Steroid profile in patients with breast cancer and in mice treated with mifepristone

Autores
Elia, Andres Maximiliano; Saldain, Leo; Lovisi, Silvia; Martínez Vazquez, Paula; Burruchaga, Javier; Lamb, Caroline Ana; Luthy, Isabel Alicia; Diez, Federico; Homer, Natalie Z.; Andrew, Ruth; Rojas, Paola Andrea; Lanari, Claudia Lee Malvina
Año de publicación
2024
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Progesterone receptors (PRs) are biomarkers used as prognostic and predictive factors in breast cancer, but they are still not used as therapeutic targets. We have proposed that the ratio between PR isoforms A and B (PRA and PRB) predicts antiprogestin responsiveness. The MIPRA trial confirmed the benefit of 200 mg mifepristone, administered to patients with tumors with a high PRA/PRB ratio, but dose-ranging has not been conducted. The aim of this study was to establish the plasma mifepristone levels of patients from the MIPRA trial, along with the resultant steroid profiles, and compare these with those observed in mifepristone-treated mice using therapeutic schemes able to induce the regression of experimental mammary carcinomas with high PRA/PRB ratios: 6 mg pellets implanted subcutaneously, or daily doses of 12 mg/kg body weight. The plasma levels of mifepristone and other 19 plasma steroids were measured by liquid chromatography–tandem mass spectometry. In mifepristone-treated mice, plasma levels were lower than those registered in mifepristone-treated patients (i.e. day 7 after treatment initiation, pellet-treated mice: 8.4 ± 3.9 ng/mL; mifepristone-treated patients: 300.3 ± 31.7 ng/mL (mean ± s.d.; P < 0.001)). The increase in corticoid related steroids observed in patients was not observed in mifepristone-treated mice. The increase in progesterone levels was the most significant side effect detected in mifepristone-treated mice after 14 or 21 days of treatment, probably due to an ovarian compensatory effect not observed in postmenopausal patients. We conclude that in future clinical trials using mifepristone, the possibility of lowering the standard daily dose of 200 mg should be considered.
Fil: Elia, Andres Maximiliano. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina
Fil: Saldain, Leo. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina
Fil: Lovisi, Silvia. Gobierno de la Provincia de Buenos Aires. Hospital Zonal General de Agudos Magdalena Villegas de Martinez.; Argentina
Fil: Martínez Vazquez, Paula. Gobierno de la Provincia de Buenos Aires. Hospital Zonal General de Agudos Magdalena Villegas de Martinez.; Argentina
Fil: Burruchaga, Javier. Gobierno de la Provincia de Buenos Aires. Hospital Zonal General de Agudos Magdalena Villegas de Martinez.; Argentina
Fil: Lamb, Caroline Ana. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina
Fil: Luthy, Isabel Alicia. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina
Fil: Diez, Federico. University of Edinburgh; Reino Unido
Fil: Homer, Natalie Z.. University of Edinburgh; Reino Unido
Fil: Andrew, Ruth. University of Edinburgh; Reino Unido
Fil: Rojas, Paola Andrea. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina
Fil: Lanari, Claudia Lee Malvina. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina
Materia
MIFEPRISTONE
PROGESTERONE RECEPTORS ISOFORMS
BREAST CANCER TREATMENT
WINDOW OPPORTUNITY TRIAL
STERPOIDO HORMONE LEVELS
PLASMA
MICE
ANTIPROGESTINS
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/233063
Acceder
id CONICETDig_8825f5af7317ddfa02309061dc258004
oai_identifier_str oai:ri.conicet.gov.ar:11336/233063
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Steroid profile in patients with breast cancer and in mice treated with mifepristoneElia, Andres MaximilianoSaldain, LeoLovisi, SilviaMartínez Vazquez, PaulaBurruchaga, JavierLamb, Caroline AnaLuthy, Isabel AliciaDiez, FedericoHomer, Natalie Z.Andrew, RuthRojas, Paola AndreaLanari, Claudia Lee MalvinaMIFEPRISTONEPROGESTERONE RECEPTORS ISOFORMSBREAST CANCER TREATMENTWINDOW OPPORTUNITY TRIALSTERPOIDO HORMONE LEVELSPLASMAMICEANTIPROGESTINShttps://purl.org/becyt/ford/3.2https://purl.org/becyt/ford/3Progesterone receptors (PRs) are biomarkers used as prognostic and predictive factors in breast cancer, but they are still not used as therapeutic targets. We have proposed that the ratio between PR isoforms A and B (PRA and PRB) predicts antiprogestin responsiveness. The MIPRA trial confirmed the benefit of 200 mg mifepristone, administered to patients with tumors with a high PRA/PRB ratio, but dose-ranging has not been conducted. The aim of this study was to establish the plasma mifepristone levels of patients from the MIPRA trial, along with the resultant steroid profiles, and compare these with those observed in mifepristone-treated mice using therapeutic schemes able to induce the regression of experimental mammary carcinomas with high PRA/PRB ratios: 6 mg pellets implanted subcutaneously, or daily doses of 12 mg/kg body weight. The plasma levels of mifepristone and other 19 plasma steroids were measured by liquid chromatography–tandem mass spectometry. In mifepristone-treated mice, plasma levels were lower than those registered in mifepristone-treated patients (i.e. day 7 after treatment initiation, pellet-treated mice: 8.4 ± 3.9 ng/mL; mifepristone-treated patients: 300.3 ± 31.7 ng/mL (mean ± s.d.; P < 0.001)). The increase in corticoid related steroids observed in patients was not observed in mifepristone-treated mice. The increase in progesterone levels was the most significant side effect detected in mifepristone-treated mice after 14 or 21 days of treatment, probably due to an ovarian compensatory effect not observed in postmenopausal patients. We conclude that in future clinical trials using mifepristone, the possibility of lowering the standard daily dose of 200 mg should be considered.Fil: Elia, Andres Maximiliano. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Saldain, Leo. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Lovisi, Silvia. Gobierno de la Provincia de Buenos Aires. Hospital Zonal General de Agudos Magdalena Villegas de Martinez.; ArgentinaFil: Martínez Vazquez, Paula. Gobierno de la Provincia de Buenos Aires. Hospital Zonal General de Agudos Magdalena Villegas de Martinez.; ArgentinaFil: Burruchaga, Javier. Gobierno de la Provincia de Buenos Aires. Hospital Zonal General de Agudos Magdalena Villegas de Martinez.; ArgentinaFil: Lamb, Caroline Ana. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Luthy, Isabel Alicia. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Diez, Federico. University of Edinburgh; Reino UnidoFil: Homer, Natalie Z.. University of Edinburgh; Reino UnidoFil: Andrew, Ruth. University of Edinburgh; Reino UnidoFil: Rojas, Paola Andrea. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaFil: Lanari, Claudia Lee Malvina. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; ArgentinaBioScientifica2024-02info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/233063Elia, Andres Maximiliano; Saldain, Leo; Lovisi, Silvia; Martínez Vazquez, Paula; Burruchaga, Javier; et al.; Steroid profile in patients with breast cancer and in mice treated with mifepristone; BioScientifica; Endocrine - Related Cancer; 31; 2; e230238; 2-2024; 1-111351-00881479-6821CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/https://erc.bioscientifica.com/view/journals/erc/31/2/ERC-23-0238.xmlinfo:eu-repo/semantics/altIdentifier/doi/10.1530/ERC-23-0238info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-03T10:07:59Zoai:ri.conicet.gov.ar:11336/233063instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982025-09-03 10:07:59.892CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Steroid profile in patients with breast cancer and in mice treated with mifepristone
title Steroid profile in patients with breast cancer and in mice treated with mifepristone
spellingShingle Steroid profile in patients with breast cancer and in mice treated with mifepristone
Elia, Andres Maximiliano
MIFEPRISTONE
PROGESTERONE RECEPTORS ISOFORMS
BREAST CANCER TREATMENT
WINDOW OPPORTUNITY TRIAL
STERPOIDO HORMONE LEVELS
PLASMA
MICE
ANTIPROGESTINS
title_short Steroid profile in patients with breast cancer and in mice treated with mifepristone
title_full Steroid profile in patients with breast cancer and in mice treated with mifepristone
title_fullStr Steroid profile in patients with breast cancer and in mice treated with mifepristone
title_full_unstemmed Steroid profile in patients with breast cancer and in mice treated with mifepristone
title_sort Steroid profile in patients with breast cancer and in mice treated with mifepristone
dc.creator.none.fl_str_mv Elia, Andres Maximiliano
Saldain, Leo
Lovisi, Silvia
Martínez Vazquez, Paula
Burruchaga, Javier
Lamb, Caroline Ana
Luthy, Isabel Alicia
Diez, Federico
Homer, Natalie Z.
Andrew, Ruth
Rojas, Paola Andrea
Lanari, Claudia Lee Malvina
author Elia, Andres Maximiliano
author_facet Elia, Andres Maximiliano
Saldain, Leo
Lovisi, Silvia
Martínez Vazquez, Paula
Burruchaga, Javier
Lamb, Caroline Ana
Luthy, Isabel Alicia
Diez, Federico
Homer, Natalie Z.
Andrew, Ruth
Rojas, Paola Andrea
Lanari, Claudia Lee Malvina
author_role author
author2 Saldain, Leo
Lovisi, Silvia
Martínez Vazquez, Paula
Burruchaga, Javier
Lamb, Caroline Ana
Luthy, Isabel Alicia
Diez, Federico
Homer, Natalie Z.
Andrew, Ruth
Rojas, Paola Andrea
Lanari, Claudia Lee Malvina
author2_role author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv MIFEPRISTONE
PROGESTERONE RECEPTORS ISOFORMS
BREAST CANCER TREATMENT
WINDOW OPPORTUNITY TRIAL
STERPOIDO HORMONE LEVELS
PLASMA
MICE
ANTIPROGESTINS
topic MIFEPRISTONE
PROGESTERONE RECEPTORS ISOFORMS
BREAST CANCER TREATMENT
WINDOW OPPORTUNITY TRIAL
STERPOIDO HORMONE LEVELS
PLASMA
MICE
ANTIPROGESTINS
purl_subject.fl_str_mv https://purl.org/becyt/ford/3.2
https://purl.org/becyt/ford/3
dc.description.none.fl_txt_mv Progesterone receptors (PRs) are biomarkers used as prognostic and predictive factors in breast cancer, but they are still not used as therapeutic targets. We have proposed that the ratio between PR isoforms A and B (PRA and PRB) predicts antiprogestin responsiveness. The MIPRA trial confirmed the benefit of 200 mg mifepristone, administered to patients with tumors with a high PRA/PRB ratio, but dose-ranging has not been conducted. The aim of this study was to establish the plasma mifepristone levels of patients from the MIPRA trial, along with the resultant steroid profiles, and compare these with those observed in mifepristone-treated mice using therapeutic schemes able to induce the regression of experimental mammary carcinomas with high PRA/PRB ratios: 6 mg pellets implanted subcutaneously, or daily doses of 12 mg/kg body weight. The plasma levels of mifepristone and other 19 plasma steroids were measured by liquid chromatography–tandem mass spectometry. In mifepristone-treated mice, plasma levels were lower than those registered in mifepristone-treated patients (i.e. day 7 after treatment initiation, pellet-treated mice: 8.4 ± 3.9 ng/mL; mifepristone-treated patients: 300.3 ± 31.7 ng/mL (mean ± s.d.; P < 0.001)). The increase in corticoid related steroids observed in patients was not observed in mifepristone-treated mice. The increase in progesterone levels was the most significant side effect detected in mifepristone-treated mice after 14 or 21 days of treatment, probably due to an ovarian compensatory effect not observed in postmenopausal patients. We conclude that in future clinical trials using mifepristone, the possibility of lowering the standard daily dose of 200 mg should be considered.
Fil: Elia, Andres Maximiliano. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina
Fil: Saldain, Leo. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina
Fil: Lovisi, Silvia. Gobierno de la Provincia de Buenos Aires. Hospital Zonal General de Agudos Magdalena Villegas de Martinez.; Argentina
Fil: Martínez Vazquez, Paula. Gobierno de la Provincia de Buenos Aires. Hospital Zonal General de Agudos Magdalena Villegas de Martinez.; Argentina
Fil: Burruchaga, Javier. Gobierno de la Provincia de Buenos Aires. Hospital Zonal General de Agudos Magdalena Villegas de Martinez.; Argentina
Fil: Lamb, Caroline Ana. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina
Fil: Luthy, Isabel Alicia. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina
Fil: Diez, Federico. University of Edinburgh; Reino Unido
Fil: Homer, Natalie Z.. University of Edinburgh; Reino Unido
Fil: Andrew, Ruth. University of Edinburgh; Reino Unido
Fil: Rojas, Paola Andrea. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina
Fil: Lanari, Claudia Lee Malvina. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina
description Progesterone receptors (PRs) are biomarkers used as prognostic and predictive factors in breast cancer, but they are still not used as therapeutic targets. We have proposed that the ratio between PR isoforms A and B (PRA and PRB) predicts antiprogestin responsiveness. The MIPRA trial confirmed the benefit of 200 mg mifepristone, administered to patients with tumors with a high PRA/PRB ratio, but dose-ranging has not been conducted. The aim of this study was to establish the plasma mifepristone levels of patients from the MIPRA trial, along with the resultant steroid profiles, and compare these with those observed in mifepristone-treated mice using therapeutic schemes able to induce the regression of experimental mammary carcinomas with high PRA/PRB ratios: 6 mg pellets implanted subcutaneously, or daily doses of 12 mg/kg body weight. The plasma levels of mifepristone and other 19 plasma steroids were measured by liquid chromatography–tandem mass spectometry. In mifepristone-treated mice, plasma levels were lower than those registered in mifepristone-treated patients (i.e. day 7 after treatment initiation, pellet-treated mice: 8.4 ± 3.9 ng/mL; mifepristone-treated patients: 300.3 ± 31.7 ng/mL (mean ± s.d.; P < 0.001)). The increase in corticoid related steroids observed in patients was not observed in mifepristone-treated mice. The increase in progesterone levels was the most significant side effect detected in mifepristone-treated mice after 14 or 21 days of treatment, probably due to an ovarian compensatory effect not observed in postmenopausal patients. We conclude that in future clinical trials using mifepristone, the possibility of lowering the standard daily dose of 200 mg should be considered.
publishDate 2024
dc.date.none.fl_str_mv 2024-02
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
http://purl.org/coar/resource_type/c_6501
info:ar-repo/semantics/articulo
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/11336/233063
Elia, Andres Maximiliano; Saldain, Leo; Lovisi, Silvia; Martínez Vazquez, Paula; Burruchaga, Javier; et al.; Steroid profile in patients with breast cancer and in mice treated with mifepristone; BioScientifica; Endocrine - Related Cancer; 31; 2; e230238; 2-2024; 1-11
1351-0088
1479-6821
CONICET Digital
CONICET
url http://hdl.handle.net/11336/233063
identifier_str_mv Elia, Andres Maximiliano; Saldain, Leo; Lovisi, Silvia; Martínez Vazquez, Paula; Burruchaga, Javier; et al.; Steroid profile in patients with breast cancer and in mice treated with mifepristone; BioScientifica; Endocrine - Related Cancer; 31; 2; e230238; 2-2024; 1-11
1351-0088
1479-6821
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
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info:eu-repo/semantics/altIdentifier/doi/10.1530/ERC-23-0238
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
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eu_rights_str_mv openAccess
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application/pdf
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publisher.none.fl_str_mv BioScientifica
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reponame_str CONICET Digital (CONICET)
collection CONICET Digital (CONICET)
instname_str Consejo Nacional de Investigaciones Científicas y Técnicas
repository.name.fl_str_mv CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas
repository.mail.fl_str_mv dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar
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