Beyond Molecular Classification in Metastatic Triple-Negative Breast Cancer: Toward Subtype-Guided Precision Oncology

Pekarek, Leonel; García-Montero, Cielo; Casanova-Martin, Carlos; Ortega, Miguel A.; Fraile-Martínez, Óscar

doi:10.3390/ijms27115040

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Beyond Molecular Classification in Metastatic Triple-Negative Breast Cancer: Toward Subtype-Guided Precision Oncology

by

Leonel Pekarek

^1,2,†

,

Cielo García-Montero

^1,2,†

,

Carlos Casanova-Martin

^1,2,

Miguel A. Ortega

^1,2,*

and

Óscar Fraile-Martínez

^1,2

¹

Department of Medicine and Medical Specialities, Faculty of Medicine and Health Sciences, University of Alcala, 28801 Alcala de Henares, Spain

²

Ramón y Cajal Institute of Sanitary Research (IRYCIS), 28034 Madrid, Spain

^*

Author to whom correspondence should be addressed.

^†

These authors contributed equally to this work.

Int. J. Mol. Sci. 2026, 27(11), 5040; https://doi.org/10.3390/ijms27115040

Submission received: 12 April 2026 / Revised: 25 May 2026 / Accepted: 27 May 2026 / Published: 2 June 2026

(This article belongs to the Special Issue Molecular Research in Triple-Negative Breast Cancer: 2nd Edition)

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Abstract

Metastatic triple-negative breast cancer (mTNBC) remains one of the most challenging therapeutic settings in oncology. Although it has traditionally been defined by the absence of hormone receptor expression—estrogen receptor (ER) and progesterone receptor (PR)—and HER2 amplification or overexpression, this simplified definition fails to capture the biological complexity that drives its marked clinical heterogeneity, therapeutic resistance, and prognostic variability. Over the past decade, multiple studies have challenged the notion of TNBC as a single disease entity, identifying distinct molecular subtypes, including Basal-like 1 (BL1), Basal-like 2 (BL2), Mesenchymal (M), Mesenchymal Stem-like (MSL), Immunomodulatory (IM), and Luminal Androgen Receptor (LAR), each characterized by specific biological programs and therapeutic vulnerabilities. In parallel, clinically oriented systems such as the Fudan classification have enabled the prospective evaluation of subtype-guided therapeutic strategies in metastatic disease, as illustrated by the FUTURE and FUTURE-SUPER trials. In this review, we examine the molecular classification and clinical behavior of mTNBC subtypes, integrating genomic, transcriptomic, epigenetic, immunologic, stromal, and biomechanical dimensions of tumor heterogeneity. We also discuss emerging tools, including single-cell RNA sequencing, spatial transcriptomics, circulating tumor DNA analysis, long non-coding RNA profiling, and surrogate immunohistochemistry-based classifiers, as well as their potential role in refining patient stratification. From a therapeutic perspective, we review subtype-guided strategies involving chemotherapy, platinum agents, PARP inhibitors, immunotherapy, antiandrogen therapy, PI3K/AKT/mTOR pathway inhibition, antiangiogenic approaches, and antibody–drug conjugates. Redefining mTNBC through biologically driven stratification represents a rational strategy to optimize treatment selection, support clinical trial design, and accelerate the development of precision oncology approaches. However, clinical implementation requires greater methodological standardization, validated predictive biomarkers, accessible diagnostic platforms, and dynamic monitoring strategies capable of capturing subtype evolution under therapeutic pressure. TNBC should therefore not be regarded as a single disease, but as a spectrum of biologically distinct and clinically evolving entities whose integrated characterization may be essential to improving outcomes in this historically poor-prognosis population.

Keywords: triple-negative breast cancer; metastatic breast cancer; molecular subtypes; biomarkers; precision oncology; antibody–drug conjugates

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MDPI and ACS Style

Pekarek, L.; García-Montero, C.; Casanova-Martin, C.; Ortega, M.A.; Fraile-Martínez, Ó. Beyond Molecular Classification in Metastatic Triple-Negative Breast Cancer: Toward Subtype-Guided Precision Oncology. Int. J. Mol. Sci. 2026, 27, 5040. https://doi.org/10.3390/ijms27115040

AMA Style

Pekarek L, García-Montero C, Casanova-Martin C, Ortega MA, Fraile-Martínez Ó. Beyond Molecular Classification in Metastatic Triple-Negative Breast Cancer: Toward Subtype-Guided Precision Oncology. International Journal of Molecular Sciences. 2026; 27(11):5040. https://doi.org/10.3390/ijms27115040

Chicago/Turabian Style

Pekarek, Leonel, Cielo García-Montero, Carlos Casanova-Martin, Miguel A. Ortega, and Óscar Fraile-Martínez. 2026. "Beyond Molecular Classification in Metastatic Triple-Negative Breast Cancer: Toward Subtype-Guided Precision Oncology" International Journal of Molecular Sciences 27, no. 11: 5040. https://doi.org/10.3390/ijms27115040

APA Style

Pekarek, L., García-Montero, C., Casanova-Martin, C., Ortega, M. A., & Fraile-Martínez, Ó. (2026). Beyond Molecular Classification in Metastatic Triple-Negative Breast Cancer: Toward Subtype-Guided Precision Oncology. International Journal of Molecular Sciences, 27(11), 5040. https://doi.org/10.3390/ijms27115040

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Beyond Molecular Classification in Metastatic Triple-Negative Breast Cancer: Toward Subtype-Guided Precision Oncology

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