Early Changes in Circulating FGF19 and Ang-2 Levels as Possible Predictive Biomarkers of Clinical Response to Lenvatinib Therapy in Hepatocellular Carcinoma

Abstract

Predictive biomarkers of the response of hepatocellular carcinoma (HCC) to Lenvatinib therapy have not yet been clarified. The aim of this study was to identify clinically significant biomarkers of response to Lenvatinib therapy, to target strategies against HCC. Levels of circulating angiogenic factors (CAFs) were analyzed in blood samples collected at baseline and after introducing lenvatinib, from 74 Child-Pugh class A HCC patients who received lenvatinib. As CAF biomarkers, serum vascular endothelial growth factor (VEGF), fibroblast growth factor 19 (FGF19), FGF23, and angiopoietin-2 (Ang-2) were measured using enzyme-linked immunosorbent assays. Results: Significantly increased FGF19 (FGF19-i) levels and decreased Ang-2 (Ang-2-d) levels were seen in Lenvatinib responders as compared to non-responders (ratio of FGF19 level at 4 weeks/baseline in responders vs. non-responders: 2.09 vs. 1.32, respectively, p = 0.0004; ratio of Ang-2 level at four weeks/baseline: 0.584 vs. 0.810, respectively, p = 0.0002). Changes in FGF23 and VEGF levels at four weeks versus baseline, however, were not significantly different in responders versus non-responders. In multivariate analysis, the combination of serum FGF19-i and Ang-2-d was the most independent predictive factor for Lenvatinib response (Odds ratio, 9.143; p = 0.0012). Furthermore, this combination biomarker showed the greatest independent association with progression-free survival (Hazard ratio, 0.171; p = 0.0240). Early changes in circulating FGF19 and Ang-2 levels might be useful for predicting clinical response and progression-free survival in HCC patients on Lenvatinib therapy.

Baseline angiopoietin‐2 and FGF19 levels predict treatment response in patients receiving multikinase inhibitors for hepatocellular carcinoma

“…Quite recently, Chuma et al, similar to our report, reported that serum ANG2 and FGF19 might be involved in treatment response of lenvatinib for patients with advanced HCC. However, in the report, they showed that, in patients with favorable responses, ANG2 level was higher at baseline but showed significant decrease along with significantly increased FGF19 levels during the treatment . The precise reason for this discrepancy in our results remains unclarified; however, there are several hypotheses.…”

“…However, in the report, they showed that, in patients with favorable responses, ANG2 level was higher at baseline but showed significant decrease along with significantly increased FGF19 levels during the treatment. 30 The precise reason for this discrepancy in our results remains unclarified; however, there are several hypotheses. In this study, we included patients with Child-Pugh grade B, while Chuma's study did not.…”

Initial experience with the combination of atezolizumab and bevacizumab in patients with unresectable hepatocellular carcinoma progressing after tyrosine kinase inhibitor therapy: A multicenter prospective observational study

“…In the nal analysis of the REFLECT study, serum FGF19 and FGF23 were increased after lenvatinib treatment [21]. Furthermore, in another study, FGF19 at week 4 and FGF23 at week 8 of HCC treatment with lenvatinib were highly elevated, and this was associated with treatment response [22]. It was also reported that FGF23 was elevated in thyroid cancer treated with lenvatinib, and this was associated with long-term treatment response [23].…”

FGF/FGFR Signaling in Hepatocellular Carcinoma: From Carcinogenesis to Recent Therapeutic Intervention

“…Higher serum FGF19 levels were associated with a better response to lenvatinib. The rate of FGF19 baseline in the objective response (OR) and non-OR groups was 2.09 vs. 1.32 at four weeks and 2.19 vs. 1.40 at eight weeks, respectively, showing the clinical response predictive value of circulating FGF19 in early HCC patients [ 108 ].…”