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Peer-reviewedCC BY-NC-ND 4.0Breast Cancer Research : BCR

Molecular and clinical predictors of NAC response and relapse in HR+/HER2− early breast cancer

  • M. Rosario Chica-Parrado1
  • Juan Luis Onieva2
  • Nuria Ribelles1,3,4
  • Ana Godoy1,3,4
  • Javier Pascual1,3,4,2,5
  • Álvaro González-Ortiz1,3
  • Alicia Garrido-Aranda2,5
  • Rocío Lavado1,3,4,2,5
  • Martina Alvarez-Perez1,3,4,6,5
  • Iñaki Comino-Mendez1,4
  • Isabel Barragan3,7,8
  • Emilio Alba1,3,4,6,2
8 affiliations
  1. 1B-01, IBIMA Plataforma BIONAND, Instituto de Investigación Biomédica de Málaga, 29590 Malaga, Spain
  2. 2CITAC-Centro de Investigación y Terapias Avanzadas del Cáncer, 29010 Málaga, Spain
  3. 3Medical Oncology Department, Hospital Universitario Virgen de la Victoria, Malaga, Spain
  4. 4Centro de Investigación Biomédica en Red de Cancer (CIBERONC - CB16, 12/00481), 28029 Madrid, Spain
  5. 5LBMC-Laboratorio de Biología Molecular del Cancer, Málaga, Spain
  6. 6Faculty of Medicine, University of Málaga, 29010 Málaga, Spain
  7. 7Medical Oncology Unit of Virgen de la Victoria Hospital, Group of Translational Research in Cancer Immunotherapy and Epigenetics (B-05), IBIMA Plataforma BIONAND, Instituto de Investigación Biomédica de Málaga, Málaga, Spain
  8. 8Precision Cancer Medicine in Lung Cancer-Preclinical, Translational & Clinical Research-Simon Ekman’s Research Group, Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden
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Abstract

Neoadjuvant chemotherapy (NAC) is the standard of care for aggressive early-stage and locally advanced hormone receptor-positive, HER2-negative (HR+/HER2−) breast cancer (BC). However, this subtype exhibits a high rate of treatment resistance, necessitating improved predictive tools for response assessment. In this study, we developed predictive models for pathological complete response (pCR) and distant relapse (DR) by integrating clinicopathological features with gene expression data from a retrospective cohort of 44 HR+ /HER2− BC patients treated with anthracycline- and taxane-based NAC. The model combining molecular and clinical variables achieved an AUC of 0.86 in both the discovery and validation cohorts, suggesting promising discriminatory performance for pCR prediction. For DR prediction, seven genes were differentially expressed between relapsed and non-relapsed patients. A combined model incorporating clinical variables and molecular features, including COL2A1 and MAPK8IP1 expression, achieved an AUC of 0.73 in residual disease samples. Notably, COL2A1 overexpression correlated with improved distant relapse-free and overall survival in external datasets. Longitudinal transcriptional analysis of matched primary, residual, and metastatic samples identified immune pathway activation in NAC-resistant tumors, contrasting with cell cycle pathway inhibition. Tumor progression to metastasis was associated with upregulation of TFEB, CD3E, and TNFRSF9, while metastatic samples exhibited increased cell cycle-related signaling and FAK pathway inhibition. Our findings support the potential value of integrating clinical and molecular features to improve response stratification in HR+/HER2− BC patients treated with NAC.

Supplementary Information: The online version contains supplementary material available at https://doi.org/10.1186/s13058-026-02365-x.

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Cite

BibTeXRIS
BibTeX
@article{chicaparrado2026molecular,
  title = {{Molecular and clinical predictors of NAC response and relapse in HR+/HER2− early breast cancer}},
  author = {M. Rosario Chica-Parrado and Juan Luis Onieva and Nuria Ribelles and Ana Godoy and Javier Pascual and Álvaro González-Ortiz and Alicia Garrido-Aranda and Rocío Lavado and Martina Alvarez-Perez and Iñaki Comino-Mendez and Isabel Barragan and Emilio Alba},
  journal = {Breast Cancer Research : BCR},
  year = {2026},
  month = aug,
  doi = {10.1186/s13058-026-02365-x},
  url = {https://doi.org/10.1186/s13058-026-02365-x},
  note = {CC BY-NC-ND 4.0},
}
RIS
TY  - JOUR
TI  - Molecular and clinical predictors of NAC response and relapse in HR+/HER2− early breast cancer
AU  - M. Rosario Chica-Parrado
AU  - Juan Luis Onieva
AU  - Nuria Ribelles
AU  - Ana Godoy
AU  - Javier Pascual
AU  - Álvaro González-Ortiz
AU  - Alicia Garrido-Aranda
AU  - Rocío Lavado
AU  - Martina Alvarez-Perez
AU  - Iñaki Comino-Mendez
AU  - Isabel Barragan
AU  - Emilio Alba
PY  - 2026
DA  - 2026/08/12
JO  - Breast Cancer Research : BCR
DO  - 10.1186/s13058-026-02365-x
UR  - https://doi.org/10.1186/s13058-026-02365-x
AB  - Neoadjuvant chemotherapy (NAC) is the standard of care for aggressive early-stage and locally advanced hormone receptor-positive, HER2-negative (HR+/HER2−) breast cancer (BC). However, this subtype exhibits a high rate of treatment resistance, necessitating improved predictive tools for response assessment. In this study, we developed predictive models for pathological complete response (pCR) and distant relapse (DR) by integrating clinicopathological features with gene expression data from a retrospective cohort of 44 HR+ /HER2− BC patients treated with anthracycline- and taxane-based NAC. The model combining molecular and clinical variables achieved an AUC of 0.86 in both the discovery and validation cohorts, suggesting promising discriminatory performance for pCR prediction. For DR prediction, seven genes were differentially expressed between relapsed and non-relapsed patients. A combined model incorporating clinical variables and molecular features, including COL2A1 and MAPK8IP1 expression, achieved an AUC of 0.73 in residual disease samples. Notably, COL2A1 overexpression correlated with improved distant relapse-free and overall survival in external datasets. Longitudinal transcriptional analysis of matched primary, residual, and metastatic samples identified immune pathway activation in NAC-resistant tumors, contrasting with cell cycle pathway inhibition. Tumor progression to metastasis was associated with upregulation of TFEB, CD3E, and TNFRSF9, while metastatic samples exhibited increased cell cycle-related signaling and FAK pathway inhibition. Our findings support the potential value of integrating clinical and molecular features to improve response stratification in HR+/HER2− BC patients treated with NAC.  Supplementary Information: The online version contains supplementary material available at https://doi.org/10.1186/s13058-026-02365-x.
SN  - 1465-5411
SN  - 1465-542X
ER  -