Dados do Trabalho

Título

Small non-coding RNAs as prognostic biomarkers to predict relapsed patients with pathologic complete response (pCR) triple-negative breast cancer: exploratory analysis of the NACATRINE trial

Introdução

Triple-negative breast cancer (TNBC) is known for its aggressive nature and poor prognosis. Despite the initial response to neoadjuvant chemotherapy (NAC), some TNBC patients experience early relapse, emphasizing the need to identify predictive biomarkers for better treatment strategies. To address this, we investigated the role of miRNAs in TNBC patients who achieved a pathological complete response (pCR) after NAC.

Objetivo

This exploratory investigation aimed to identify potential miRNA biomarkers that could predict relapse in TNBC patients who attained pCR after NAC, thus contributing valuable insights for personalized treatment strategies in this challenging cancer subtype.

Métodos

In this study, we conducted an exploratory analysis of the NACATRINE clinical trial. We collected circulating miRNAs from patients with TNBC who underwent NAC and achieved pCR. The nCounter® Human v3 miRNA assay was employed to analyze nearly 800 human miRNAs in plasma samples from these patients. To ensure the robustness of the data, normalization was carried out using a low coefficient of variation (low CV) method. Subsequent analyses included calculations of fold change and area under the curve (AUC) to assess miRNA expression differences between relapsed and non-relapsed patients who achieved pCR. Additionally, we determined the odds ratio (OR) to measure the association of specific miRNAs with the likelihood of recurrence. Furthermore, we conducted an overall survival (OS) analysis to explore the impact of miRNA expression on patients' survival outcomes.

Resultados

A comprehensive analysis revealed 33 distinctively expressed miRNAs differentiating between patients who achieved pCR without relapse and those who experienced a relapse. Notably, three upregulated miRNAs (miR-520c-3p, miR-376a-2-5p, and miR-506-5p) displayed remarkable accuracy, with miR-520c-3p demonstrating a sensitivity of 0.833, specificity of 0.80, and an AUC of 0.80 (OR 1.151, CI 11.32–32). Similarly, miR-376a-2-5p exhibited a sensitivity of 0.90, a specificity of 0.91, and an impressive AUC of 95 (OR 2.201, CI 17.79–18.82). Additionally, miR-506-5p showcased a sensitivity of 0.83, a specificity of 0.79, and an AUC of 0.77 (OR915, CI 10.48–12.95). Moreover, during the in-silico analysis of OS, elevated expression levels of miR-506-5p and miR-376a-2-5p emerged as statistically significant, correlating strongly with poorer survival outcomes (p-value:1.2e-5, HR:2.07, CI 1.48–2.89; p-value:0.007, HR: 1.68, CI 1.14–2.45, respectively). Network analysis identified the main pathways: "TGF-beta signaling", "Cancer transcriptional dysregulation" and "JAK-STAT signaling" enriched with the target genes of these miRNAs.

Conclusões

These findings suggest that these miRNAs can be useful as good non-invasive biomarkers for identifying TNBC patients who are more likely to develop recurrence even after achieving pCR. Such biomarkers could aid in devising personalized treatment strategies for improving outcomes in TNBC patients.

Palavras-chave

Triple-negative breast cancer, biomarkers, pathological complete response

Financiador do resumo

Department of Science and Technology–DECIT, Ministry of Health (grant no. 879848/2018)