Mifepristone for Breast Cancer Patients With Higher Levels of Progesterone Receptor Isoform A Than Isoform B.

Summary

* Seventy per cent of breast cancers express estrogen (ER) and progesterone receptors (PR) and respond to endocrine treatment. * Actual therapy targets ER. * There is enough evidence that progestins participate regulating breast cancer growth. * Antiprogestins block cell proliferation and increase apoptosis in breast cancer models which express high levels of PRA. * Antiprogestins have been used to treat breast cancer patients that failed to other treatments; benefits were seen in selected patients. * Mifepristone (MFP) is currently used for medical abortion and for the treatment of Cushing disease. * MFP might exert agonistic effects when PRB isoform is activated by cAMP. This makes mandatory the evaluation of the PR isoform ratio in breast cancer patients in which MFP is a therapeutic possibility. Main Goal To evaluate if therapeutic doses of MFP exert beneficial effects on breast cancers expressing levels of PRA higher than those of PRB, evaluated as an inhibition in proliferation markers and/or an increase in apoptotic markers. * Eligibility * Postmenopausal women (one year after menses stop). * Women with tumors showing ratios of PRA/PRB higher than 1.5 and PR higher than 50%. * Women without previous treatment. * All clinical stages with tumors larger than 1.5 cm. * Patients without autoimmune diseases and/or asthma. * Study design * Open Interventional. * Twenty women will take MFP (200 mg) p.o. once /day during 14 days. As for preliminary studies, to reach this number the investigators will have to evaluate 80-100 patients. * Surgery is performed 14 days after treatment initiation, 24 hs after last dose. * PR isoform ratio will be evaluated by western blots (WB) in one core biopsy. Additional cores will be used for diagnosis, immunohistochemistry (IHC) of PR, Ki-67 and other markers. * At surgery samples will be frozen for molecular studies and fixed and processed for pathological evaluation. * Wilcoxon signed rank test will be used to evaluate differences in biomarker expression between core biopsy and surgical samples of each patient. * Blood will be collected before treatment initiation and prior to final surgery. * Mammographic and echographic studies will be carried out before and after treatment.

Timeline

Start

2016-04

Primary completion

2019-10-31

Completion

2019-10-31

Publications

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• Background Wargon V, Helguero LA, Bolado J, Rojas P, Novaro V, Molinolo A, Lanari C. Reversal of antiprogestin resistance and progesterone receptor isoform ratio in acquired resistant mammary carcinomas. Breast Cancer Res Treat. 2009 Aug;116(3):449-60. doi: 10.1007/s10549-008-0150-y. Epub 2008 Aug 3.
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• Background Goldhirsch A, Winer EP, Coates AS, Gelber RD, Piccart-Gebhart M, Thurlimann B, Senn HJ; Panel members. Personalizing the treatment of women with early breast cancer: highlights of the St Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer 2013. Ann Oncol. 2013 Sep;24(9):2206-23. doi: 10.1093/annonc/mdt303. Epub 2013 Aug 4.
• Elia A, Saldain L, Lovisi S, Martinez Vazquez P, Burruchaga J, Lamb CA, Luthy IA, Diez F, Homer NZM, Andrew R, Rojas P, Lanari C. Steroid profile in patients with breast cancer and in mice treated with mifepristone. Endocr Relat Cancer. 2023 Dec 13;31(2):e230238. doi: 10.1530/ERC-23-0238. Print 2024 Feb 1.
• Elia A, Saldain L, Vanzulli SI, Helguero LA, Lamb CA, Fabris V, Pataccini G, Martinez-Vazquez P, Burruchaga J, Caillet-Bois I, Spengler E, Acosta Haab G, Liguori M, Castets A, Lovisi S, Abascal MF, Novaro V, Sanchez J, Munoz J, Belizan JM, Abba MC, Gass H, Rojas P, Lanari C. Beneficial Effects of Mifepristone Treatment in Patients with Breast Cancer Selected by the Progesterone Receptor Isoform Ratio: Results from the MIPRA Trial. Clin Cancer Res. 2023 Mar 1;29(5):866-877. doi: 10.1158/1078-0432.CCR-22-2060.

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