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KEY DATA FROM THE 2022 EUROPEAN THYROID ASSOCIATION

CONGRESS. Role of molecular biology in aggressive thyroid cancer

Haissaguerre Magalie Caron Philippe MD

PII: S0003-4266(23)00106-3
DOI: https://doi.org/doi:10.1016/j.ando.2023.05.003
Reference: ANDO 1515

To appear in: Annales d’Endocrinologie

Please cite this article as: Magalie H, Philippe C, KEY DATA FROM THE 2022 EUROPEAN
THYROID ASSOCIATION CONGRESS. Role of molecular biology in aggressive thyroid
cancer, Annales d’Endocrinologie (2023), doi: https://doi.org/10.1016/j.ando.2023.05.003

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KEY DATA FROM THE 2022 EUROPEAN THYROID
ASSOCIATION CONGRESS
Role of molecular biology in aggressive thyroid cancer.

HAISSAGUERRE Magalie1, CARON Philippe2.

1
Department of Endocrinology and Endocrine Oncology, Haut
Lévêque Hospital, Bordeaux University Hospital, Pessac, France.

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2
Department of Endocrinology, Metabolic Diseases and Nutrition,
Cardiovascular and Metabolic Unit, CHU Larrey, Toulouse, France.
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Address of corresponding author:
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Philippe Caron, M.D.

Department of Endocrinology and Metabolic Diseases
Cardiovascular and Metabolic Unit, CHU Larrey.
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24 chemin de Pouvourville, TSA 30030, 31059 Toulouse Cedex,

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France
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Telephone: +33 (0)5 67 77 17 01, Fax: +33 (0)5 67 77 16 72

Email: caron.p@chu-toulouse.fr
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ORCID number: 0000-0001-5391-7582

Keywords: molecular biology, aggressive thyroid cancer, BRAF

mutations

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Dear Pr Frédéric Castinetti,
Editor-in-Chief
Annales d’Endocrinologie

The 44th congress of the European Thyroid Association (ETA) was

held from September 10 to 13, 2022 in Brussels (Belgium). This letter
discusses data presented on the role of molecular biology in
aggressive thyroid cancer.

In recent years, a better understanding of the pathophysiological

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mechanisms involved in thyroid carcinogenesis has led to the

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identification of molecular anomalies that can potentially be targeted
therapeutically. Moreover, these anomalies could also impact
diagnosis (fine-needle aspiration: FNA) and prognosis (TERT), with
investigations ongoing.
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Differentiated cancer of follicular origin. In 70% of papillary
cancers, mutually exclusive molecular anomalies activating the
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MAPK pathway are identified [1]. The MAPK pathway consists of

RAS, RAF, MEK and ERK proteins, which are activated sequentially
via a phosphorylation cascade. These are chromosomal
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rearrangements, generally of the RET/PTC type (10%), activating

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point mutations of the three isoforms of the RAS oncogene (10%), or

BRAF oncogene (50%). The B-RAFV600E hot-spot mutation,
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associated with risk of recurrence and death, is the one most

frequently identified.
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In follicular cancers, molecular anomalies involve the PI3K signaling

pathway in almost 50% of patients. PI3K can act directly with
receptor tyrosine kinase activity or via RAS. PI3K can be inhibited by
PTEN. The PIP3 compound recruits AKT, which activates numerous
downstream targets, including mTOR. These two signaling cascades
result in activation of ERK or mTOR, which modulate the expression
of numerous genes involved in cell proliferation.

2
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Poorly differentiated cancer. The molecular profile is rather
variable, with RAS or BRAF as well as TERT, TP53, EIF1AX, PTEN
and PIK3CA mutations [2]. TERT or TP53 mutations are usually
associated with poorer prognosis.

Undifferentiated or anaplastic cancer. 45% have a BRAF mutation,

20-30% a RAS mutation, and 30-40% a PI3K/Akt/mTOR pathway
mutation. NTRK, ALK or RET fusions are possible (1%) [3].

Medullary thyroid cancer. 30% of MTCs are linked to a germ-line

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mutation of RET in a MEN2 context, whereas 70% are sporadic. 50-

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70% of sporadic MTCs carry somatic RET mutations and 15-20%
RAS mutations (HRAS > KRAS). Other mutations have been
described, involving mTOR, MET or VEGF. The frequency of RET
mutation is higher in metastatic MTC (70-90%). Mutations observed
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at the primary site versus metastases may differ, RET being associated
with selection of more aggressive tumor clones. RET anomalies
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include classical mutations, notably in codon 918, but also double

mutations or increases in RET copy number [4]. They are all
associated with risk of residual disease or reduced progression-free
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and overall survival.

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a) How does molecular biology function?

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Molecular biology analyses are requested by the clinician to discuss

follow-up and/or treatment. Some molecular anomalies that can be
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targeted can be investigated individually by immunohistochemistry

(IHC) or on paraffin slides (BRAF or ALK), but must be confirmed
using a molecular biology technique (FISH or PCR or NGS). NGS is
the most widely used because it simultaneously detects fusions and
mutations on DNA or RNA, in tumor tissue and potentially also in
plasma (liquid biopsy). As mutations may differ between the primary
and metastatic sites, preference should be given to the most recent
tumor tissue. If no targets are detected, a broader analysis within the

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framework of the France Génomique (France Genomic) program can
be carried out on frozen tissue. To repeat the biopsy can sometimes be
useful [5].

b) What is the difference between mutation and fusion?

A genetic mutation is a spontaneous change that occurs in the genome,
in germ cells or somatic cells. Mutations cause a change in the DNA
sequence, which can lead to cancer.
A chromosomal rearrangement is an abnormal chromosomal mutation
involving a change in the original structure of a chromosome. Such

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changes may involve fusions, deletions, duplications, inversions or

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translocations. These rearrangements are associated with the
production of fusion transcripts that lead to the synthesis of chimeric
proteins with constitutive kinase activity.
These abnormal proteins trigger oncogenic addiction (an abnormality
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required for the cancer cell to survive), which can sometimes be
targeted by tyrosine kinase inhibitors (theranostic impact). Caution
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should nevertheless be exercised, and patients should be told that the

presence of such an abnormality is not necessarily synonymous with
tumor response to treatment.
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c) When should molecular biology be performed? See Table 1.

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d) Predictive markers of response to immunotherapy in many

cancers:
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- microsatellite instability (MSI) profile (marker of a defect in the

DNA repair system): rare in thyroid cancer (< 3%);
- tumor mutation burden (TMB) (number of mutations in tumor
DNA): generally low in thyroid cancer;
- expression of PDL1 by tumor cells: not investigated to any
extent in thyroid cancer. In bronchial cancer, a minimum 50% PD1
expression by tumor cells is required for prescription of
immunotherapy in 1st line and 1% in 2nd line.

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e) Prognostic molecular markers: the telomerase reverse
transcriptase (TERT) mutation (hyperactivity of TERT promoter) has
been shown to be an aggressive molecular marker for differentiated
thyroid cancer [6]. TERT mutation is associated with both radio-
iodine uptake characteristics and poor clinical outcome. The
coexistence of TERT and BRAF mutations form a genetic background
that define PTC with the worst clinical outcomes. Prevalence of TERT
mutation varies significantly from 4.1% to 25.5% for PTC and from
5.9% to 36.4% for follicular thyroid cancer.

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f) When should systemic treatment be proposed? See Table 2.

g) What do the guidelines say?

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Currently, the ATA 2021 [7] and ESMO 2022 guidelines [8] agree
that targeted anti-BRAF therapy should be proposed as a matter of
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urgency and as first-line treatment for unresectable BRAF-mutated

anaplastic cancer.
At present, the role of specific anti-RET agents (selpercatinib or
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pralsetinib) as 1st-line treatment, compared to reference treatment with

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multikinase inhibitors (vandetanib or cabozantinib), remains uncertain

for RET-mutated MTCs requiring systemic treatment [6]. The
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LIBRETTO 531 phase III study comparing these two strategies will
help to answer this question.
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For iodine-refractory cancer requiring targeted systemic treatment, the

ESMO 2022 recommendations include the option of first-line targeted
treatment rather than conventional treatment with lenvatinib or
sorafenib [8].

h) New data were presented at the 2022 ETA congress:

A specific score known as the ESCAT (ESMO Scale for Clinical
Actionability of molecular Targets) is used to assess the clinical

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 importance of known molecular targets in thyroid cancer, based on
published data [9]. In patients with RET-mutated MTC progressing
over 14 months, the efficacy of RET-specific inhibitors (selpercatinib:
LIBRETTO-001) seems remarkable, with disease control rates of 96%
in 1st-line and 93% in 2nd-line after failure of vandetanib or
cabozantinib reference treatment. Treatment response times were
prolonged, with 81% and 64% 24-month progression-free survival,
respectively. Patients (n = 22) with progressive iodine-refractory
cancer and RET fusion treated with selpercatinib displayed complete
response in 9% of cases and partial response with prolonged disease

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control in 68% [10]. A phase III study is ongoing (LIBRETTO-531) to

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compare the efficacy and safety of selpercatinib versus vantetanib or
cabozantinib reference treatment as first-line therapy in the
management of metastatic and progressive RET-mutated MTC.
Many questions remain unanswered regarding the best therapeutic
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sequence for patients with a molecular abnormality that can be
targeted: problems of onset of treatment resistance, questions
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regarding response times, and the option of taking a therapeutic break

depending on the benefit/risk/toxicity ratio.
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Acknowledgements
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The authors are extremely grateful to the HAC Pharma Laboratory for
their support during the authors’ participation in the 44th ETA Congress in
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Brussels.

REFERENCES

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medicine era. Cancer Treat Rev. 2022; 106, 102380.

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https://doi.org/10.3390/cancers14081951
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Y.E. Spectrum of TERT promoter mutations and mechanisms of

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M.E., Clark, T.J., et al. 2021 American Thyroid Association
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8) Filetti, S., Durante, C., Hartl, D.M., Leboulleux, S., Locati, L.D.,
Newbold, K., et al. ESMO Guidelines Committee. ESMO
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https://doi.org/10.1093/annonc/mdy263

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Weiss, J., et al. Tumour-agnostic efficacy and safety of
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1/2, open-label, basket trial. Lancet Oncol. 2022; 23, 1261–73.
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19, 2023. For personal use only. No other uses without permission. Copyright ©2023. Elsevier Inc. All rights reserved.
TABLES

Table 1: When should molecular biology be performed?

Molecular Biology Anaplastic Sporadic Iodine-

cancer medullary refractory
cancer cancer

When? From diagnosis Sporadic Iodine-

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onwards, metastatic refractory

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Regardless of MTC: metastasis:
stage, In case of When systemic
If the patient is
treatable
pr large
volume or
treatment is
being
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progressio considered
n
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Panel BRAF (50%) RET (50- BRAF

1st line 70%) mutations (40 to
Fusions: 1% 80%)
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RET/ALK/NTR RAS (poorly

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K diff.)
(BRAF FGFR Fusions: 1 to
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ROS) 7%
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RET/ALK/NTR
MSI/TMB K
status (BRAF FGFR
ROS)

MSI/TMB
status

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2nd line Urgent NGS
RAS if NGS
RET-
RET/ALK
fusions
possible,
MSI/TMB
status
Optional/Investigat Circulatin TERT
ed g tumor TP53
(prognosis) DNA?

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"France Genomic"? From diagnosis In case of In case of

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(Frozen tissue) onwards if there therapeuti therapeutic
is no NGS c impasse impasse
target and if the
patient is
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treatable
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Table 2: When should systemic treatment be proposed?

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Systemic Anaplastic Medullary Iodine-

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Treatment cancer cancer refractory

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Validated cancer
TUTHYREF
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MTM
When? From diagnosis Inoperable Iodine-
onwards, or metastatic refractory
Regardless of MTC: metastasis:
stage, if large If large
If the patient is volume or volume or
treatable symptoms or symptoms or
if RECIST if RECIST

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 progression progression in
in 12-18 12-18 months
months
Which 1st If BRAF +: Vandetanib Lenvatinib
line dabrafenib Or Or
treatment? +trametinib Cabozantinib Sorafenib
Otherwise: Or
Chemotherapy Tests
(Libretto)
As 2nd line Tests If RET +: If no target:

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treatment? Palliative care Selpercatinib Cabozantinib

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If RET-: If target:
Cabozantinib targeted
or
vandetanib
treatment
discussion
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Depending If BRAF+: dabrefenib + trametinib
on target? If RET mutation/fusion: selpercatinib or
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pralsetinib
If ALK fusion: crizotinib
If NTRK fusion: entrectinib or larotrectinib
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If RAS mutation: discuss KRAS G12C

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inhibitor?
If PD1+/TMB/MSI: discuss immunotherapy
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Abbreviations

AKT (AKR T-cell lymphoma)

MTC (Medullary Thyroid Cancer)
ERK (Extra-cellular signal-Regulated Kinase)
MAPK (Mitogen-Activated Protein Kinases)

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MEK (Mitogen-activated Extracellular signal-regulated Kinase)
MSS (Microsatellite Instability)
mTOR (Mammalian Target of Rapamycin)
NTRK (Neurotrophic Tyrosine Receptor Kinase - NTRK1/2/3)
PD1 (Programmed Cell-Death Protein 1)
PI3K (Phosphatidylinositol 3-kinase)
RAF (Rapidly Accelerated Fibrosarcoma)
RAS (Rat Sarcoma)

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TERT (Telomerase Reverse Transcriptase)
TMB (Tumor Mutation Burden)
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