Mechanism-related circulating proteins as biomarkers for clinical outcome in patients with unresectable hepatocellular carcinoma receiving sunitinib

Charles S Harmon, Samuel E DePrimo, Eric Raymond, Ann-Lii Cheng, Eveline Boucher, Jean-Yves Douillard, Ho Y Lim, Jun S Kim, Maria José Lechuga, Silvana Lanzalone, Xun Lin, Sandrine Faivre, Charles S Harmon, Samuel E DePrimo, Eric Raymond, Ann-Lii Cheng, Eveline Boucher, Jean-Yves Douillard, Ho Y Lim, Jun S Kim, Maria José Lechuga, Silvana Lanzalone, Xun Lin, Sandrine Faivre

Abstract

Background: Several proteins that promote angiogenesis are overexpressed in hepatocellular carcinoma (HCC) and have been implicated in disease pathogenesis. Sunitinib has antiangiogenic activity and is an oral multitargeted inhibitor of vascular endothelial growth factor receptors (VEGFRs)-1, -2, and -3, platelet-derived growth factor receptors (PDGFRs)-α and -β, stem-cell factor receptor (KIT), and other tyrosine kinases. In a phase II study of sunitinib in advanced HCC, we evaluated the plasma pharmacodynamics of five proteins related to the mechanism of action of sunitinib and explored potential correlations with clinical outcome.

Methods: Patients with advanced HCC received a starting dose of sunitinib 50 mg/day administered orally for 4 weeks on treatment, followed by 2 weeks off treatment. Plasma samples from 37 patients were obtained at baseline and during treatment and were analyzed for vascular endothelial growth factor (VEGF)-A, VEGF-C, soluble VEGFR-2 (sVEGFR-2), soluble VEGFR-3 (sVEGFR-3), and soluble KIT (sKIT).

Results: At the end of the first sunitinib treatment cycle, plasma VEGF-A levels were significantly increased relative to baseline, while levels of plasma VEGF-C, sVEGFR-2, sVEGFR-3, and sKIT were significantly decreased. Changes from baseline in VEGF-A, sVEGFR-2, and sVEGFR-3, but not VEGF-C or sKIT, were partially or completely reversed during the first 2-week off-treatment period. High levels of VEGF-C at baseline were significantly associated with Response Evaluation Criteria in Solid Tumors (RECIST)-defined disease control, prolonged time to tumor progression (TTP), and prolonged overall survival (OS). Baseline VEGF-C levels were an independent predictor of TTP by multivariate analysis. Changes from baseline in VEGF-A and sKIT at cycle 1 day 14 or cycle 2 day 28, and change in VEGF-C at the end of the first off-treatment period, were significantly associated with both TTP and OS, while change in sVEGFR-2 at cycle 1 day 28 was an independent predictor of OS.

Conclusions: Baseline plasma VEGF-C levels predicted disease control (based on RECIST) and were positively associated with both TTP and OS in this exploratory analysis, suggesting that this VEGF family member may have utility in predicting clinical outcome in patients with HCC who receive sunitinib.

Trial registration: ClinicalTrials.gov: NCT00247676.

Figures

Figure 1
Figure 1
Plasma pharmacodynamics of soluble protein biomarkers during treatment with sunitinib. (A) VEGF-A and VEGF-C; (B) sKIT and sVEGFRs-2 and -3. C, cycle; D, day.
Figure 2
Figure 2
Plasma pharmacodynamics of VEGF-C in patients with baseline VEGF-C levels above or below the median value of 822.2 pg/mL. C, cycle; D, day.
Figure 3
Figure 3
Receiver operating characteristic (ROC) curves for prediction of disease control (partial response [PR] or stable disease [SD] > 12 weeks) by baseline level of soluble protein. Arrows indicate ROC curve-derived cut-points.
Figure 4
Figure 4
Final Kaplan-Meier estimate of time to progression (TTP) and overall survival (OS) in patients stratified by above/below median baseline levels of VEGF-C.
Figure 5
Figure 5
Kaplan-Meier estimate of time to progression (TTP) and overall survival (OS) in patients stratified by above/below median ratio to baseline levels of sKIT (A and B), sVEGF-A (C and D), and VEGF-C (E and F) at post-baseline time points. Graphs A, C, and E show TTP and graphs B, D, and F show OS. C, cycle; D, day.

References

    1. Yao DF, Wu XH, Zhu Y, Shi GS, Dong ZZ, Yao DB, Wu W, Qiu LW, Meng XY. Quantitative analysis of vascular endothelial growth factor, microvascular density and their clinicopathologic features in human hepatocellular carcinoma. Hepatobiliary Pancreat Dis Int. 2005;4:220–226.
    1. Zhang ZL, Liu ZS, Sun Q. Expression of angiopoietins, Tie2 and vascular endothelial growth factor in angiogenesis and progression of hepatocellular carcinoma. World J Gastroenterol. 2006;12:4241–4245.
    1. Amaoka N, Saio M, Nonaka K, Imai H, Tomita H, Sakashita F, Takahashi T, Sugiyama Y, Takami T, Adachi Y. Expression of vascular endothelial growth factor receptors is closely related to the histological grade of hepatocellular carcinoma. Oncol Rep. 2006;16:3–10.
    1. Thelen A, Scholz A, Benckert C, von Marschall Z, Schröder M, Wiedenmann B, Neuhaus P, Rosewicz S, Jonas S. VEGF-D promotes tumor growth and lymphatic spread in a mouse model of hepatocellular carcinoma. Int J Cancer. 2008;122:2471–2481. doi: 10.1002/ijc.23439.
    1. Semela D, Dufour JF. Angiogenesis and hepatocellular carcinoma. J Hepatol. 2004;41:864–880. doi: 10.1016/j.jhep.2004.09.006.
    1. Park YN, Kim YB, Yang KM, Park C. Increased expression of vascular endothelial growth factor and angiogenesis in the early stage of multistep hepatocarcinogenesis. Arch Pathol Lab Med. 2000;124:1061–1065.
    1. Kim SJ, Choi IK, Park KH, Yoon SY, Oh SC, Seo JH, Choi CW, Kim BS, Shin SW, Kim YH, Kim JS. Serum vascular endothelial growth factor per platelet count in hepatocellular carcinoma: correlations with clinical parameters and survival. Jpn J Clin Oncol. 2004;34:184–190. doi: 10.1093/jjco/hyh039.
    1. Poon RT, Ng IO, Lau C, Yu WC, Fan ST, Wong J. Correlation of serum basic fibroblast growth factor levels with clinicopathologic features and postoperative recurrence in hepatocellular carcinoma. Am J Surg. 2001;182:298–304. doi: 10.1016/S0002-9610(01)00708-5.
    1. Kong SY, Park JW, Lee JA, Park JE, Park KW, Hong EK, Kim CM. Association between vascular endothelial growth factor gene polymorphisms and survival in hepatocellular carcinoma patients. Hepatology. 2007;46:446–455. doi: 10.1002/hep.21720.
    1. Moon EJ, Jeong CH, Jeong JW, Kim KR, Yu DY, Murakami S, Kim CW, Kim KW. Hepatitis B virus X protein induces angiogenesis by stabilizing hypoxia-inducible factor-1alpha. FASEB J. 2004;18:382–384.
    1. Cheng AL, Kang YK, Chen Z, Tsao CJ, Qin S, Kim JS, Luo R, Feng J, Ye S, Yang TS, Xu J, Sun Y, Liang H, Liu J, Wang J, Tak WY, Pan H, Burock K, Zou J, Voliotis D, Guan Z. Efficacy and safety of sorafenib in patients in the Asia-Pacific region with advanced hepatocellular carcinoma: a phase III randomised, double-blind, placebo-controlled trial. Lancet Oncol. 2009;10:25–34. doi: 10.1016/S1470-2045(08)70285-7.
    1. Llovet JM, Ricci S, Mazzaferro V, Hilgard P, Gane E, Blanc JF, de Oliveira AC, Santoro A, Raoul JL, Forner A, Schwartz M, Porta C, Zeuzem S, Bolondi L, Greten TF, Galle PR, Seitz JF, Borbath I, Häussinger D, Giannaris T, Shan M, Moscovici M, Voliotis D, Bruix J. the SHARP Investigators Study Group. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med. 2008;359:378–390. doi: 10.1056/NEJMoa0708857.
    1. Zhu AX, Sahani DV, Duda DG, di Tomaso E, Ancukiewicz M, Catalano OA, Sindhwani V, Blaszkowsky LS, Yoon SS, Lahdenranta J, Bhargava P, Meyerhardt J, Clark JW, Kwak EL, Hezel AF, Miksad R, Abrams TA, Enzinger PC, Fuchs CS, Ryan DP, Jain RK. Efficacy, safety, and potential biomarkers of sunitinib monotherapy in advanced hepatocellular carcinoma: a phase II study. J Clin Oncol. 2009;27:3027–3035. doi: 10.1200/JCO.2008.20.9908.
    1. Faivre S, Raymond E, Boucher E, Douillard J, Lim HY, Kim JS, Zappa M, Lanzalone S, Lin X, Deprimo S, Harmon C, Ruiz-Garcia A, Lechuga MJ, Cheng AL. Safety and efficacy of sunitinib in patients with advanced hepatocellular carcinoma: an open-label, multicentre, phase II study. Lancet Oncol. 2009;10:794–800. doi: 10.1016/S1470-2045(09)70171-8.
    1. Koeberle D, Montemurro M, Samaras P, Majno P, Simcock M, Limacher A, Lerch S, Kovàcs K, Inauen R, Hess V, Saletti P, Borner M, Roth A, Bodoky G. Continuous sunitinib treatment in patients with advanced hepatocellular carcinoma: a Swiss Group for Clinical Cancer Research (SAKK) and Swiss Association for the Study of the Liver (SASL) multicenter phase II trial (SAKK 77/06) Oncologist. 2010;15:285–292. doi: 10.1634/theoncologist.2009-0316.
    1. Abrams TJ, Lee LB, Murray LJ, Pryer NK, Cherrington JM. SU11248 inhibits KIT and platelet-derived growth factor receptor beta in preclinical models of human small cell lung cancer. Mol Cancer Ther. 2003;2:471–478.
    1. Kim DW, Jo YS, Jung HS, Chung HK, Song JH, Park KC, Park SH, Hwang JH, Rha SY, Kweon GR, Lee SJ, Jo KW, Shong M. An orally administered multitarget tyrosine kinase inhibitor, SU11248, is a novel potent inhibitor of thyroid oncogenic RET/papillary thyroid cancer kinases. J Clin Endocrinol Metab. 2006;91:4070–4076. doi: 10.1210/jc.2005-2845.
    1. Mendel DB, Laird AD, Xin X, Louie SG, Christensen JG, Li G, Schreck RE, Abrams TJ, Ngai TJ, Lee LB, Murray LJ, Carver J, Chan E, Moss KG, Haznedar JO, Sukbuntherng J, Blake RA, Sun L, Tang C, Miller T, Shirazian S, McMahon G, Cherrington JM. In vivo antitumor activity of SU11248, a novel tyrosine kinase inhibitor targeting vascular endothelial growth factor and platelet-derived growth factor receptors: determination of a pharmacokinetic/pharmacodynamic relationship. Clin Cancer Res. 2003;9:327–337.
    1. Murray LJ, Abrams TJ, Long KR, Ngai TJ, Olson LM, Hong W, Keast PK, Brassard JA, O'Farrell AM, Cherrington JM, Pryer NK. SU11248 inhibits tumor growth and CSF-1R-dependent osteolysis in an experimental breast cancer bone metastasis model. Clin Exp Metastasis. 2003;20:757–766.
    1. O'Farrell AM, Abrams TJ, Yuen HA, Ngai TJ, Louie SG, Yee KW, Wong LM, Hong W, Lee LB, Town A, Smolich BD, Manning WC, Murray LJ, Heinrich MC, Cherrington JM. SU11248 is a novel FLT3 tyrosine kinase inhibitor with potent activity in vitro and in vivo. Blood. 2003;101:3597–3605. doi: 10.1182/blood-2002-07-2307.
    1. Kodera Y, Katanasaka Y, Kitamura Y, Hitoshi T, Nishio K, Tamura T, Koizumi F. Sunitinib inhibits lymphatic endothelial cell functions and lymph node metastasis in a breast cancer model through inhibition of vascular endothelial growth factor receptor 3. Breast Cancer Res. 2011. in press .
    1. Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L, Verweij J, Van Glabbeke M, van Oosterom AT, Christian MC, Gwyther SG. New guidelines to evaluate the response to treatment in solid tumors. J Natl Cancer Inst. 2000;92:205–216. doi: 10.1093/jnci/92.3.205.
    1. Faivre S, Zappa M, Vilgrain V, Boucher E, Douillard JY, Lim HY, Kim JS, Im SA, Kang YK, Bouattour M, Dokmak S, Dreyer C, Sablin MP, Serrate C, Cheng AL, Lanzalone S, Lin X, Lechuga MJ, Raymond E. Changes in Tumor Density in Patients with Advanced Hepatocellular Carcinoma Treated with Sunitinib. Clin Cancer Res. 2011;17:4504–4512. doi: 10.1158/1078-0432.CCR-10-1708.
    1. DePrimo SE, Bello CL, Smeraglia J, Baum CM, Spinella D, Rini BI, Michaelson MD, Motzer RJ. Circulating protein biomarkers of pharmacodynamic activity of sunitinib in patients with metastatic renal cell carcinoma: modulation of VEGF and VEGF-related proteins. J Transl Med. 2007;5:32. doi: 10.1186/1479-5876-5-32.
    1. Bello CL, DePrimo SE, Friece C, Smeraglia J, Sherman L, Tye L, Baum CM, Meropol NJ, Lenz H, Kulke MH. Analysis of circulating biomarkers of sunitinib malate in patients with unresectable neuroendocrine tumors (NET): VEGF, IL-8, and soluble VEGF receptors 2 and 3. J Clin Oncol. 2006;24(Suppl 18S) Abstract 4045.
    1. Burstein HJ, Elias AD, Rugo HS, Cobleigh MA, Wolff AC, Eisenberg PD, Lehman M, Adams BJ, Bello CL, DePrimo SE, Baum CM, Miller KD. Phase II study of sunitinib malate, an oral multitargeted tyrosine kinase inhibitor, in patients with metastatic breast cancer previously treated with an anthracycline and a taxane. J Clin Oncol. 2008;26:1810–1816. doi: 10.1200/JCO.2007.14.5375.
    1. Faivre S, Delbaldo C, Vera K, Robert C, Lozahic S, Lassau N, Bello C, Deprimo S, Brega N, Massimini G, Armand JP, Scigalla P, Raymond E. Safety, pharmacokinetic, and antitumor activity of SU11248, a novel oral multitarget tyrosine kinase inhibitor, in patients with cancer. J Clin Oncol. 2006;24:25–35. doi: 10.1200/JCO.2005.02.2194.
    1. Motzer RJ, Michaelson MD, Redman BG, Hudes GR, Wilding G, Figlin RA, Ginsberg MS, Kim ST, Baum CM, DePrimo SE, Li JZ, Bello CL, Theuer CP, George DJ, Rini BI. Activity of SU11248, a multitargeted inhibitor of vascular endothelial growth factor receptor and platelet-derived growth factor receptor, in patients with metastatic renal cell carcinoma. J Clin Oncol. 2006;24:16–24. doi: 10.1200/JCO.2005.02.2574.
    1. Norden-Zfoni A, Desai J, Manola J, Beaudry P, Force J, Maki R, Folkman J, Bello C, Baum C, DePrimo SE, Shalinsky DR, Demetri GD, Heymach JV. Blood-based biomarkers of SU11248 activity and clinical outcome in patients with metastatic imatinib-resistant gastrointestinal stromal tumor. Clin Cancer Res. 2007;13:2643–2650. doi: 10.1158/1078-0432.CCR-06-0919.
    1. George S, Blay JY, Casali PG, Le Cesne A, Stephenson P, DePrimo SE, Harmon CS, Law CN, Morgan JA, Ray-Coquard I, Tassell V, Cohen DP, Demetri GD. Clinical evaluation of continuous daily dosing of sunitinib malate in patients with advanced gastrointestinal stromal tumor after imatinib failure. Eur J Cancer. 2009;45:1959–1968. doi: 10.1016/j.ejca.2009.02.011.
    1. DePrimo SE, Huang X, Blackstein ME, Garrett CR, Harmon CS, Schöffski P, Shah MH, Verweij J, Baum CM, Demetri GD. Circulating levels of soluble KIT serve as a biomarker for clinical outcome in gastrointestinal stromal tumor patients receiving sunitinib following imatinib failure. Clin Cancer Res. 2009;15:5869–5877. doi: 10.1158/1078-0432.CCR-08-2480.
    1. Choi H, Charnsangavej C, Faria SC, Macapinlac HA, Burgess MA, Patel SR, Chen LL, Podoloff DA, Benjamin RS. Correlation of computed tomography and positron emission tomography in patients with metastatic gastrointestinal stromal tumor treated at a single institution with imatinib mesylate: proposal of new computed tomography response criteria. J Clin Oncol. 2007;25:1753–1759. doi: 10.1200/JCO.2006.07.3049.
    1. Lohela M, Bry M, Tammela T, Alitalo K. VEGFs and receptors involved in angiogenesis versus lymphangiogenesis. Curr Opin Cell Biol. 2009;21:154–165. doi: 10.1016/j.ceb.2008.12.012.
    1. Cao Y, Linden P, Farnebo J, Cao R, Eriksson A, Kumar V, Qi JH, Claesson-Welsh L, Alitalo K. Vascular endothelial growth factor C induces angiogenesis in vivo. Proc Natl Acad Sci USA. 1998;95:14389–14394. doi: 10.1073/pnas.95.24.14389.
    1. Clarijs R, Schalkwijk L, Hofmann UB, Ruiter DJ, de Waal RM. Induction of vascular endothelial growth factor receptor-3 expression on tumor microvasculature as a new progression marker in human cutaneous melanoma. Cancer Res. 2002;62:7059–7065.
    1. Grau SJ, Trillsch F, Herms J, Thon N, Nelson PJ, Tonn JC, Goldbrunner R. Expression of VEGFR3 in glioma endothelium correlates with tumor grade. J Neurooncol. 2007;82:141–150. doi: 10.1007/s11060-006-9272-4.
    1. Valtola R, Salven P, Heikkilä P, Taipale J, Joensuu H, Rehn M, Pihlajaniemi T, Weich H, deWaal R, Alitalo K. VEGFR-3 and its ligand VEGF-C are associated with angiogenesis in breast cancer. Am J Pathol. 1999;154:1381–1390. doi: 10.1016/S0002-9440(10)65392-8.
    1. Achen MG, Williams RA, Baldwin ME, Lai P, Roufail S, Alitalo K, Stacker SA. The angiogenic and lymphangiogenic factor vascular endothelial growth factor-D exhibits a paracrine mode of action in cancer. Growth Factors. 2002;20:99–107. doi: 10.1080/08977190290031969.
    1. Rini BI, Michaelson MD, Rosenberg JE, Bukowski RM, Sosman JA, Stadler WM, Hutson TE, Margolin K, Harmon CS, DePrimo SE, Kim ST, Chen I, George DJ. Antitumor activity and biomarker analysis of sunitinib in patients with bevacizumab-refractory metastatic renal cell carcinoma. J Clin Oncol. 2008;26:3743–3748. doi: 10.1200/JCO.2007.15.5416.
    1. Motzer RJ, Hudes GR, Ginsberg MS, Baum MS, Harmon CS, Kim ST, Chen I, Redman BG. Phase I/II trial of sunitinib plus gefitinib in patients with metastatic renal cell carcinoma. Am J Clin Oncol. 2010;33:614–618. doi: 10.1097/COC.0b013e3181c4454d.
    1. Becker G, Schmitt-Graeff A, Ertelt V, Blum HE, Allgaier HP. CD117 (c-kit) expression in human hepatocellular carcinoma. Clin Oncol (R Coll Radiol) 2007;19:204–208.
    1. Knight B, Tirnitz-Parker JE, Olynyk JK. C-kit inhibition by imatinib mesylate attenuates progenitor cell expansion and inhibits liver tumor formation in mice. Gastroenterology. 2008;135:969–979. doi: 10.1053/j.gastro.2008.05.077. 979.e1.
    1. Tandon P, Garcia-Tsao G. Prognostic indicators in hepatocellular carcinoma: a systematic review of 72 studies. Liver Int. 2009;29:502–510. doi: 10.1111/j.1478-3231.2008.01957.x.
    1. Ogawa E, Takenaka K, Yanagihara K, Kurozumi M, Manabe T, Wada H, Tanaka F. Clinical significance of VEGF-C status in tumour cells and stromal macrophages in non-small cell lung cancer patients. Br J Cancer. 2004;91:498–503. doi: 10.1038/sj.bjc.6601992.
    1. Liu P, Chen W, Zhu H, Liu B, Song S, Shen W, Wang F, Tucker S, Zhong B, Wang D. Expression of VEGF-C correlates with a poor prognosis based on analysis of prognostic factors in 73 patients with esophageal squamous cell carcinomas. Jpn J Clin Oncol. 2009;39:644–650. doi: 10.1093/jjco/hyp079.
    1. Tsutsumi S, Kuwano H, Shimura T, Morinaga N, Mochiki E, Asao T. Vascular endothelial growth factor C (VEGF-C) expression in pT2 gastric cancer. Hepatogastroenterology. 2005;52:629–632.
    1. Miyazaki T, Okada N, Ishibashi K, Ogata K, Ohsawa T, Ishiguro T, Nakada H, Yokoyama M, Matsuki M, Kato H, Kuwano H, Ishida H. Clinical significance of plasma level of vascular endothelial growth factor-C in patients with colorectal cancer. Jpn J Clin Oncol. 2008;38:839–843. doi: 10.1093/jjco/hyn106.

Source: PubMed

Szponzorok és közreműködők

Egészségi állapot

Kábítószer-beavatkozások

3
Iratkozz fel