Inhibidores de la tirosina-cinasa en cáncer de tiroides

Introducción: el carcinoma de tiroides es la neoplasia endocrina más común. Su prevalencia está en aumento por varias causas, entre las cuales se encuentra el sobrediagnóstico. A pesar de lo anterior, también existe un incremento en los tumores más grandes, más agresivos y en la mortalidad que producen. A la fecha, la causa de esto es desconocida. La mayoría de los pacientes con cáncer de tiroides tienen enfermedad localizada. Sin embargo, el 15 % de los pacientes puede tener enfermedad metastásica y hasta la mitad de ellos puede tener enfermedad resistente al yodo. Para estos pacientes, las opciones han sido pocas.
Metodología: se revisaron los estudios aleatorizados y controlados con placebo de los inhibidores de tirosina-cinasa en pacientes con carcinoma de tiroides y se presentó una síntesis de sus resultados, lo mismo que las indicaciones generales para al manejo de dicha enfermedad.
Resultados: a la fecha, el único medicamento aprobado en Colombia para usar en cáncer de tiroides metastásico o irresecable, resistente a yodo y en progresión es el sorafenib. Aprobados en otros países se encuentra el lenvatinib y la FDA recientemente aprobó la combinación dabrafenib más trametinib para pacientes BRAF mutados o con cáncer anaplásico BRAF mutado. El manejo de los efectos adversos de estos medicamentos es esencial para el éxito de la terapia. Se discute también la evidencia de tratamiento en carcinoma medular de tiroides, terapias futuras y el papel de la inmunoterapia.
Conclusiones: el cáncer de tiroides resistente a yodo es un reto clínico. Los inhibidores de la tirosina-cinasa son una opción para estos pacientes. El manejo de los efectos adversos es esencial para un uso adecuado y una terapia exitosa.

1. Román-González A, Simón-Duque C, Camilo-Pérez J, Vélez-Hoyo A. [Trabecular hyalinizing adenoma of the thyroid (HAT): A report of two cases]. Gac Med Mex. 2016;152(1):111-5.
2. Cabanillas ME, McFadden DG, Durante C. Thyroid cancer. Lancet. 2016;388(10061):2783-95. doi: 10.1016/S0140-6736(16)30172-6
3. Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68(6):394- 424. doi: 10.3322/caac.21492
4. Galofré JC, Santamaría-Sandi J, Capdevila J, Navarro-González E, ZafónLlopis C, Ramón Y Cajal Asensio T, et al. Consensus on the management of advanced medullary thyroid carcinoma on behalf of the Working Group of Thyroid Cancer of the Spanish Society of Endocrinology (SEEN) and the Spanish Task Force Group for Orphan and Infrequent Tumors (GETHI). Endocrinol Nutr. 2015;62(4):e37-46. doi: 10.1016/j.endonu.2015.01.005
5. Spitzweg C, Morris JC, Bible KC. New drugs for medullary thyroid cancer: new promises? Endocr Relat Cancer. 2016;23(6):R287-97. doi: 10.1530/ ERC-16-0104
6. Brose MS, Nutting CM, Jarzab B, Elisei R, Siena S, Bastholt L, et al. Sorafenib in radioactive iodine-refractory, locally advanced or metastatic differentiated thyroid cancer: a randomised, double-blind, phase 3 trial. Lancet. 2014;384(9940):319-28. doi: 10.1016/S0140-6736(14)60421-9
7. Schlumberger M, Tahara M, Wirth LJ, Robinson B, Brose MS, Elisei R, et al. Lenvatinib versus placebo in radioiodine-refractory thyroid cancer. N Engl J Med. 2015;372(7):621-30. doi: 10.1056/NEJMoa1406470
8. Leboulleux S, Bastholt L, Krause T, de la Fouchardiere C, Tennvall J, Awada A, et al. Vandetanib in locally advanced or metastatic differentiated thyroid cancer: a randomised, double-blind, phase 2 trial. Lancet Oncol. 2012;13(9):897-905. doi: 10.1016/S1470-2045(12)70335-2
9. Thornton K, Kim G, Maher VE, Chattopadhyay S, Tang S, Moon YJ, et al. Vandetanib for the treatment of symptomatic or progressive medullary thyroid cancer in patients with unresectable locally advanced or metastatic disease: U.S. Food and Drug Administration drug approval summary. Clin Cancer Res. 2012;18(14):3722-30. doi: 10.1158/1078-0432.CCR-12- 0411
10. Wells SA, Robinson BG, Gagel RF, Dralle H, Fagin JA, Santoro M, et al. Vandetanib in patients with locally advanced or metastatic medullary thyroid cancer: a randomized, double-blind phase III trial. J Clin Oncol. 2012;30(2):134-41. doi: 10.1200/JCO.2011.35.5040
11. Hoy SM. Cabozantinib: a review of its use in patients with medullary thyroid cancer. Drugs. 2014;74(12):1435-44. doi: 10.1007/s40265-014- 0265-x
12. Haroon Al Rasheed MR, Xu B. Molecular Alterations in Thyroid Carcinoma. Surg Pathol Clin. 2019;12(4):921-30. doi: 10.1016/j.path.2019.08.002
13. Brose MS, Cabanillas ME, Cohen EE, Wirth LJ, Riehl T, Yue H, et al. Vemurafenib in patients with BRAF(V600E)-positive metastatic or unresectable papillary thyroid cancer refractory to radioactive iodine: a non-randomised, multicentre, open-label, phase 2 trial. Lancet Oncol. 2016;17(9):1272-82. doi: 10.1016/S1470-2045(16)30166-8
14. Jhiang SM. The RET proto-oncogene in human cancers. Oncogene. 2000;19(49):5590-7. doi: 10.1038/sj.onc.1203857
15. Takahashi M, Ritz J, Cooper GM. Activation of a novel human transforming gene, ret, by DNA rearrangement. Cell. 1985;42(2):581-8. doi: 10.1016/0092-8674(85)90115-1
16. Drilon A, Hu ZI, Lai GGY, Tan DSW. Targeting RET-driven cancers: lessons from evolving preclinical and clinical landscapes. Nat Rev Clin Oncol. 2018;15(3):151-67. doi: 10.1038/nrclinonc.2017.175
17. Ji JH, Oh YL, Hong M, Yun JW, Lee HW, Kim D, et al. Identification of Driving ALK Fusion Genes and Genomic Landscape of Medullary Thyroid Cancer. PLoS Genet. 2015;11(8):e1005467. doi: 10.1371/journal.pgen.1005467
18. Bagheri-Yarmand R, Williams MD, Grubbs EG, Gagel RF. ATF4 Targets RET for Degradation and Is a Candidate Tumor Suppressor Gene in Medullary Thyroid Cancer. J Clin Endocrinol Metab. 2017;102(3):933-41. doi: 10.1210/jc.2016-2878
19. Wells SA, Asa SL, Dralle H, Elisei R, Evans DB, Gagel RF, et al. Revised American Thyroid Association guidelines for the management of medullary thyroid carcinoma. Thyroid. 2015;25(6):567-610. doi: 10.1089/ thy.2014.0335
20. Barroso-Sousa R, Lerario AM, Evangelista J, Papadia C, Lourenço DM, Lin CS, et al. Complete resolution of hypercortisolism with sorafenib in a patient with advanced medullary thyroid carcinoma and ectopic ACTH (adrenocorticotropic hormone) syndrome. Thyroid. 2014;24(6):1062-6. doi: 10.1089/thy.2013.0571
21. Baudry C, Paepegaey AC, Groussin L. Reversal of Cushing’s syndrome by vandetanib in medullary thyroid carcinoma. N Engl J Med. 2013;369(6):584-6. doi: 10.1056/NEJMc1301428
22. Hadoux J, Pacini F, Tuttle RM, Schlumberger M. Management of advanced medullary thyroid cancer. Lancet Diabetes Endocrinol. 2016;4(1):64-71. doi: 10.1016/S2213-8587(15)00337-X
23. Dadu R, Hu MN, Grubbs EG, Gagel RF. Use of Tyrosine Kinase Inhibitors for Treatment of Medullary Thyroid Carcinoma. Recent Results Cancer Res. 2015;204:227-49. doi: 10.1007/978-3-319-22542-5_11
24. Frampton JE. Vandetanib: in medullary thyroid cancer. Drugs. 2012;72(10):1423-36. doi: 10.2165/11209300-000000000-00000
25. Gómez K, Varghese J, Jiménez C. Medullary thyroid carcinoma: molecular signaling pathways and emerging therapies. J Thyroid Res. 2011;2011:815826. doi: 10.4061/2011/815826
26. Yakes FM, Chen J, Tan J, Yamaguchi K, Shi Y, Yu P, et al. Cabozantinib (XL184), a novel MET and VEGFR2 inhibitor, simultaneously suppresses metastasis, angiogenesis, and tumor growth. Mol Cancer Ther. 2011;10(12):2298- 308. doi: 10.1158/1535-7163.MCT-11-0264
27. Gordon MS, Vogelzang NJ, Schoffski P, Daud A, Spira AI, O’Keeffe BA, et al. Activity of cabozantinib (XL184) in soft tissue and bone: Results of a phase II randomized discontinuation trial (RDT) in patients (pts) with advanced solid tumors. J Clin Oncol. 2011;29 (Suppl 15)3010-3010. doi: 10.1200/ jco.2011.29.15_suppl.3010
28. Al-Salama ZT, Keating GM. Cabozantinib: A Review in Advanced Renal Cell Carcinoma. Drugs. 2016;76(18):1771-8. doi: 10.1007/s40265-016-0661-5
29. Jimenez C, Waguespack S, Habra M, Busaidy N, Dadu R, Tamsen G, et al. Cabozantanib in patients with unresectable metastatic pheochromocytoma and paraganglioma. Global Academic Programs of Cancer Centers Symposium; Houston, Tx2017.
30. Roman-Gonzalez A, Jimenez C. Malignant pheochromocytoma-paraganglioma: pathogenesis, TNM staging, and current clinical trials. Curr Opin Endocrinol Diabetes Obes. 2017;24(3):174-183. doi: 10.1097/ MED.0000000000000330
31. Cohen EE, Tortorici M, Kim S, Ingrosso A, Pithavala YK, Bycott P. A Phase II trial of axitinib in patients with various histologic subtypes of advanced thyroid cancer: long-term outcomes and pharmacokinetic/pharmacodynamic analyses. Cancer Chemother Pharmacol. 2014;74(6):1261-70. doi: 10.1007/s00280-014-2604-8
32. Frank-Raue K, Ganten M, Kreissl MC, Raue F. Rapid response to sorafenib in metastatic medullary thyroid carcinoma. Exp Clin Endocrinol Diabetes. 2011;119(3):151-5. doi: 10.1055/s-0030-1262836
33. Ravaud A, de la Fouchardière C, Asselineau J, Delord JP, Do Cao C, Niccoli P, et al. Efficacy of sunitinib in advanced medullary thyroid carcinoma: intermediate results of phase II THYSU. Oncologist. 2010;15(2):212-3; author reply 4. doi: 10.1634/theoncologist.2009-0303
34. van Geel RM, Beijnen JH, Schellens JH. Concise drug review: pazopanib and axitinib. Oncologist. 2012;17(8):1081-9. doi: 10.1634/theoncologist.2012-0055
35. Bass MB, Sherman SI, Schlumberger MJ, Davis MT, Kivman L, Khoo HM, et al. Biomarkers as predictors of response to treatment with motesanib in patients with progressive advanced thyroid cancer. J Clin Endocrinol Metab. 2010;95(11):5018-27. doi: 10.1210/jc.2010-0947
36. Sherman SI, Wirth LJ, Droz JP, Hofmann M, Bastholt L, Martins RG, et al. Motesanib diphosphate in progressive differentiated thyroid cancer. N Engl J Med. 2008;359(1):31-42. doi: 10.1056/NEJMoa075853
37. Kummar S, Lassen UN. TRK Inhibition: A New Tumor-Agnostic Treatment Strategy. Target Oncol. 2018;13(5):545-56. doi: 10.1007/s11523-018- 0590-1
38. Cocco E, Scaltriti M, Drilon A. NTRK fusion-positive cancers and TRK inhibitor therapy. Nat Rev Clin Oncol. 2018;15(12):731-47. doi: 10.1038/ s41571-018-0113-0
39. Scott LJ. Larotrectinib: First Global Approval. Drugs. 2019;79(2):201-6. doi: 10.1007/s40265-018-1044-x
40. Laetsch TW, Hawkins DS. Larotrectinib for the treatment of TRK fusion solid tumors. Expert Rev Anticancer Ther. 2019;19(1):1-10. doi: 10.1080/14737140.2019.1538796
41. Drilon A, Laetsch TW, Kummar S, DuBois SG, Lassen UN, Demetri GD, et al. Efficacy of Larotrectinib in TRK Fusion-Positive Cancers in Adults and Children. N Engl J Med. 2018;378(8):731-9. doi: 10.1056/NEJMoa1714448
42. Berger S, Martens UM, Bochum S. Larotrectinib (LOXO-101). Recent Results Cancer Res. 2018;211:141-51. doi: 10.1007/978-3-319-91442-8_10
43. Laetsch TW, DuBois SG, Mascarenhas L, Turpin B, Federman N, Albert CM, et al. Larotrectinib for paediatric solid tumours harbouring NTRK gene fusions: phase 1 results from a multicentre, open-label, phase 1/2 study. Lancet Oncol. 2018;19(5):705-14. doi: 10.1016/S1470-2045(18)30119-0
44. Hong DS, Bauer TM, Lee JJ, Dowlati A, Brose MS, Farago AF, et al. Larotrectinib in adult patients with solid tumours: a multicentre, open-label, phase I dose-escalation study. Ann Oncol. 2019;30(2):325-31. doi: 10.1093/annonc/mdy539
45. Sabari JK, Siau ED, Drilon A. Targeting RET-rearranged lung cancers with multikinase inhibitors. Oncoscience. 2017;4(3-4):23-4. doi: 10.18632/ oncoscience.345
46. Wells SA, Gosnell JE, Gagel RF, Moley J, Pfister D, Sosa JA, et al. Vandetanib for the treatment of patients with locally advanced or metastatic hereditary medullary thyroid cancer. J Clin Oncol. 2010;28(5):767-72. doi: 10.1200/JCO.2009.23.6604
47. Karras S, Anagnostis P, Krassas GE. Vandetanib for the treatment of thyroid cancer: an update. Expert Opin Drug Metab Toxicol. 2014;10(3):469- 81. doi: 10.1517/17425255.2014.885015
48. BLU-667 Targets RET-Altered Cancers. Cancer Discov. 2018;8(6):OF8. doi: 10.1158/2159-8290.CD-NB2018-050
49. Subbiah V, Gainor JF, Rahal R, Brubaker JD, Kim JL, Maynard M, et al. Precision Targeted Therapy with BLU-667 for RET-Driven Cancers. Cancer Discov. 2018;8(7):836-49. doi: 10.1158/2159-8290.CD-18-0338
50. Cabanillas ME, Ferrarotto R, Garden AS, Ahmed S, Busaidy NL, Dadu R, et al. Neoadjuvant BRAF- and Immune-Directed Therapy for Anaplastic Thyroid Carcinoma. Thyroid. 2018;28(7):945-51. doi: 10.1089/thy.2018.0060
51. Cabanillas ME, Patel A, Danysh BP, Dadu R, Kopetz S, Falchook G. BRAF Inhibitors: Experience in Thyroid Cancer and General Review of Toxicity. Horm Cancer. 2015;6(1):21-36. doi: 10.1007/s12672-014-0207-9
52. Hauschild A, Dummer R, Schadendorf D, Santinami M, Atkinson V, Mandalà M, et al. Longer Follow-Up Confirms Relapse-Free Survival Benefit With Adjuvant Dabrafenib Plus Trametinib in Patients With Resected BRAF V600-Mutant Stage III Melanoma. J Clin Oncol. 2018;36(35):3441-3449. doi: 10.1200/JCO.18.01219
53. Odogwu L, Mathieu L, Blumenthal G, Larkins E, Goldberg KB, Griffin N, et al. FDA Approval Summary: Dabrafenib and Trametinib for the Treatment of Metastatic Non-Small Cell Lung Cancers Harboring. Oncologist. 2018;23(6):740-5. doi: 10.1634/theoncologist.2017-0642
54. Subbiah V, Kreitman RJ, Wainberg ZA, Cho JY, Schellens JHM, Soria JC, et al. Dabrafenib and Trametinib Treatment in Patients With Locally Advanced or Metastatic BRAF V600-Mutant Anaplastic Thyroid Cancer. J Clin Oncol. 2018;36(1):7-13. doi: 10.1200/JCO.2017.73.6785
55. Dobosz T, Lukienczuk T, Sasiadek M, Kuczy?ska A, Jankowska E, Blin N. Microsatellite instability in thyroid papillary carcinoma and multinodular hyperplasia. Oncology. 2000;58(4):305-10. doi: 10.1159/000012117
56. Genutis LK, Tomsic J, Bundschuh R, Brock P, Williams MD, Roychowdhury S, et al. Microsatellite Instability Occurs in a Subset of Follicular Thyroid Cancers. Thyroid. 2019;29(4):523-29. doi: 10.1089/thy.2018.0655
57. Naoum GE, Morkos M, Kim B, Arafat W. Novel targeted therapies and immunotherapy for advanced thyroid cancers. Mol Cancer. 2018;17(1):51. doi: 10.1186/s12943-018-0786-0
58. Weitzman SP, Sherman SI. Novel Drug Treatments of Progressive Radioiodine-Refractory Differentiated Thyroid Cancer. Endocrinol Metab Clin North Am. 2019;48(1):253-68. doi: 10.1016/j.ecl.2018.10.009
59. Antonelli A, Ferrari SM, Fallahi P. Current and future immunotherapies for thyroid cancer. Expert Rev Anticancer Ther. 2018;18(2):149-59. doi: 10.1080/14737140.2018.1417845

proteínas proto-oncogénicas B-raf
neoplasias de la tiroides
lenvatinib
sorafenib
inhibidores de proteínas quinasas