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. 2020 Mar 15;12(3):301-310.
doi: 10.4251/wjgo.v12.i3.301.

Circulating cytokines and outcome in metastatic colorectal cancer patients treated with regorafenib

Vincenzo Ricci  1 , Cristina Granetto  2 , Antonella Falletta  3 , Matteo Paccagnella  3 , Andrea Abbona  3 , Elena Fea  2 , Teresa Fabozzi  4 , Cristiana Lo Nigro  5 , Marco Carlo Merlano  2
Affiliations

Circulating cytokines and outcome in metastatic colorectal cancer patients treated with regorafenib

Vincenzo Ricci et al. World J Gastrointest Oncol. .

Abstract

Background: Regorafenib is an oral small-molecule multikinase inhibitor approved in third or later line of treatment for patients with metastatic colorectal cancer (mCRC). Regorafenib has shown significant benefits in overall survival and progression free survival in two phase III trials compared to placebo in patients with mCRC who had progressed on previous therapy.

Aim: To identify an immune profile that might specifically correlate with the outcome in patients treated with regorafenib.

Methods: Blood samples were collected from 17 patients before treatment with regorafenib and from 6 healthy volunteers. The proteins evaluated (TNF-α, TGF-β, VEGF, CCL-2, CCL-4, and CCL-5) were selected on the basis of their roles in angiogenesis and colorectal cancer pathogenesis.

Results: We found that TNF-α basal level was significantly higher in mCRC patients compared to healthy individuals. Non Responder (NR) patients showing progression of disease (n = 12) had higher basal level of TGF-β, TNF-α, VEGF, CCL-2 and CCL-5 compared to Responder (R) patients (complete response CR, n = 1; partial response PR, n = 1; Stable Disease SD, n = 3). On the contrary, plasma basal level of CCL-4 was higher in R compared to NR patients. High values of TGF-β and TNF-α negatively correlated with progression free survival.

Conclusion: These results suggest a cytokine signature potentially able to discriminate between R and NR patients to treatment with regorafenib.

Keywords: Angiogenesis; Colorectal cancer; Cytokines; Multikinase inhibitor.

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Conflict of interest statement

Conflict-of-interest statement: The authors have no conflicts of interest to declare.

Figures

Figure 1
Figure 1
Plasma cytokines levels. Basal evaluation of 6 cytokines in non-responder patients (n = 12), Responder patients (n = 5) and in healthy volunteers (n = 6). Cytokine concentration is expressed in pg/mL. Data are shown as median with range. The difference in median values was computed using the non-parametric Mann Whitney U test. P < 0.05 was considered the statistical significance. aP < 0.05 NR vs R; cP < 0.05 NR vs Healthy. NR: Non-responder; R: Responder; TNF-α: Tumor necrosis alpha; TGF-β: Transforming growth factor alpha; VEGF: Vascular endothelial growth factor; CCL-2: Chemokine ligand 2; CCL-4: Chemokine ligand 4; CCL-5: Chemokine ligand 5.
Figure 2
Figure 2
Correlation analysis. A: Correlation between tumor necrosis alpha and progression free survival in all metastatic colorectal cancer (mCRC) patients (n = 17) (rs = -0.52, P = 0.033); B: Correlation between transforming growth factor alpha and progression free survival in all mCRC patients (n = 17) (rs = -0.52, P = 0.038); C: Correlation between tumor necrosis alpha and transforming growth factor alpha in all mCRC patients (n = 17) (rs = 0.53, P = 0.028). P < 0.05 was considered the statistical significance. Each dot represents the value of one patients. Transforming growth factor alpha and tumor necrosis alpha are expressed as a concentration (pg/mL). Progression free survival is expressed in months. PFS: Progression free survival; TNF-α: Tumor necrosis alpha; TGF-β: Transforming growth factor alpha.
Figure 3
Figure 3
Receiver operating characteristic curve analysis, progression free survival and overall survival Kaplan-Meier curves. A: Receiver operating characteristic curve with area under the curve (0.908, 95CI: 0.758–1.000, P = 0.010) for predicting survival by plasma TNF-α basal levels in patients with metastatic colorectal cancer treated with regorafenib according to the baseline TNF-α levels ≤ (―, n = 5) or > (―, n = 12) the cut-off value (determined by receiver operating characteristic curve analysis); B: Progression free survival (5.2 vs 2.6 mo, Log-rank test, P = 0.005); one patient in Group A is not shown because of a graphic choice; C: Overall survival (16.6 vs 7.3 mo, Log-rank test, P = 0.010). PFS: Progression free survival; OS: Overall survival; ROC: Receiver operating characteristic; TNF-α: Tumor necrosis alpha; TGF-β: Transforming growth factor alpha.
Figure 4
Figure 4
Univariate Cox analysis to predict risk of disease progression. Difference between the two survival curves was assessed by long rank test, the HR with 95%CI was calculated by the Cox regression model (HR = 7.203; 95%CI: 1.531–33.882; P = 0.012). PFS: Progression free survival; TNF-α: Tumor necrosis alpha.
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