In recent years, the breast cancer has become the second leading cause of cancer death among women after lung cancer in the United States (1). It is also the most common cancer and the sixth leading cause of cancer death in Chinese women (2). Recurrent and metastatic breast cancer is currently the most difficult part to diagnosis and treatment. The sensitivity of imaging tests (such as ultrasound, mammography, MRI, and PET/CT) and peripheral blood tumor markers currently used in clinical practice is not high enough (3–5). Early detection of disease progression is also a hot topic of current research. Blood components such as free DNA and RNA, proteins, peptides, circulating tumor cells, and metabolites, are indicators of health status as well as disease status (6). And protein complexes assembled by non-covalent bond interactions have already showed potentials in differentiation of disease in different status (7–9). Disease-specific immune response-related protein complexes in the blood are associated with disease conditions, especially for cancer (10). Previous study has revealed that inflammation regulated by immunoglobulin and immune complexes might be a functionally significant factor in cancer progression (11). Serum immunoinflammation-related protein complexes (IIRPCs) were found significantly different between cancer patients and healthy control, which including immune-related proteins, inflammation-related proteins, and complement-related proteins (12). The levels of IIRPCs in non-small cell lung cancer patients had been found to vary with cancer progression (13). And monitoring IIRPCs may help guide therapeutic management (13). We therefore attempted to monitor IIRPCs in patients with metastatic breast cancer to explore whether it could reflect disease changes.

Serum IIRPCs protein complexes are composed of variable inflammation and immunity related protein molecules through non-covalent interactions, mainly including complement factor H, complement C3, C4, C7 components, haptoglobin, immunoglobulin α, γ, and κ components, apolipoprotein A-I and so on (12). It has been shown that peripheral blood complement and immunoglobulins are associated with the development and progression of cancer (10, 14–16). And previous studies have found significant differences in the levels of IIRPCs between tumor patients and healthy individuals (12). In patients with advanced non-small cell lung cancer, changes in the levels of IIRPCs were associated with patient response to treatment and changes in disease status (13). We selected some breast cancer patients to initially explore whether the IIRPCs levels and patterns were associated with breast cancer disease progression.

The results of our pre-experiment found that the IIRPCs bands patterns of all breast cancer patients were classified into seven major patterns (from a to g), which were consistent with previous studies (12, 13, 17). And no new banding pattern was identified. The patients in our cases had no severe infection, other primary tumor, pregnancy, lactation, other serious medical conditions, or other diseases known to be significantly associated with IIRPCs. The patterns of IIRPCs in our assay did not correlate significantly with patient age, tumor stage, grade, and whether metastasis was present. Therefore we mainly want to monitor the changes in the levels of IIRPCs dynamically. We initially found higher concentrations of IIRPCs protein bands in patients with metastatic breast cancer than in patients without metastasis (as shown in Figure 1C ). As mentioned above, IIRPCs contains many immune-inflammatory related proteins including haptoglobin, complements. It has been found that higher level of haptoglobin was related to pooler survival of breast cancer (18). And haptoglobin could regulated cell cycle progression and apoptosis in breast cancer cells (19). Lisa J had reported the level of apolipoprotein A-I might be positively correlated with the risk of breast cancer (20). Complement C3 also had been researched as a predictive biomarker in breast cancer (21).

In the first patient, IIRPCs levels decreased after treatment, consistent with the patient’s remission. In contrast, the second patient responded poorly to treatment, failed to achieve disease remission, and IIRPCs remained at high levels. However, tumor markers represented by CEA and CA15-3 were consistently elevated with disease progression only in the second patient. We think it may be because the second patient had more metastatic lesions and the first patient had only local recurrence and regional lymph node metastasis. The sensitivity of CEA and CA15-3 for detecting disease progression in breast cancer is not high (22, 23). So personalized IIRPCs could be a potential indicator that reflects the tumor burden in breast cancer patients, which might have good sensitivity. We will continue to collect samples for IIRPCs assays and will follow up with statistical analysis to further explore the role of IIRPCs

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

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CC performed the result analysis and wrote the draft manuscript. YX and ZLL designed the study. CC and ZZL performed the experiments and the data analysis. QS edited the draft. All authors contributed to the article and approved the submitted version.