Neutrophils, G-CSF, and Breast Cancer Metastasis: A Reason for Caution?

Evidence is growing that neutrophils, the most abundant type of white blood cell, have a role in breast cancer progression to metastasis, though the role of granulocyte colony stimulating factor (G-CSF) in neutrophil biology in a cancer setting remains undefined. However, Australian researchers Kellie A. Mouchemore, PhD, and colleagues urge caution in the use of G-CSF in neutrophil recovery following chemotherapy for breast cancer because there is increasing evidence that G-CSF can promote metastasis. Mouchemore and coauthors reviewed the most recent clinical and experimental evidence for neutrophils and G-CSF in the promotion of metastasis in The FEBS Journal, demonstrating a potential link between neutrophils and G-CSF.

The number of studies reporting a role for neutrophils in breast cancer progression has increased markedly in recent years, the researchers say. Whereas neutrophils were once described as purely an indicator of chemotherapeutic side effects—and the major priority was in avoiding their depletion (neutropenia)—they are now being recognized as having the capacity to enhance progression to metastasis in many cancer types. “While knowledge of neutrophil function is growing, the known effects of G-CSF itself on progression to metastasis are scarce in terms of patient data, which is of particular concern as it is used routinely for recovery from neutropenia in myelosuppressed patients undergoing chemotherapy,” they note.

Reports suggesting that neutrophils may be a marker of poor patient prognosis go back to the late 1990s, and elevated levels of neutrophils prior to beginning therapy were identified as an independent risk factor for shorter overall survival (OS).

Since then, elevated neutrophil numbers or a high neutrophil-to-lymphocyte ratio (NLR) have been associated with poor prognosis in many human cancers. Only recently has information on the prognostic significance of neutrophils in breast cancer become less scarce. A large meta-analysis of 15 studies incorporating more than 8500 breast cancer patients found that a high NLR was associated with worse rates of OS and disease-free survival (DFS), with a high NFR being particularly prognostic for reduced DFS in patients with ER-negative and HER2-negative breast cancers.

Studies have also shown a clear association of increasing NLR with metastasis, and NLR has been reported to increase with increasing tumor stage. “In our opinion, monitoring of NLR after surgical removal of the primary tumor may be the best application of NLR, as we see continued elevation of neutrophil numbers in the blood of mice that develop lung metastasis following surgery to remove primary tumor in our preclinical models of breast cancer,” the authors state.

The researchers note that the simple presence of neutrophils alone in patients’ blood or tumors may not be sufficient to predict outcome. It is important to identify other markers associated with neutrophils that may predict outcomes or provide guidance for treatment, they say, and attention is turning to the prognostic significance of G-CSF. Recent studies have implicated G-CSF in exacerbating progression of neutrophil extracellular traps (NETs), which are implicated in promoting tumor growth and metastasis in mouse models of breast cancer.

If G-CSF underlies or perhaps enhances the pro-metastatic functions of neutrophils, then interrupting G-CSF signaling may be an attractive strategy, the researchers hypothesize. Based on the evidence presented in this review on the major role for G-CSF in promoting metastasis, the authors recommend undertaking in vivo investigations to test strategies disrupting G-CSF signaling, careful monitoring of G-CSF-mediated support of neutrophils during chemotherapy in breast cancer patients, and investigations of long-term outcome.