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

被引：42

作者：

Chuma, Makoto ^{[1
]}

Uojima, Haruki ^{[2
]}

Numata, Kazushi ^{[1
]}

Hidaka, Hisashi ^{[2
]}

Toyoda, Hidenori ^{[3
]}

Hiraoka, Atsushi ^{[4
]}

Tada, Toshifumi ^{[3
]}

Hirose, Shunji ^{[5
]}

Atsukawa, Masanori ^{[6
]}

Itokawa, Norio ^{[7
]}

Arai, Taeang ^{[6
,8
]}

Kako, Makoto ^{[9
]}

Nakazawa, Takahide ^{[2
]}

Wada, Naohisa ^{[2
]}

Iwasaki, Shuitirou ^{[2
]}

Miura, Yuki ^{[10
]}

Hishiki, Satoshi ^{[11
]}

Nishigori, Shuhei ^{[12
]}

Morimoto, Manabu ^{[13
]}

Hattori, Nobuhiro ^{[14
]}

Ogushi, Katsuaki ^{[1
]}

Nozaki, Akito ^{[1
]}

Fukuda, Hiroyuki ^{[1
]}

Kagawa, Tatehiro ^{[5
]}

Michitaka, Kojiro ^{[4
]}

Kumada, Takashi ^{[3
]}

Maeda, Shin ^{[15
]}

机构：

[1] Yokohama City Univ, Gastroenterol Ctr, Med Ctr, Yokohama, Kanagawa 2320024, Japan

[2] Kitasato Univ, Dept Gastroenterol, Internal Med, Sch Med, Sagamihara, Kanagawa 2520375, Japan

[3] Ogaki Municipal Hosp, Dept Gastroenterol & Hepatol, Ogaki 5038502, Japan

[4] Ehime Prefectural Cent Hosp, Gastroenterol Ctr, Matsuyama, Ehime 7900024, Japan

[5] Tokai Univ, Dept Internal Med, Div Gastroenterol & Hepatol, Sch Med, Isehara, Kanagawa 2591193, Japan

[6] Nippon Med Sch, Div Gastroenterol & Hepatol, Tokyo 1138603, Japan

[7] Chiba Hokusoh Hosp, Div Gastroenterol, Nippon Med Sch, Inzai 2701694, Japan

[8] Musashi Kosugi Hosp, Div Gastroenterol, Nippon Med Sch, Kawasaki, Kanagawa 2118533, Japan

[9] Shonan Kamakura Gen Hosp, Dept Gastroenterol, Kamakura, Kanagawa 2478533, Japan

[10] Hadano Red Cross Hosp, Gastroenterol Div, Hadano 2570017, Japan

[11] Saiseikai Yokohamashi Nanbu Hosp, Div Gastroenterol, Yokohama, Kanagawa 2340054, Japan

[12] Yokohama Minami Kyosai Hosp, Dept Gastroenterol, Yokohama, Kanagawa 2360037, Japan

[13] Kanagawa Canc Ctr Hosp, Hepatobiliary & Pancreat Med Oncol, Yokohama, Kanagawa 2418585, Japan

[14] St Marianna Univ, Dept Internal Med, Div Gastroenterol & Hepatol, Sch Med, Kawasaki, Kanagawa 2168511, Japan

[15] Yokohama City Univ Med, Dept Gastroenterol, Yokohama, Kanagawa 2360004, Japan

来源：

CANCERS | 2020年 / 12卷 / 02期

关键词：

hepatocellular carcinoma; lenvatinib; vascular endothelial growth factor; fibroblast growth factor 19; angiopoietin-2; biomarker; tyrosine kinase inhibitor; ENDOTHELIAL GROWTH-FACTOR; KINASE INHIBITOR; PHASE-I; CANCER; SURVIVAL; E7080; ANGIOPOIETIN-2; ANGIOGENESIS; RESISTANCE; SORAFENIB;

D O I：

10.3390/cancers12020293

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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.

引用

页数：16

共 36 条

[1] Modes of resistance to anti-angiogenic therapy [J].

Bergers, Gabriele ;

Hanahan, Douglas .

NATURE REVIEWS CANCER, 2008, 8 (08) :592-603

[2] A phase I study of E7080, a multitargeted tyrosine kinase inhibitor, in patients with advanced solid tumours [J].

Boss, D. S. ;

Glen, H. ;

Beijnen, J. H. ;

Keesen, M. ;

Morrison, R. ;

Tait, B. ;

Copalu, W. ;

Mazur, A. ;

Wanders, J. ;

O'Brien, J. P. ;

Schellens, J. H. M. ;

Evans, T. R. J. .

BRITISH JOURNAL OF CANCER, 2012, 106 (10) :1598-1604

[3] Strategies for Hepatocellular Carcinoma Therapy and Diagnostics: Lessons Learned from High Throughput and Profiling Approaches [J].

Breuhahn, Kai ;

Gores, Gregory ;

Schirmacher, Peter .

HEPATOLOGY, 2011, 53 (06) :2111-2120

[4] Epidemiology of Viral Hepatitis and Hepatocellular Carcinoma [J].

El-Serag, Hashem B. .

GASTROENTEROLOGY, 2012, 142 (06) :1264-+

[5]

European Assoc Study Liver, 2018, J HEPATOL, V69, P182, DOI 10.1016/j.jhep.2018.03.019

[6] Liver Angiopoietin-2 Is a Key Predictor of De Novo or Recurrent Hepatocellular Cancer After Hepatitis C Virus Direct-Acting Antivirals [J].

Faillaci, Francesca ;

Marzi, Luca ;

Critelli, Rosina ;

Milosa, Fabiola ;

Schepis, Filippo ;

Turola, Elena ;

Andreani, Silvia ;

Vandelli, Gabriele ;

Bernabucci, Veronica ;

Lei, Barbara ;

D'Ambrosio, Federica ;

Bristot, Laura ;

Cavalletto, Luisa ;

Chemello, Liliana ;

Sighinolfi, Pamela ;

Manni, Paola ;

Maiorana, Antonino ;

Caporali, Cristian ;

Bianchini, Marcello ;

Marsico, Maria ;

Turco, Laura ;

de Maria, Nicola ;

Del Buono, Mariagrazia ;

Todesca, Paola ;

di Lena, Luca ;

Romagnoli, Dante ;

Magistri, Paolo ;

di Benedetto, Fabrizio ;

Bruno, Savino ;

Taliani, Gloria ;

Giannelli, Gianluigi ;

Martinez-Chantar, Maria-Luz ;

Villa, Erica .

HEPATOLOGY, 2018, 68 (03) :1010-1024

[7]

Finn RS., 2018, Ann Oncol, V29, pviii17, DOI DOI 10.1093/ANNONC/MDY269.057

[8] Identification of serum angiopoietin-2 as a biomarker for clinical outcome of colorectal cancer patients treated with bevacizumab-containing therapy [J].

Goede, V. ;

Coutelle, O. ;

Neuneier, J. ;

Reinacher-Schick, A. ;

Schnell, R. ;

Koslowsky, T. C. ;

Weihrauch, M. R. ;

Cremer, B. ;

Kashkar, H. ;

Odenthal, M. ;

Augustin, H. G. ;

Schmiegel, W. ;

Hallek, M. ;

Hacker, U. T. .

BRITISH JOURNAL OF CANCER, 2010, 103 (09) :1407-1414

[9] Exploring mechanisms of FGF signalling through the lens of structural biology [J].

Goetz, Regina ;

Mohammadi, Moosa .

NATURE REVIEWS MOLECULAR CELL BIOLOGY, 2013, 14 (03) :166-180

[10] Clinical features of lenvatinib for unresectable hepatocellular carcinoma in real-world conditions: Multicenter analysis [J].

Hiraoka, Atsushi ;

Kumada, Takashi ;

Kariyama, Kazuya ;

Takaguchi, Koichi ;

Atsukawa, Masanori ;

Itobayashi, Ei ;

Tsuji, Kunihiko ;

Tajiri, Kazuto ;

Hirooka, Masashi ;

Shimada, Noritomo ;

Shibata, Hiroshi ;

Ishikawa, Toru ;

Ochi, Hironori ;

Tada, Toshifumi ;

Toyoda, Hidenori ;

Nouso, Kazuhiro ;

Tsutsui, Akemi ;

Itokawa, Norio ;

Imai, Michitaka ;

Joko, Kouji ;

Hiasa, Yoichi ;

Michitaka, Kojiro .

CANCER MEDICINE, 2019, 8 (01) :137-146

← 1 2 3 4 →