To identify differential proteins in the blood of tumor-bearing patients, numerous studies have employed various rigorous proteomics assays. However, challenges in sensitivity and time efficiency, especially in detecting low-abundance proteins, persist. In this study, we addressed these challenges by utilizing Proteograph technology. Through the analysis of plasma samples from eight dogs, Proteograph identified a higher number of proteins, including low-abundance ones, and detected more differentially expressed proteins (DEPs) compared to previous studies using conventional LC-MS/MS. Further exploration of cancer-upregulated DEPs revealed enrichments in immune and complement-related gene ontology terms in GO analysis, while proteins related to proteasome and complement activation clustered in PPI analysis. Notably, proteins involved in epigenetic mechanisms, such as methylation, were identified as cancer-upregulated proteins, a finding not observed in previous studies. Comparison with published human studies revealed a higher consistency in the directionality of common proteins among cancer-upregulated ones. Additionally, by utilizing the TCGA and GTEx databases, we identified CDH11 and PSMA5 as proteins upregulated at both RNA and protein levels in breast cancer, with high levels associated with poor prognosis, suggesting their potential as biomarkers in cancer progression. We plan to further investigate CDH11, identified as a DEP exclusively by Proteograph, to understand how circulating cadherins might contribute to tumor prognosis in patients.