TREATMENT OF BRAF^V600E POSITIVE ANAPLASTIC THYROID CARCINOMA: CASE REPORT

Anaplastic thyroid cancer is one of the most aggressive and fatal human carcinomas. A significant experience in using various kinase inhibitors for anaplastic thyroid cancer therapy has been accumulated worldwide. The most encouraging results were obtained after using a combination of b-Raf and MEK kinase inhibitors (vemurafenib/dabrafenib and trametinib/cobimetinib, respectively) for the treatment of the unresectable BRAF^V600E-positive anaplastic thyroid cancer. This drug combination makes it possible to perform surgery followed by chemoradiotherapy and other targeted therapies. Here we report a clinical case of anaplastic thyroid cancer in a 69-year-old woman, who was treated with neoadjuvant targeted therapy. The treatment was carried out on the basis of three medical institutions: the National Medical Research Radiological Centre (Moscow), the N.I. Pirogov Clinic of Advanced Medical Technologies (St. Petersburg) and the Endocrinology Research Center (Moscow). Since there is still no universal protocol for treating ATC patients, and only palliative therapy is used in most cases, we emphasized on diagnostic and treatment errors of this disease. Special attention was paid to the importance of using molecular diagnostics and modern medical imaging technologies.

anaplastic thyroid cancer, BRAFV600E mutation, targeted therapy, neoadjuvant therapy

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., Shah M.H., Shaha A.R., Tuttle R.M.; American Thyroid Association Anaplastic Thyroid Cancer Guidelines Taskforce. American Thyroid Association guidelines for management of patients with anaplastic thyroid cancer. Thyroid. 2012 Nov; 22(11): 1104–39. doi: 10.1089/thy.2012.0302.

2. Giuffrida D., Gharib H. Anaplastic thyroid carcinoma: current diagnosis and treatment. Ann Oncol. 2000; 11(9): 1083–9. doi: 10.1023/a:1008322002520.

3. Nikiforov Y.E., Nikiforova M.N. Molecular genetics and diagnosis of thyroid cancer. Nat Rev Endocrinol. 2011; 7(10): 569–80. doi: 10.1038/ nrendo.2011.142.

4. Ahmed S., Ghazarian M.P., Cabanillas M.E., Zafereo M.E., Williams M.D., Vu T., Schomer D.F., Debnam J.M. Imaging of Anaplastic Thyroid Carcinoma. AJNR Am J Neuroradiol. 2018 Mar; 39(3): 547–551. doi: 10.3174/ajnr.A5487.

5. Rao S.N., Zafereo M., Dadu R., Busaidy N.L., Hess K., Cote G.J., Williams M.D., William W.N., Sandulache V., Gross N., Gunn G.B., Lu C., Ferrarotto R., Lai S.Y., Cabanillas M.E. Patterns of Treatment Failure in Anaplastic Thyroid Carcinoma. Thyroid. 2017 May; 27(5): 672–681. doi: 10.1089/thy.2016.0395.

6. FDA approves dabrafenib plus trametinib for anaplastic thyroid cancer with BRAF V600E mutation [Internet]. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-dabrafenibplus-trametinib-anaplastic-thyroid-cancer-braf-v600e-mutation (cited 18.08.2020).

7. 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., Mookerjee B., Wang D., Rangwala F., Keam B. Dabrafenib and Trametinib Treatment in Patients With Locally Advanced or Metastatic BRAF V600- Mutant Anaplastic Thyroid Cancer. J Clin Oncol. 2018 Jan 1; 36(1): 7–13. doi: 10.1200/JCO.2017.73.6785.

8. Pylev A.L., Zhandarova A.A., Petrov K.S., Romanov D.S., Lisovoy V.A., Golub S.V. Anaplastic thyroid cancer. Is there a light at the end of the tunnel? Head and Neck Tumors. 2020; 10(1): 10–19. (in Russian).

9. Ciarallo A., Marcus C., Taghipour M., Subramaniam R.M. Value of Fluorodeoxyglucose PET/Computed Tomography Patient Management and Outcomes in Thyroid Cancer. PET Clin. 2015 Apr; 10(2): 265–78. doi: 10.1016/j.cpet.2014.12.009.

10. Santhanam P., Khthir R., Solnes L.B., Ladenson P.W. The relationship of braf.v600e mutation status to fdg pet/ct avidity in thyroid cancer: a review and meta-analysis. Endocr Pract. 2018; 24(1): 21–26. doi: 10.4158/EP-2017-0080.

11. 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., Schultz N., Berger M.F., Sander C., Taylor B.S., Ghossein R., Ganly I., Fagin J.A. Genomic and transcriptomic hallmarks of poorly differentiated and anaplastic thyroid cancers. J Clin Invest. 2016 Mar 1; 126(3): 1052–66. doi: 10.1172/JCI85271.

12. Quiros R.M., Ding H.G., Gattuso P., Prinz R.A., Xu X. Evidence that one subset of anaplastic thyroid carcinomas are derived from papillary carcinomas due to BRAF and p53 mutations. Cancer. 2005; 103(11): 2261–8. doi: 10.1002/cncr.21073.

13. Lim A.M., Taylor G.R., Fellowes A., Cameron L., Lee B., Hicks R.J., McArthur G.A., Angel C., Solomon B., Rischin D. BRAF Inhibition in BRAFV600E-Positive Anaplastic Thyroid Carcinoma. J Natl Compr Canc Netw. 2016 Mar; 14(3): 249–54. doi: 10.6004/jnccn.2016.0030.

14. Paraiso K.H., Fedorenko I.V., Cantini L.P., Munko A.C., Hall M., Sondak V.K., Messina J.L., Flaherty K.T., Smalley K.S. Recovery of phospho-ERK activity allows melanoma cells to escape from BRAF inhibitor therapy. Br J Cancer. 2010 Jun 8; 102(12): 1724–30. doi: 10.1038/sj.bjc.6605714.

15. Flaherty K.T., Infante J.R., Daud A., Gonzalez R., Kefford R.F., Sosman J., Hamid O., Schuchter L., Cebon J., Ibrahim N., Kudchadkar R., Burris H.A.3rd, Falchook G., Algazi A., Lewis K., Long G.V., Puzanov I., Lebowitz P., Singh A., Little S., Sun P., Allred A., Ouellet D., Kim K.B., Patel K., Weber J. Combined BRAF and MEK inhibition in melanoma with BRAF V600 mutations. N Engl J Med. 2012 Nov 1; 367(18): 1694–703. doi: 10.1056/NEJMoa1210093.

16. Cabanillas M.E., Ferrarotto R., Garden A.S., Ahmed S., Busaidy N.L., Dadu R., Williams M.D., Skinner H., Gunn G.B., Grosu H., Iyer P., Hofmann M.C., Zafereo M. Neoadjuvant BRAF- and Immune-Directed Therapy for Anaplastic Thyroid Carcinoma. Thyroid. 2018 Jul; 28(7): 945–951. doi: 10.1089/thy.2018.0060.

17. Wang J.R., Zafereo M.E., Dadu R., Ferrarotto R., Busaidy N.L., Lu C., Ahmed S., Gule-Monroe M.K., Williams M.D., Sturgis E.M., Goepfert R.P., Gross N.D., Lai S.Y., Gunn G.B., Phan J., Rosenthal D.I., Fuller C.D., Morrison W.H., Iyer P., Cabanillas M.E. Complete Surgical Resection Following Neoadjuvant Dabrafenib Plus Trametinib in BRAFV600E-Mutated Anaplastic Thyroid Carcinoma. Thyroid. 2019 Aug; 29(8): 1036–43. doi: 10.1089/thy.2019.0133.

18. Cabanillas M.E., Dadu R., Iyer P., Wanland K.B., Busaidy N.L., Ying A., Gule-Monroe M., Wang J.R., Zafereo M., Hofmann M.C. Acquired Secondary RAS Mutation in BRAFV600E-Mutated Thyroid Cancer Patients Treated with BRAF Inhibitors. Thyroid. 2020; 30(9): 1288–96. doi: 10.1089/thy.2019.0514.

19. Midthun L., Shaheen S., Deisch J., Senthil M., Tsai J., Hsueh C.T. Concomitant KRAS and BRAF mutations in colorectal cancer. J Gastrointest Oncol. 2019 Jun; 10(3): 577–581. doi: 10.21037/jgo.2019.01.10.

20. Abravanel D.L., Nishino M., Sholl L.M., Ambrogio C., Awad M.M. An Acquired NRAS Q61K Mutation in BRAF V600E-Mutant Lung Adenocarcinoma Resistant to Dabrafenib Plus Trametinib. J Thorac Oncol. 2018 Aug; 13(8): e131e133. doi: 10.1016/j.jtho.2018.03.026.

21. Bunney P.E., Zink A.N., Holm A.A., Billington C.J., Kotz C.M. Orexin activation counteracts decreases in nonexercise activity thermogenesis (NEAT) caused by high-fat diet. Physiol Behav. 2017 Jul 1; 176: 139–48. doi: 10.1016/j.physbeh.2017.03.040.

22. Bastman J.J., Serracino H.S., Zhu Y., Koenig M.R., Mateescu V., Sams S.B., French J.D. Tumor-Infiltrating T Cells and the PD-1 Checkpoint Pathway in Advanced Differentiated and Anaplastic Thyroid Cancer. J Clin Endocrinol Metab. 2016; 101(7): 2863–2873. doi: 10.1210/jc.2015-4227.

23. Naing A., Gainor J.F., Gelderblom H., Forde P.M., Butler M.O., Lin C.C., Sharma S., Ochoa de Olza M., Varga A., Taylor M., Schellens J.H.M., Wu H., Sun H., Silva A.P., Faris J., Mataraza J., Cameron S., Bauer T.M. A first-in-human phase 1 dose escalation study of spartalizumab (PDR001), an anti-PD-1 antibody, in patients with advanced solid tumors. J Immunother Cancer. 2020 Mar; 8(1): e000530. doi: 10.1136/jitc-2020-000530.

24. Capdevila J., Wirth L.J., Ernst T., Ponce Aix S., Lin C.C., Ramlau R., Butler M.O., Delord J.P., Gelderblom H., Ascierto P.A., Fasolo A., Führer D., Hütter-Krönke M.L., Forde P.M., Wrona A., Santoro A., Sadow P.M., Szpakowski S., Wu H., Bostel G., Faris J., Cameron S, Varga A., Taylor M. PD-1 Blockade in Anaplastic Thyroid Carcinoma. J Clin Oncol. 2020 Aug 10; 38(23): 2620–2627. doi: 10.1200/JCO.19.02727.