In some clinical studies, it was found that serum ferritin levels were closely related to the prognosis in patients with lung cancer, breast cancer, stomach carcinoma, hepatocellular carcinoma and other malignant solid tumors. Based on those, we focused on the prognostic significance of pretreatment serum ferritin for survival in advanced cancer patients who were treated with apatinib.
Notably, our cohort study population had inferior performance status (52.4% ECOS-PS≥2) and was more heavily pretreated (all patients had ≥2 prior systemic treatment regimens) compared to clinical trials that led to the approval of apatinib for solid tumors. Given these key differences, it is not surprising that the PFS and OS in our study group are inferior to the published trials. Therefore, this study only represented patients with advanced cancer after multi-line drug resistance. In the univariate analysis and multivariate analysis, only high SF was associated with shorter OS and PFS, while poor ECOS-PS(≥2), age of previous treatment and line number did not affect.
From this retrospective analysis, we found that SF was correlated with significant improvements in clinical outcomes in advanced cancer patients who were treated with apatinib. It was supported that SF may be a predictive biomarker for the effectiveness of apatinib treatment in this advanced cancer patient. Besides, the median OS and PFS of people with low SF were significantly higher than those with high SF. Finally, the SF level was considered to be an independent prognostic factor in univariate analysis and multivariate analyses.
Ferritin, an iron storage protein consisting of ferritin H-subunit and ferritin L-subunit, plays a critical role. However, there were many controversies about the cellular origin and subunit composition of serum ferritin. Some have reported that SF was mainly derived from macrophages through nonclassical secretion pathways, particularly originated from macrophages in the tumor microenvironment(14). TAM plays a critical role in the development of tumors. The direct mechanism is the secretion of proto-oncogenic molecules, while the indirect mechanism is iron-binding and ferritin release. TAM’s Elevated serum ferritin may be associated with local release in the breast cancer microenvironment, which can promote tumor cell proliferation and growth(14, 27, 40-42). Moreover, elevated serum ferritin may represent increased macrophage infiltration, which is strongly correlated with tumor invasion in the surrounding stroma.
In terms of its regulatory role in angiogenesis, ferritin in the tumor microenvironment directly stimulates tumorigenesis, proliferation and angiogenesis. Ferritin contains a large number of L-subunits, which can bind to high molecular weight kininogen and prevent its antiangiogenic effect on endothelial cells, thereby accelerating migration and tube formation (14, 15). In this retrospective study, we found that OS and PFS were significantly worse in cancer patients receiving apatinib in the high serum ferritin group than in the low serum ferritin group. And apatinib is an anti-angiogenic agent, which selectively inhibits the activity of VEGFR-2 tyrosine kinase and blocks the binding of VEGF to its signal transduction receptor, thus inhibiting tumor angiogenesis and exerting an anti-tumor effect. We can boldly assume that TAM secretes high concentrations of ferritin bound to the high molecular weight kininogen, which affects the binding of apatinib to the ATP junction of VEGFR-2 and inhibits or attenuates the antiangiogenic effect of apatinib.
The results showed that serum ferritin can predict the survival prognosis of advanced cancer patients. As mentioned earlier, the primary source of ferritin was TAM, which suggested that SF was secreted by the host rather than the tumor. Therefore, ferritin can be used as a unique biomarker to predict prognosis, representing the tumor burden, reflecting the overall degree of disease progression of patients and providing information about tumor progression. To verify the clinical significance of serum ferritin in tumor angiogenesis, it is necessary to further study the pathophysiology related to tumor and host.
In clinical practice, serum ferritin predicts survival and provides useful information for the treatment of patients with advanced cancer. Besides, low-cost testing has economic advantages. Therefore, serum ferritin can be used in a variety of clinical settings.
The current study has several limitations. First, the small sample and retrospective design of this study may bias the results. No basic medical studies have been conducted to investigate the biological mechanisms underlying the prognostic significance of SF. However, our study is the first to demonstrate the prognostic value of SF in apatinib therapy and provides evidence and inspiration for future studies. Multicenter randomized controlled trials are needed in the future to confirm our findings, and basic medical research is urgently needed to elucidate the specific mechanisms of the subject. Secondly, due to the retrospective nature of the study, the time of the CT scan isn’t determined in advance. In each hospital, a CT scan is performed every six to eight weeks in routine care(43). Finally, even with careful use of the RECIST 1.1 standard, misclassification can occur. We believe that the assessment of two independent observers can reduce the information bias in this study. Our results were obtained in a homogeneous population of advanced cancer patients with apatinib therapy after multiline drug resistance treatment and cannot be extrapolated to other populations. Besides, further prospective multicenter studies and a sufficient number of samples are needed to determine the validity of our results.