Skip to main content

Advertisement

SpringerLink
Log in

Expression of fibroblast growth factor receptor 4 and clinical response to lenvatinib in patients with anaplastic thyroid carcinoma: a pilot study

  • Pharmacokinetics and Disposition
  • Published:
European Journal of Clinical Pharmacology Aims and scope Submit manuscript

Abstract

Purpose

Fibroblast growth factor receptor 4 (FGFR4) expression has association with tumor malignancy. In thyroid cancers, FGFR4 has been reported to be characteristically expressed in aggressive thyroid tumors, such as anaplastic thyroid carcinoma (ATC).

Methods

We investigated FGFR4 expression in patients with ATC and analyzed their clinical responses to lenvatinib. Primary tumor samples were obtained from 12 patients with ATC who underwent surgery or core needle biopsy. FGFR4 protein expression in all ATC samples was analyzed via immunohistochemistry, and the treatment efficacy of lenvatinib was evaluated.

Results

The proportion of FGFR4-positive cells in the samples ranged from 0 to 50%. Four patients had partial responses, and three patients had stable diseases as a best clinical response to lenvatinib. The median PFS durations of patients with none, weak, and moderate intensity were 0.5, 3.2 (95% CI 1.1–not estimable [NE]), and 4.6 (95% CI 1.1–NE) months, respectively (p = 0.003).

Conclusions

Because FGFR4 was expressed in ATC tissues, the FGFR4 expression might be associated with the treatment efficacy of lenvatinib in a part of ATC patients. To clarify whether FGFR4 can serve as a prognostic or predictive factor for lenvatinib therapy, more cases must be accumulated.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Powers CJ, McLeskey SW, Wellstein A (2000) Fibroblast growth factors, their receptors and signalling. Endocr Relat Cancer 7(3):165–197

    CAS  PubMed  Google Scholar 

  2. Beenken A, Mohammadi M (2009) The FGF family: biology, pathophysiology and therapy. Nat Rev Drug Discov 8:235–253

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Haugsten EM, Wiedlocha A, Olsnes S, Wesche J (2010) Roles of fibroblast growth factor receptors in carcinogenesis. Mol Cancer Res 8:1439–1452

    CAS  PubMed  Google Scholar 

  4. Ornitz DM, Itoh N (2015) The fibroblast growth factor signaling pathway. Wiley Interdiscip Rev Dev Biol 4:215–266

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Aschebrook-Kilfoy B, Ward MH, Sabra MM, Devesa SS (2011) Thyroid cancer incidence patterns in the United States by histologic type, 1992-2006. Thyroid 21:125–134

    PubMed  PubMed Central  Google Scholar 

  6. Matsuzu K, Sugino K, Masudo K, Nagahama M, Kitagawa W, Shibuya H, Ohkuwa K, Uruno T, Suzuki A, Magoshi S, Akaishi J, Masaki C, Kawano M, Suganuma N, Rino Y, Masuda M, Kameyama K, Takami H, Ito K (2014) Thyroid lobectomy for papillary thyroid cancer: long-term follow-up study of 1,088 cases. World J Surg 38:68–79

    PubMed  Google Scholar 

  7. Sugitani I, Kasai N, Fujimoto Y, Yanagisawa A (2001) Prognostic factors and therapeutic strategy for anaplastic carcinoma of the thyroid. World J Surg 25:617–622

    CAS  PubMed  Google Scholar 

  8. Tiedje V, Stuschke M, Weber F, Dralle H, Moss L, Führer D (2018) Anaplastic thyroid carcinoma: review of treatment protocols. Endocr Relat Cancer 25:153–161

    Google Scholar 

  9. Onoda N, Sugino K, Higashiyama T, Kammori M, Toda K, Ito K, Yoshida A, Suganuma N, Nakashima N, Suzuki S, Tsukahara K, Noguchi H, Koizumi M, Nemoto T, Hara H, Miyauchi A, Sugitani I (2016) The safety and efficacy of weekly paclitaxel administration for anaplastic thyroid cancer patients: a nationwide prospective study. Thyroid 26:1293–1299

    CAS  PubMed  Google Scholar 

  10. Schlumberger M, Tahara M, Wirth LJ, Robinson B, Brose MS, Elisei R, Habra MA, Newbold K, Shah MH, Hoff AO, Gianoukakis AG, Kiyota N, Taylor MH, Kim SB, Krzyzanowska MK, Dutcus CE, de las Heras B, Zhu J, Sherman SI (2015) Lenvatinib versus placebo in radioiodine-refractory thyroid cancer. N Engl J Med 372:621–630

    PubMed  Google Scholar 

  11. Takahashi S, Tahara M, Kiyota N, Yamazaki T, Chayahara N, Nakano K, Inagaki R, Toda K, Enokida T, Minami H, Imamura Y, Sasaki T, Suzuki T, Fujino K, Dutcus C (2014) Phase II study of lenvatinib (LEN), a multi-targeted tyrosine kinase inhibitor, in patients (PTS) with all histologic subtypes of advanced thyroid cancer (differentiated, medullary and anaplastic). Ann Oncol 25(Suppl 4):iv340–iv356

    Google Scholar 

  12. Kasaian K, Wiseman SM, Walker BA, Schein JE, Zhao Y, Hirst M, Moore RA, Mungall AJ, Marra MA, Jones SJ (2015) The genomic and transcriptomic landscape of anaplastic thyroid cancer: implications for therapy. BMC Cancer 15:984

    PubMed  PubMed Central  Google Scholar 

  13. Dumke AK, Pelz T, Vordermark D (2014) Long-term results of radiotherapy in anaplastic thyroid cancer. Radiat Oncol 9:90

    PubMed  PubMed Central  Google Scholar 

  14. Tahara M, Schlumberger M, Elisei R, Habra MA, Kiyota N, Paschke R, Dutcus CE, Hihara T, McGrath S, Matijevic M, Kadowaki T, Funahashi Y, Sherman SI (2017) Exploratory analysis of biomarkers associated with clinical outcomes from the study of lenvatinib in differentiated cancer of the thyroid. Eur J Cancer 75:213–221

    CAS  PubMed  Google Scholar 

  15. Shingu K, Fujimori M, Ito K, Hama Y, Kasuga Y, Kobayashi S, Itoh N, Amano J (1998) Expression of fibroblast growth factor-2 and fibroblast growth factor receptor-1 in thyroid diseases: difference between neoplasms and hyperplastic lesions. Endocr J 45:35–43

    CAS  PubMed  Google Scholar 

  16. Redler A, Di Rocco G, Giannotti D, Frezzotti F, Bernieri MG, Ceccarelli S, D'Amici S, Vescarelli E, Mitterhofer AP, Angeloni A, Marchese C (2013) Fibroblast growth factor receptor-2 expression in thyroid tumor progression: potential diagnostic application. PLoS One 8(8):e72224

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Kondo T, Zhu X, Asa SL, Ezzat S (2007) The cancer/testis antigen melanoma-associated antigen-A3/A6 is a novel target of fibroblast growth factor receptor 2-IIIb through histone H3 modifications in thyroid cancer. Clin Cancer Res 13:4713–4720

    CAS  PubMed  Google Scholar 

  18. St Bernard R, Zheng L, Liu W, Winer D, Asa SL, Ezzat S (2005) Fibroblast growth factor receptors as molecular targets in thyroid carcinoma. Endocrinology 146:1145–1153

    CAS  PubMed  Google Scholar 

  19. Huang SM, Lee JC, Wu TJ, Chow NH (2001) Clinical relevance of vascular endothelial growth factor for thyroid neoplasms. World J Surg 25:302–306

    CAS  PubMed  Google Scholar 

  20. Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey J, Arbuck S, Gwyther S, Mooney M, Rubinstein L, Shankar L, Dodd L, Kaplan R, Lacombe D, Verweij J (2009) New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 45:228–247

    CAS  PubMed  Google Scholar 

  21. Kanda Y (2013) Investigation of the freely available easy-to-use software 'EZR' for medical statistics. Bone Marrow Transplant 48:452–458

    CAS  PubMed  Google Scholar 

  22. Shi S, Li X, You B, Shan Y, Cao X, You Y (2015) High expression of FGFR4 enhances tumor growth and metastasis in nasopharyngeal carcinoma. J Cancer 6:1245–1254

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  24. Heinzle C, Erdem Z, Paur J, Grasl-Kraupp B, Holzmann K, Grusch M, Berger W, Marian B (2014) Is fibroblast growth factor receptor 4 a suitable target of cancer therapy? Curr Pharm Des 20:2881–2898

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Sugitani I, Miyauchi A, Sugino K, Okamoto T, Yoshida A, Suzuki S (2012) Prognostic factors and treatment outcomes for anaplastic thyroid carcinoma: ATC Research Consortium of Japan cohort study of 677 patients. World J Surg 36:1247–1254

    PubMed  Google Scholar 

  26. Fourati A, El Amine O, Ben Ayoub W, Cherni I, Goucha A, El May MV, Gamoudi A, El May A (2017) Expression profile of biomarkers altered in papillary and anaplastic thyroid carcinoma: contribution of Tunisian patients. Bull Cancer 104:433–441

    PubMed  Google Scholar 

  27. Xu YF, Yang XQ, Lu XF, Guo S, Liu Y, Iqbal M, Ning SL, Yang H, Suo N, Chen YX (2014) Fibroblast growth factor receptor 4 promotes progression and correlates to poor prognosis in cholangiocarcinoma. Biochem Biophys Res Commun 446:54–60

    CAS  PubMed  Google Scholar 

  28. Zaid TM, Yeung TL, Thompson MS, Leung CS, Harding T, Co NN, Schmandt RS, Kwan SY, Rodriguez-Aguay C, Lopez-Berestein G, Sood AK, Wong KK, Birrer MJ, Mok SC (2013) Identification of FGFR4 as a potential therapeutic target for advanced-stage, high-grade serous ovarian cancer. Clin Cancer Res 19:809–820

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Chen H, Shen DP, Zhang ZZ, Liu JH, Shen YY, Ni XZ (2015) Fibroblast growth factor receptor 4 protein expression and clinicopathological features in gastric cancer. World J Gastroenterol 21:1838–1844

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Li CS, Zhang SX, Liu HJ, Shi YL, Li LP, Guo XB, Zhang ZH (2014) Fibroblast growth factor receptor 4 as a potential prognostic and therapeutic marker in colorectal cancer. Biomarkers 19:81–85

    PubMed  Google Scholar 

  31. Gauglhofer C, Paur J, Schrottmaier WC, Wingelhofer B, Huber D, Naegelen I, Pirker C, Mohr T, Heinzle C, Holzmann K, Marian B, Schulte-Hermann R, Berger W, Krupitza G, Grusch M, Grasl-Kraupp B (2014) Fibroblast growth factor receptor 4: a putative key driver for the aggressive phenotype of hepatocellular carcinoma. Carcinogenesis 35:2331–2338

    CAS  PubMed  Google Scholar 

  32. Motoda N, Matsuda Y, Onda M, Ishiwata T, Uchida E, Naito Z (2011) Overexpression of fibroblast growth factor receptor 4 in high-grade pancreatic intraepithelial neoplasia and pancreatic ductal adenocarcinoma. Int J Oncol 38:133–143

    CAS  PubMed  Google Scholar 

  33. Peláez-García A, Barderas R, Torres S, Hernández-Varas P, Teixidó J, Bonilla F, de Herreros AG, Casal JI (2013) FGFR4 role in epithelial-mesenchymal transition and its therapeutic value in colorectal cancer. PLoS One 8(5):e63695

    PubMed  PubMed Central  Google Scholar 

  34. Hagel M, Miduturu C, Sheets M, Rubin N, Weng W, Stransky N, Bifulco N, Kim JL, Hodous B, Brooijmans N, Shutes A, Winter C, Lengauer C, Kohl NE, Guzi T (2015) First selective small molecule inhibitor of FGFR4 for the treatment of hepatocellular carcinomas with an activated FGFR4 signaling pathway. Cancer Discov 5:424–437

    CAS  PubMed  Google Scholar 

  35. Ezzat S, Huang P, Dackiw A, Asa SL (2005) Dual inhibition of RET and FGFR4 restrains medullary thyroid cancer cell growth. Clin Cancer Res 11:1336–1341

    CAS  PubMed  Google Scholar 

  36. Pinto MP, Sotomayor P, Carrasco-Avino G, Corvalan AH, Owen GI (2016) Escaping antiangiogenic therapy: strategies employed by cancer cells. Int J Mol Sci 17:E1489

    PubMed  Google Scholar 

  37. Yamamoto Y, Matsui J, Matsushima T, Obaishi H, Miyazaki K, Nakamura K, Tohyama O, Semba T, Yamaguchi A, Hoshi SS, Mimura F, Haneda T, Fukuda Y, Kamata JI, Takahashi K, Matsukura M, Wakabayashi T, Asada M, Nomoto KI, Watanabe T, Dezso Z, Yoshimatsu K, Funahashi Y, Tsuruoka A (2014) Lenvatinib, an angiogenesis inhibitor targeting VEGFR/FGFR, shows broad antitumor activity in human tumor xenograft models associated with microvessel density and pericyte coverage. Vasc Cell 6:18

    PubMed  PubMed Central  Google Scholar 

  38. Yamazaki H, Yokose T, Hayashi H, Iwasaki H, Osanai S, Suganuma N, Nakayama H, Masudo K, Rino Y, Masuda M (2018) Expression of vascular endothelial growth factor receptor 2 and clinical response to lenvatinib in patients with anaplastic thyroid cancer. Cancer Chemother Pharmacol 82:649–654

    PubMed  Google Scholar 

  39. Hoshi T, Watanabe Miyano S, Watanabe H, Sonobe RMK, Seki Y, Ohta E, Nomoto K, Matsui J, Funahashi Y (2019) Lenvatinib induces death of human hepatocellular carcinoma cells harboring an activated FGF signaling pathway through inhibition of FGFR-MAPK cascades. Biochem Biophys Res Commun 513:1–7

    CAS  PubMed  Google Scholar 

  40. van Heeckeren WJ, Ortiz J, Cooney MM, Remick SC (2007) Hypertension, proteinuria, and antagonism of vascular endothelial growth factor signaling: clinical toxicity, therapeutic target, or novel biomarker? J Clin Oncol 25:2993–2995

    PubMed  Google Scholar 

  41. Robinson B, Schlumberger M, Wirth LJ, Dutcus CE, Song J, Taylor MH, Kim SB, Krzyzanowska MK, Capdevila J, Sherman SI, Tahara M (2016) Characterization of tumor size changes over time from the phase 3 study of lenvatinib in thyroid cancer. J Clin Endocrinol Metab 101:4103–4109

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgments

We thank Enago (https://www.enago.jp/) for editing a draft of this manuscript.

Author information

Authors and Affiliations

  1. Department of Breast and Endocrine Surgery, Kanagawa Cancer Center, 2-3-2 Nakao, Asahiku, Yokohama City, Kanagawa, Japan

    Haruhiko Yamazaki, Hiroyuki Iwasaki & Nobuyasu Suganuma

  2. Department of Pathology, Kanagawa Cancer Center, 2-3-2 Nakao, Asahiku, Yokohama City, Kanagawa, Japan

    Tomoyuki Yokose, Hiroyuki Hayashi & Sachie Osanai

  3. Department of Surgery, Yokohama City University School of Medicine, 3-9 Fukuura, Kanazawaku, Yokohama City, Kanagawa, Japan

    Hirotaka Nakayama, Yasushi Rino & Munetaka Masuda

  4. Department of Breast and Thyroid Surgery, Yokohama City University Medical Center, 4-57 Urafunecho, Minamiku, Yokohama City, Kanagawa, Japan

    Katsuhiko Masudo

Authors
  1. Haruhiko Yamazaki
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Tomoyuki Yokose
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Hiroyuki Hayashi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Hiroyuki Iwasaki
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Sachie Osanai
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Nobuyasu Suganuma
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Hirotaka Nakayama
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Katsuhiko Masudo
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Yasushi Rino
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Munetaka Masuda
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

HY prepared the manuscript. TY, HH, and SO performed pathological and immunohistochemical examinations. HI, NS, HN, and KM cared for the patient. YR and MM comprehensively supervised this case report. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Haruhiko Yamazaki.

Ethics declarations

Written informed consent was obtained from all patients before inclusion in the study. The study protocol was approved by the institutional review board of Kanagawa Cancer Center.

Conflict of interest

The authors declare that they have no competing interests.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Yamazaki, H., Yokose, T., Hayashi, H. et al. Expression of fibroblast growth factor receptor 4 and clinical response to lenvatinib in patients with anaplastic thyroid carcinoma: a pilot study. Eur J Clin Pharmacol 76, 703–709 (2020). https://doi.org/10.1007/s00228-020-02842-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00228-020-02842-y

Keywords

Search

Navigation