Download PDF
Horm Metab Res 2019; 51(01): 69-75
DOI: 10.1055/a-0765-9078
Endocrine Care
© Georg Thieme Verlag KG Stuttgart · New York

BRAF V600E and Retinoic Acid in Radioiodine-Refractory Papillary Thyroid Cancer

Jan Benedikt Groener  
1   Department of Endocrinology and Clinical Chemistry, Heidelberg University Hospital, Heidelberg, Germany
,
Debora Gelen  
1   Department of Endocrinology and Clinical Chemistry, Heidelberg University Hospital, Heidelberg, Germany
,
Carolin Mogler
2   Department of Pathology, Technical University of Munich, Munich, Germany
,
Esther Herpel
3   Tissue Bank of the National Center for Tumor Diseases (NCT) Heidelberg, Heidelberg, Germany
4   Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany
,
Csaba Toth
3   Tissue Bank of the National Center for Tumor Diseases (NCT) Heidelberg, Heidelberg, Germany
4   Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany
,
Zoltan Kender
1   Department of Endocrinology and Clinical Chemistry, Heidelberg University Hospital, Heidelberg, Germany
,
Marco Peichl
5   Department of Nuclear Medicine, Heidelberg University Hospital, Heidelberg, Germany
,
Sabine Haufe
5   Department of Nuclear Medicine, Heidelberg University Hospital, Heidelberg, Germany
,
Uwe Haberkorn
5   Department of Nuclear Medicine, Heidelberg University Hospital, Heidelberg, Germany
6   Clinical Cooperation Unit Nuclear Medicine, Deutsches Krebsforschungszentrum, Heidelberg, Germany
,
Alba Sulaj
1   Department of Endocrinology and Clinical Chemistry, Heidelberg University Hospital, Heidelberg, Germany
,
Johanna Zemva
1   Department of Endocrinology and Clinical Chemistry, Heidelberg University Hospital, Heidelberg, Germany
,
Stefan Kopf
1   Department of Endocrinology and Clinical Chemistry, Heidelberg University Hospital, Heidelberg, Germany
,
Peter Paul Nawroth
1   Department of Endocrinology and Clinical Chemistry, Heidelberg University Hospital, Heidelberg, Germany
,
Maik Brune  
1   Department of Endocrinology and Clinical Chemistry, Heidelberg University Hospital, Heidelberg, Germany
,
Gottfried Rudofsky  
1   Department of Endocrinology and Clinical Chemistry, Heidelberg University Hospital, Heidelberg, Germany
7   Department of Endocrinology, Cantonal Hospital Olten, Olten, Switzerland
› Author Affiliations
Further Information

Publication History

received 22 August 2018

accepted 11 October 2018

Publication Date:
05 November 2018 (online)

Also available at
    Permissions and Reprints

Abstract

Radioiodine refractoriness in differentiated thyroid cancer remains an unsolved therapeutic problem. Response to retinoids might depend on specific genetic markers. In this retrospective analysis, associations between BRAF V600E and clinical outcomes after redifferentiation with retinoic acid (RA) and radioiodine therapy (RIT) were investigated. Thirteen patients with radioiodine-refractory (RAI-R) papillary thyroid cancer (PTC) were treated with 13-cis-RA followed by iodine-131 treatment at the Department of Endocrinology, Heidelberg University Hospital, Heidelberg, Germany. DNA sequencing was performed in formalin-fixed paraffin-embedded tissue. Clinical outcome parameters were tumor size, thyroglobulin, and radioiodine uptake in correlation to mutational status. Differences of each parameter were compared before and after RA/RIT. Initial response showed no difference in patients with BRAF V600E compared to patients with wild type. However, after a median follow-up of 2 and a half years, 2 out of 3 patients with BRAF V600E showed response compared to 5 out of 9 with wild type under consideration of all 3 parameters. In this small cohort, more RAI-R PTC patients with BRAF V600E receiving redifferentiation therapy showed response. Verification in a larger study population analyzing mutational status in patients with RAI-R PTC might be helpful to identify patients where redifferentiation therapy might lead to an improved outcome.

Key words

differentiated thyroid cancer - radioiodine therapy - retinoic acid - genetic markers

* These 2 authors contributed equally to this publication and share first authorship


#  These 2 authors contributed equally to this publication and share senior authorship


 

  • References

  • 1 Xing M, Alzahrani AS, Carson KA, Shong YK, Kim TY, Viola D, Elisei R, Bendlova B, Yip L, Mian C, Vianello F, Tuttle RM, Robenshtok E, Fagin JA, Puxeddu E, Fugazzola L, Czarniecka A, Jarzab B, O'Neill CJ, Sywak MS, Lam AK, Riesco-Eizaguirre G, Santisteban P, Nakayama H, Clifton-Bligh R, Tallini G, Holt EH, Sykorova V. Association between BRAF V600E mutation and recurrence of papillary thyroid cancer. J Clin Oncol 2015; 33: 42-50
    PubMedGoogle Scholar
  • 2 Ehlers M, Allelein S, Schwarz F, Hautzel H, Kuebart A, Schmidt M, Haase M, Dringenberg T, Schott M. Increased numbers of circulating tumor cells in thyroid cancer patients. Horm Metab Res 2018; 50: 602-608
    Article in Thieme ConnectPubMedGoogle Scholar
  • 3 Brose MS, Nutting CM, Jarzab B, Elisei R, Siena S, Bastholt L, de la Fouchardiere C, Pacini F, Paschke R, Shong YK, Sherman SI, Smit JW, Chung J, Kappeler C, Pena C, Molnar I, Schlumberger MJ. Sorafenib in radioactive iodine-refractory, locally advanced or metastatic differentiated thyroid cancer: A randomised, double-blind, phase 3 trial. Lancet 2014; 384: 319-328
    CrossrefPubMedGoogle Scholar
  • 4 Ho AL, Grewal RK, Leboeuf R, Sherman EJ, Pfister DG, Deandreis D, Pentlow KS, Zanzonico PB, Haque S, Gavane S, Ghossein RA, Ricarte-Filho JC, Dominguez JM, Shen R, Tuttle RM, Larson SM, Fagin JA. Selumetinib-enhanced radioiodine uptake in advanced thyroid cancer. N Engl J Med 2013; 368: 623-632
    CrossrefPubMedGoogle Scholar
  • 5 Kasperk C, Anamaterou C, Haufe S, Schimmack S. Schilddrüsenkarzinom. Heidelberg: Nationales Centrum für Tumorerkrankungen Heidelberg; 2015
    Google Scholar
  • 6 Durante C, Haddy N, Baudin E, Leboulleux S, Hartl D, Travagli JP, Caillou B, Ricard M, Lumbroso JD, De Vathaire F, Schlumberger M. Long-term outcome of 444 patients with distant metastases from papillary and follicular thyroid carcinoma: Benefits and limits of radioiodine therapy. J Clin Endocrinol Metab 2006; 91: 2892-2899
    CrossrefPubMedGoogle Scholar
  • 7 Spitzweg C, Bible KC, Hofbauer LC, Morris JC. Advanced radioiodine-refractory differentiated thyroid cancer: The sodium iodide symporter and other emerging therapeutic targets. Lancet Diabetes Endocrinol 2014; 2: 830-842
    CrossrefPubMedGoogle Scholar
  • 8 Dadu R, Cabanillas ME. Optimizing therapy for radioactive iodine-refractory differentiated thyroid cancer: Current state of the art and future directions. Minerva Endocrinol 2012; 37: 335-356
    PubMedGoogle Scholar
  • 9 Xing M. Molecular pathogenesis and mechanisms of thyroid cancer. Nat Rev Cancer 2013; 13: 184-199
    CrossrefPubMedGoogle Scholar
  • 10 Holzer K, Drucker E, Oliver S, Winkler J, Eiteneuer E, Herpel E, Breuhahn K, Singer S. Cellular apoptosis susceptibility (CAS) is overexpressed in thyroid carcinoma and maintains tumor cell growth: A potential link to the BRAFV600E mutation. Int J Oncol 2016; 48: 1679-1687
    CrossrefPubMedGoogle Scholar
  • 11 Cantwell-Dorris ER, O'Leary JJ, Sheils OM. BRAFV600E: Implications for carcinogenesis and molecular therapy. Mol Cancer Therap 2011; 10: 385-394
    CrossrefPubMedGoogle Scholar
  • 12 Schmidt A, Iglesias L, Klain M, Pitoia F, Schlumberger MJ. Radioactive iodine-refractory differentiated thyroid cancer: An uncommon but challenging situation. Arch Endocrinol Metab 2017; 61: 8189
    PubMedGoogle Scholar
  • 13 Coelho SM, Vaisman F, Buescu A, Mello RC, Carvalho DP, Vaisman M. Follow-up of patients treated with retinoic acid for the control of radioiodine non-responsive advanced thyroid carcinoma. Braz J Med Biol Res 2011; 44: 73-77
    PubMedGoogle Scholar
  • 14 Elisei R, Ugolini C, Viola D, Lupi C, Biagini A, Giannini R, Romei C, Miccoli P, Pinchera A, Basolo F. BRAF(V600E) mutation and outcome of patients with papillary thyroid carcinoma: A 15-year median follow-up study. J Clin Endocrinol Metab 2008; 93: 3943-3949
    CrossrefPubMedGoogle Scholar
  • 15 Ricarte-Filho JC, Ryder M, Chitale DA, Rivera M, Heguy A, Ladanyi M, Janakiraman M, Solit D, Knauf JA, Tuttle RM, Ghossein RA, Fagin JA. Mutational profile of advanced primary and metastatic radioactive iodine-refractory thyroid cancers reveals distinct pathogenetic roles for BRAF, PIK3CA, and AKT1. Cancer Res 2009; 69: 4885-4893
    CrossrefPubMedGoogle Scholar
  • 16 Yang K, Wang H, Liang Z, Liang J, Li F, Lin Y. BRAFV600E mutation associated with non-radioiodine-avid status in distant metastatic papillary thyroid carcinoma. Clin Nucl Med 2014; 39: 675-679
    CrossrefPubMedGoogle Scholar
  • 17 Spitzweg C, Auernhammer CJ, Geisler J, Bock S, Heinemann V, Bartenstein P, Goke B. [Advanced radioiodine-refractory differentiated thyroid cancer]. Dtsch Med Wochenschr (1946) 2015; 140: 168-171
    Article in Thieme ConnectPubMedGoogle Scholar
  • 18 Chung JK, Youn HW, Kang JH, Lee HY, Kang KW. Sodium iodide symporter and the radioiodine treatment of thyroid carcinoma. Nucl Med Mol Imag 2010; 44: 4-14
    PubMedGoogle Scholar
  • 19 Xia Y, Chen J, Gong C, Chen H, Sun J. alpha-Mangostin, a Natural Agent, Enhances the Response of NRAS Mutant Melanoma to Retinoic Acid. Med Sci Monit 2016; 22: 1360-1367
    CrossrefPubMedGoogle Scholar
  • 20 Fernandez CA, Puig-Domingo M, Lomena F, Estorch M, Camacho Marti V, Bittini AL, Marazuela M, Santamaria J, Castro J, Martinez de Icaya P, Moraga I, Martin T, Megia A, Porta M, Mauricio D, Halperin I. Effectiveness of retinoic acid treatment for redifferentiation of thyroid cancer in relation to recovery of radioiodine uptake. J Endocrinol Invest 2009; 32: 228-233
    CrossrefPubMedGoogle Scholar
  • 21 Haberkorn U, Haufe S, Kasperk C. Standardprotokoll der Vitamin-A-Säure-Redifferenzierungstherapie der Universitätsklinik Heidelberg. Heidelberg: Abteilung Nuklearmedizin in Kooperation mit Innere Medizin I, Universitätsklinik Heidelberg; 2004
    Google Scholar
  • 22 Simon D, Korber C, Krausch M, Segering J, Groth P, Gorges R, Grunwald F, Muller-Gartner HW, Schmutzler C, Kohrle J, Roher HD, Reiners C. Clinical impact of retinoids in redifferentiation therapy of advanced thyroid cancer: Final results of a pilot study. Eur J Nucl Med Mol Imag 2002; 29: 775-782
    CrossrefPubMedGoogle Scholar
  • 23 Verburg FA, Mader U, Grelle I, Giovanella L, Reiners C, Hanscheid H. Only a Rapid Complete Biochemical Remission After 131I-Therapy is Associated with an Unimpaired Life Expectancy in Differentiated Thyroid Cancer. Horm Metab Res 2017; 49: 860-868
    Article in Thieme ConnectPubMedGoogle Scholar
  • 24 Oh SW, Moon SH, Park DJ, Cho BY, Jung KC, Lee DS, Chung JK. Combined therapy with 131I and retinoic acid in Korean patients with radioiodine-refractory papillary thyroid cancer. Eur J Nucl Med Mol Imag. 2011; 38: 1798-1805
    PubMedGoogle Scholar
  • 25 Frohlich E, Wahl R. The current role of targeted therapies to induce radioiodine uptake in thyroid cancer. Cancer Treat Rev 2014; 40: 665-674
    CrossrefPubMedGoogle Scholar
  • 26 Kim WG, Kim EY, Kim TY, Ryu JS, Hong SJ, Kim WB, Shong YK. Redifferentiation therapy with 13-cis retinoic acids in radioiodine-resistant thyroid cancer. Endocr J 2009; 56: 105-112
    CrossrefPubMedGoogle Scholar
  • 27 Gruber JJ, Colevas AD. Differentiated thyroid cancer: Focus on emerging treatments for radioactive iodine-refractory patients. Oncologist 2015; 20: 113-126
    CrossrefPubMedGoogle Scholar
  • 28 Rothenberg SM, McFadden DG, Palmer EL, Daniels GH, Wirth LJ. Redifferentiation of iodine-refractory BRAF V600E-mutant metastatic papillary thyroid cancer with dabrafenib. Clin Cancer Res 2015; 21: 1028-1035
    CrossrefPubMedGoogle Scholar
  • 29 Grunwald F, Pakos E, Bender H, Menzel C, Otte R, Palmedo H, Pfeifer U, Biersack HJ. Redifferentiation therapy with retinoic acid in follicular thyroid cancer. J Nucl Med 1998; 39: 1555-1558
    PubMedGoogle Scholar
  • 30 Fallahi P, Mazzi V, Vita R, Ferrari SM, Materazzi G, Galleri D, Benvenga S, Miccoli P, Antonelli A. New therapies for dedifferentiated papillary thyroid cancer. Int J Mol Sci 2015; 16: 6153-6182
    CrossrefPubMedGoogle Scholar
  • 31 Kogai T, Brent GA. The sodium iodide symporter (NIS): Regulation and approaches to targeting for cancer therapeutics. Pharmacol Therap 2012; 135: 355-370
    CrossrefPubMedGoogle Scholar
  • 32 Mann K, Möller LC, Bockisch A, Quadbeck B, Schmid KW, Janssen OE. Chemotherapie beim Schilddrüsenkarzinom. Onkologe 2005; 11: 78-86
    CrossrefPubMedGoogle Scholar
  • 33 Hussein O, Karen D, Zidan J. Cisplatin based chemotherapy in patients with advanced differentiated thyroid carcinoma refractory to I131 treatment. Indian J Med Paediatr Oncol 2013; 34: 234-237
    Article in Thieme ConnectPubMedGoogle Scholar
  • 34 Gruning T, Tiepolt C, Zophel K, Bredow J, Kropp J, Franke WG. Retinoic acid for redifferentiation of thyroid cancer–does it hold its promise?. Eur J Endocrinol 2003; 148: 395-402
    CrossrefPubMedGoogle Scholar
  • 35 Coelho SM, Corbo R, Buescu A, Carvalho DP, Vaisman M. Retinoic acid in patients with radioiodine non-responsive thyroid carcinoma. J Endocrinol Invest 2004; 27: 334-339
    CrossrefPubMedGoogle Scholar
  • 36 Short SC, Suovuori A, Cook G, Vivian G, Harmer C. A phase II study using retinoids as redifferentiation agents to increase iodine uptake in metastatic thyroid cancer. Clinical oncology (Royal College of Radiologists (Great Britain)) 2004; 16: 569-574
    CrossrefPubMedGoogle Scholar
  • 37 Simon D, Koehrle J, Reiners C, Boerner AR, Schmutzler C, Mainz K, Goretzki PE, Roeher HD. Redifferentiation therapy with retinoids: Therapeutic option for advanced follicular and papillary thyroid carcinoma. World J Surg 1998; 22: 569-574
    CrossrefPubMedGoogle Scholar
  • 38 Sherman SI, Wirth LJ, Droz JP, Hofmann M, Bastholt L, Martins RG, Licitra L, Eschenberg MJ, Sun YN, Juan T, Stepan DE, Schlumberger MJ. Motesanib diphosphate in progressive differentiated thyroid cancer. N Eng J Med 2008; 359: 31-42
    CrossrefPubMedGoogle Scholar
  • 39 Ferrari SM, Politti U, Spisni R, Materazzi G, Baldini E, Ulisse S, Miccoli P, Antonelli A, Fallahi P. Sorafenib in the treatment of thyroid cancer. Exp Rev Anticancer Ther 2015; 15: 863-874
    CrossrefPubMedGoogle Scholar
  • 40 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. Lenvatinib versus placebo in radioiodine-refractory thyroid cancer. N Eng J Med 2015; 372: 621-630
    CrossrefPubMedGoogle Scholar
  • 41 Guerra A, Fugazzola L, Marotta V, Cirillo M, Rossi S, Cirello V, Forno I, Moccia T, Budillon A, Vitale M. A high percentage of BRAFV600E alleles in papillary thyroid carcinoma predicts a poorer outcome. J Clin Endocrinol Metab 2012; 97: 2333-2340
    CrossrefPubMedGoogle Scholar
  • 42 Kang SH, Pyo JY, Yang SW, Hong SW. Detection of BRAF V600E mutation with thyroid tissue using pyrosequencing: Comparison with PNA-clamping and real-time PCR. Am J Clin Pathol 2013; 139: 759-764
    CrossrefPubMedGoogle Scholar
  • 43 Krajewska J, Handkiewicz-Junak D, Jarzab B. Sorafenib for the treatment of thyroid cancer: An updated review. Exp Opin Pharmacother 2015; 16: 573-583
    CrossrefPubMedGoogle Scholar
  • 44 Schlumberger M, Tahara M, Wirth LJ. Lenvatinib in radioiodine-refractory thyroid cancer. N Engl J Med 2015; 372: 1868
    CrossrefPubMedGoogle Scholar