Novel Targeted Therapies for Metastatic Thyroid Cancer-A Comprehensive Review

Mohammad Al-Jundi, Shilpa Thakur, Sriram Gubbi, Joanna Klubo-Gwiezdzinska, Mohammad Al-Jundi, Shilpa Thakur, Sriram Gubbi, Joanna Klubo-Gwiezdzinska

Abstract

The knowledge on thyroid cancer biology has grown over the past decade. Thus, diagnostic and therapeutic strategies to manage thyroid cancer are rapidly evolving. With new insights into tumor biology and cancer genetics, several novel therapies have been approved for the treatment of thyroid cancer. Tyrosine kinase inhibitors (TKIs), such as lenvatinib and sorafenib, have been successfully utilized for the treatment of radioactive iodine (RAI)-refractory metastatic differentiated thyroid cancer (DTC). In addition, pretreatment with mitogen-activated protein kinase (MAPK) inhibitors (trametinib and selumetinib) has been shown to restore RAI avidity in previously RAI-refractory DTCs. Local therapies, such as external beam radiation and radiofrequency/ethanol ablation, have also been employed for treatment of DTC. Vandetanib and cabozantinib are the two TKIs currently approved by the Food and Drug Administration (FDA) for the treatment of medullary thyroid cancer (MTC). Other novel therapies, such as peptide receptor radionuclide therapy and carcinoembryonic antigen (CEA) vaccine, have also been utilized in treating MTC. Ongoing trials on selective rearranged-during-transfection (RET) protooncogene inhibitors, such as LOXO-292 and BLU-667, have demonstrated promising results in the treatment of metastatic MTC resistant to non-selective TKIs. The FDA-approved BRAF/MEK inhibitor combination of dabrafenib and trametinib has revolutionized treatment of BRAFV600E mutation positive anaplastic thyroid cancer. Several other emerging classes of medications, such as gene fusion inhibitors and immune checkpoint inhibitors, are being actively investigated in several clinical trials. In this review, we describe the molecular landscape of thyroid cancer and novel targeted therapies and treatment combinations available for the treatment of metastatic thyroid cancer.

Keywords: immunotherapy; targeted therapy; thyroid cancer; tyrosine kinase inhibitors.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Genetic alterations affecting MAPK and PI3K signaling pathways in thyroid cancer.
Figure 2
Figure 2
Genetic alterations affecting nuclear processes in thyroid cancer. The figure shows mutations/gene fusions affecting nuclear processes such as transcription, DNA repair, and epigenetic regulation of genes to promote oncogenesis. The genes that have been observed to be mutated in thyroid cancer are shown in red with an asterisk.
Figure 3
Figure 3
Mechanism of RAI resistance and its reversal with targeted therapies. (A) Under normal conditions, expression of sodium-iodine symporter (NIS) is regulated through TSHR, resulting in stimulation of thyroid-specific transcriptional factors such as PAX8, which promotes NIS transcription and its expression on the cell surface. (B) In thyroid tumor cells with hyperactive MAPK and PI3K/AKT signaling, the NIS transcription is repressed, resulting in loss of its cell surface expression and RAI resistance. (C) Targeted treatment with inhibitors that block the MAPK/PI3K signaling pathways improves NIS expression and RAI avidity. * Trastuzumab has been tested in breast cancer model to target HER2 signaling but not in thyroid cancer model.
Figure 4
Figure 4
Targeted therapies for the treatment of thyroid cancer. The figure shows inhibitor drug molecules targeting various RTKs, components of MAPK and PI3K signaling pathways, and gene fusions in thyroid cancer. The immunotherapeutic agents, PRRT molecules, and a vaccine with the potential for the treatment of thyroid cancer are also included in the figure.

References

    1. American Cancer Society . Cancer Facts and Figures. American Cancer Society; Atlanta, GA, USA: 2020.
    1. Fagin J.A., Wells S.A., Jr. Biologic and clinical perspectives on thyroid cancer. N. Engl. J. Med. 2016;375:1054–1067. doi: 10.1056/NEJMra1501993.
    1. Haugen B.R., Alexander E.K., Bible K.C., Doherty G.M., Mandel S.J., Nikiforov Y.E., Pacini F., Randolph G.W., Sawka A.M., Schlumberger M., et al. 2015 American Thyroid Association Management Guidelines for Adult Patients with Thyroid Nodules and Differentiated Thyroid Cancer: The American Thyroid Association Guidelines Task Force on Thyroid Nodules and Differentiated Thyroid Cancer. Thyroid Off. J. Am. Thyroid Assoc. 2016;26:1–133. doi: 10.1089/thy.2015.0020.
    1. Tuttle R.M., Ahuja S., Avram A.M., Bernet V.J., Bourguet P., Daniels G.H., Dillehay G., Draganescu C., Flux G., Führer D. Controversies, Consensus, and Collaboration in the Use of 131I Therapy in Differentiated Thyroid Cancer: A Joint Statement from the American Thyroid Association, the European Association of Nuclear Medicine, the Society of Nuclear Medicine and Molecular Imaging, and the European Thyroid Association. Thyroid. 2019;29:461–470.
    1. Wells S.A., Jr., Asa S.L., Dralle H., Elisei R., Evans D.B., Gagel R.F., Lee N., Machens A., Moley J.F., Pacini F. Revised American Thyroid Association guidelines for the management of medullary thyroid carcinoma: The American Thyroid Association Guidelines Task Force on medullary thyroid carcinoma. Thyroid. 2015;25:567–610. doi: 10.1089/thy.2014.0335.
    1. Roman S., Lin R., Sosa J.A. Prognosis of medullary thyroid carcinoma: Demographic, clinical, and pathologic predictors of survival in 1252 cases. Cancer Interdiscip. Int. J. Am. Cancer Soc. 2006;107:2134–2142. doi: 10.1002/cncr.22244.
    1. Tirro E., Martorana F., Romano C., Vitale S.R., Motta G., Di Gregorio S., Massimino M., Pennisi M.S., Stella S., Puma A., et al. Molecular Alterations in Thyroid Cancer: From Bench to Clinical Practice. Genes. 2019;10:709. doi: 10.3390/genes10090709.
    1. Khatami F., Tavangar S.M. A Review of Driver Genetic Alterations in Thyroid Cancers. Iran. J. Pathol. 2018;13:125–135. doi: 10.30699/ijp.13.2.125.
    1. Kebebew E., Weng J., Bauer J., Ranvier G., Clark O.H., Duh Q.Y., Shibru D., Bastian B., Griffin A. The prevalence and prognostic value of BRAF mutation in thyroid cancer. Ann. Surg. 2007;246:466–470. doi: 10.1097/SLA.0b013e318148563d.
    1. Ganly I., Makarov V., Deraje S., Dong Y., Reznik E., Seshan V., Nanjangud G., Eng S., Bose P., Kuo F., et al. Integrated Genomic Analysis of Hurthle Cell Cancer Reveals Oncogenic Drivers, Recurrent Mitochondrial Mutations, and Unique Chromosomal Landscapes. Cancer Cell. 2018;34:256–270.e5. doi: 10.1016/j.ccell.2018.07.002.
    1. Cancer Genome Atlas Research N. Integrated genomic characterization of papillary thyroid carcinoma. Cell. 2014;159:676–690. doi: 10.1016/j.cell.2014.09.050.
    1. Censi S., Cavedon E., Bertazza L., Galuppini F., Watutantrige-Fernando S., De Lazzari P., Nacamulli D., Pennelli G., Fassina A., Iacobone M., et al. Frequency and Significance of Ras, Tert Promoter, and Braf Mutations in Cytologically Indeterminate Thyroid Nodules: A Monocentric Case Series at a Tertiary-Level Endocrinology Unit. Front. Endocrinol. (Lausanne) 2017;8:273. doi: 10.3389/fendo.2017.00273.
    1. Ciampi R., Mian C., Fugazzola L., Cosci B., Romei C., Barollo S., Cirello V., Bottici V., Marconcini G., Rosa P.M., et al. Evidence of a low prevalence of RAS mutations in a large medullary thyroid cancer series. Thyroid Off. J. Am. Thyroid Assoc. 2013;23:50–57. doi: 10.1089/thy.2012.0207.
    1. Ciampi R., Romei C., Ramone T., Prete A., Tacito A., Cappagli V., Bottici V., Viola D., Torregrossa L., Ugolini C., et al. Genetic Landscape of Somatic Mutations in a Large Cohort of Sporadic Medullary Thyroid Carcinomas Studied by Next-Generation Targeted Sequencing. iScience. 2019;20:324–336. doi: 10.1016/j.isci.2019.09.030.
    1. Xing M. Clinical utility of RAS mutations in thyroid cancer: A blurred picture now emerging clearer. BMC Med. 2016;14:12. doi: 10.1186/s12916-016-0559-9.
    1. Schulten H.J., Salama S., Al-Ahmadi A., Al-Mansouri Z., Mirza Z., Al-Ghamdi K., Al-Hamour O.A., Huwait E., Gari M., Al-Qahtani M.H., et al. Comprehensive survey of HRAS, KRAS, and NRAS mutations in proliferative thyroid lesions from an ethnically diverse population. Anticancer Res. 2013;33:4779–4784.
    1. Howell G.M., Hodak S.P., Yip L. RAS mutations in thyroid cancer. Oncologist. 2013;18:926–932. doi: 10.1634/theoncologist.2013-0072.
    1. Xing M., Westra W.H., Tufano R.P., Cohen Y., Rosenbaum E., Rhoden K.J., Carson K.A., Vasko V., Larin A., Tallini G., et al. BRAF mutation predicts a poorer clinical prognosis for papillary thyroid cancer. J. Clin. Endocrinol. Metab. 2005;90:6373–6379. doi: 10.1210/jc.2005-0987.
    1. Paragliola R.M., Corsello A., Del Gatto V., Papi G., Pontecorvi A., Corsello S.M. Lenvatinib for thyroid cancer treatment: Discovery, pre-clinical development and clinical application. Expert Opin. Drug Discov. 2020;15:11–26. doi: 10.1080/17460441.2020.1674280.
    1. Bond J.A., Wyllie F.S., Rowson J., Radulescu A., Wynford-Thomas D. In vitro reconstruction of tumour initiation in a human epithelium. Oncogene. 1994;9:281–290.
    1. Liu Z., Hou P., Ji M., Guan H., Studeman K., Jensen K., Vasko V., El-Naggar A.K., Xing M. Highly prevalent genetic alterations in receptor tyrosine kinases and phosphatidylinositol 3-kinase/akt and mitogen-activated protein kinase pathways in anaplastic and follicular thyroid cancers. J. Clin. Endocrinol. Metab. 2008;93:3106–3116. doi: 10.1210/jc.2008-0273.
    1. Pozdeyev N., Gay L.M., Sokol E.S., Hartmaier R., Deaver K.E., Davis S., French J.D., Borre P.V., LaBarbera D.V., Tan A.C., et al. Genetic Analysis of 779 Advanced Differentiated and Anaplastic Thyroid Cancers. Clin. Cancer Res. 2018;24:3059–3068. doi: 10.1158/1078-0432.CCR-18-0373.
    1. Guigon C.J., Zhao L., Willingham M.C., Cheng S.Y. PTEN deficiency accelerates tumour progression in a mouse model of thyroid cancer. Oncogene. 2009;28:509–517. doi: 10.1038/onc.2008.407.
    1. Shinohara M., Chung Y.J., Saji M., Ringel M.D. AKT in thyroid tumorigenesis and progression. Endocrinology. 2007;148:942–947. doi: 10.1210/en.2006-0937.
    1. Ringel M.D., Hayre N., Saito J., Saunier B., Schuppert F., Burch H., Bernet V., Burman K.D., Kohn L.D., Saji M. Overexpression and overactivation of Akt in thyroid carcinoma. Cancer Res. 2001;61:6105–6111.
    1. Garcia-Rostan G., Costa A.M., Pereira-Castro I., Salvatore G., Hernandez R., Hermsem M.J., Herrero A., Fusco A., Cameselle-Teijeiro J., Santoro M. Mutation of the PIK3CA gene in anaplastic thyroid cancer. Cancer Res. 2005;65:10199–10207. doi: 10.1158/0008-5472.CAN-04-4259.
    1. Jhiang S.M., Sagartz J.E., Tong Q., Parker-Thornburg J., Capen C.C., Cho J.Y., Xing S., Ledent C. Targeted expression of the ret/PTC1 oncogene induces papillary thyroid carcinomas. Endocrinology. 1996;137:375–378. doi: 10.1210/endo.137.1.8536638.
    1. Putzer B.M., Drosten M. The RET proto-oncogene: A potential target for molecular cancer therapy. Trends Mol. Med. 2004;10:351–357. doi: 10.1016/j.molmed.2004.06.002.
    1. Taccaliti A., Silvetti F., Palmonella G., Boscaro M. Genetic alterations in medullary thyroid cancer: Diagnostic and prognostic markers. Curr. Genom. 2011;12:618–625. doi: 10.2174/138920211798120835.
    1. Huang F.W., Feng F.Y. A Tumor-Agnostic NTRK (TRK) Inhibitor. Cell. 2019;177:8. doi: 10.1016/j.cell.2019.02.049.
    1. Murugan A.K., Xing M. Anaplastic thyroid cancers harbor novel oncogenic mutations of the ALK gene. Cancer Res. 2011;71:4403–4411. doi: 10.1158/0008-5472.CAN-10-4041.
    1. Gerber T.S., Schad A., Hartmann N., Springer E., Zechner U., Musholt T.J. Targeted next-generation sequencing of cancer genes in poorly differentiated thyroid cancer. Endocr. Connect. 2018;7:47–55. doi: 10.1530/EC-17-0290.
    1. Du Z., Lovly C.M. Mechanisms of receptor tyrosine kinase activation in cancer. Mol. Cancer. 2018;17:58. doi: 10.1186/s12943-018-0782-4.
    1. Sastre-Perona A., Santisteban P. Role of the wnt pathway in thyroid cancer. Front. Endocrinol. (Lausanne) 2012;3:31. doi: 10.3389/fendo.2012.00031.
    1. Manzella L., Stella S., Pennisi M.S., Tirro E., Massimino M., Romano C., Puma A., Tavarelli M., Vigneri P. New Insights in Thyroid Cancer and p53 Family Proteins. Int. J. Mol. Sci. 2017;18:1325. doi: 10.3390/ijms18061325.
    1. Raman P., Koenig R.J. Pax-8-PPAR-gamma fusion protein in thyroid carcinoma. Nat. Rev. Endocrinol. 2014;10:616–623. doi: 10.1038/nrendo.2014.115.
    1. Liu R., Xing M. TERT promoter mutations in thyroid cancer. Endocr. Relat. Cancer. 2016;23:R143–R155. doi: 10.1530/ERC-15-0533.
    1. Landa I., Ibrahimpasic T., Boucai L., Sinha R., Knauf J.A., Shah R.H., Dogan S., Ricarte-Filho J.C., Krishnamoorthy G.P., Xu B., et al. Genomic and transcriptomic hallmarks of poorly differentiated and anaplastic thyroid cancers. J. Clin. Investig. 2016;126:1052–1066. doi: 10.1172/JCI85271.
    1. Murugan A.K., Bojdani E., Xing M. Identification and functional characterization of isocitrate dehydrogenase 1 (IDH1) mutations in thyroid cancer. Biochem. Biophys. Res. Commun. 2010;393:555–559. doi: 10.1016/j.bbrc.2010.02.095.
    1. Xing M. BRAF mutation in thyroid cancer. Endocr. Relat. Cancer. 2005;12:245–262. doi: 10.1677/erc.1.0978.
    1. Xing M. Molecular pathogenesis and mechanisms of thyroid cancer. Nat. Rev. Cancer. 2013;13:184–199. doi: 10.1038/nrc3431.
    1. Hou P., Ji M., Xing M. Association of PTEN gene methylation with genetic alterations in the phosphatidylinositol 3-kinase/AKT signaling pathway in thyroid tumors. Cancer. 2008;113:2440–2447. doi: 10.1002/cncr.23869.
    1. Li Z., Zhang Y., Wang R., Zou K., Zou L. Genetic alterations in anaplastic thyroid carcinoma and targeted therapies. Exp. Med. 2019;18:2369–2377. doi: 10.3892/etm.2019.7869.
    1. Ricarte-Filho J.C., Ryder M., Chitale D.A., Rivera M., Heguy A., Ladanyi M., Janakiraman M., Solit D., Knauf J.A., Tuttle R.M., et al. 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. doi: 10.1158/0008-5472.CAN-09-0727.
    1. Paes J.E., Ringel M.D. Dysregulation of the phosphatidylinositol 3-kinase pathway in thyroid neoplasia. Endocrinol. Metab. Clin. N. Am. 2008;37:375–387. doi: 10.1016/j.ecl.2008.01.001.
    1. Agrawal N., Jiao Y., Sausen M., Leary R., Bettegowda C., Roberts N.J., Bhan S., Ho A.S., Khan Z., Bishop J., et al. Exomic sequencing of medullary thyroid cancer reveals dominant and mutually exclusive oncogenic mutations in RET and RAS. J. Clin. Endocrinol. Metab. 2013;98:E364–E369. doi: 10.1210/jc.2012-2703.
    1. Suzuki K., Saenko V., Yamashita S., Mitsutake N. Radiation-Induced Thyroid Cancers: Overview of Molecular Signatures. Cancers. 2019;11:1290. doi: 10.3390/cancers11091290.
    1. Santoro M., Moccia M., Federico G., Carlomagno F. RET Gene Fusions in Malignancies of the Thyroid and Other Tissues. Genes. 2020;11:424. doi: 10.3390/genes11040424.
    1. Amatu A., Sartore-Bianchi A., Siena S. NTRK gene fusions as novel targets of cancer therapy across multiple tumour types. ESMO Open. 2016;1:e000023. doi: 10.1136/esmoopen-2015-000023.
    1. Greco A., Miranda C., Pierotti M.A. Rearrangements of NTRK1 gene in papillary thyroid carcinoma. Mol. Cell Endocrinol. 2010;321:44–49. doi: 10.1016/j.mce.2009.10.009.
    1. Yakushina V.D., Lerner L.V., Lavrov A.V. Gene Fusions in Thyroid Cancer. Thyroid. 2018;28:158–167. doi: 10.1089/thy.2017.0318.
    1. Krampitz G.W., Norton J.A. RET gene mutations (genotype and phenotype) of multiple endocrine neoplasia type 2 and familial medullary thyroid carcinoma. Cancer. 2014;120:1920–1931. doi: 10.1002/cncr.28661.
    1. Kouvaraki M.A., Shapiro S.E., Perrier N.D., Cote G.J., Gagel R.F., Hoff A.O., Sherman S.I., Lee J.E., Evans D.B. RET proto-oncogene: A review and update of genotype-phenotype correlations in hereditary medullary thyroid cancer and associated endocrine tumors. Thyroid. 2005;15:531–544. doi: 10.1089/thy.2005.15.531.
    1. Chernock R.D., Hagemann I.S. Molecular pathology of hereditary and sporadic medullary thyroid carcinomas. Am. J. Clin. Pathol. 2015;143:768–777. doi: 10.1309/AJCPHWACTTUYJ7DD.
    1. Frank-Raue K., Raue F. Hereditary Medullary Thyroid Cancer Genotype-Phenotype Correlation. Recent Results Cancer Res. 2015;204:139–156. doi: 10.1007/978-3-319-22542-5_6.
    1. Hillier K., Hughes A., Shamberger R.C., Shusterman S., Perez-Atayde A.R., Wassner A.J., Iafrate A.J., Dubuc A., Janeway K.A., Rothenberg S.M., et al. A Novel ALK Fusion in Pediatric Medullary Thyroid Carcinoma. Thyroid. 2019;29:1704–1707. doi: 10.1089/thy.2019.0041.
    1. Armstrong M.J., Yang H., Yip L., Ohori N.P., McCoy K.L., Stang M.T., Hodak S.P., Nikiforova M.N., Carty S.E., Nikiforov Y.E. PAX8/PPARgamma rearrangement in thyroid nodules predicts follicular-pattern carcinomas, in particular the encapsulated follicular variant of papillary carcinoma. Thyroid. 2014;24:1369–1374. doi: 10.1089/thy.2014.0067.
    1. Worden F. Treatment strategies for radioactive iodine-refractory differentiated thyroid cancer. Adv. Med. Oncol. 2014;6:267–279. doi: 10.1177/1758834014548188.
    1. Paladino S., Melillo R.M. Editorial: Novel Mechanism of Radioactive Iodine Refractivity in Thyroid Cancer. J. Natl. Cancer Inst. 2017;109 doi: 10.1093/jnci/djx106.
    1. Kogai T., Brent G.A. The sodium iodide symporter (NIS): Regulation and approaches to targeting for cancer therapeutics. Pharmacol. Ther. 2012;135:355–370. doi: 10.1016/j.pharmthera.2012.06.007.
    1. Liu J., Liu Y., Lin Y., Liang J. Radioactive Iodine-Refractory Differentiated Thyroid Cancer and Redifferentiation Therapy. Endocrinol. Metab. (Seoul) 2019;34:215–225. doi: 10.3803/EnM.2019.34.3.215.
    1. Costamagna E., Garcia B., Santisteban P. The functional interaction between the paired domain transcription factor Pax8 and Smad3 is involved in transforming growth factor-beta repression of the sodium/iodide symporter gene. J. Biol. Chem. 2004;279:3439–3446. doi: 10.1074/jbc.M307138200.
    1. Aashiq M., Silverman D.A., Na’ara S., Takahashi H., Amit M. Radioiodine-Refractory Thyroid Cancer: Molecular Basis of Redifferentiation Therapies, Management, and Novel Therapies. Cancers. 2019;11:1382. doi: 10.3390/cancers11091382.
    1. Zhang Z., Liu D., Murugan A.K., Liu Z., Xing M. Histone deacetylation of NIS promoter underlies BRAFV600E-promoted NIS silencing in thyroid cancer. Endocr. Relat. Cancer. 2014;21:161–173. doi: 10.1530/ERC-13-0399.
    1. Jaber T., Waguespack S.G., Cabanillas M.E., Elbanan M., Vu T., Dadu R., Sherman S.I., Amit M., Santos E.B., Zafereo M., et al. Targeted Therapy in Advanced Thyroid Cancer to Resensitize Tumors to Radioactive Iodine. J. Clin. Endocrinol. Metab. 2018;103:3698–3705. doi: 10.1210/jc.2018-00612.
    1. Zhang H., Chen D. Synergistic inhibition of MEK/ERK and BRAFV600E with PD98059 and PLX4032 induces sodium/iodide symporter (NIS) expression and radioiodine uptake in BRAF mutated papillary thyroid cancer cells. Thyroid Res. 2018;11:13. doi: 10.1186/s13044-018-0057-6.
    1. Oh J.M., Kalimuthu S., Gangadaran P., Baek S.H., Zhu L., Lee H.W., Rajendran R.L., Hong C.M., Jeong S.Y., Lee S.W., et al. Reverting iodine avidity of radioactive-iodine refractory thyroid cancer with a new tyrosine kinase inhibitor (K905-0266) excavated by high-throughput NIS (sodium iodide symporter) enhancer screening platform using dual reporter gene system. Oncotarget. 2018;9:7075–7087. doi: 10.18632/oncotarget.24159.
    1. Vaisman F., Carvalho D.P., Vaisman M. A new appraisal of iodine refractory thyroid cancer. Endocr. Relat. Cancer. 2015;22:R301–R310. doi: 10.1530/ERC-15-0300.
    1. Kogai T., Sajid-Crockett S., Newmarch L.S., Liu Y.Y., Brent G.A. Phosphoinositide-3-kinase inhibition induces sodium/iodide symporter expression in rat thyroid cells and human papillary thyroid cancer cells. J. Endocrinol. 2008;199:243–252. doi: 10.1677/JOE-08-0333.
    1. Yang X., Li J., Li X., Liang Z., Gao W., Liang J., Cheng S., Lin Y. TERT Promoter Mutation Predicts Radioiodine-Refractory Character in Distant Metastatic Differentiated Thyroid Cancer. J. Nucl. Med. 2017;58:258–265. doi: 10.2967/jnumed.116.180240.
    1. Chen H., Luthra R., Routbort M.J., Patel K.P., Cabanillas M.E., Broaddus R.R., Williams M.D. Molecular Profile of Advanced Thyroid Carcinomas by Next-Generation Sequencing: Characterizing Tumors Beyond Diagnosis for Targeted Therapy. Mol. Cancer. 2018;17:1575–1584. doi: 10.1158/1535-7163.MCT-17-0871.
    1. Zou M., Baitei E.Y., Alzahrani A.S., BinHumaid F.S., Alkhafaji D., Al-Rijjal R.A., Meyer B.F., Shi Y. Concomitant RAS, RET/PTC, or BRAF mutations in advanced stage of papillary thyroid carcinoma. Thyroid. 2014;24:1256–1266. doi: 10.1089/thy.2013.0610.
    1. Yoo S.K., Song Y.S., Lee E.K., Hwang J., Kim H.H., Jung G., Kim Y.A., Kim S.J., Cho S.W., Won J.K., et al. Integrative analysis of genomic and transcriptomic characteristics associated with progression of aggressive thyroid cancer. Nat. Commun. 2019;10:2764. doi: 10.1038/s41467-019-10680-5.
    1. Huang M., Yan C., Xiao J., Wang T., Ling R. Relevance and clinicopathologic relationship of BRAFV600E, TERT and NRAS mutations for papillary thyroid carcinoma patients in Northwest China. Diagn. Pathol. 2019;14:74. doi: 10.1186/s13000-019-0849-6.
    1. Lee S.E., Hwang T.S., Choi Y.L., Han H.S., Kim W.S., Jang M.H., Kim S.K., Yang J.H. Prognostic Significance of TERT Promoter Mutations in Papillary Thyroid Carcinomas in a BRAF(V600E) Mutation-Prevalent Population. Thyroid. 2016;26:901–910. doi: 10.1089/thy.2015.0488.
    1. Liu X., Qu S., Liu R., Sheng C., Shi X., Zhu G., Murugan A.K., Guan H., Yu H., Wang Y., et al. TERT promoter mutations and their association with BRAFV600E mutation and aggressive clinicopathological characteristics of thyroid cancer. J. Clin. Endocrinol. Metab. 2014;99:E1130–E1136. doi: 10.1210/jc.2013-4048.
    1. Vuong H.G., Altibi A.M.A., Duong U.N.P., Hassell L. Prognostic implication of BRAF and TERT promoter mutation combination in papillary thyroid carcinoma-A meta-analysis. Clin. Endocrinol. (Oxf.) 2017;87:411–417. doi: 10.1111/cen.13413.
    1. Liu R., Zhang T., Zhu G., Xing M. Regulation of mutant TERT by BRAFV600E/MAP kinase pathway through FOS/GABP in human cancer. Nat. Commun. 2018;9:579. doi: 10.1038/s41467-018-03033-1.
    1. Brose M.S., Nutting C.M., Jarzab B., Elisei R., Siena S., Bastholt L., De La Fouchardiere C., Pacini F., Paschke R., Shong Y.K. Sorafenib in radioactive iodine-refractory, locally advanced or metastatic differentiated thyroid cancer: A randomised, double-blind, phase 3 trial. Lancet. 2014;384:319–328. doi: 10.1016/S0140-6736(14)60421-9.
    1. Food and Drug Administration. [(accessed on 5 June 2020)]; Available online: .
    1. Schlumberger M., Tahara M., Wirth L.J., Robinson B., Brose M.S., Elisei R., Habra M.A., Newbold K., Shah M.H., Hoff A.O. Lenvatinib versus placebo in radioiodine-refractory thyroid cancer. N. Engl. J. Med. 2015;372:621–630. doi: 10.1056/NEJMoa1406470.
    1. Food and Drug Administration. [(accessed on 5 June 2020)]; Available online: .
    1. Sun Y., Du F., Gao M., Ji Q., Li Z., Zhang Y., Guo Z., Wang J., Chen X., Wang J. Anlotinib for the treatment of patients with locally advanced or metastatic medullary thyroid cancer. Thyroid. 2018;28:1455–1461. doi: 10.1089/thy.2018.0022.
    1. Li D., Tang P.Z., Chen X., Ge M., Zhang Y., Guo Z., Wang J., Shi F., Zhang J., Cheng Y. Anlotinib Treatment in Locally Advanced or Metastatic Medullary Thyroid Carcinoma: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Phase IIB Trial. J. Clin. Oncol. 2019;37:6019. doi: 10.1200/JCO.2019.37.15_suppl.6019.
    1. Cohen E.E., Rosen L.S., Vokes E.E., Kies M.S., Forastiere A.A., Worden F.P., Kane M.A., Sherman E., Kim S., Bycott P. Axitinib is an active treatment for all histologic subtypes of advanced thyroid cancer: Results from a phase II study. J. Clin. Oncol. 2008;26:4708. doi: 10.1200/JCO.2007.15.9566.
    1. Capdevila J., Trigo J.M., Aller J., Manzano J.L., Adrián S.G., Llopis C.Z., Reig Ò., Bohn U., y Cajal T.R., Duran-Poveda M. Axitinib treatment in advanced RAI-resistant differentiated thyroid cancer (DTC) and refractory medullary thyroid cancer (MTC) Eur. J. Endocrinol. 2017;177:309–317. doi: 10.1530/EJE-17-0243.
    1. Lim S.M., Chung W.Y., Nam K.-H., Kang S.-W., Lim J.Y., Kim H.-G., Shin S.H., Sun J.-M., Kim S.-G., Kim J.-H. An open label, multicenter, phase II study of dovitinib in advanced thyroid cancer. Eur. J. Cancer. 2015;51:1588–1595. doi: 10.1016/j.ejca.2015.05.020.
    1. Schlumberger M., Jarzab B., Cabanillas M.E., Robinson B., Pacini F., Ball D.W., McCaffrey J., Newbold K., Allison R., Martins R.G. A phase II trial of the multitargeted tyrosine kinase inhibitor lenvatinib (E7080) in advanced medullary thyroid cancer. Clin. Cancer Res. 2016;22:44–53. doi: 10.1158/1078-0432.CCR-15-1127.
    1. Tahara M., Kiyota N., Yamazaki T., Chayahara N., Nakano K., Inagaki L., Toda K., Enokida T., Minami H., Imamura Y. Lenvatinib for anaplastic thyroid cancer. Front. Oncol. 2017;7:25. doi: 10.3389/fonc.2017.00025.
    1. Bible K.C., Suman V.J., Molina J.R., Smallridge R.C., Maples W.J., Menefee M.E., Rubin J., Sideras K., Morris III J.C., McIver B. Efficacy of pazopanib in progressive, radioiodine-refractory, metastatic differentiated thyroid cancers: Results of a phase 2 consortium study. Lancet Oncol. 2010;11:962–972. doi: 10.1016/S1470-2045(10)70203-5.
    1. Bible K.C., Suman V.J., Molina J.R., Smallridge R.C., Maples W.J., Menefee M.E., Rubin J., Karlin N., Sideras K., Morris III J.C. A multicenter phase 2 trial of pazopanib in metastatic and progressive medullary thyroid carcinoma: MC057H. J. Clin. Endocrinol. Metab. 2014;99:1687–1693. doi: 10.1210/jc.2013-3713.
    1. Bible K.C., Suman V.J., Menefee M.E., Smallridge R.C., Molina J.R., Maples W.J., Karlin N.J., Traynor A.M., Kumar P., Goh B.C. A multiinstitutional phase 2 trial of pazopanib monotherapy in advanced anaplastic thyroid cancer. J. Clin. Endocrinol. Metab. 2012;97:3179–3184. doi: 10.1210/jc.2012-1520.
    1. Lam E.T., Ringel M.D., Kloos R.T., Prior T.W., Knopp M.V., Liang J., Sammet S., Hall N.C., Wakely P.E., Jr., Vasko V.V. Phase II clinical trial of sorafenib in metastatic medullary thyroid cancer. J. Clin. Oncol. 2010;28:2323. doi: 10.1200/JCO.2009.25.0068.
    1. Capdevila J., Iglesias L., Halperin I., Segura A., Martínez-Trufero J., Vaz M.Á., Corral J., Obiols G., Grande E., Grau J.J. Sorafenib in metastatic thyroid cancer. Endocr. Relat. Cancer. 2012;19:e209. doi: 10.1530/ERC-11-0351.
    1. Bikas A., Kundra P., Desale S., Mete M., O’Keefe K., Clark B.G., Wray L., Gandhi R., Barett C., Jelinek J.S. Phase 2 clinical trial of sunitinib as adjunctive treatment in patients with advanced differentiated thyroid cancer. Eur. J. Endocrinol. 2016;174:373–380. doi: 10.1530/EJE-15-0930.
    1. Carr L.L., Mankoff D.A., Goulart B.H., Eaton K.D., Capell P.T., Kell E.M., Bauman J.E., Martins R.G. Phase II study of daily sunitinib in FDG-PET–positive, iodine-refractory differentiated thyroid cancer and metastatic medullary carcinoma of the thyroid with functional imaging correlation. Clin. Cancer Res. 2010;16:5260–5268. doi: 10.1158/1078-0432.CCR-10-0994.
    1. Ravaud A., de la Fouchardière C., Caron P., Doussau A., Do Cao C., Asselineau J., Rodien P., Pouessel D., Nicolli-Sire P., Klein M. A multicenter phase II study of sunitinib in patients with locally advanced or metastatic differentiated, anaplastic or medullary thyroid carcinomas: Mature data from the THYSU study. Eur. J. Cancer. 2017;76:110–117. doi: 10.1016/j.ejca.2017.01.029.
    1. Leboulleux S., Bastholt L., Krause T., de la Fouchardiere C., Tennvall J., Awada A., Gómez J.M., Bonichon F., Leenhardt L., Soufflet C. Vandetanib in locally advanced or metastatic differentiated thyroid cancer: A randomised, double-blind, phase 2 trial. Lancet Oncol. 2012;13:897–905. doi: 10.1016/S1470-2045(12)70335-2.
    1. Falchook G.S., Millward M., Hong D., Naing A., Piha-Paul S., Waguespack S.G., Cabanillas M.E., Sherman S.I., Ma B., Curtis M. BRAF inhibitor dabrafenib in patients with metastatic BRAF-mutant thyroid cancer. Thyroid. 2015;25:71–77. doi: 10.1089/thy.2014.0123.
    1. Brose M.S., Cabanillas M.E., Cohen E.E., Wirth L.J., Riehl T., Yue H., Sherman S.I., Sherman E.J. Vemurafenib in patients with BRAFV600E-positive metastatic or unresectable papillary thyroid cancer refractory to radioactive iodine: A non-randomised, multicentre, open-label, phase 2 trial. Lancet Oncol. 2016;17:1272–1282. doi: 10.1016/S1470-2045(16)30166-8.
    1. Lim S., Chang H., Yoon M., Hong Y., Kim H., Chung W., Park C., Nam K., Kang S., Kim M. A multicenter, phase II trial of everolimus in locally advanced or metastatic thyroid cancer of all histologic subtypes. Ann. Oncol. 2013;24:3089–3094. doi: 10.1093/annonc/mdt379.
    1. Hanna G.J., Busaidy N.L., Chau N.G., Wirth L.J., Barletta J.A., Calles A., Haddad R.I., Kraft S., Cabanillas M.E., Rabinowits G. Genomic correlates of response to everolimus in aggressive radioiodine-refractory thyroid cancer: A phase II study. Clin. Cancer Res. 2018;24:1546–1553. doi: 10.1158/1078-0432.CCR-17-2297.
    1. Elisei R., Schlumberger M.J., Müller S.P., Schöffski P., Brose M.S., Shah M.H., Licitra L., Jarzab B., Medvedev V., Kreissl M.C. Cabozantinib in progressive medullary thyroid cancer. J. Clin. Oncol. 2013;31:3639. doi: 10.1200/JCO.2012.48.4659.
    1. Wells S.A., Jr., Robinson B.G., Gagel R.F., Dralle H., Fagin J.A., Santoro M., Baudin E., Elisei R., Jarzab B., Vasselli J.R. Vandetanib in patients with locally advanced or metastatic medullary thyroid cancer: A randomized, double-blind phase III trial. J. Clin. Oncol. 2012;30:134. doi: 10.1200/JCO.2011.35.5040.
    1. Hyman D.M., Puzanov I., Subbiah V., Faris J.E., Chau I., Blay J.-Y., Wolf J., Raje N.S., Diamond E.L., Hollebecque A. Vemurafenib in multiple nonmelanoma cancers with BRAF V600 mutations. N. Engl. J. Med. 2015;373:726–736. doi: 10.1056/NEJMoa1502309.
    1. Subbiah V., Kreitman R.J., Wainberg Z.A., Cho J.Y., Schellens J.H.M., Soria J.C., Wen P.Y., Zielinski C., Cabanillas M.E., Urbanowitz G., et al. Dabrafenib and Trametinib Treatment in Patients With Locally Advanced or Metastatic BRAF V600-Mutant Anaplastic Thyroid Cancer. J. Clin. Oncol. 2018;36:7–13. doi: 10.1200/JCO.2017.73.6785.
    1. Drilon A., Laetsch T.W., Kummar S., DuBois S.G., Lassen U.N., Demetri G.D., Nathenson M., Doebele R.C., Farago A.F., Pappo A.S. Efficacy of larotrectinib in TRK fusion–positive cancers in adults and children. N. Engl. J. Med. 2018;378:731–739. doi: 10.1056/NEJMoa1714448.
    1. Doebele R.C., Drilon A., Paz-Ares L., Siena S., Shaw A.T., Farago A.F., Blakely C.M., Seto T., Cho B.C., Tosi D. Entrectinib in patients with advanced or metastatic NTRK fusion-positive solid tumours: Integrated analysis of three phase 1–2 trials. Lancet Oncol. 2020;21:271–282. doi: 10.1016/S1470-2045(19)30691-6.
    1. Ho A.L., Grewal R.K., Leboeuf R., Sherman E.J., Pfister D.G., Deandreis D., Pentlow K.S., Zanzonico P.B., Haque S., Gavane S. Selumetinib-enhanced radioiodine uptake in advanced thyroid cancer. N. Engl. J. Med. 2013;368:623–632. doi: 10.1056/NEJMoa1209288.
    1. Iravani A., Solomon B., Pattison D.A., Jackson P., Ravi Kumar A., Kong G., Hofman M.S., Akhurst T., Hicks R.J. Mitogen-Activated Protein Kinase Pathway Inhibition for Redifferentiation of Radioiodine Refractory Differentiated Thyroid Cancer: An Evolving Protocol. Thyroid. 2019;29:1634–1645. doi: 10.1089/thy.2019.0143.
    1. Budiawan H., Salavati A., Kulkarni H.R., Baum R.P. Peptide receptor radionuclide therapy of treatment-refractory metastatic thyroid cancer using (90)Yttrium and (177)Lutetium labeled somatostatin analogs: Toxicity, response and survival analysis. Am. J. Nucl. Med. Mol. Imaging. 2013;4:39–52.
    1. Versari A., Sollini M., Frasoldati A., Fraternali A., Filice A., Froio A., Asti M., Fioroni F., Cremonini N., Putzer D., et al. Differentiated thyroid cancer: A new perspective with radiolabeled somatostatin analogues for imaging and treatment of patients. Thyroid. 2014;24:715–726. doi: 10.1089/thy.2013.0225.
    1. Lapa C., Werner R.A., Schmid J.S., Papp L., Zsótér N., Biko J., Reiners C., Herrmann K., Buck A.K., Bundschuh R.A. Prognostic value of positron emission tomography-assessed tumor heterogeneity in patients with thyroid cancer undergoing treatment with radiopeptide therapy. Nucl. Med. Biol. 2015;42:349–354. doi: 10.1016/j.nucmedbio.2014.12.006.
    1. Mehnert J.M., Varga A., Brose M.S., Aggarwal R.R., Lin C.-C., Prawira A., De Braud F., Tamura K., Doi T., Piha-Paul S.A. Safety and antitumor activity of the anti–PD-1 antibody pembrolizumab in patients with advanced, PD-L1–positive papillary or follicular thyroid cancer. BMC Cancer. 2019;19:196. doi: 10.1186/s12885-019-5380-3.
    1. Tiedje V., Fagin J.A. Therapeutic breakthroughs for metastatic thyroid cancer. Nat. Rev. Endocrinol. 2020;16:77–78. doi: 10.1038/s41574-019-0307-2.
    1. Smallridge R.C., Ain K.B., Asa S.L., Bible K.C., Brierley J.D., Burman K.D., Kebebew E., Lee N.Y., Nikiforov Y.E., Rosenthal M.S. American Thyroid Association guidelines for management of patients with anaplastic thyroid cancer. Thyroid. 2012;22:1104–1139. doi: 10.1089/thy.2012.0302.
    1. Food and Drug Administration. [(accessed on 23 March 2020)]; Available online: .
    1. Food and Drug Administration. [(accessed on 23 March 2020)]; Available online: .
    1. Subbiah V., Gainor J.F., Rahal R., Brubaker J.D., Kim J.L., Maynard M., Hu W., Cao Q., Sheets M.P., Wilson D., et al. Precision Targeted Therapy with BLU-667 for RET-Driven Cancers. Cancer Discov. 2018;8:836–849. doi: 10.1158/-18-0338.
    1. Subbiah V., Taylor M., Lin J., Hu M., Ou S., Brose M., Garralda E., Clifford C., Palmer M., Tugnait M. Highly potent and selective RET inhibitor, BLU-667, achieves proof of concept in ARROW, a phase 1 study of advanced, RET-altered solid tumors; Proceedings of the American Association for Cancer Research Annual Meeting; Chicago, IL, USA. 14–18 April 2018; pp. 14–18.
    1. Subbiah V., Velcheti V., Tuch B., Ebata K., Busaidy N.L., Cabanillas M.E., Wirth L., Stock S., Smith S., Lauriault V. Selective RET kinase inhibition for patients with RET-altered cancers. Ann. Oncol. 2018;29:1869–1876. doi: 10.1093/annonc/mdy137.
    1. Taylor M.H., Gainor J.F., Hu M.I.-N., Zhu V.W., Lopes G., Leboulleux S., Brose M.S., Schuler M.H., Bowles D.W., Kim D.-W., et al. Activity and tolerability of BLU-667, a highly potent and selective RET inhibitor, in patients with advanced RET-altered thyroid cancers. J. Clin. Oncol. 2019;37:6018. doi: 10.1200/JCO.2019.37.15_suppl.6018.
    1. Lassen U., Albert C., Kummar S., van Tilburg C., Dubois S., Geoerger B., Mascarenhas L., Federman N., Schilder R., Doz F. 409O Larotrectinib efficacy and safety in TRK fusion cancer: An expanded clinical dataset showing consistency in an age and tumor agnostic approach. Ann. Oncol. 2018;29:mdy279.397. doi: 10.1093/annonc/mdy279.397.
    1. Giordano T.J., Haugen B.R., Sherman S.I., Shah M.H., Caoili E.M., Koenig R.J. Pioglitazone Therapy of PAX8-PPAR γ Fusion Protein Thyroid Carcinoma. J. Clin. Endocrinol. Metab. 2018;103:1277–1281. doi: 10.1210/jc.2017-02533.
    1. Haddad R.I., Nasr C., Bischoff L., Busaidy N.L., Byrd D., Callender G., Dickson P., Duh Q.Y., Ehya H., Goldner W., et al. NCCN Guidelines Insights: Thyroid Carcinoma, Version 2.2018. J. Natl. Compr. Cancer Netw. 2018;16:1429–1440. doi: 10.6004/jnccn.2018.0089.
    1. . Efficacy of MEK (Trametinib) and BRAFV600E (Dabrafenib) Inhibitors with Radioactive Iodine (RAI) for the Treatment of Refractory Metastatic Differentiated Thyroid Cancer (MERAIODE) [(accessed on 23 March 2020)]; Available online: .
    1. Brown S.R., Hall A., Buckley H.L., Flanagan L., Gonzalez de Castro D., Farnell K., Moss L., Gregory R., Newbold K., Du Y., et al. Investigating the potential clinical benefit of Selumetinib in resensitising advanced iodine refractory differentiated thyroid cancer to radioiodine therapy (SEL-I-METRY): Protocol for a multicentre UK single arm phase II trial. BMC Cancer. 2019;19:582. doi: 10.1186/s12885-019-5541-4.
    1. Papotti M., Croce S., Bellò M., Bongiovanni M., Allìa E., Schindler M., Bussolati G. Expression of somatostatin receptor types 2, 3 and 5 in biopsies and surgical specimens of human lung tumours. Virchows Arch. 2001;439:787–797. doi: 10.1007/s004280100494.
    1. Zatelli M.C., Tagliati F., Taylor J.E., Rossi R., Culler M.D., degli Uberti E.C. Somatostatin receptor subtypes 2 and 5 differentially affect proliferation in vitro of the human medullary thyroid carcinoma cell line tt. J. Clin. Endocrinol. Metab. 2001;86:2161–2169. doi: 10.1210/jc.86.5.2161.
    1. Vaisman F., de Castro P.H.R., Lopes F.P.P.L., Kendler D.B., Pessoa C.H., Bulzico D.A., de Carvalho Leal D., Vilhena B., Vaisman M., Carneiro M. Is there a role for peptide receptor radionuclide therapy in medullary thyroid cancer? Clin. Nucl. Med. 2015;40:123–127. doi: 10.1097/RLU.0000000000000628.
    1. Iten F., Müller B., Schindler C., Rochlitz C., Oertli D., Mäcke H.R., Müller-Brand J., Walter M.A. Response to [90Yttrium-DOTA]-TOC treatment is associated with long-term survival benefit in metastasized medullary thyroid cancer: A phase II clinical trial. Clin. Cancer Res. 2007;13:6696–6702. doi: 10.1158/1078-0432.CCR-07-0935.
    1. Beukhof C.M., Brabander T., van Nederveen F.H., van Velthuysen M.-L.F., de Rijke Y.B., Hofland L.J., Franssen G.J., Fröberg L.A., Kam B.L., Visser W.E. Peptide receptor radionuclide therapy in patients with medullary thyroid carcinoma: Predictors and pitfalls. BMC Cancer. 2019;19:325. doi: 10.1186/s12885-019-5540-5.
    1. Pardoll D.M. The blockade of immune checkpoints in cancer immunotherapy. Nat. Rev. Cancer. 2012;12:252–264. doi: 10.1038/nrc3239.
    1. Fu G., Polyakova O., MacMillan C., Ralhan R., Walfish P.G. Programmed death-ligand 1 expression distinguishes invasive encapsulated follicular variant of papillary thyroid carcinoma from noninvasive follicular thyroid neoplasm with papillary-like nuclear features. EBioMedicine. 2017;18:50–55. doi: 10.1016/j.ebiom.2017.03.031.
    1. Aghajani M., Graham S., McCafferty C., Shaheed C.A., Roberts T., DeSouza P., Yang T., Niles N. Clinicopathologic and prognostic significance of programmed cell death ligand 1 expression in patients with non-medullary thyroid cancer: A systematic review and meta-analysis. Thyroid. 2018;28:349–361. doi: 10.1089/thy.2017.0441.
    1. Ulisse S., Tuccilli C., Sorrenti S., Antonelli A., Fallahi P., D’Armiento E., Catania A., Tartaglia F., Amabile M.I., Giacomelli L. PD-1 Ligand Expression in Epithelial Thyroid Cancers: Potential Clinical Implications. Int. J. Mol. Sci. 2019;20:1405. doi: 10.3390/ijms20061405.
    1. Chowdhury S., Veyhl J., Jessa F., Polyakova O., Alenzi A., MacMillan C., Ralhan R., Walfish P.G. Programmed death-ligand 1 overexpression is a prognostic marker for aggressive papillary thyroid cancer and its variants. Oncotarget. 2016;7:32318. doi: 10.18632/oncotarget.8698.
    1. Lawrence M.S., Stojanov P., Polak P., Kryukov G.V., Cibulskis K., Sivachenko A., Carter S.L., Stewart C., Mermel C.H., Roberts S.A. Mutational heterogeneity in cancer and the search for new cancer-associated genes. Nature. 2013;499:214–218. doi: 10.1038/nature12213.
    1. Gopal R.K., Kubler K., Calvo S.E., Polak P., Livitz D., Rosebrock D., Sadow P.M., Campbell B., Donovan S.E., Amin S., et al. Widespread Chromosomal Losses and Mitochondrial DNA Alterations as Genetic Drivers in Hurthle Cell Carcinoma. Cancer Cell. 2018;34:242–255.e5. doi: 10.1016/j.ccell.2018.06.013.
    1. Schott M., Seissler J., Lettmann M., Fouxon V., Scherbaum W.A., Feldkamp J. Immunotherapy for medullary thyroid carcinoma by dendritic cell vaccination. J. Clin. Endocrinol. Metab. 2001;86:4965–4969. doi: 10.1210/jcem.86.10.7949.
    1. Bachleitner-Hofmann T., Friedl J., Hassler M., Hayden H., Dubsky P., Sachet M., Rieder E., Pfragner R., Brostjan C., Riss S. Pilot trial of autologous dendritic cells loaded with tumor lysate (s) from allogeneic tumor cell lines in patients with metastatic medullary thyroid carcinoma. Oncol. Rep. 2009;21:1585–1592. doi: 10.3892/or_00000391.
    1. Bilusic M., Heery C.R., Arlen P.M., Rauckhorst M., Apelian D., Tsang K.Y., Tucker J.A., Jochems C., Schlom J., Gulley J.L., et al. Phase I trial of a recombinant yeast-CEA vaccine (GI-6207) in adults with metastatic CEA-expressing carcinoma. Cancer Immunol. Immunother. 2014;63:225–234. doi: 10.1007/s00262-013-1505-8.
    1. Madan R.A., Singh N.K., Gramza A.W., Fojo A.T., Heery C.R., Kim J.W., McMahon S., Rauckhorst M., King T.H., Apelian D., et al. A phase II study of a yeast-based therapeutic cancer vaccine, GI-6207, targeting CEA in patients with minimally symptomatic, metastatic medullary thyroid cancer. J. Clin. Oncol. 2013;31:TPS3127. doi: 10.1200/jco.2013.31.15_suppl.tps3127.
    1. Dy G.K., Adjei A.A. Understanding, recognizing, and managing toxicities of targeted anticancer therapies. CA Cancer J. Clin. 2013;63:249–279. doi: 10.3322/caac.21184.
    1. Brose M.S., Bible K.C., Chow L.Q., Gilbert J., Grande C., Worden F., Haddad R. Management of treatment-related toxicities in advanced medullary thyroid cancer. Cancer Treat. Rev. 2018;66:64–73. doi: 10.1016/j.ctrv.2018.04.007.
    1. Jimenez C., Mimi I., Hu N., Gagel R.F. Management of medullary thyroid carcinoma. Endocrinol. Metab. Clin. N. Am. 2008;37:481–496. doi: 10.1016/j.ecl.2008.03.001.
    1. Isenberg J.S., Martin-Manso G., Maxhimer J.B., Roberts D.D. Regulation of nitric oxide signalling by thrombospondin 1: Implications for anti-angiogenic therapies. Nat. Rev. Cancer. 2009;9:182–194. doi: 10.1038/nrc2561.
    1. Kappers M.H., van Esch J.H., Sluiter W., Sleijfer S., Danser A.J., van den Meiracker A.H. Hypertension induced by the tyrosine kinase inhibitor sunitinib is associated with increased circulating endothelin-1 levels. Hypertension. 2010;56:675–681. doi: 10.1161/HYPERTENSIONAHA.109.149690.
    1. Herrmann J. Tyrosine kinase inhibitors and vascular toxicity: Impetus for a classification system? Curr. Oncol. Rep. 2016;18:33. doi: 10.1007/s11912-016-0514-0.
    1. Macdonald J.B., Macdonald B., Golitz L.E., LoRusso P., Sekulic A. Cutaneous adverse effects of targeted therapies: Part II: Inhibitors of intracellular molecular signaling pathways. J. Am. Acad. Dermatol. 2015;72:221–236. doi: 10.1016/j.jaad.2014.07.033.
    1. Stanculeanu D.L., Daniela Z., Oana Catalina T., Georgescu B., Papagheorghe L., Mihaila R.I. Cutaneous toxicities of molecular targeted therapies. Maedica. 2017;12:48.
    1. Sibaud V., Dalenc F., Chevreau C., Roché H., Delord J.-P., Mourey L., Lacaze J.-L., Rahhali N., Taïeb C. HFS-14, a specific quality of life scale developed for patients suffering from hand–foot syndrome. Oncologist. 2011;16:1469. doi: 10.1634/theoncologist.2011-0033.
    1. Cebollero A., Puértolas T., Pajares I., Calera L., Antón A. Comparative safety of BRAF and MEK inhibitors (vemurafenib, dabrafenib and trametinib) in first-line therapy for BRAF-mutated metastatic melanoma. Mol. Clin. Oncol. 2016;5:458–462. doi: 10.3892/mco.2016.978.
    1. Blevins D.P., Dadu R., Hu M., Baik C., Balachandran D., Ross W., Gunn B., Cabanillas M.E. Aerodigestive fistula formation as a rare side effect of antiangiogenic tyrosine kinase inhibitor therapy for thyroid cancer. Thyroid. 2014;24:918–922. doi: 10.1089/thy.2012.0598.
    1. Kwekkeboom D.J., Krenning E.P. Peptide Receptor Radionuclide Therapy in the Treatment of Neuroendocrine Tumors. Hematol. Oncol. Clin. N. Am. 2016;30:179–191. doi: 10.1016/j.hoc.2015.09.009.
    1. Rolleman E.J., Valkema R., de Jong M., Kooij P.P., Krenning E.P. Safe and effective inhibition of renal uptake of radiolabelled octreotide by a combination of lysine and arginine. Eur. J. Nucl. Med. Mol. Imaging. 2003;30:9–15. doi: 10.1007/s00259-002-0982-3.
    1. Bodei L., Cremonesi M., Ferrari M., Pacifici M., Grana C.M., Bartolomei M., Baio S.M., Sansovini M., Paganelli G. Long-term evaluation of renal toxicity after peptide receptor radionuclide therapy with 90 Y-DOTATOC and 177 Lu-DOTATATE: The role of associated risk factors. Eur. J. Nucl. Med. Mol. Imaging. 2008;35:1847–1856. doi: 10.1007/s00259-008-0778-1.
    1. De Oliveira M.A., e Martins F.M., Wang Q., Sonis S., Demetri G., George S., Butrynski J., Treister N.S. Clinical presentation and management of mTOR inhibitor-associated stomatitis. Oral Oncol. 2011;47:998–1003. doi: 10.1016/j.oraloncology.2011.08.009.
    1. Peterson M.E. Management of adverse events in patients with hormone receptor-positive breast cancer treated with everolimus: Observations from a phase III clinical trial. Supportive Care Cancer. 2013;21:2341–2349. doi: 10.1007/s00520-013-1826-3.
    1. Ramirez-Fort M.K., Case E.C., Rosen A.C., Cerci F.B., Wu S., Lacouture M.E. Rash to the mTOR inhibitor everolimus: Systematic review and meta-analysis. Am. J. Clin. Oncol. 2014;37:266–271. doi: 10.1097/COC.0b013e318277d62f.
    1. Campistol J.M., de Fijter J.W., Flechner S.M., Langone A., Morelon E., Stockfleth E. mTOR inhibitor-associated dermatologic and mucosal problems. Clin. Transpl. 2010;24:149–156. doi: 10.1111/j.1399-0012.2010.01232.x.
    1. Hutson T.E., Figlin R.A., Kuhn J.G., Motzer R.J. Targeted therapies for metastatic renal cell carcinoma: An overview of toxicity and dosing strategies. Oncologist. 2008;13:1084–1096. doi: 10.1634/theoncologist.2008-0120.
    1. Shi V.J., Rodic N., Gettinger S., Leventhal J.S., Neckman J.P., Girardi M., Bosenberg M., Choi J.N. Clinical and histologic features of lichenoid mucocutaneous eruptions due to anti–programmed cell death 1 and anti–programmed cell death ligand 1 immunotherapy. JAMA Derm. 2016;152:1128–1136. doi: 10.1001/jamadermatol.2016.2226.
    1. Saw S., Lee H.Y., Ng Q.S. Pembrolizumab-induced Stevens–Johnson syndrome in non-melanoma patients. Eur. J. Cancer. 2017;81:237–239. doi: 10.1016/j.ejca.2017.03.026.
    1. Scarpati G.D.V., Fusciello C., Perri F., Sabbatino F., Ferrone S., Carlomagno C., Pepe S. Ipilimumab in the treatment of metastatic melanoma: Management of adverse events. Oncotargets Ther. 2014;7:203. doi: 10.2147/OTT.S57335.
    1. Gupta A., De Felice K., Loftus E.V., Jr., Khanna S. Systematic review: Colitis associated with anti-CTLA-4 therapy. Aliment. Pharmacol. Ther. 2015;42:406–417. doi: 10.1111/apt.13281.
    1. Brahmer J.R., Lacchetti C., Schneider B.J., Atkins M.B., Brassil K.J., Caterino J.M., Chau I., Ernstoff M.S., Gardner J.M., Ginex P. Management of immune-related adverse events in patients treated with immune checkpoint inhibitor therapy: American Society of Clinical Oncology Clinical Practice Guideline. J. Clin. Oncol. 2018;36:1714. doi: 10.1200/JCO.2017.77.6385.
    1. Yanai S., Nakamura S., Matsumoto T. Nivolumab-induced colitis treated by infliximab. Clin. Gastroenterol. Hepatol. 2017;15:e80–e81. doi: 10.1016/j.cgh.2016.09.017.
    1. Barroso-Sousa R., Barry W.T., Garrido-Castro A.C., Hodi F.S., Min L., Krop I.E., Tolaney S.M. Incidence of endocrine dysfunction following the use of different immune checkpoint inhibitor regimens: A systematic review and meta-analysis. JAMA Oncol. 2018;4:173–182. doi: 10.1001/jamaoncol.2017.3064.
    1. Naidoo J., Wang X., Woo K.M., Iyriboz T., Halpenny D., Cunningham J., Chaft J.E., Segal N.H., Callahan M.K., Lesokhin A.M. Pneumonitis in patients treated with anti–programmed death-1/programmed death ligand 1 therapy. J. Clin. Oncol. 2017;35:709. doi: 10.1200/JCO.2016.68.2005.
    1. Kim K.W., Ramaiya N.H., Krajewski K.M., Jagannathan J.P., Tirumani S.H., Srivastava A., Ibrahim N. Ipilimumab associated hepatitis: Imaging and clinicopathologic findings. Investig. New Drugs. 2013;31:1071–1077. doi: 10.1007/s10637-013-9939-6.
    1. Johnson D.B., Balko J.M., Compton M.L., Chalkias S., Gorham J., Xu Y., Hicks M., Puzanov I., Alexander M.R., Bloomer T.L. Fulminant myocarditis with combination immune checkpoint blockade. N. Engl. J. Med. 2016;375:1749–1755. doi: 10.1056/NEJMoa1609214.
    1. Cortazar F.B., Marrone K.A., Troxell M.L., Ralto K.M., Hoenig M.P., Brahmer J.R., Le D.T., Lipson E.J., Glezerman I.G., Wolchok J. Clinicopathological features of acute kidney injury associated with immune checkpoint inhibitors. Kidney Int. 2016;90:638–647. doi: 10.1016/j.kint.2016.04.008.
    1. Viola D., Valerio L., Molinaro E., Agate L., Bottici V., Biagini A., Lorusso L., Cappagli V., Pieruzzi L., Giani C., et al. Treatment of advanced thyroid cancer with targeted therapies: Ten years of experience. Endocr. Relat. Cancer. 2016;23:R185–R205. doi: 10.1530/ERC-15-0555.
    1. Chau N.G., Haddad R.I. Vandetanib for the treatment of medullary thyroid cancer. Clin. Cancer Res. 2013;19:524–529. doi: 10.1158/1078-0432.CCR-12-2353.
    1. Naoum G.E., Morkos M., Kim B., Arafat W. Novel targeted therapies and immunotherapy for advanced thyroid cancers. Mol. Cancer. 2018;17:51. doi: 10.1186/s12943-018-0786-0.
    1. Palmer R.H., Vernersson E., Grabbe C., Hallberg B. Anaplastic lymphoma kinase: Signalling in development and disease. Biochem. J. 2009;420:345–361. doi: 10.1042/BJ20090387.

Source: PubMed

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