Efect of chemotherapy timing in triple‐negative breast cancer: a real‐world evidence study

Purpose: Triple-negative breast cancer (TNBC) is an aggressive, heterogeneous malignancy with poor prognosis. The optimal timing of chemotherapy-neoadjuvant (NACT) versus adjuvant (ACT)-remains controversial. This study assessed real-world outcomes in non-metastatic TNBC patients according to chemot...

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Autores:
Rodríguez Jaramillo, Carlos Andrés
Zapata Muñoz, Maycos Leandro
González Ramírez, Diego Mauricio
Graciano, Noiver
López, Lucelly
Montoya, Katherine
Gómez, Luis Rodolfo
Cortés, Javier
Tipo de recurso:
Article of investigation
Fecha de publicación:
2025
Institución:
Universidad de Antioquia
Repositorio:
Repositorio UdeA
Idioma:
eng
OAI Identifier:
oai:bibliotecadigital.udea.edu.co:10495/46272
Acceso en línea:
https://hdl.handle.net/10495/46272
Palabra clave:
Quimioterapia
Antineoplastic Combined Chemotherapy Protocols
Protocolos de Quimioterapia Combinada Antineoplásica
Chemotherapy
Quimioterapia
Neoadjuvant Therapy
Terapia Neoadyuvante
Neoplasm Staging
Estadificación de Neoplasias
Prognosis
Pronóstico
Retrospective Studies
Estudios Retrospectivos
Time Factors
Factores de Tiempo
Triple Negative Breast Neoplasms
Neoplasias de la Mama Triple Negativas
https://id.nlm.nih.gov/mesh/D000971
https://id.nlm.nih.gov/mesh/D004358
https://id.nlm.nih.gov/mesh/D020360
https://id.nlm.nih.gov/mesh/D009367
https://id.nlm.nih.gov/mesh/D011379
https://id.nlm.nih.gov/mesh/D012189
https://id.nlm.nih.gov/mesh/D013997
https://id.nlm.nih.gov/mesh/D064726
ODS 3: Salud y bienestar. Garantizar una vida sana y promover el bienestar de todos a todas las edades
Rights
openAccess
License
http://creativecommons.org/licenses/by/4.0/
id UDEA2_7c98d517340fa9f8f3cf9ba08f34acdf
oai_identifier_str oai:bibliotecadigital.udea.edu.co:10495/46272
network_acronym_str UDEA2
network_name_str Repositorio UdeA
repository_id_str
dc.title.eng.fl_str_mv Efect of chemotherapy timing in triple‐negative breast cancer: a real‐world evidence study
title Efect of chemotherapy timing in triple‐negative breast cancer: a real‐world evidence study
spellingShingle Efect of chemotherapy timing in triple‐negative breast cancer: a real‐world evidence study
Quimioterapia
Antineoplastic Combined Chemotherapy Protocols
Protocolos de Quimioterapia Combinada Antineoplásica
Chemotherapy
Quimioterapia
Neoadjuvant Therapy
Terapia Neoadyuvante
Neoplasm Staging
Estadificación de Neoplasias
Prognosis
Pronóstico
Retrospective Studies
Estudios Retrospectivos
Time Factors
Factores de Tiempo
Triple Negative Breast Neoplasms
Neoplasias de la Mama Triple Negativas
https://id.nlm.nih.gov/mesh/D000971
https://id.nlm.nih.gov/mesh/D004358
https://id.nlm.nih.gov/mesh/D020360
https://id.nlm.nih.gov/mesh/D009367
https://id.nlm.nih.gov/mesh/D011379
https://id.nlm.nih.gov/mesh/D012189
https://id.nlm.nih.gov/mesh/D013997
https://id.nlm.nih.gov/mesh/D064726
ODS 3: Salud y bienestar. Garantizar una vida sana y promover el bienestar de todos a todas las edades
title_short Efect of chemotherapy timing in triple‐negative breast cancer: a real‐world evidence study
title_full Efect of chemotherapy timing in triple‐negative breast cancer: a real‐world evidence study
title_fullStr Efect of chemotherapy timing in triple‐negative breast cancer: a real‐world evidence study
title_full_unstemmed Efect of chemotherapy timing in triple‐negative breast cancer: a real‐world evidence study
title_sort Efect of chemotherapy timing in triple‐negative breast cancer: a real‐world evidence study
dc.creator.fl_str_mv Rodríguez Jaramillo, Carlos Andrés
Zapata Muñoz, Maycos Leandro
González Ramírez, Diego Mauricio
Graciano, Noiver
López, Lucelly
Montoya, Katherine
Gómez, Luis Rodolfo
Cortés, Javier
dc.contributor.author.none.fl_str_mv Rodríguez Jaramillo, Carlos Andrés
Zapata Muñoz, Maycos Leandro
González Ramírez, Diego Mauricio
Graciano, Noiver
López, Lucelly
Montoya, Katherine
Gómez, Luis Rodolfo
Cortés, Javier
dc.contributor.researchgroup.none.fl_str_mv Grupo de Investigación en Farmacología y Toxicología
dc.subject.mesh.none.fl_str_mv Quimioterapia
topic Quimioterapia
Antineoplastic Combined Chemotherapy Protocols
Protocolos de Quimioterapia Combinada Antineoplásica
Chemotherapy
Quimioterapia
Neoadjuvant Therapy
Terapia Neoadyuvante
Neoplasm Staging
Estadificación de Neoplasias
Prognosis
Pronóstico
Retrospective Studies
Estudios Retrospectivos
Time Factors
Factores de Tiempo
Triple Negative Breast Neoplasms
Neoplasias de la Mama Triple Negativas
https://id.nlm.nih.gov/mesh/D000971
https://id.nlm.nih.gov/mesh/D004358
https://id.nlm.nih.gov/mesh/D020360
https://id.nlm.nih.gov/mesh/D009367
https://id.nlm.nih.gov/mesh/D011379
https://id.nlm.nih.gov/mesh/D012189
https://id.nlm.nih.gov/mesh/D013997
https://id.nlm.nih.gov/mesh/D064726
ODS 3: Salud y bienestar. Garantizar una vida sana y promover el bienestar de todos a todas las edades
dc.subject.decs.none.fl_str_mv Antineoplastic Combined Chemotherapy Protocols
Protocolos de Quimioterapia Combinada Antineoplásica
Chemotherapy
Quimioterapia
Neoadjuvant Therapy
Terapia Neoadyuvante
Neoplasm Staging
Estadificación de Neoplasias
Prognosis
Pronóstico
Retrospective Studies
Estudios Retrospectivos
Time Factors
Factores de Tiempo
Triple Negative Breast Neoplasms
Neoplasias de la Mama Triple Negativas
dc.subject.meshuri.none.fl_str_mv https://id.nlm.nih.gov/mesh/D000971
https://id.nlm.nih.gov/mesh/D004358
https://id.nlm.nih.gov/mesh/D020360
https://id.nlm.nih.gov/mesh/D009367
https://id.nlm.nih.gov/mesh/D011379
https://id.nlm.nih.gov/mesh/D012189
https://id.nlm.nih.gov/mesh/D013997
https://id.nlm.nih.gov/mesh/D064726
dc.subject.ods.none.fl_str_mv ODS 3: Salud y bienestar. Garantizar una vida sana y promover el bienestar de todos a todas las edades
description Purpose: Triple-negative breast cancer (TNBC) is an aggressive, heterogeneous malignancy with poor prognosis. The optimal timing of chemotherapy-neoadjuvant (NACT) versus adjuvant (ACT)-remains controversial. This study assessed real-world outcomes in non-metastatic TNBC patients according to chemotherapy timing. Methods: This retrospective study (2008-2023) evaluated the impact of chemotherapy timing on overall survival (OS) and event-free survival (EFS) in a cohort of 711 patients. Propensity score (PS) matching with preoperative variables was used to adjust for baseline imbalances, and Cox regression models were applied to account for treatment-related variables. Results: NACT was administered to 525 patients (73.8%), with a 37.3% pathological complete response (pCR) rate. PS matching yielded 177 patient pairs; tumor stage, age and histologic grade remained unbalanced. In the unadjusted analysis, NACT was associated with worse OS (HR 1.56, 95% CI1.08-2.25, p = 0.018). However, multivariate analysis adjusting for unmatched and postoperative variables showed a potential benefit of NACT for OS (HR 0.53, 95% CI 0.07-4.13, p = 0.545) and EFS (HR 0.94, 95% CI 0.21-4.17, p = 0.932). Tumor stage acted as an effect modifier, and stratified analyses revealed that NACT was superior to ACT in patients with advanced-stage disease who achieved pCR (HR 0.22, 95% CI 0.07-0.7, p < 0.010). Conclusions: In our TNBC cohort, chemotherapy timing significantly influenced OS and EFS, particularly in relation to initial tumor stage and pCR status. NACT was more beneficial than ACT in patients with advanced disease who achieve pCR, underscoring its role in both prognostic stratification and therapeutic decision-making.
publishDate 2025
dc.date.accessioned.none.fl_str_mv 2025-06-06T22:53:26Z
dc.date.issued.none.fl_str_mv 2025-07
dc.type.none.fl_str_mv Artículo de investigación
dc.type.coar.none.fl_str_mv http://purl.org/coar/resource_type/c_2df8fbb1
dc.type.redcol.none.fl_str_mv http://purl.org/redcol/resource_type/ART
dc.type.content.none.fl_str_mv Text
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dc.type.driver.none.fl_str_mv info:eu-repo/semantics/article
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dc.identifier.citation.none.fl_str_mv Graciano N, López L, Rodriguez CA, Montoya K, González DM, Gómez LR, Zapata ML, Cortés J. Effect of chemotherapy timing in triple-negative breast cancer: a real-world evidence study. Breast Cancer Res Treat. 2025 Jul;212(2):225-236. doi: 10.1007/s10549-025-07716-4.
dc.identifier.issn.none.fl_str_mv 0167-6806
dc.identifier.uri.none.fl_str_mv https://hdl.handle.net/10495/46272
dc.identifier.eissn.none.fl_str_mv 1573-7217
dc.identifier.pmid.none.fl_str_mv 40399665
identifier_str_mv Graciano N, López L, Rodriguez CA, Montoya K, González DM, Gómez LR, Zapata ML, Cortés J. Effect of chemotherapy timing in triple-negative breast cancer: a real-world evidence study. Breast Cancer Res Treat. 2025 Jul;212(2):225-236. doi: 10.1007/s10549-025-07716-4.
0167-6806
1573-7217
40399665
url https://hdl.handle.net/10495/46272
dc.language.iso.none.fl_str_mv eng
language eng
dc.relation.ispartofjournalabbrev.none.fl_str_mv Breast. Cancer. Res. Treat.
dc.relation.citationedition.none.fl_str_mv 12 páginas
dc.relation.citationendpage.none.fl_str_mv 236
dc.relation.citationissue.none.fl_str_mv 2
dc.relation.citationstartpage.none.fl_str_mv 225
dc.relation.citationvolume.none.fl_str_mv 212
dc.relation.ispartofjournal.none.fl_str_mv Breast Cancer Research and Treatment
dc.rights.uri.none.fl_str_mv http://creativecommons.org/licenses/by/4.0/
dc.rights.accessrights.none.fl_str_mv info:eu-repo/semantics/openAccess
dc.rights.license.en.fl_str_mv Attribution 4.0 International
dc.rights.coar.none.fl_str_mv http://purl.org/coar/access_right/c_abf2
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dc.format.extent.none.fl_str_mv 12 páginas
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dc.publisher.none.fl_str_mv Springer
dc.publisher.place.none.fl_str_mv Dordrecht, Países Bajos
publisher.none.fl_str_mv Springer
institution Universidad de Antioquia
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spelling Rodríguez Jaramillo, Carlos AndrésZapata Muñoz, Maycos LeandroGonzález Ramírez, Diego MauricioGraciano, NoiverLópez, LucellyMontoya, KatherineGómez, Luis RodolfoCortés, JavierGrupo de Investigación en Farmacología y Toxicología2025-06-06T22:53:26Z2025-07Graciano N, López L, Rodriguez CA, Montoya K, González DM, Gómez LR, Zapata ML, Cortés J. Effect of chemotherapy timing in triple-negative breast cancer: a real-world evidence study. Breast Cancer Res Treat. 2025 Jul;212(2):225-236. doi: 10.1007/s10549-025-07716-4.0167-6806https://hdl.handle.net/10495/462721573-721740399665Purpose: Triple-negative breast cancer (TNBC) is an aggressive, heterogeneous malignancy with poor prognosis. The optimal timing of chemotherapy-neoadjuvant (NACT) versus adjuvant (ACT)-remains controversial. This study assessed real-world outcomes in non-metastatic TNBC patients according to chemotherapy timing. Methods: This retrospective study (2008-2023) evaluated the impact of chemotherapy timing on overall survival (OS) and event-free survival (EFS) in a cohort of 711 patients. Propensity score (PS) matching with preoperative variables was used to adjust for baseline imbalances, and Cox regression models were applied to account for treatment-related variables. Results: NACT was administered to 525 patients (73.8%), with a 37.3% pathological complete response (pCR) rate. PS matching yielded 177 patient pairs; tumor stage, age and histologic grade remained unbalanced. In the unadjusted analysis, NACT was associated with worse OS (HR 1.56, 95% CI1.08-2.25, p = 0.018). However, multivariate analysis adjusting for unmatched and postoperative variables showed a potential benefit of NACT for OS (HR 0.53, 95% CI 0.07-4.13, p = 0.545) and EFS (HR 0.94, 95% CI 0.21-4.17, p = 0.932). Tumor stage acted as an effect modifier, and stratified analyses revealed that NACT was superior to ACT in patients with advanced-stage disease who achieved pCR (HR 0.22, 95% CI 0.07-0.7, p < 0.010). Conclusions: In our TNBC cohort, chemotherapy timing significantly influenced OS and EFS, particularly in relation to initial tumor stage and pCR status. NACT was more beneficial than ACT in patients with advanced disease who achieve pCR, underscoring its role in both prognostic stratification and therapeutic decision-making.COL003990212 páginasapplication/pdfengSpringerDordrecht, Países Bajoshttp://creativecommons.org/licenses/by/4.0/info:eu-repo/semantics/openAccessAttribution 4.0 Internationalhttp://purl.org/coar/access_right/c_abf2QuimioterapiaAntineoplastic Combined Chemotherapy ProtocolsProtocolos de Quimioterapia Combinada AntineoplásicaChemotherapyQuimioterapiaNeoadjuvant TherapyTerapia NeoadyuvanteNeoplasm StagingEstadificación de NeoplasiasPrognosisPronósticoRetrospective StudiesEstudios RetrospectivosTime FactorsFactores de TiempoTriple Negative Breast NeoplasmsNeoplasias de la Mama Triple Negativashttps://id.nlm.nih.gov/mesh/D000971https://id.nlm.nih.gov/mesh/D004358https://id.nlm.nih.gov/mesh/D020360https://id.nlm.nih.gov/mesh/D009367https://id.nlm.nih.gov/mesh/D011379https://id.nlm.nih.gov/mesh/D012189https://id.nlm.nih.gov/mesh/D013997https://id.nlm.nih.gov/mesh/D064726ODS 3: Salud y bienestar. Garantizar una vida sana y promover el bienestar de todos a todas las edadesEfect of chemotherapy timing in triple‐negative breast cancer: a real‐world evidence studyArtículo de investigaciónhttp://purl.org/coar/resource_type/c_2df8fbb1http://purl.org/redcol/resource_type/ARTTexthttp://purl.org/coar/version/c_970fb48d4fbd8a85info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionBreast. Cancer. Res. 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