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Influence of Circulating Tumour Cells on Production of IL-1α, IL-1β and IL-12 in Sera of Patients with Primary Diagnosis of Breast Cancer Before Treatment.

BACKGROUND
Circulating tumour cells (CTCs) have been found to be a prognostic marker for reduced disease-free survival (DFS), distant DFS, breast cancer-specific survival, and overall survival (OS) before the start of systemic treatment. Determination of CTCs with the CellSearch System (Veridex, Raritan, NJ, USA) is a valuable but time-consuming and costly method. Therefore, the aim of this study was to evaluate cytokine profiles as a marker for CTC involvement.


PATIENTS AND METHODS
Patients chosen for this study were defined as women with breast cancer who agreed to participate in the phase I SUCCESS study. CTC analysis, the blood sampling time points, and the methodology were prospectively designed, and the prognostic value of the CTCs was defined as a scientific objective of the study protocol. A total of 100 patients positive for CTCs and an additional 100 patients negative for CTCs were matched into pairs. Matching criteria were histopathological grading, lymph node status, hormone receptor type, TNM classification and survival vs. tumour associated death. Commercial enzyme-linked immunosorbent assay (ELISA) was used to screen the blood serum samples for the Th1 cytokines: interferon gamma (IFN-γ), tumor necrosis factor alpha (TNF-α), interleukin 12 (IL-12), IL-1α, IL-1β, IL-2 and IL-18. The correlation of cytokine levels to the matching criteria listed above were analyzed with the Spearman correlation coefficient and the Mann-Whitney-U rank-sum test.


RESULTS
The IL-1α level was significantly lower in the CTC-positive patient group (p=0.043) but significantly higher in the CTC-negative progesterone receptor-positive collective (p=0.029). Furthermore, in patients who survived, significantly higher IL-12p40 levels were found in those with lymph node involvement (p=0.041) and those with triple-negative breast cancer (p=0.043). Of patients who died, those with oestrogen receptor-negative disease had higher IL-1α (p=0.050) and higher IL-1β (p=0.034) levels. Moreover, of those who died, those with triple-negative breast cancer had significantly higher IL-1α levels (p=0.033). In patients with grade 2 tumour, patients with HER2/neu expression had significantly higher IFN-γ levels (p=0.031) and those with no lymph node involvement had significantly higher IL-1α levels (p=0.014). In the collective with grade 3 tumour, patients with progesterone receptor-negative disease had significantly higher IL12p70 concentrations (p=0.048), while those with triple-negative breast cancer had lower IL12p40 levels (p=0.033).


CONCLUSION
Regarding CTC involvement, we speculate that IL-1α might be a marker for the release of tumour cells into the circulation and not into the lymphatic system. In addition, IL-1α like IL-1β appears to be related to CTC release in patients with breast cancer.