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Treatment of breast cancer with different antiprogestins: preclinical and clinical studies
G H Bakker1, B Setyono-Han, H Portengen
1Division of Endocrine Oncology, Biochemistry and Endocrinology, Dr Daniel Den Hoed Cancer Center, Rotterdam, The Netherlands.
Unlabelled:
Treatment with antiprogestins is a new treatment modality for breast cancer. Previously, in rats with DMBA-induced mammary tumors we observed significant growth inhibitory effects of chronic treatment with the antiprogestin mifepristone (RU486). In addition, in 11 postmenopausal breast cancer patients, we observed one objective response, six instances of short-term stable disease, and four instances of progressive disease. Side-effects appeared mainly due to antiglucocorticoid properties of the drug. Increased plasma estradiol levels were observed which probably resulted from ovarian (rat) and adrenal (patients) steroidogenesis. Combined treatment with an antiestrogen in the rat model caused additive growth inhibitory effects. Tumor inhibition after single treatment with mifepristone or tamoxifen was 90 and 75%, respectively. In contrast, when combined, tumor remission similar to that caused by LHRH-agonist treatment (50%) was observed. Even higher tumor remission was found after combined treatment with mifepristone plus LHRH-agonist (75%). In first studies in the rat model we observed significant tumor growth inhibitory effects with two new antiprogestins of seemingly greater potency which cause less unfavorable endocrine side-effects.
In Conclusion:
combined treatment (antiprogestin plus antiestrogen or LHRH-agonist) may be of value in endocrine therapy of breast cancer.
Insights
Antiprogestins show promise for breast cancer treatment. Combined therapies with antiestrogens or LHRH-agonists enhance tumor inhibition, suggesting value in endocrine therapy.
Area of Science:
- Endocrinology
- Oncology
- Pharmacology
Background:
- Antiprogestins represent a novel therapeutic approach for breast cancer.
- Mifepristone (RU486), an antiprogestin, demonstrated significant mammary tumor growth inhibition in a rat model.
- Initial patient studies with mifepristone showed mixed responses and side effects related to antiglucocorticoid properties.
Purpose of the Study:
- To evaluate the efficacy of antiprogestins, alone and in combination, for breast cancer treatment.
- To investigate the potential of combining antiprogestins with antiestrogens or LHRH-agonists.
- To explore novel antiprogestins with improved potency and reduced side effects.
Main Methods:
- DMBA-induced mammary tumor model in rats.
- Clinical evaluation in postmenopausal breast cancer patients.
- Assessment of tumor growth inhibition and remission rates.
- Monitoring of endocrine side effects and hormonal level changes.
Main Results:
- Mifepristone monotherapy showed significant tumor inhibition (90%) in rats and limited efficacy in patients.
- Combined treatment with mifepristone and tamoxifen (antiestrogen) resulted in additive tumor inhibition.
- Combination therapy with mifepristone and LHRH-agonist achieved substantial tumor remission (50-75%).
- Newer antiprogestins demonstrated potent tumor growth inhibition with fewer adverse endocrine effects in rats.
Conclusions:
- Combined antiprogestin therapy with antiestrogens or LHRH-agonists holds potential for breast cancer endocrine treatment.
- Novel antiprogestins warrant further investigation due to enhanced efficacy and improved side-effect profiles.