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Value of FGFR2 expression for advanced gastric cancer patients receiving pazopanib plus CapeOX (capecitabine and oxaliplatin)

Abstract

Purpose

The aim of this study was to use immunohistochemistry (IHC) to determine the effect of FGFR2 and VEGFR2 expression on treatment outcomes for patients with metastatic or recurrent advanced gastric cancer (AGC) receiving a combination of pazopanib with CapeOx (capecitabine and oxaliplatin).

Methods

We conducted a single-arm, open-label phase II study to determine the efficacy and toxicity of the combination of pazopanib with CapeOx in 66 patients with metastatic or recurrent AGC (ClinicalTrials.gov NCT01130805). IHC analysis of FGFR2 and VEGFR2 was possible in 54 patients (81.8 %).

Results

Among 54 patients, the median age was 51.5 years (range 23–72 years). Male patients were 59.3 %. Seven patients (13.5 %) had tumor tissues that expressed FGFR2 by IHC. No patients had tumors that expressed VEGFR2. Among seven patients with tumors with FGFR2 expression, six achieved partial response (PR) with a 85.7 % response rate and one patient with stable disease. Among 47 patients with tumors without FGFR2 expression, one had complete response and 27 had PR (59.5 %). A significant difference in PFS was seen between patients who were positive and negative for FGFR2 using IHC (8.5 vs. 5.6 months, P = 0.050). By prognostic analysis for PFS, only FGFR2 status by IHC (positive vs. negative) had significant prognostic value for predicting PFS.

Conclusions

FGFR2 expression by IHC might be a useful biomarker for predicting treatment outcomes of patients with metastatic or recurrent AGC treated with a combination of pazopanib and CapeOx.

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References

  • Bang YJ, Van Cutsem E, Feyereislova A, Chung HC, Shen L, Sawaki A, Lordick F, Ohtsu A, Omuro Y, Satoh T, Aprile G, Kulikov E, Hill J, Lehle M, Ruschoff J, Kang YK (2010) Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial. Lancet 376:687–697. doi:10.1016/s0140-6736(10)61121-x

    CAS  Article  PubMed  Google Scholar 

  • Burris HA 3rd, Dowlati A, Moss RA, Infante JR, Jones SF, Spigel DR, Levinson KT, Lindquist D, Gainer SD, Dar MM, Suttle AB, Ball HA, Tan AR (2012) Phase I study of pazopanib in combination with paclitaxel and carboplatin given every 21 days in patients with advanced solid tumors. Mol Cancer Ther 11:1820–1828. doi:10.1158/1535-7163.mct-11-0997

    CAS  Article  PubMed  Google Scholar 

  • Clarke JM, Hurwitz HI (2013) Targeted inhibition of VEGF receptor 2: an update on ramucirumab. Expert Opin Biol Ther 13:1187–1196. doi:10.1517/14712598.2013.810717

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  • Cunningham D, Starling N, Rao S, Iveson T, Nicolson M, Coxon F, Middleton G, Daniel F, Oates J, Norman AR (2008) Capecitabine and oxaliplatin for advanced esophagogastric cancer. N Engl J Med 358:36–46. doi:10.1056/NEJMoa073149

    CAS  Article  PubMed  Google Scholar 

  • Escudier B, Porta C, Bono P, Powles T, Eisen T, Sternberg CN, Gschwend JE, De Giorgi U, Parikh O, Hawkins R, Sevin E, Negrier S, Khan S, Diaz J, Redhu S, Mehmud F, Cella D (2014) Randomized, controlled, double-blind, cross-over trial assessing treatment preference for pazopanib versus sunitinib in patients with metastatic renal cell carcinoma: PISCES Study. J Clin Oncol 32:1412–1418. doi:10.1200/jco.2013.50.8267

    CAS  Article  PubMed  Google Scholar 

  • Gozgit JM, Wong MJ, Moran L, Wardwell S, Mohemmad QK, Narasimhan NI, Shakespeare WC, Wang F, Clackson T, Rivera VM (2012) Ponatinib (AP24534), a multitargeted pan-FGFR inhibitor with activity in multiple FGFR-amplified or mutated cancer models. Mol Cancer Ther 11:690–699. doi:10.1158/1535-7163.mct-11-0450

    CAS  Article  PubMed  Google Scholar 

  • Gravalos C, Jimeno A (2008) HER2 in gastric cancer: a new prognostic factor and a novel therapeutic target. Ann Oncol 19:1523–1529. doi:10.1093/annonc/mdn169

    CAS  Article  PubMed  Google Scholar 

  • Hamberg P, Verweij J, Sleijfer S (2010) (Pre-)clinical pharmacology and activity of pazopanib, a novel multikinase angiogenesis inhibitor. Oncologist 15:539–547. doi:10.1634/theoncologist.2009-0274

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  • Hamerlik P, Lathia JD, Rasmussen R, Wu Q, Bartkova J, Lee M, Moudry P, Bartek J Jr, Fischer W, Lukas J, Rich JN, Bartek J (2012) Autocrine VEGF-VEGFR2-Neuropilin-1 signaling promotes glioma stem-like cell viability and tumor growth. J Exp Med 209:507–520. doi:10.1084/jem.20111424

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  • Heinrich MC, Corless CL, Duensing A, McGreevey L, Chen CJ, Joseph N, Singer S, Griffith DJ, Haley A, Town A, Demetri GD, Fletcher CD, Fletcher JA (2003) PDGFRA activating mutations in gastrointestinal stromal tumors. Science 299:708–710. doi:10.1126/science.1079666

    CAS  Article  PubMed  Google Scholar 

  • Hu B, El Hajj N, Sittler S, Lammert N, Barnes R, Meloni-Ehrig A (2012) Gastric cancer: Classification, histology and application of molecular pathology. J Gastrointest Oncol 3:251–261. doi:10.3978/j.issn.2078-6891.2012.021

    PubMed  PubMed Central  Google Scholar 

  • Jung KW, Park S, Kong HJ, Won YJ, Lee JY, Seo HG, Lee JS (2012) Cancer statistics in Korea: incidence, mortality, survival, and prevalence in 2009. Cancer Res Treat 44:11–24. doi:10.4143/crt.2012.44.1.11

    Article  PubMed  PubMed Central  Google Scholar 

  • Karaman MW, Herrgard S, Treiber DK, Gallant P, Atteridge CE, Campbell BT, Chan KW, Ciceri P, Davis MI, Edeen PT, Faraoni R, Floyd M, Hunt JP, Lockhart DJ, Milanov ZV, Morrison MJ, Pallares G, Patel HK, Pritchard S, Wodicka LM, Zarrinkar PP (2008) A quantitative analysis of kinase inhibitor selectivity. Nat Biotechnol 26:127–132. doi:10.1038/nbt1358

    CAS  Article  PubMed  Google Scholar 

  • Kim HK, Choi IJ, Kim CG, Kim HS, Oshima A, Yamada Y, Arao T, Nishio K, Michalowski A, Green JE (2012) Three-gene predictor of clinical outcome for gastric cancer patients treated with chemotherapy. Pharmacogenomics J 12:119–127. doi:10.1038/tpj.2010.87

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  • Kim ST, Jang HL, Lee SJ, Lee J, Choi YL, Kim KM, Cho J, Park SH, Park YS, Lim HY, Yashiro M, Kang WK, Park JO (2014) Pazopanib, a novel multitargeted kinase inhibitor, shows potent in vitro antitumor activity in gastric cancer cell lines with FGFR2 amplification. Mol Cancer Ther 13:2527–2536. doi:10.1158/1535-7163.mct-14-0255

    CAS  Article  PubMed  Google Scholar 

  • Kumar R, Crouthamel MC, Rominger DH, Gontarek RR, Tummino PJ, Levin RA, King AG (2009) Myelosuppression and kinase selectivity of multikinase angiogenesis inhibitors. Br J Cancer 101:1717–1723. doi:10.1038/sj.bjc.6605366

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  • Kunii K, Davis L, Gorenstein J, Hatch H, Yashiro M, Di Bacco A, Elbi C, Lutterbach B (2008) FGFR2-amplified gastric cancer cell lines require FGFR2 and Erbb3 signaling for growth and survival. Cancer Res 68:2340–2348. doi:10.1158/0008-5472.can-07-5229

    CAS  Article  PubMed  Google Scholar 

  • Landry J, Tepper JE, Wood WC, Moulton EO, Koerner F, Sullinger J (1990) Patterns of failure following curative resection of gastric carcinoma. Int J Radiat Oncol Biol Phys 19:1357–1362

    CAS  Article  PubMed  Google Scholar 

  • Lim DH, Kim DY, Kang MK, Kim YI, Kang WK, Park CK, Kim S, Noh JH, Joh JW, Choi SH, Sohn TS, Heo JS, Park CH, Park JO, Lee JE, Park YJ, Nam HR, Park W, Ahn YC, Huh SJ (2004) Patterns of failure in gastric carcinoma after D2 gastrectomy and chemoradiotherapy: a radiation oncologist’s view. Br J Cancer 91:11–17. doi:10.1038/sj.bjc.6601896

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  • Matsumoto K, Arao T, Hamaguchi T, Shimada Y, Kato K, Oda I, Taniguchi H, Koizumi F, Yanagihara K, Sasaki H, Nishio K, Yamada Y (2012) FGFR2 gene amplification and clinicopathological features in gastric cancer. Br J Cancer 106:727–732. doi:10.1038/bjc.2011.603

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  • Nadauld LD, Ford JM (2013) Molecular profiling of gastric cancer: toward personalized cancer medicine. J Clin Oncol 31:838–839. doi:10.1200/jco.2012.47.1714

    CAS  Article  PubMed  Google Scholar 

  • Park YS, Na YS, Ryu MH, Lee CW, Park HJ, Lee JK, Park SR, Ryoo BY, Kang YK (2015) FGFR2 assessment in gastric cancer using quantitative real-time polymerase chain reaction, fluorescent in situ hybridization, and immunohistochemistry. Am J Clin Pathol 143:865–872. doi:10.1309/ajcpnflsmwwpp8dr

    CAS  Article  PubMed  Google Scholar 

  • Peng DF, Sugihara H, Mukaisho K, Tsubosa Y, Hattori T (2003) Alterations of chromosomal copy number during progression of diffuse-type gastric carcinomas: metaphase- and array-based comparative genomic hybridization analyses of multiple samples from individual tumours. J Pathol 201:439–450. doi:10.1002/path.1459

    CAS  Article  PubMed  Google Scholar 

  • Plummer R, Madi A, Jeffels M, Richly H, Nokay B, Rubin S, Ball HA, Weller S, Botbyl J, Gibson DM, Scheulen ME (2013) A Phase I study of pazopanib in combination with gemcitabine in patients with advanced solid tumors. Cancer Chemother Pharmacol 71:93–101. doi:10.1007/s00280-012-1982-z

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  • Scagliotti GV, Felip E, Besse B, von Pawel J, Mellemgaard A, Reck M, Bosquee L, Chouaid C, Lianes-Barragan P, Paul EM, Ruiz-Soto R, Sigal E, Ottesen LH, Lechevalier T (2013) An open-label, multicenter, randomized, phase II study of pazopanib in combination with pemetrexed in first-line treatment of patients with advanced-stage non-small-cell lung cancer. J Thorac Oncol 8:1529–1537. doi:10.1097/jto.0000000000000005

    CAS  Article  PubMed  Google Scholar 

  • Takeda M, Arao T, Yokote H, Komatsu T, Yanagihara K, Sasaki H, Yamada Y, Tamura T, Fukuoka K, Kimura H, Saijo N, Nishio K (2007) AZD2171 shows potent antitumor activity against gastric cancer over-expressing fibroblast growth factor receptor 2/keratinocyte growth factor receptor. Clin Cancer Res 13:3051–3057. doi:10.1158/1078-0432.ccr-06-2743

    CAS  Article  PubMed  Google Scholar 

  • Tanaka M, Ma E, Tanaka H, Ioka A, Nakahara T, Takahashi H (2012) Trends of stomach cancer mortality in Eastern Asia in 1950-2004: comparative study of Japan, Hong Kong and Singapore using age, period and cohort analysis. Int J Cancer 130:930–936. doi:10.1002/ijc.26080

    CAS  Article  PubMed  Google Scholar 

  • Turner N, Grose R (2010) Fibroblast growth factor signalling: from development to cancer. Nat Rev Cancer 10:116–129. doi:10.1038/nrc2780

    CAS  Article  PubMed  Google Scholar 

  • Van Cutsem E, Moiseyenko VM, Tjulandin S, Majlis A, Constenla M, Boni C, Rodrigues A, Fodor M, Chao Y, Voznyi E, Risse ML, Ajani JA (2006) Phase III study of docetaxel and cisplatin plus fluorouracil compared with cisplatin and fluorouracil as first-line therapy for advanced gastric cancer: a report of the V325 Study Group. J Clin Oncol 24:4991–4997. doi:10.1200/jco.2006.06.8429

    Article  PubMed  Google Scholar 

  • Xie L, Su X, Zhang L, Yin X, Tang L, Zhang X, Xu Y, Gao Z, Liu K, Zhou M, Gao B, Shen D, Zhang L, Ji J, Gavine PR, Zhang J, Kilgour E, Zhang X, Ji Q (2013) FGFR2 gene amplification in gastric cancer predicts sensitivity to the selective FGFR inhibitor AZD4547. Clin Cancer Res 19:2572–2583. doi:10.1158/1078-0432.ccr-12-3898

    CAS  Article  PubMed  Google Scholar 

  • Yashiro M, Shinto O, Nakamura K, Tendo M, Matsuoka T, Matsuzaki T, Kaizaki R, Miwa A, Hirakawa K (2010) Synergistic antitumor effects of FGFR2 inhibitor with 5-fluorouracil on scirrhous gastric carcinoma. Int J Cancer 126:1004–1016. doi:10.1002/ijc.24763

    CAS  PubMed  Google Scholar 

  • Yoo CH, Noh SH, Shin DW, Choi SH, Min JS (2000) Recurrence following curative resection for gastric carcinoma. Br J Surg 87:236–242. doi:10.1046/j.1365-2168.2000.01360.x

    CAS  Article  PubMed  Google Scholar 

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Acknowledgments

This work was partly supported by the Samsung Medical Center Grant CRS-1110531 (J.O. Park) and by a Grant from the Korean Health Technology R&D Project, Ministry of Health & Welfare, Republic of Korea (HI14C1731 and HI14C3418). Support was also provided by a Grant from the 20 by 20 project of Samsung Medical Center (GF01140111).

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Correspondence to Joon Oh Park.

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All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards.

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Informed consent was obtained from all individual participants included in the study.

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Kim, S.T., Ahn, S., Lee, J. et al. Value of FGFR2 expression for advanced gastric cancer patients receiving pazopanib plus CapeOX (capecitabine and oxaliplatin). J Cancer Res Clin Oncol 142, 1231–1237 (2016). https://doi.org/10.1007/s00432-016-2143-2

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  • DOI: https://doi.org/10.1007/s00432-016-2143-2

Keywords

  • Pazopanib
  • FGFR2
  • Immunohistochemistry