Neuerungen in der Systemtherapie des Anaplastischen Schilddrüsenkarzinoms

Das anaplastische Schilddrüsenkarzinom ist eine hochaggressive Tumorerkrankung mit einer sehr schlechten Prognose, und fast alle Patient*innen benötigen eine Systemtherapie. Dieser Review gibt einen Überblick über alle systemischen Therapiemöglichkeiten von der klassischen Chemotherapie über Immuntherapien und molekular-basierte Kinase-Inhibitoren und zeigt auf, welch enormes Potenzial in den neuen Therapieformen steckt.

Kernaussagen

• Anaplastische Schilddrüsenkarzinome haben eine sehr schlechte Prognose von 4–5 Monaten trotz multimodaler Therapien mit Operation, Bestrahlung und Chemotherapie.

• Ein schneller Therapiebeginn ist aufgrund des aggressiven Tumorwachstums von entscheidender Bedeutung.

• Klassische Chemotherapien als Erstlinientherapien haben eine begrenzte Wirksamkeit.

• Die frühe molekulare Diagnostik auf BRAF-Mutationen, RET- und NTRK-Fusionen ist von entscheidender Bedeutung.

• Beim BRAF-V600E-mutierten ATC ist die Kombination aus Dabrafenib/Trametinib (BRAF- und MEK-Inhibitor) einer Dabrafenib-Monotherapie überlegen.

• RET- und NTRK-fusionierte ATCs können mit spezifischen Kinase-Inhibitoren therapiert werden.

• 75% der ATCs haben keine spezifische Mutation und können effektiv mit einer Kombination aus dem Kinase-Inhibitor Lenvatinib und dem Immuncheckpoint-Inhibitor Pembrolizumab behandelt werden.

• Eine Whole-Exome-Sequenzierung und RNA-Sequenzierung im Rahmen des Master-Programms eröffnen häufig weitere Therapieoptionen.

Schlüsselwörter

Anaplastisches Schilddrüsenkarzinom - ATC - Immuntherapie - Molekulare Diagnostik - Kinaseinhibitor

Publication History

Article published online:
03 August 2022

• Literatur

• 1 Dumke AK, Pelz T, Vordermark D. Long-term results of radiotherapy in anaplastic thyroid cancer. Radiat Oncol 2014; 9: 90 DOI: 10.1186/1748-717X-9-90. (PMID: 24685141)
• 2 Perri F, Lorenzo GD, Scarpati GD. et al. Anaplastic thyroid carcinoma: A comprehensive review of current and future therapeutic options. World J Clin Oncol 2011; 2: 150-157 DOI: 10.5306/wjco.v2.i3.150. (PMID: 21611089)
• 3 Smallridge RC. Approach to the patient with anaplastic thyroid carcinoma. J Clin Endocrinol Metab 2012; 97: 2566-2572
• 4 Prasongsook N. et al. Survival in Response to Multimodal Therapy in Anaplastic Thyroid Cancer. J Clin Endocrinol Metab 2017; 102: 4506-4514 DOI: 10.1210/jc.2017-01180. (PMID: 29029287)
• 5 Smallridge RC, Copland JA. Anaplastic thyroid carcinoma: pathogenesis and emerging therapies. Clin Oncol (R Coll Radiol) 2010; 22: 486-497 DOI: 10.1016/j.clon.2010.03.013. (PMID: 20418080)
• 6 Wendler J. et al. Clinical presentation, treatment and outcome of anaplastic thyroid carcinoma: results of a multicenter study in Germany. Eur J Endocrinol 2016; 175: 521-529 DOI: 10.1530/EJE-16-0574. (PMID: 27926471)
• 7 Salehian B, Liem SY, Mojazi Amiri H. et al. Clinical Trials in Management of Anaplastic Thyroid Carcinoma; Progressions and Set Backs: A Systematic Review. Int J Endocrinol Metab 2019; 17: e67759 DOI: 10.5812/ijem.67759. (PMID: 30881466)
• 8 Dierks C. et al. Combination of Lenvatinib and Pembrolizumab Is an Effective Treatment Option for Anaplastic and Poorly Differentiated Thyroid Carcinoma. Thyroid 2021; 31: 1076-1085 DOI: 10.1089/thy.2020.0322. (PMID: 33509020)
• 9 Al-Jundi M, Thakur S, Gubbi S. et al. Novel Targeted Therapies for Metastatic Thyroid Cancer-A Comprehensive Review. Cancers (Basel) 2020; 12 DOI: 10.3390/cancers12082104. (PMID: 32751138)
• 10 Nikiforova MN. et al. BRAF mutations in thyroid tumors are restricted to papillary carcinomas and anaplastic or poorly differentiated carcinomas arising from papillary carcinomas. J Clin Endocrinol Metab 2003; 88: 5399-5404 DOI: 10.1210/jc.2003-030838. (PMID: 14602780)
• 11 Takano T, Ito Y, Hirokawa M. et al. BRAF V600E mutation in anaplastic thyroid carcinomas and their accompanying differentiated carcinomas. Br J Cancer 2007; 96: 1549-1553 DOI: 10.1038/sj.bjc.6603764. (PMID: 17453004)
• 12 Xu B. et al. Dissecting Anaplastic Thyroid Carcinoma: A Comprehensive Clinical, Histologic, Immunophenotypic, and Molecular Study of 360 Cases. Thyroid 2020; 30: 1505-1517 DOI: 10.1089/thy.2020.0086 . (PMID: 32284020)
• 13 Yoo SK. 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. (PMID: 31235699)
• 14 Duan H. et al. Mutational profiling of poorly differentiated and anaplastic thyroid carcinoma by the use of targeted next-generation sequencing. Histopathology 2019; 75: 890-899 DOI: 10.1111/his.13942. (PMID: 31230400)
• 15 Bonhomme B. et al. Molecular Pathology of Anaplastic Thyroid Carcinomas: A Retrospective Study of 144 Cases. Thyroid 2017; 27: 682-692 DOI: 10.1089/thy.2016.0254 . (PMID: 28351340)
• 16 Kunstman JW. et al. Characterization of the mutational landscape of anaplastic thyroid cancer via whole-exome sequencing. Hum Mol Genet 2015; 24: 2318-2329 DOI: 10.1093/hmg/ddu749. (PMID: 25576899)
• 17 Lai WA, Liu CY, Lin SY. et al. Characterization of Driver Mutations in Anaplastic Thyroid Carcinoma Identifies RAS and PIK3CA Mutations as Negative Survival Predictors. Cancers (Basel) 2020; 12 DOI: 10.3390/cancers12071973. (PMID: 32698386)
• 18 Nikiforova MN, Biddinger PW, Caudill CM. et al. PAX8-PPARgamma rearrangement in thyroid tumors: RT-PCR and immunohistochemical analyses. Am J Surg Pathol 2002; 26: 1016-1023 DOI: 10.1097/00000478-200208000-00006. (PMID: 12170088)
• 19 Park JW. et al. Treatment outcomes of radiotherapy for anaplastic thyroid cancer. Radiat Oncol J 2018; 36: 103-113 DOI: 10.3857/roj.2018.00045. (PMID: 29983030)
• 20 Derbel O. et al. Results of combined treatment of anaplastic thyroid carcinoma (ATC). BMC Cancer 2011; 11: 469 DOI: 10.1186/1471-2407-11-469. (PMID: 22044775)
• 21 Fan D. et al. Outcomes of multimodal therapy in a large series of patients with anaplastic thyroid cancer. Cancer 2020; 126: 444-452 DOI: 10.1002/cncr.32548. (PMID: 31593317)
• 22 Ekman ET, Lundell G, Tennvall J. et al. Chemotherapy and multimodality treatment in thyroid carcinoma. Otolaryngol Clin North Am 1990; 23: 523-527 (PMID: 1694985)
• 23 Shimaoka K, Schoenfeld DA, DeWys WD. et al. A randomized trial of doxorubicin versus doxorubicin plus cisplatin in patients with advanced thyroid carcinoma. Cancer 1985; 56: 2155-2160 DOI: 10.1002/1097-0142(19851101)56:9<2155::aid-cncr2820560903>3.0.co;2-e. (PMID: 3902203)
• 24 Ain KB, Egorin MJ, DeSimone PA. Treatment of anaplastic thyroid carcinoma with paclitaxel: phase 2 trial using ninety-six-hour infusion. Collaborative Anaplastic Thyroid Cancer Health Intervention Trials (CATCHIT) Group. Thyroid 2000; 10: 587-594 DOI: 10.1089/thy.2000.10.587. (PMID: 10958311)
• 25 Sosa JA. et al. Randomized safety and efficacy study of fosbretabulin with paclitaxel/carboplatin against anaplastic thyroid carcinoma. Thyroid 2014; 24: 232-240 DOI: 10.1089/thy.2013.0078. (PMID: 23721245)
• 26 Crispo F. et al. BRAF Inhibitors in Thyroid Cancer: Clinical Impact, Mechanisms of Resistance and Future Perspectives. Cancers (Basel) 2019; 11 DOI: 10.3390/cancers11091388. (PMID: 31540406)
• 27 Subbiah V. 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. (PMID: 29072975)
• 28 Wang JR. et al. Complete Surgical Resection Following Neoadjuvant Dabrafenib Plus Trametinib in BRAF(V600E)-Mutated Anaplastic Thyroid Carcinoma. Thyroid 2019; 29: 1036-1043 DOI: 10.1089/thy.2019.0133. (PMID: 31319771)
• 29 Ciampi R. 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. (PMID: 31605946)
• 30 Liu Z. et al. 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. (PMID: 18492751)
• 31 Landa I. et al. Genomic and transcriptomic hallmarks of poorly differentiated and anaplastic thyroid cancers. J Clin Invest 2016; 126: 1052-1066 DOI: 10.1172/JCI85271. (PMID: 26878173)
• 32 Pozdeyev N. 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. (PMID: 29615459)
• 33 Nikiforov YE, Rowland JM, Bove KE. et al. Distinct pattern of ret oncogene rearrangements in morphological variants of radiation-induced and sporadic thyroid papillary carcinomas in children. Cancer Res 1997; 57: 1690-1694 (PMID: 9135009)
• 34 Ciampi R, Nikiforov YE. RET/PTC rearrangements and BRAF mutations in thyroid tumorigenesis. Endocrinology 2007; 148: 936-941 DOI: 10.1210/en.2006-0921. (PMID: 16946010)
• 35 Ciampi R, Giordano TJ, Wikenheiser-Brokamp K. et al. HOOK3-RET: a novel type of RET/PTC rearrangement in papillary thyroid carcinoma. Endocr Relat Cancer 2007; 14: 445-452 DOI: 10.1677/ERC-07-0039. (PMID: 17639057)
• 36 Vanden Borre P. et al. Pediatric, Adolescent, and Young Adult Thyroid Carcinoma Harbors Frequent and Diverse Targetable Genomic Alterations, Including Kinase Fusions. Oncologist 2017; 22: 255-263
• 37 Su X. et al. Radiation exposure, young age, and female gender are associated with high prevalence of RET/PTC1 and RET/PTC3 in papillary thyroid cancer: a meta-analysis. Oncotarget 2016; 7: 16716-16730 DOI: 10.18632/oncotarget.7574. (PMID: 26918339)
• 38 Wirth LJ. et al. Efficacy of Selpercatinib in RET-Altered Thyroid Cancers. N Engl J Med 2020; 383: 825-835 DOI: 10.1056/NEJMoa2005651. (PMID: 32846061)
• 39 Dias-Santagata D. et al. Response to RET-Specific Therapy in RET Fusion-Positive Anaplastic Thyroid Carcinoma. Thyroid 2020; 30: 1384-1389 DOI: 10.1089/thy.2019.0477. (PMID: 32292131)
• 40 Amatu A. et al. Tropomyosin receptor kinase (TRK) biology and the role of NTRK gene fusions in cancer. Ann Oncol 2019; 30: viii5-viii15 DOI: 10.1093/annonc/mdz383. (PMID: 31738427)
• 41 Cocco E, Scaltriti M, Drilon A. NTRK fusion-positive cancers and TRK inhibitor therapy. Nat Rev Clin Oncol 2018; 15: 731-747 DOI: 10.1038/s41571-018-0113-0. (PMID: 30333516)
• 42 Drilon A. et al. Efficacy of Larotrectinib in TRK Fusion-Positive Cancers in Adults and Children. N Engl J Med 2018; 378: 731-739 DOI: 10.1056/NEJMoa1714448. (PMID: 29466156)
• 43 Doebele RC. et al. 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 . (PMID: 31838007)
• 44 Park JC, Ashok A, Liu C. et al. Real-World Experience of NTRK Fusion-Positive Thyroid Cancer. JCO Precis Oncol 2022; 6: e2100442 DOI: 10.1200/PO.21.00442. (PMID: 35171659)
• 45 Matsui J. et al. E7080, a novel inhibitor that targets multiple kinases, has potent antitumor activities against stem cell factor producing human small cell lung cancer H146, based on angiogenesis inhibition. Int J Cancer 2008; 122: 664-671 DOI: 10.1002/ijc.23131. (PMID: 17943726)
• 46 Okamoto K. et al. Antitumor activities of the targeted multi-tyrosine kinase inhibitor lenvatinib (E7080) against RET gene fusion-driven tumor models. Cancer Lett 2013; 340: 97-103 DOI: 10.1016/j.canlet.2013.07.007. (PMID: 23856031)
• 47 Yamamoto Y. et al. 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 2014; 6: 18 DOI: 10.1186/2045-824X-6-18. (PMID: 25197551)
• 48 Tohyama O. et al. Antitumor activity of lenvatinib (e7080): an angiogenesis inhibitor that targets multiple receptor tyrosine kinases in preclinical human thyroid cancer models. J Thyroid Res 2014; 2014: 638747 DOI: 10.1155/2014/638747. (PMID: 25295214)
• 49 Kiyota N. et al. Subgroup analysis of Japanese patients in a phase 3 study of lenvatinib in radioiodine-refractory differentiated thyroid cancer. Cancer Sci 2015; 106: 1714-1721 DOI: 10.1111/cas.12826. (PMID: 26426092)
• 50 Schlumberger M, Tahara M, Wirth LJ. Lenvatinib in radioiodine-refractory thyroid cancer. N Engl J Med 2015; 372: 1868 DOI: 10.1056/NEJMc1503150. (PMID: 25946295)
• 51 Koyama S. et al. Lenvatinib for Anaplastic Thyroid Cancer and Lenvatinib-Induced Thyroid Dysfunction. Eur Thyroid J 2018; 7: 139-144 DOI: 10.1159/000485972. (PMID: 30023346)
• 52 Takahashi S. et al. A Phase II study of the safety and efficacy of lenvatinib in patients with advanced thyroid cancer. Future Oncol 2019; 15: 717-726 DOI: 10.2217/fon-2018-0557. (PMID: 30638399)
• 53 Tahara M. et al. Lenvatinib for Anaplastic Thyroid Cancer. Front Oncol 2017; 7: 25 DOI: 10.3389/fonc.2017.00025. (PMID: 28299283)
• 54 Wirth LJ. et al. Open-Label, Single-Arm, Multicenter, Phase II Trial of Lenvatinib for the Treatment of Patients With Anaplastic Thyroid Cancer. J Clin Oncol 2021; 39: 2359-2366 DOI: 10.1200/JCO.20.03093. (PMID: 33961488)
• 55 Adam P. et al. FGF-Receptors and PD-L1 in Anaplastic and Poorly Differentiated Thyroid Cancer: Evaluation of the Preclinical Rationale. Front Endocrinol (Lausanne) 2021; 12: 712107 DOI: 10.3389/fendo.2021.712107. (PMID: 34475850)
• 56 Gandhi L. et al. Pembrolizumab plus Chemotherapy in Metastatic Non-Small-Cell Lung Cancer. N Engl J Med 2018; 378: 2078-2092 DOI: 10.1056/NEJMoa1801005. (PMID: 29658856)
• 57 Garon EB. et al. Five-Year Overall Survival for Patients With Advanced NonSmall-Cell Lung Cancer Treated With Pembrolizumab: Results From the Phase I KEYNOTE-001 Study. J Clin Oncol 2019; 37: 2518-2527 DOI: 10.1200/JCO.19.00934. (PMID: 31154919)
• 58 Villaruz LC. et al. Comparison of PD-L1 immunohistochemistry assays and response to PD-1/L1 inhibitors in advanced non-small-cell lung cancer in clinical practice. Histopathology 2019; 74: 269-275 DOI: 10.1111/his.13729. (PMID: 30105871)
• 59 Borghaei H. et al. Nivolumab versus Docetaxel in Advanced Nonsquamous Non-Small-Cell Lung Cancer. N Engl J Med 2015; 373: 1627-1639 DOI: 10.1056/NEJMoa1507643. (PMID: 26412456)
• 60 Capdevila J. et al. PD-1 Blockade in Anaplastic Thyroid Carcinoma. J Clin Oncol 2020; 38: 2620-2627 DOI: 10.1200/JCO.19.02727. (PMID: 32364844)
• 61 Gunda V. et al. Anti-PD-1/PD-L1 therapy augments lenvatinibʼs efficacy by favorably altering the immune microenvironment of murine anaplastic thyroid cancer. Int J Cancer 2019; 144: 2266-2278 DOI: 10.1002/ijc.32041. (PMID: 30515783)
• 62 Makker V. et al. Lenvatinib plus pembrolizumab in patients with advanced endometrial cancer: an interim analysis of a multicentre, open-label, single-arm, phase 2 trial. Lancet Oncol 2019; 20: 711-718 DOI: 10.1016/S1470-2045(19)30020-8. (PMID: 30922731)
• 63 Taylor MH. et al. The LEAP program: lenvatinib plus pembrolizumab for the treatment of advanced solid tumors. Future Oncol 2021; 17: 637-648 DOI: 10.2217/fon-2020-0937. (PMID: 33300372)
• 64 Finn RS. et al. Phase Ib Study of Lenvatinib Plus Pembrolizumab in Patients With Unresectable Hepatocellular Carcinoma. J Clin Oncol 2020; 38: 2960-2970 DOI: 10.1200/JCO.20.00808. (PMID: 32716739)