Combined Hormonal Ablation for Premenopausal Breast Cancer
September 1, 2000 3 minutes read
Combined Hormonal Ablation for Premenopausal Breast Cancer
ABSTRACT & COMMENTARY
Synopsis: Combined tamoxifen and buserelin treatment for metastatic, hormone receptor-positive breast cancer in premenopausal women was shown in a randomized, prospective, clinical trial to be superior to either agent administered singly. Patients who received buserelin, either alone or with tamoxifen, had reduced serum estradiol levels and this effect on estradiol may be the explanation for the improved clinical outcomes.
Source: Klijn JGM. J Natl Cancer Inst 2000;92:
903-911.
Premenopausal women with metastatic, estrogen receptor (ER)-positive breast cancer have been treated successfully with hormonal ablation. Ovariectomy had been the treatment of choice but, in recent years, comparable success has been achieved with tamoxifen.1 A summation of the published series in which tamoxifen was used in this situation reveals an objective response rate of 30%.2 However, endogenous estradiol levels rise in premenopausal women treated with tamoxifen and this has led to the speculation that additional ablative therapy would be useful.3 In this regard, buserelin, a lutenizing hormone-releasing hormone (LHRH) agonist offers theoretical advantage because its use might inhibit the production of estradiol that has been observed in tamoxifen-treated patients.
Researchers from the European Organization for Research and Treatment of Cancer-Breast Cancer Cooperative Group report the results from a randomized, three-armed, multi-institutional clinical trial in which tamoxifen alone, or buserelin alone, were compared to combined tamoxifen/buserelin treatment for premenopausal women (n = 161) with locally advanced or metastatic ER-positive breast cancer. The median follow-up was 7.3 years, during which 76% of the patients died, all of breast cancer.
Tamoxifen was administered at a dose of 40 mg/d and the buserelin was given by subcutaneous infection at a dose of 6.6 mg every eight weeks. The doses were the same for the patients receiving combined treatment as well as for those in the single treatment groups.
The results indicated that the combined treatment of buserelin and tamoxifen did better than either treatment alone with regard to objective response rate (48% for combined, 34% buserelin, and 28% for tamoxifen), median progression-free survival (9.7 months vs 6.3 months and 5.7 months) and overall survival (3.7 years vs 2.5 years and 2.9 years). There was no significant difference between tamoxifen and buserelin when administered as a single agent, but the combined treatment was statistically significantly better in each of these outcome parameters.
Estradiol levels increased several-fold in those patients treated with tamoxifen alone, but fell by several-fold in those that received buserelin, either alone or in combination with tamoxifen.
COMMENT by william b. ershler, MD
The treatment of metastatic breast cancer remains a challenge, particularly in premenopausal patients. Once the standard of care, ovariectomy has been replaced by tamoxifen because clinical trials have indicated comparable responses.1 However, responses have been of relatively short duration and the majority of patients succumb to progressive disease. Patients treated with tamoxifen have been shown to have increased estradiol levels in their blood and this may reduce the effectiveness of the drug with regard to inhibition of breast cancer cell proliferation. As a single agent, buserelin has been shown previously to be comparable to tamoxifen and to ovariectomy in the treatment of metastatic breast cancer. As an LHRH agonist, it is known to inhibit estradiol synthesis. Thus, the combined hormonal approach makes sense.
Oftentimes, things that make such sense theoretically don’t translate in the clinical sphere. Gratifyingly, however, this is not the case with the combined hormonal approach. Not only did the addition of buserelin impede the estradiol surge in tamoxifen-treated patients, but the combination also was shown to enhance the response rate, progression-free, and overall survival in patients with advanced disease. This may well immediately translate into clinical practice.
However, several questions remain. Does it make sense to use combined hormonal ablation in adjuvant setting, particularly for premenopausal patients with ER-positive tumors? To what extent will combined hormonal therapy influence subsequent or concurrent chemotherapy responses? Will the addition of an aromatase inhibitor further lower estradiol levels and result in even greater clinical outcomes? These questions can only be answered by future clinical investigation.
References
1. Ingle JN, et al. J Clin Oncol 1986;4:178-185.
2. Santen RJ, et al. Endocr Rev 1990;11:221-265.
3. Osborne CK. N Engl J Med 1998;339:1609-1618.
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