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Increased FGF19 copy number is frequently detected in hepatocellular carcinoma with a complete response after sorafenib treatment.

ABSTRACT: The multi-kinase inhibitor sorafenib is clinically approved for the treatment of patients with advanced hepatocellular carcinoma (HCC). We previously reported that fibroblast growth factor 3 and 4 (FGF3/FGF4) amplification is a predictor of a response to sorafenib. This study aims to analyze the relationship between FGF-FGF receptor (FGFR) genetic alterations and the response to sorafenib. Formalin-fixed, paraffin-embedded tissue specimens from HCC patients who had achieved a complete response (CR, N=6) or non-CR (N=39) to sorafenib were collected and were examined for FGF-FGFR gene alterations using next generation sequencing and copy number assay. FGFR mutations were detected in 5 of 45 (11.1%) cases. There was no significant association between FGFR mutation status and the response to sorafenib. We detected no increase in the FGF3/FGF4 copy number in CR cases. An FGF19 copy number gain was detected more frequently among CR cases (2/6, 33.3%) than among non-CR cases (2/39, 5.1%) (P = 0.024, Chi-squared test). In conclusion, a copy number gain for FGF19 may be a predictor of a response to sorafenib, in addition to FGF3/FGF4 amplification.

SUBMITTER: Kaibori M

PROVIDER: S-EPMC5226492 | biostudies-literature | 2016 Aug

REPOSITORIES: biostudies-literature

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Increased FGF19 copy number is frequently detected in hepatocellular carcinoma with a complete response after sorafenib treatment.

Kaibori Masaki M Sakai Kazuko K Ishizaki Morihiko M Matsushima Hideyuki H De Velasco Marco A MA Matsui Kosuke K Iida Hiroya H Kitade Hiroaki H Kwon A-Hon AH Nagano Hiroaki H Wada Hiroshi H Haji Seiji S Tsukamoto Tadashi T Kanazawa Akishige A Takeda Yutaka Y Takemura Shigekazu S Kubo Shoji S Nishio Kazuto K

Oncotarget 20160801 31

The multi-kinase inhibitor sorafenib is clinically approved for the treatment of patients with advanced hepatocellular carcinoma (HCC). We previously reported that fibroblast growth factor 3 and 4 (FGF3/FGF4) amplification is a predictor of a response to sorafenib. This study aims to analyze the relationship between FGF-FGF receptor (FGFR) genetic alterations and the response to sorafenib. Formalin-fixed, paraffin-embedded tissue specimens from HCC patients who had achieved a complete response ( ...[more]

PMID: 27384874

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Project description:BackgroundAlthough sorafenib is the global standard first-line systemic treatment for unresectable hepatocellular carcinoma (HCC), it does not have reliable predictive or prognostic biomarkers. Circulating cell-free DNA (cfDNA) has shown promise as a biomarker for various cancers. We investigated the use of cfDNA to predict clinical outcomes in HCC patients treated with sorafenib.MethodsThis prospective biomarker study analyzed plasma cfDNA from 151 HCC patients who received first-line sorafenib and 14 healthy controls. The concentration and VEGFA-to-EIF2C1 ratios (the VEGFA ratio) of cfDNA were measured. Low depth whole-genome sequencing of cfDNA was used to identify genome-wide copy number alteration (CNA), and the I-score was developed to express genomic instability. The I-score was defined as the sum of absolute Z-scores of sequenced reads on each chromosome. The primary aim of this study was to develop cfDNA biomarkers predicting treatment outcomes of sorafenib, and the primary study outcome was the association between biomarkers with treatment efficacy including disease control rate (DCR), time to progression (TTP) and overall survival (OS) in these patients.ResultsThe cfDNA concentrations were significantly higher in HCC patients than in healthy controls (0.71 vs. 0.34 ng/μL; P < 0.0001). Patients who did not achieve disease control with sorafenib had significantly higher cfDNA levels (0.82 vs. 0.63 ng/μL; P = 0.006) and I-scores (3405 vs. 1024; P = 0.0017) than those achieving disease control. The cfDNA-high group had significantly worse TTP (2.2 vs. 4.1 months; HR = 1.71; P = 0.002) and OS (4.1 vs. 14.8 months; HR = 3.50; P < 0.0001) than the cfDNA-low group. The I-score-high group had poorer TTP (2.2 vs. 4.1 months; HR = 2.09; P < 0.0001) and OS (4.6 vs. 14.8 months; HR = 3.35; P < 0.0001). In the multivariable analyses, the cfDNA remained an independent prognostic factor for OS (P < 0.0001), and the I-score for both TTP (P = 0.011) and OS (P = 0.010). The VEGFA ratio was not significantly associated with treatment outcomes.ConclusionPretreatment cfDNA concentration and genome-wide CNA in cfDNA are potential biomarkers predicting outcomes in advanced HCC patients receiving first-line sorafenib.

Dataset Information

Increased FGF19 copy number is frequently detected in hepatocellular carcinoma with a complete response after sorafenib treatment.

Publications

Increased FGF19 copy number is frequently detected in hepatocellular carcinoma with a complete response after sorafenib treatment.

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