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Scientific Highlights: Annual Meeting of the American Thyroid Association

Scientific Highlights: Annual Meeting of the American Thyroid Association
  • Endocrinology and metabolism
  • Thyroid disorder

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International meeting
thyroid disease
Cancer

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88th Annual Meeting of the American Thyroid Association

3-7 October 2018
Washington, USA

This year, the first ‘Latin American International Satellite Symposium’ was held during the ATA meeting with several members of the Latin American Thyroid Society participating. This was an excellent opportunity to share the research experience from LATAM countries with North American colleagues. 

Several studies were presented at ATA 2018 that advanced management of thyroid nodules and thyroid cancers. Indeterminate results from cytopathological testing still occur in 20 to 30% of cases. There are 2 molecular diagnostic methods used most often for differential diagnosis and results of their use were widely discussed during this meeting.

Afirma (Veracyte; South San Francisco, CA, USA) is a proprietary gene-expression classifier with a high negative predictive value. However, it has been improved by the next generation: Afirma Genomic Sequencing Classifier (GSC). The new version maintains a high sensitivity (91%) and has increased its specificity to 68%, retaining a high negative predictive value of 96%. Additionally, the new Xpression Atlas (XA) has been added to provide genomic information to stratify patient risk – in total, 511 genes are sequenced to detect 761 variants and 130 fusion pairs. Dr Trevor E. Angell (Brigham and Women’s Hospital and Harvard Medical School, USA) presented the results of analysing 190 indeterminate nodules. The findings suggest that when XA is positive, GSC suspicious nodules expressed mainly RASvariants and GSC benign nodules expressed TSHRvariants. The presenter concluded that while the negative predictive value of GSC is still higher than XA, the addition of XA to GSC suspicious nodules may provide additional insights into pathway activation and potential cancer treatment targets. Dr Allan C. Golding (Memorial Healthcare System, Weston, USA) added that in GSC benign nodules, XA analysis could thus be avoided, retaining its value in GSC suspicious nodules. 

Alternatively, ThyroSeq (CBLPath Inc, USA) is another molecular test also based on next generation sequencing of DNA and RNA collected from thyroid nodules and that identifies mutations with high positive and negative predictive values that have been associated with thyroid cancer. The diagnostic accuracy of a newer version, the multigene classifier (GC) test (ThyroSeq v3) for cytologically indeterminate thyroid nodules was validated in a prospective, blinded cohort study conducted at 10 medical centers, where a total of 286 FNA samples from thyroid nodules underwent molecular analysis. In Bethesda III and IV nodules combined, the test demonstrated a 94% sensitivity and 82% specificity. With a cancer/NIFTP prevalence of 28%, the negative predictive value (NPV) was 97% and the positive predictive value (PPV) was 66%. Accordingly, the GC test may obviate diagnostic surgery in up to 61% of patients with Bethesda III to IV indeterminate nodules, and up to 82% of all benign nodules with indeterminate cytology. Information on specific genetic alterations obtained from FNA may help inform individualized treatment of patients with a positive test result.1These two tests appear to reduce the incidence of unnecessary surgery, although their reliability in various clinical-practice settings remains to be established.

The Cancer Genome Atlas (TCGA) project, which describes the genomic landscape of 496 PTCs, was quoted in several presentations as the cornerstone of new results in the field of thyroid cancer. In ‘Genetic landscapes in advanced thyroid cancers’, Dr James A. Fagin (Memorial Sloan Kettering Cancer Centre, New York, USA) explained that papillary thyroid carcinoma (PTC) encompasses several tumour types that each have mutually exclusive gene mutations encoding effectors that signal through the mitogen-activated protein kinase (MAPK) pathway. The most common mutation in thyroid cancer is BRAFV600E, which is present in ~40% of patients with PTC. BRAFV600E constitutively activates a serine/threonine kinase and initiates malignant transformation by activating the MAPK pathway.

Patients with PTC with both the BRAF V600E and TERT mutations have markedly shorter progression-free survival compared with those with BRAF V600E mutations alone. Coexisting BRAFV600E and TERT promoter mutations are associated with higher mortality but occur in only 3-6% of patients with PTC. Considering that BRAF V600E mutations are present in almost half of PTC, other yet unexplained mechanisms (other than TERT) might be responsible for aggressive behaviour in certain tumours. 

Another mutation present in 15-30% of thyroid carcinomas is RAS. However, endogenous expression of mutant RASis insufficient to initiate thyroid tumorigenesis in murine models, indicating that additional genetic alterations are required. The use of Sleeping Beauty (SB) transposon mutagenesis has helped identify events that cooperate with HRASG12V in thyroid tumour development. In fact, transposon mutagenesis identified chromatin modifiers such as ATXN7 mutants cooperating with RASto induce thyroid cell proliferation, pointing to ATXN7 as a previously unrecognized cancer gene.2

In advanced thyroid cancer, the role of the eukaryotic translation initiation factor 1A X-linked (EIF1AX)mutation has also been revealed. Eukaryotic initiation factors 1A (EIF1A) are proteins or protein complexes involved in the initiation phase of eukaryotic translation. Indeed,EIF1AXmutations are present in 11% of poorly differentiated thyroid cancer and anaplastic cancer and are almost invariably associated with oncogenicRASDr Fagin described the identification of the key signaling drivers of transformation by EIF1AXmutantsin vitroand in vivo, particularly EIF1AX-A113splice, alone and in the context of RAS, and the therapeutic dependencies they confer. In these models, RASstabilizes c-MYC, an effect augmented by EIF1AX-A113splice.EIF1AXA113splicealsodrives an ATF4-induced dephosphorylation of EIF2α, resulting in increased protein synthesis. ATF4, a sensor of cellular stress, and c-MYC induce expression of amino acid transporters and enhance sensitivity of mTOR to amino acid supply. These mutually reinforcing events generate therapeutic vulnerabilities to MEK, BRD4 and mTOR kinase inhibitors.In short it has been shown that EIF1AXis enriched in advanced thyroid cancers, where it displays a striking co-occurrence with RAS, which co-operates to induce tumorigenesis in mice and isogenic cell lines.3

Dr Fagin also mentioned new research in mice regarding selumetinib, a MAPK kinase (MEK) inhibitor that decreases extracellular signal-regulated kinase activation and restores expression of the sodium iodide transporter and other thyroid differentiation genes in mice with Braf V600E-driven papillary thyroid carcinoma. This drug may restore RAI uptake/efficacy in a subset of BRAF mutant, radioactive iodine-refractory thyroid cancerpatients, likely by upregulating thyroid-specific gene expression via MAPK pathway inhibition. Dr AllenHo (Cedars-Sinai Medical Centre, Los Angeles, USA) presented prospective data from ASTRA, a phase III randomized placebo-controlled study evaluating complete remission rate with short-course selumetinib plus adjuvant radioactive iodine in patients with differentiated thyroid cancer.In this study, complete remission rate with selumetinib was not higher than with placebo.

Dr Steven Sherman (MD Anderson Cancer Center, Houston, USA) devoted his presentation to RET targeting.4He described how the REarranged during Transfection (RET) protooncogene was originally identified as an oncogenic driver in thyroid cancer. In addition, the ATP-competitive multikinase-inhibitors vandetanib and cabozantinib effectively block activity and signaling of both full length and fusion RET proteins. These drugs have been approved for use in patients with progressive, unresectable medullary thyroid cancer (MTC) or treatment-resistant PTC. They have significantly improved progression-free survival, leading to stable disease or increased duration of response in patients with advanced or metastatic MTC. Nevertheless, they are associated with significant toxicities, likely due to systemic effects of the “off-target” inhibition of other kinases such as EGFR or VEGFR family kinases.

The next generation of novel RET selective agents show potent inhibition of RET activity in vitroand in preclinical models, and are broadly effective against RET full length and fusion proteins as well as the RET gatekeeper mutants5,6Two of these inhibitors, BLU308 667 and LOXO-292 have >100 fold greater selectivity for RET compared with other kinases in cell-based and preclinical animal models.5-7Phase I trials for both of these agents are currently underway and early results are promising, showing low toxicity and significantly improved inhibition of the range of RET mutants.5.6 Dr Mimi I Hu (MD Anderson Cancer Center, Houston, USA)presented new data on BLU-667 from the phase 1 Arrow study and Dr LJWirth (Massachusetts General Hospital Cancer Center, Boston, USA)did the same with LOXO -292 from the LIBRETTO-001 phase 1/2 study for patients with advanced solid tumours, including RET fusion+thyroid and RET mutant-MTC

Dr Sherman also mentioned that the combination of RET and mTOR inhibitors induces synergistic growth inhibition in MTC cells and may enhance RET inhibitor delivery to the central nervous system.8,9In summary, the RET receptor has the potential to be exploited in precision medicine strategies to “personalize” cancer therapy to improve individual care outcomes. 

Dr Sherman also mentioned the discovery of dinaciclib, a CDK1/2/5/9 inhibitor which markedly reduced RNA polymerase II-dependent transcription in MTC - thus revealing a novel mechanism of RET transcription regulation that could potentially be exploited to improve RET therapeutic targeting.10

Fusions involving one of three tropomyosin receptor kinases (TRK) encoded by neurotrophic TRK (NTRK) occur in diverse cancers in children and adults. Dr MarciaBrose (University of Pennsylvania School of Medicine, USA)presentedthe efficacy and safety of larotrectinib, a highly selective TRK inhibitor, in adults and children who had tumours with these fusions. In this study, larotrectinib was highly active and well tolerated in patients harboring NTRK gene fusions, supporting its inclusion as part of the molecular testing for patients with advanced thyroid cancer.

A French multicenter retrospective matched cohort study presented by Dr D Taieb (Service Central de Biophysique et de Médecine Nucléaire, Marseille, France)revealed that preparation with recombinant TSH versus withdrawal for radioiodine therapy was non-inferior in patients with differentiated thyroid cancer staged pT1-3/N1/M0.

Dr Anthony Hollenberg (Weill Cornell Medicine and NewYork-Presbyterian, USA) received the Sidney H Ingbar award and delivered a lecture entitled “New insights into thyroid hormone action”. In his lecture, he made revealing descriptions of the anti-ageing effects of hydrogen sulfide (H2S). Apparently decreased growth hormone and thyroid hormone signaling are associated with longevity and metabolic fitness. The mechanisms are similar to those of dietary restriction, which also result in prolongation of life and are mediated by increased levels of H2S. Studies were presented where increased hepatic H2S production was found in long-lived mouse strains with reduced growth hormone and/or thyroid hormone action, and in a cell-autonomous manner upon serum withdrawal in vitro.11

Cardiac thyroid hormone metabolism and heart failure was addressed by Dr Simonides, who stated that following myocardium infarction a reduction of cardiac thyroid hormone signaling is thought to play a role in pathological ventricular remodeling and the development of heart failure. In rodent models of heart disease, a higher activity of cardiac type III deiodinase (DIO3) has been proved with a consequent decrease in thyroid hormone. The role of increased DIO3 activity in impairment of T3 signaling and maladaptive remodeling is still under debate. Analysis of pathological remodeling using a cardiomyocyte-specific, conditional DIO3 knockout model is needed to determine the role of DIO3 activity in the impairment of TH signaling in post-MI remodeling.12


References

  1. Steward DL, et al. JAMA Oncol 2018 Nov 8. doi: 10.1001/jamaoncol.2018.4616. [Epub ahead of print].

  2. Montero-Conde C,et al. Proc Natl Acad Sci USA 2017 Jun 20;114(25):E4951-E4960. 

  3. Krishnamoorthy GP,et al. Cancer Discov 2018 Oct 10. pii: CD-18-0606. doi: 10.1158/2159-8290.CD-18-0606. [Epub ahead of print].

  4. Mulligan LM. Endocrine-Related Cancer 2018;25(8):T189-T200. 

  5. Subbiah V, et al. Ann Oncol 2018 Aug 1;29(8):1869-1876. 

  6. Subbiah V, et al. Cancer Discov 2018 Jul;8(7):836-849.

  7. Drilon et al. Nat Rev Clin Oncol 2018 Mar;15(3):150.

  8. Gild ML, et al.Endocr Relat Cancer 2013 Aug 21;20(5):659-67.

  9. Subbiah V, et al. Lung Cancer 2015 Jul;89(1):76-9.

  10. Valenciaga A,et al. JCI Insight. 2018 Aug 23;3(16). pii: 122225. doi: 10.1172/jci.insight.122225. [Epub ahead of print].

  11. Hine C, et al. Cell Metab 2017 Jun 6;25(6):1320-1333.

  12. Janssen R, et al. Eur Thyroid J 2017 Jul;6(3):130-137.

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