Abstract
Purpose
Radioiodine (RAI) therapy remains the gold-standard approach for distant metastatic differentiated thyroid cancer (TC). The main objective of our work was to identify the clinical and molecular markers that may help to predict RAI avidity and RAI therapy response of metastatic lesions in a cohort of papillary thyroid cancer (PTC) patients.
Methods
We performed a retrospective analysis of 122 PTC patients submitted to RAI therapy due to distant metastatic disease. We also analysed, through next-generation sequencing, a custom panel of 78 genes and rearrangements, in a smaller cohort of 31 metastatic PTC, with complete follow-up, available RAI therapy data, and existing tumour sample at our centre.
Results
The most frequent outcome after RAI therapy was progression of disease in 59.0% of cases (n = 71), with median estimate progression-free survival of 30 months. RAI avidity was associated with PTC subtype, age and stimulated thyroglobulin at first RAI therapy for metastatic disease. The most frequently altered genes in the cohort of 31 PTC patients’ primary tumours were RAS isoforms (54.8%) and TERT promoter (TERTp) (51.6%). The presence of BRAF p.V600E or RET/PTC alterations was associated with lower avidity (p = 0.012). TERTp mutations were not associated with avidity (p = 1.000) but portended a tendency for a higher rate of progression (p = 0.063); similar results were obtained when RAS and TERTp mutations coexisted (p = 1.000 and p = 0.073, respectively).
Conclusions
Early identification of molecular markers in primary tumours may help to predict RAI therapy avidity, the response of metastatic lesions and to select the patients that may benefit the most from other systemic therapies.
Similar content being viewed by others
References
J.A. Fagin, S.A. Wells, Biologic and clinical perspectives on thyroid cancer. N. Engl. J. Med. 375, 1054–1067 (2016)
B.R. Haugen, E.K. Alexander, K.C. Bible, G.M. Doherty, S.J. Mandel, Y.E. Nikiforov, F. Pacini, G.W. Randolph, A.M. Sawka, M. Schlumberger, K.G. Schuff, S.I. Sherman, J.A. Sosa, D.L. Steward, R.M. Tuttle, L. Wartofsky, 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 26, 1–133 (2016)
C. Durante, N. Haddy, E. Baudin, S. Leboulleux, D. Hartl, J.P. Travagli, B. Caillou, M. Ricard, J.D. Lumbroso, F. De Vathaire, M. Schlumberger, 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. 91, 2892–2899 (2006)
R.M. Tuttle, S. Ahuja, A.M. Avram, V.J. Bernet, P. Bourguet, G.H. Daniels, G. Dillehay, C. Draganescu, G. Flux, D. Führer, L. Giovanella, B. Greenspan, M. Luster, K. Muylle, J.W.A. Smit, D. Van Nostrand, F.A. Verburg, L. Hegedüs, 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 29, 461–470 (2019)
Cancer Genome Atlas Research Network., Integrated genomic characterization of papillary thyroid carcinoma. Cell 159, 676–690 (2014)
N. Pozdeyev, L.M. Gay, E.S. Sokol, R. Hartmaier, K.E. Deaver, S. Davis, J.D. French, P.V. Borre, D.V. LaBarbera, A.C. Tan, R.E. Schweppe, L. Fishbein, J.S. Ross, B.R. Haugen, D.W. Bowles, Genetic analysis of 779 advanced differentiated and anaplastic thyroid cancers. Clin. Cancer Res. 24, 3059–3068 (2018)
T. Ibrahimpasic, B. Xu, I. Landa, S. Dogan, S. Middha, V. Seshan, S. Deraje, D.L. Carlson, J. Migliacci, J.A. Knauf, B. Untch, M.F. Berger, L. Morris, R.M. Tuttle, T. Chan, J.A. Fagin, R. Ghossein, I. Ganly, Genomic alterations in fatal forms of non-anaplastic thyroid cancer: identification of MED12 and RBM10 as novel thyroid cancer genes associated with tumor virulence. Clin. Cancer Res. 23, 5970–5980 (2017)
I. Landa, T. Ibrahimpasic, L. Boucai, R. Sinha, J.A. Knauf, R.H. Shah, S. Dogan, J.C. Ricarte-Filho, G.P. Krishnamoorthy, B. Xu, N. Schultz, M.F. Berger, C. Sander, B.S. Taylor, R. Ghossein, I. Ganly, J.A. Fagin, Genomic and transcriptomic hallmarks of poorly differentiated and anaplastic thyroid cancers. J. Clin. Invest. 126, 1052–1066 (2016)
J.W. Kunstman, C.C. Juhlin, G. Goh, T.C. Brown, A. Stenman, J.M. Healy, J.C. Rubinstein, M. Choi, N. Kiss, C. Nelson-Williams, S. Mane, D.L. Rimm, M.L. Prasad, A. Höög, J. Zedenius, C. Larsson, R. Korah, R.P. Lifton, T. Carling, Characterization of the mutational landscape of anaplastic thyroid cancer via whole-exome sequencing. Hum. Mol. Genet. 24, 2318–2329 (2015)
M.M. Sabra, J.M. Dominguez, R.K. Grewal, S.M. Larson, R.A. Ghossein, R.M. Tuttle, J.A. Fagin, Clinical outcomes and molecular profile of differentiated thyroid cancers with radioiodine-avid distant metastases. J. Clin. Endocrinol. Metab 98, E829–E836 (2013)
L. Shobab, C. Gomes-Lima, A. Zeymo, R. Feldman, J. Jonklaas, L. Wartofsky, K.D. Burman, Clinical, pathological, and molecular profiling of radioactive iodine refractory differentiated thyroid cancer. Thyroid 29, 1262–1268 (2019)
I. Ganly, V. Makarov, S. Deraje, Y. Dong, E. Reznik, V. Seshan, G. Nanjangud, S. Eng, P. Bose, F. Kuo, L.G.T. Morris, I. Landa, P.B. Carrillo Albornoz, N. Riaz, Y.E. Nikiforov, K. Patel, C. Umbricht, M. Zeiger, E. Kebebew, E. Sherman, R. Ghossein, J.A. Fagin, T.A. Chan, Integrated genomic analysis of hürthle cell cancer reveals oncogenic drivers, recurrent mitochondrial mutations, and unique chromosomal landscapes. Cancer Cell 34, 256–270 (2018)
J. Simões-Pereira, N. Mourinho, T.C. Ferreira, E. Limbert, B.M. Cavaco, V. Leite, Avidity and outcomes of radioiodine therapy for distant metastasis of distinct types of differentiated thyroid cancer. J. Clin. Endocrinol. Metab. 106, e3911–e3922 (2021)
L. Lamartina, G. Grani, E. Arvat, A. Nervo, M.C. Zatelli, R. Rossi, E. Puxeddu, S. Morelli, M. Torlontano, M. Massa, R. Bellantone, A. Pontecorvi, T. Montesano, L. Pagano, L. Daniele, L. Fugazzola, G. Ceresini, R. Bruno, R. Rossetto, S. Tumino, M. Centanni, D. Meringolo, M.G. Castagna, D. Salvatore, A. Nicolucci, G. Lucisano, S. Filetti, C. Durante, 8th edition of the AJCC/TNM staging system of thyroid cancer: what to expect (ITCO#2). Endocr. Relat. Cancer 25, L7–L11 (2018)
E.A. Eisenhauer, P. Therasse, J. Bogaerts, L.H. Schwartz, D. Sargent, R. Ford, J. Dancey, S. Arbuck, S. Gwyther, M. Mooney, L. Rubinstein, L. Shankar, L. Dodd, R. Kaplan, D. Lacombe, J. Verweij, New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur. J. Cancer 45, 228–247 (2009)
M.E. Cabanillas, M. Ryder, C. Jimenez, Targeted therapy for advanced thyroid cancer: kinase inhibitors and beyond. Endocr. Rev. 40, 1573–1604 (2019)
Van Nostrand., Radioiodine refractory differentiated thyroid cancer: time to update the classifications. Thyroid 28, 1083–1093 (2018)
S.H. Malgundkar, I. Burney, M. Al Moundhri, M. Al Kalbani, R. Lakhtakia, A. Okamoto, Y. Tamimi, FAT4 silencing promotes epithelial-to-mesenchymal transition and invasion via regulation of YAP and β-catenin activity in ovarian cancer. BMC Cancer 20, 374 (2020)
K. van der Tuin, M. Ventayol Garcia, W.E. Corver, M.N. Khalifa, D. Ruano Neto, E.P.M. Corssmit, F.J. Hes, T.P. Links, J.W.A. Smit, T.S. Plantinga, E. Kapiteijn, T. van Wezel, H. Morreau, Targetable gene fusions identified in radioactive iodine refractory advanced thyroid carcinoma. Eur. J. Endocrinol. 180, 235–241 (2019)
N.M. Iñiguez-Ariza, S. Jasim, M.M. Ryder, A.V. Chintakuntlawar, J.C. Morris, C.R. Hilger, M.E. Menefee, R.C. Smallridge, N.J. Karlin, C. Alcaino, K.C. Bible, Foundation one genomic interrogation of thyroid cancers in patients with metastatic disease requiring systemic therapy. J. Clin. Endocrinol. Metab. 105, e2346–e2357 (2020)
E. Song, D.E. Song, J. Ahn, T.Y. Kim, W.B. Kim, Y.K. Shong, M.J. Jeon, W.G. Kim, Genetic profile of advanced thyroid cancers in relation to distant metastasis. Endocr. Relat. Cancer 27, 285–293 (2020)
C.J. Gomes-Lima, L. Shobab, D. Wu, D. Ylli, A. Bikas, M. McCoy, R. Feldman, W. Lee, S.N. Rao, K. Jensen, V. Vasko, L.C. Castro, J. Jonklaas, L. Wartofsky, K.D. Burman, Do molecular profiles of primary versus metastatic radioiodine refractory differentiated thyroid cancer differ? Front. Endocrinol. 12, 623182 (2021)
Acknowledgements
Authors are thankful to Teresa Pereira, to Ana Paula Cardoso and to José Cabeçadas from Pathology Department, Instituto Português de Oncologia de Lisboa Francisco Gentil, Lisboa, Portugal, for providing all the staff and facilities for FFPE tumour samples preparation, and to Manuel R. Teixeira and Paula Paulo, from Genetics Department, Instituto Português de Oncologia do Porto Francisco Gentil, Porto, Portugal, for tumour samples analysis in a NextSeq sequencer.
Author contributions
J.S.-P. designed the work, acquired the data (clinical and genetic), designed the custom panel, analysed the data, and wrote the manuscript; A.S., R.R. and C.P. performed the genetic analysis; M.P. designed the custom panel and acquired the FFPE material; M.H. reviewed the images to assess the structural response of metastases; D.L.-P., M.R. and R.C. reviewed the pathological slides and selected the tumour and normal counterparts; T.C.F. reviewed the post-RAI therapy WBS to assess avidity; B.M.C. planned the project, designed the custom panel, provided substantial contribution to the interpretation of the genetic data, and revised critically the manuscript; Valeriano Leite provided substantial contribution for the clinical data and revised critically the manuscript.
Funding
This study was funded by iNOVA4Health Research Unit (LISBOA-01-0145-FEDER-007344; UID/Multi/00462; UIDB/04462/2020), a program co-funded by Fundação para a Ciência e Tecnologia/Ministério da Ciência e do Ensino Superior, Sociedade Portuguesa de Endocrinologia, Diabetes e Metabolismo (SPEDM), and Instituto Português de Oncologia de Lisboa Francisco Gentil (IPOLFG). J.S.-P. was supported by iNOVA4Health – UIDB/04462/2020. M.P. was granted by Liga Portuguesa Contra o Cancro, Núcleo Regional do Sul (LPCC-NRS). R.R. was granted with a PhD scholarship by iNOVA4Health Research Unit - UIDP/04462/2020; UI/BD/154256/2022. C.P. was granted with a PhD scholarship by FCT – 2020.07120.BD.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
The authors declare no competing interests.
Consent to participate
The collection of biological samples from all subjects involved in this study was performed after written informed consent.
Ethics approval
This study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the Ethical Committee of IPOLFG (approval number 1056).
Additional information
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary information
Rights and permissions
Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
About this article
Cite this article
Simões-Pereira, J., Saramago, A., Rodrigues, R. et al. Clinical and molecular characterisation of metastatic papillary thyroid cancer according to radioiodine therapy outcomes. Endocrine 84, 625–634 (2024). https://doi.org/10.1007/s12020-023-03633-y
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12020-023-03633-y