Treatment with Granulocyte-colony Stimulating Factor (G-CSF) is not associated with Increased Risk of Brain Metastasis in Patients with De Novo Stage IV Breast Cancer

Background: Survival outcome after developing brain metastasis is poor and there is an unmet need to identify factors that can promote brain metastasis. Granulocyte-colony stimulating factor (G-CSF) is given to support neutrophil recovery after myelosuppressive chemotherapy to some patients. However, there is emerging evidence that neutrophils can promote metastasis, including through the formation of neutrophil extracellular traps (NETs), scaffolds of chromatin with enzymes expelled from neutrophils to the extracellular space. In animal models, G-CSFs can induce NETs to promote liver and lung metastasis. The primary objective of this study was to test the association between G-CSF use and the later incidence of brain metastasis. Methods: Patients with de novo Stage IV breast cancer, without known brain metastasis at the time of initial diagnosis, were identified from electronic medical records covering the period from 1/1/2013 to 12/31/2020 at Northwell Health. Univariate and multivariate logistic regression models were used to test the association between variables of interest, including G-CSF use, and brain metastasis. Results: A total of 78 patients were included in the final analysis. Among those 78 patients, 24 patients (30.8%) had received G-CSF along with chemotherapy at least once. In logistic regression models, G-CSF use was not a significant factor to predict brain metastasis (OR 1.89 [95%CI 1.89-5.33]; P=0.23). Interestingly, in multivariate logistic models, pulmonary embolism (PE)/deep venous thrombosis (DVT) was a significant predictive factor of brain metastasis (OR 6.74 [95%CI 1.82-25.01]; P=0.004) (38.5% vs 21.5%). Conclusions: The use of G-CSF was not associated with increased risk of brain metastasis in patients with de novo Stage IV breast cancer. Interestingly, PE/DVT, which can be associated with elevated NETs, was associated with brain metastasis. Further studies are warranted to determine whether DVT/PE with or without elevated NETs levels in the blood, is predictive of developing brain metastasis in patients with de novo Stage IV breast cancer.