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Clinical and molecular characterisation of metastatic papillary thyroid cancer according to radioiodine therapy outcomes

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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.

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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.

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Authors and Affiliations

  1. Serviço de Endocrinologia, Instituto Português de Oncologia de Lisboa Francisco Gentil, Lisboa, Portugal

    Joana Simões-Pereira & Valeriano Leite

  2. Unidade de Investigação em Patobiologia Molecular (UIPM), Instituto Português de Oncologia de Lisboa Francisco Gentil, Lisboa, Portugal

    Joana Simões-Pereira, Ana Saramago, Ricardo Rodrigues, Marta Pojo, Carolina Pires, Valeriano Leite & Branca M. Cavaco

  3. NOVA Medical School | Faculdade de Ciências Médicas da Universidade Nova de Lisboa, Lisboa, Portugal

    Joana Simões-Pereira, Ricardo Rodrigues, Carolina Pires & Valeriano Leite

  4. Serviço de Radiologia, Instituto Português de Oncologia de Lisboa Francisco Gentil, Lisboa, Portugal

    Mariana Horta

  5. Serviço de Anatomia Patológica, Hospital Santa Maria, Centro Hospitalar Universitário Lisboa Norte, E.P.E., Avenida Professor Egas Moniz, 1649-035, Lisboa, Portugal

    Dolores López-Presa

  6. Serviço de Anatomia Patológica, Instituto Português de Oncologia de Lisboa Francisco Gentil, Lisboa, Portugal

    Miguel Rito & Rafael Cabrera

  7. Serviço de Medicina Nuclear, Instituto Português de Oncologia de Lisboa Francisco Gentil, Lisboa, Portugal

    Teresa C. Ferreira

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  1. Joana Simões-Pereira
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  2. Ana Saramago
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  9. Rafael Cabrera
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  10. Teresa C. Ferreira
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  12. Branca M. Cavaco
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Corresponding author

Correspondence to Branca M. Cavaco.

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The collection of biological samples from all subjects involved in this study was performed after written informed consent.

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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).

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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

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