Exploratory Analysis of Plasma Angiotensin-Converting Enzyme 2 and Angiotensin Peptides as Candidate Discriminatory Signals in Breast Cancer: A Pilot Case–Control Study

Background: The renin-angiotensin system (RAS), traditionally known for its role in cardiovascular regulation, has also emerged as a key regulator of tumor progression and metastasis. Dysregulation of the RAS components has been implicated in breast cancer due to the significant presence of the RAS-related proteins in the breast tissue. This study aims to identify the dysregulated RAS components and investigate their potential as candidate biomarkers. Methods: A pilot case–control study was carried out with 21 treatment-naïve breast cancer patients and 17 healthy controls. Plasma levels of Ang 1-7, Ang II, ACE2 and selected cytokines (IL-6, IL-8, IL-10 and IFN-γ) were measured using LC-MS/MS and ELISA. ROC curves were used to assess changes in biomarker levels across the RAS components. Results: This pilot cohort showed evidence of altered circulating RAS-related analytes and IL-10 in treatment-naïve breast cancer patients compared with controls. The ratio of Ang 1-7/Ang II was reduced by over two-fold in breast cancer patients (p = 0.0442). While plasma ACE2 was significantly elevated in breast cancer patients (p = 0.0005), IL-10 was significantly suppressed (p = 0.0420). In exploratory logistic regression analysis, ACE2 showed potential as a classifier with improved discrimination when combined with Ang 1-7 and Ang II (AUC = 0.9396 [95% bootstrap CI: 0.84–1.00], accuracy = 92.59% at the Youden-optimized threshold). However, due to the small sample size and methodological limitations, these findings require further validation. Conclusions: In this exploratory pilot study, plasma ACE2, the Ang 1-7/Ang II ratio, and IL-10 showed promising discriminatory performance. However, these findings are hypothesis-generating and require external validation in larger, prospectively enrolled cohorts before any clinical inference can be drawn.