Breast cancer remains the most prevalent malignancy and a leading cause of cancer-related mortality among women globally, with over 2.3 million new cases and nearly 685,000 deaths annually [1]. Despite significant advances in early detection and treatment modalities, prognostic outcomes continue to vary widely due to the inherent heterogeneity of the disease and differences in tumor biology [2]. While established prognostic factors such as tumor stage, molecular subtype, and hormone receptor status provide valuable insights, there is a growing need for additional biomarkers to enhance risk stratification and guide personalized treatment decisions [3, 4].

Telomere length has emerged as a potential biomarker of cancer prognosis due to its fundamental role in maintaining genomic stability [5]. Telomeres, repetitive nucleotide sequences (TTAGGG) located at the ends of chromosomes, protect genomic integrity by preventing chromosomal end-to-end fusions and instability [6]. Telomeres progressively shorten with each cell division due to incomplete DNA replication, a process further accelerated by oxidative stress and chronic inflammation [7, 8]. This progressive shortening can lead to genomic instability, cellular senescence, and oncogenesis [9]. In cancer, telomere dysfunction is associated with tumor progression, metastasis, and poor clinical outcomes [10, 11].

Short telomeres are associated with increased genomic instability, a hallmark of cancer progression, and poor outcomes in patients with breast cancer [12, 13]. Research on specific subtypes reveals telomere shortening in aggressive forms of breast cancer, including triple-negative breast cancer (TNBC) and human epidermal growth factor receptor 2 (HER2)-positive breast cancer [14–16]. Although numerous studies have explored the relationship between telomere length and breast cancer outcomes, findings remain inconsistent. Some studies report shorter telomeres as a risk factor for worse survival [17–22], while others demonstrate weak or non-significant associations [23–25]. These discrepancies are likely due to variations in telomere measurement techniques, differences in sample types, and population heterogeneity [26]. Furthermore, population-specific differences in telomere biology and genetic predispositions, such as BRCA2 mutations, have been shown to increase the risk of breast cancer development and progression, adding another layer of complexity to prognostic interpretations [27].

This systematic review and meta-analysis aims to evaluate the association between telomere length and breast cancer survival outcomes, including overall survival (OS), disease-specific survival (DSS), disease-free survival (DFS), and recurrence-free survival (RFS). By integrating data from multiple studies, this research seeks to clarify the prognostic significance of telomere length and identify gaps that must be addressed to advance its clinical utility.

This meta-analysis provides a comprehensive evaluation of telomere length as a prognostic biomarker for survival outcomes in breast cancer, specifically focusing on OS, DSS, DFS, and RFS. Our findings indicate that shorter telomere length is significantly associated with increased recurrence risk (DFS/RFS) (pooled HR: 1.97; 95% CI: 1.04–3.74; P = 0.039), indicating a nearly twofold increase in recurrence risk for patients with shorter telomeres. While trends toward worse OS (pooled HR: 1.60; 95% CI: 0.90–2.86, P = 0.110) and DSS (pooled HR: 1.09; 95% CI: 0.80–1.49, P = 0.565) were observed for shorter telomeres, these associations did not reach statistical significance. These findings reinforce the emerging role of telomere length as a valuable prognostic marker in breast cancer, with shorter telomeres linked to poorer outcomes and altered telomerase activity, further emphasizing the role of telomere dynamics in disease progression [35, 36].

Telomere shortening affects genomic stability and promotes cancer recurrence by increasing chromosomal instability, activating oncogenes, and inactivating tumor suppressor genes [10, 37]. This instability accelerates cell proliferation and malignant transformation, contributing to higher recurrence rates after treatment [10, 37]. While telomere shortening can trigger cell cycle arrest as a protective mechanism against tumorigenesis, senescent cells can also create a pro-tumorigenic microenvironment. Through the senescence-associated secretory phenotype (SASP), these cells promote inflammation and alter the tissue microenvironment, further influencing recurrence [38]. The role of telomere shortening in genomic instability likely explains the higher recurrence rates observed in patients with shorter telomeres [18–21], although one study reports differing results [25]. These inconsistencies may arise from variations in telomere measurement techniques, sample types, and patient characteristics.

Subgroup analyses revealed important insights regarding the influence of telomere measurement methods. TC showed stronger associations with prognosis (pooled HR: 2.87; 95% CI: 1.74–4.74; P < 0.001) than RTL (T/S ratio). The slot blot assay also demonstrated a stronger correlation with poor prognosis (pooled HR: 2.87, 95% CI: 1.74–4.74, P < 0.001) compared to qPCR. Southern blotting remains the most accurate and reliable method for precise telomere length measurement. While qPCR is faster, it is less precise and may not capture specific telomere dynamics, such as the shortest telomeres or sub-telomeric regions, highlighting the need for caution when using qPCR, especially in longitudinal studies [39, 40]. These findings underscore the importance of telomere measurement methodology and suggest that absolute telomere length measurements could be more informative for prognostic purposes [41].

Moreover, telomere length measured in tumor tissue exhibited a stronger association with survival outcomes (pooled HR: 2.92; 95% CI: 1.61–5.28; P < 0.001) than measurements from blood plasma samples. Telomere shortening is more pronounced in tumor tissues than in adjacent non-cancerous tissues, reflecting cancer-specific dynamics more accurately than plasma telomeric cfDNA, which may be influenced by systemic factors [42, 43]. Tumor tissue telomeres are typically shorter due to the high proliferative activity and genomic instability of cancer cells, emphasizing the importance of tissue-specific telomere dynamics [43, 44]. While liquid biopsy methods, such as plasma cfDNA are non-invasive, they may miss localized telomere changes seen in tumor tissues, which offer a more accurate reflection of the tumor microenvironment [43]. This highlights the need to carefully consider sample types in future studies and clinical applications.

The geographic variability observed in our analysis, with American studies showing a significant association between shorter telomeres and poorer prognosis (pooled HR: 1.67, 95% CI: 1.18–2.35, P = 0.003), while European studies did not, warrants further investigation. This discrepancy may stem from genetic variation, geographic factors, and socioeconomic conditions that influence cancer risk and prognosis [45, 46]. These findings emphasize the importance of considering regional variations in telomere biology research.

Additionally, the association between shorter telomeres and premenopausal status (pooled OR: 1.34, 95% CI: 1.06–1.70, P = 0.01), suggests that telomere length may be particularly relevant for younger breast cancer patients. A case-control study in a Chinese Han population found a significant link between shorter telomeres and increased breast cancer risk, supporting the role of telomere length as a potential biomarker for breast cancer susceptibility in premenopausal women [47]. Furthermore, research on prediagnostic leukocyte telomere length has demonstrated an association with breast cancer risk, reinforcing the importance of telomere length as an indicator for premenopausal breast cancer [48]. Another study highlighted that shorter RTL was associated with increased breast cancer risk, although it primarily focused on postmenopausal women. These findings collectively broaden the context, reinforcing the relevance of telomere length as a potential biomarker for breast cancer risk across different populations [49]. Future studies should focus on validating telomere length as a prognostic marker, particularly in this high-risk subgroup.

Our analysis confirms the significant association between shorter telomere length and poorer survival outcomes in breast cancer patients. Telomere dysfunction, which leads to genomic instability by impairing DNA repair mechanisms, increasing oxidative stress, and promoting chromosomal fusions, has been widely recognized as a critical factor in cancer progression [7–9, 50]. This instability can contribute to tumor growth and recurrence, aligning with our findings that shorter telomeres correlate with worse DFS and RFS.

While the mechanisms underlying telomere dysfunction are well understood, the clinical utility of telomere length as a biomarker remains limited due to variability in measurement techniques. Studies have shown that the lack of standardized telomere measurement protocols is a key barrier to its widespread clinical application [26]. This underscores the need for future research to address these challenges and establish standardized protocols to enhance the reliability and applicability of telomere length as a prognostic biomarker for breast cancer.

The relationship between telomere dysfunction and BRCA2 mutations also warrants further exploration. Since BRCA2 mutations impair DNA repair mechanisms, telomere shortening may play a particularly critical role in increasing the risk of cancer progression in patients with this genetic predisposition [27]. This could potentially open up opportunities for using telomere length as an additional marker for identifying high-risk breast cancer patients, particularly those with hereditary breast cancer linked to BRCA mutations.

Despite its strengths, this meta-analysis has limitations. The small number of included studies reduces the generalizability of the findings and limits the statistical power of subgroup analyses, particularly for DSS and certain clinicopathological characteristics. The reliance on retrospective data may introduce selection bias, and the precision of HRs estimated from Kaplan-Meier curves is inherently limited compared to directly reported values [29]. Furthermore, while no significant publication bias was detected, the small sample size warrants cautious interpretation of these results.

In conclusion, our meta-analysis provides evidence for the potential of telomere length as a prognostic biomarker in breast cancer, particularly for predicting recurrence risk. The prognostic value of telomere length appears to be influenced by measurement method and sample type, highlighting the need for standardization. While challenges remain in translating these findings into clinical practice, the integration of telomere biology into personalized medicine approaches holds promise for improving breast cancer management. Future research should focus on addressing methodological inconsistencies, exploring telomere-based therapies, and validating the clinical utility of telomere length measurements in large-scale, prospective studies.