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. 2025 May 4.
doi: 10.1007/s12094-025-03933-x. Online ahead of print.

Dysfunctional mismatch repair in patients with early triple-negative breast cancer

María Muñiz-Castrillo  1   2 , Noel Blaya Boluda  3   4 , Esmeralda García-Torralba  3   4 , Paula Jiménez-Fonseca  5   6 , Carmen González Del Rey  7 , Milagros Balbín  8 , Ginés Luengo-Gil  4   9 , Francisco Ayala de la Peña  3   4 , Emilio Esteban González  5   6 , Alberto Carmona-Bayonas  3   4
Affiliations

Dysfunctional mismatch repair in patients with early triple-negative breast cancer

María Muñiz-Castrillo et al. Clin Transl Oncol. .

Abstract

Background: While mismatch repair (MMR) deficiency is well-characterized in several cancers, its role in triple-negative breast cancer (TNBC) remains unclear. We comprehensively assessed MMR in early-stage TNBC, examining its prevalence, clinical correlations, prognostic value, relationship with microsatellite instability (MSI), and patterns of intratumoral heterogeneity.

Methods: Two early-stage TNBC cohorts were investigated for germline mutations using next-generation sequencing, protein expression by immunohistochemistry, and MSI status through molecular detection. Associations with clinicopathological characteristics and survival were examined. Results were validated using The Cancer Genome Atlas (TCGA) data.

Results: Among 259 patients, MMR deficiency was observed in 8.2%, all showing PMS2 loss, while 2 germline PMS2 mutations (2.7%) were detected. At the somatic level, 35.8% showed heterogeneous MMR expression, more frequently in earlier stages (IA-IIA 41.4% vs. IIB-III 22.4%, p = 0.04) and smaller tumors (cT1-2 39.1% vs. cT3-4 18.5%, p = 0.01). MMR status showed no significant associations with other clinicopathological variables or survival. No MSI was detected in MMR-deficient cases. The 5-year recurrence rate was 16.0% (95% CI 10.0-24.0) for MMR-intact, 20.0% (95% CI 4.5-43.0) for MMR-deficient, and 17.9% (95% CI 9.8-28.1) for heterogeneous tumors (p = 0.75). Pathological complete response to neoadjuvant chemotherapy was similar across MMR status groups. These findings were consistent with analyses using TCGA data.

Conclusion: MMR system shows a low rate of alterations in TNBC, with its deficiency being infrequent and not correlated with MSI. Although MMR system isolated evaluation may not be justified in early-stage TNBC due to its limited clinical impact, its inclusion in multigene panels should be further considered.

Keywords: Biomarkers; Immunotherapy; MMR; Microsatellite instability; Mismatch repair system; Triple-negative breast cancer.

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Conflict of interest statement

Declarations. Conflict of interest: All authors declare that they have no conflict of interest regarding the scope of this work. This is an academic study. Consent for publication: Informed consent and approval by the competent national authorities includes permission for the publication and dissemination of the data. Ethical statement and informed consent: This study was performed in accordance with the ethical standards of the Declaration of Helsinki and its subsequent amendments. This observational, noninterventional trial was approved by the Research Ethics Committee of the Principality of Asturias. Written informed consent or a substitute for it was obtained from all patients before they were included in the study. Data confidentiality was ensured through data coding and restricted access to patients' personal information.

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