The study finding aligns with existing evidence done by Lin Q et al.,[12] and Dufresne F et al.[13] that increasing age is often a critical factor in disease onset or progression, potentially due to age-related physiological changes, accumulated genetic mutations, or altered immune responses.

The marked disparity between the two age groups underscores the importance of considering age as a risk factor in clinical assessments and interventions. The study also suggests that preventive measures or targeted screening strategies could be particularly beneficial for individuals above 50 years to improve outcomes.

Tumor size is a critical prognostic factor in clinical practice, with larger tumors often associated with increased invasiveness, higher risk of metastasis, and poorer outcomes. The significant finding underscores the importance of continuous efforts in early detection to manage tumor size and potentially improve survival rates. Singh R.[14]

Tumor budding is a well-established indicator of aggressive tumor behavior and has been linked to increased invasiveness and metastatic potential. The high frequency of tumors with >10 buds suggests that many of the cases in this cohort may exhibit aggressive phenotypic characteristics Patel R.[15] This emphasizes the importance of monitoring tumor budding as a key factor in predicting prognosis and guiding therapeutic strategies. HER2-positive tumors are known for their aggressive nature and poorer outcomes, though targeted therapies like trastuzumab have significantly improved prognosis in HER2-positive cases Kim JH et al.[16–18]

Our findings collectively emphasize the heterogeneity of breast cancer in the cohort. While tumor budding and PR negativity suggest aggressive features, the predominance of HER2 negativity may reflect a subgroup of patients with a better overall prognosis.

Interleukin-8 (IL-8) is recognized as one of the most potent chemotactic factors and promoters of neutrophil recruitment and activation. Activated neutrophils release excessive amounts of proteases, heparin, and matrix-degrading enzymes, which collectively contribute to the degradation of the extracellular matrix. This degradation is a critical process that facilitates the increased invasiveness of malignant cells and promotes metastasis.

In the study by Zaki Abu Rabi et al, Yang X et al.
[10,18] a positive correlation was observed between IL-8 and Matrix Metalloproteinase-9 (MMP-9). The findings suggested that patients with elevated levels of IL-8 also demonstrated significantly higher MMP-9 expression, indicating a possible mechanistic link between these two markers. However, our study did not replicate these findings, as we observed differing patterns of IL-8 and MMP-9 expression.

Despite these differences, it is well-established that patients exhibiting high levels of IL-8 and MMP-9, along with other tumor-associated markers, are more likely to have poor clinical outcomes, including increased rates of recurrence and reduced survival. This underscores the importance of understanding the molecular pathways driving their co-regulation.

IL-8, known for its potent chemotactic activity and ability to attract neutrophils, plays a pivotal role in creating a pro-inflammatory tumor microenvironment. This can lead to the release of proteases and other enzymes that promote extracellular matrix remodeling, enhancing tumor invasiveness and metastatic potential. The high prevalence of IL-8-positive cases in this cohort suggests its strong association with aggressive tumor behavior and poor prognosis.

One possible explanation for the observed discrepancies is the role of transcriptional factors that simultaneously influence IL-8 expression and MMP-9 activity. Regulatory networks involving Nuclear Factor kappa B (NF-κB), Hypoxia-Inducible Factor-1 alpha (HIF-1α), and other signaling molecules may differentially modulate these markers depending on tumor microenvironmental factors. Additionally, variations in study populations, sample handling, or technical methodologies might contribute to the differences in observed correlations.

The lack of statistical significance suggests that MMP-9 expression alone may not be a strong determinant of tumor behavior or prognosis in this cohort. However, MMP-9, a key matrix metalloproteinase involved in extracellular matrix degradation, has been widely implicated in enhancing tumor invasiveness and metastasis in various cancers.

Interestingly, prior studies of Zaki Abu Rabi et al., Yang X et al., Su L et al., Chen Y et al. have indicated a positive correlation between IL-8 and MMP-9, with simultaneous elevation of these markers often linked to worse clinical outcomes. However, in this cohort, the statistical insignificance of MMP-9 expression contrasts with the significance of IL-8, suggesting independent or context-specific regulatory mechanisms. Transcriptional factors influencing IL-8 expression may not uniformly impact MMP-9 activity, indicating potential variability in tumor microenvironment dynamics.[18–21]