, whereas LHRH agonists decrease it to a postmenopausal level. Indeed, the study by Klijn et al. (2) suggests that these divergent effects on the level of serum 17bestradiol are not clinically significant because there was no major difference in clinical outcomes for the tamoxifen or buserelin groups. But our ability to interpret the results of the trial is undermined by three features. First, the sample size is small because the trial was stopped early as a result of poor accrual; this could possibly give anomalous results. Second, for pragmatic reasons, it was not possible to carry out the perfect clinical experiment—a crossover design where all patients received both tamoxifen and ovarian ablation and only the order of administration varied. Finally, our ability to generalize these results to current clinical practice is limited because a minority of the patients in this trial had received any form of adjuvant systemic therapy. In particular, only four patients had taken adjuvant tamoxifen. Thus, these trial results may not apply to today’s premenopausal women with advanced hormone-responsive breast cancer, most of whom will have received adjuvant tamoxifen and/or chemotherapy. For these reasons, it is difficult to draw a definitive conclusion that a combination of ovarian ablation and tamoxifen should be the standard of care for premenopausal women with metastatic endocrine-responsive breast cancer. A key question is what these results might teach us about approaches to adjuvant therapy and chemoprevention. The Early Breast Cancer Trialists’ Collaborative Group meta-analyses of tamoxifen and ovarian ablation (4,5) demonstrate unequivocally that tamoxifen and ovarian ablation are effective adjuvant strategies for women under 50 years of age, particularly for those whose tumor expresses estrogen receptor. Indirect comparison of results from these analyses suggests comparable effects, but direct comparison is not possible. Results of randomized trials that address questions of ovarian ablation and tamoxifen in steroid receptor-positive, early-stage breast cancer in premenopausal women are beginning to emerge. Regrettably, their design in aggregate fails to shed much light on