N - Associazione Italiana di Medicina Nucleare ed Imaging Molecolare
Predictive value of bRAF V600E mutational analysis in
patients with differentiated thyroid cancer (DTC)
submitted to radioiodine treatment (RAI)
D.A. Pizzuto1, S. Annunziata1, C. Brunelli2, G. Perotti1, E. D. Rossi2, M. Martini2,
L. M. Larocca2, G. Fadda2, M.Salvatori1.
1Servizio di Medicina Nucleare
2Istituto di Anatomia Patologica.
Università Cattolica del Sacro Cuore, Roma
N - Associazione Italiana di Medicina Nucleare ed Imaging Molecolare
Disclosure Slide
Il sottoscritto DANIELE ANTONIO PIZZUTO
DICHIARA
 che, nell’esercizio delle funzioni di Relatore, NON E’ in alcun modo portatore di interessi commerciali
propri o di terzi; dichiara altresì che gli eventuali rapporti avuti negli ultimi due anni con soggetti portatori
di interessi commerciali non sono tali da permettere a tali soggetti di influenzare le proprie funzioni al
fine di trarne vantaggio;
 che negli ultimi due anni HA AVUTO i seguenti rapporti anche di finanziamento con soggetti portatori di
interessi commerciali in campo sanitario (aziende farmaceutiche, biomedicali e di diagnostica):
1……………………………………………………………………………………………………………………
2……………………………………………………………………………………………………………………
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N - Associazione Italiana di Medicina Nucleare ed Imaging Molecolare
Background
bRAF
Protein
Protein which
which activate
activate the
the MAP
MAP kinase,
kinase, cell
cell mitosis
mitosis
and
and growth,
growth, so
so directly
directly involved
involved in
in cell
cell proliferation.
proliferation.
Possible Clinical Utility in DTC

 Guide
Guide to
to therapy
therapy
-- Preoperative
Preoperative bRAF
bRAF analysis
analysis could
could be
be used
used as
as aa guide
guide
for
for extension
extension of
of the
the initial
initial surgery
surgery or
or radioioidine
radioioidine therapy.
therapy.

 Prognostic
Prognostic significance
significance
-- Association
Association with
with extra-thyroid
extra-thyroid extension
extension and
and
LN
LN metastases.
metastases.
-- Loss
Loss of
of radioiodine
radioiodine uptake.
uptake.
N - Associazione Italiana di Medicina Nucleare ed Imaging Molecolare
Background
 Advanced tumors with bRAF mutation tend to lose
the ability of uptake iodine, primarily by the
inactivation of sodium/iodine symporter (NIS).
Barollo Eur J Endocrinol 2010
N - Associazione Italiana di Medicina Nucleare ed Imaging Molecolare
Background
Gandolfi IJC 2014
N - Associazione Italiana di Medicina Nucleare ed Imaging Molecolare
Aim of the study
To evaluate the predictive value of bRAF
mutation in DTC patients submitted to
total thyroidectomy (TT) and RAI.
N - Associazione Italiana di Medicina Nucleare ed Imaging Molecolare
Materials and Methods

 Type
Type of
of study
study
Retrospective
Retrospective cohort.
cohort.

 Population
Population
46
46 patients
patients with
with DTC
DTC submitted
submitted to
to TT
TT and
and RAI
RAI therapy
therapy between
between 2005-2015.
2005-2015.

 bRAF
bRAF analysis
analysis
mutational
mutational analysis
analysis of
of bRAF
bRAF was
was performed
performed before
before TT
TT and
and after
after FNAC
FNAC by
by using
using "Anti"AntiEGFR
EGFR MoAb
MoAb response
response (bRAF
(bRAF status)"
status)" (Diatech
(Diatech pharmacogenetics,
pharmacogenetics, REF:
REF: UP033).
UP033).

 Radioiodine
Radioiodine Activities
Activities
mean
mean 2.54
2.54 GBq
GBq (range
(range 1.1–7.4
1.1–7.4 GBq).
GBq).

 TxWBS
TxWBS
anterior
anterior and
and posterior
posterior planar
planar WBS
WBS and,
and, in
in selected
selected cases,
cases, SPECT/CT
SPECT/CT images
images
obtained
obtained 2-3
2-3 days
days after
after RAI
RAI administration.
administration.
N - Associazione Italiana di Medicina Nucleare ed Imaging Molecolare
Materials and Methods
Predictive
Predictive factors
factors analyzed
analyzed



age
age
sex
sex
histology
histology

pTNM
pTNM

lymph
lymph node
node status
status

ATA
ATA risk
risk stage
stage

TxWBS
TxWBS results
results

first
first TSH-Tg
TSH-Tg

last
last Tg
Tg on
on LT4
LT4
Comparison
Comparison between
between predictive
predictive parameters
parameters and
and BRAF
BRAF mutation
mutation
N - Associazione Italiana di Medicina Nucleare ed Imaging Molecolare
Results
Characteristics
Patients (%)
Age (range, mean)
14ys-73ys
43 ys
Age (group)
< 45ys
> 45ys
29/46 (63)
17/46 (37)
Sex
Male
Female
13/46 (28)
33/46 (72)
Histologic type
Follicular
Papillary
PDTC
6/46 (13)
30/46 (65)
10/46 (22)
T stage
T1-T2
T3-T4
26/46 (56)
20/46 (44)
N stage
N0-N1a
N1b
26/46 (56)
20/46 (44)
M stage
M negative
M positive
42/46 (91)
4/46 (9)
PDTC: poorly-differentiated thyroid cancer.
N - Associazione Italiana di Medicina Nucleare ed Imaging Molecolare
Results
Characteristics
Patients (%)
TSH-Tg
undetectable
0.5-5 ng/ml
5-10 ng/ml
>10 ng/ml
14/46 (30)
20/46 (43)
4/46 (9)
8/46 (18)
Tg-onLT4
undetectable
0.2-2 ng/ml
>2 ng/ml
34/46 (74)
7/46 (15)
5/46 (11)
ATA risk
low
intermediate
high
7/46 (15)
35/46 (76)
4/46 (9)
B-RAF mutation status
mutated
absent
24/46 (52)
22/46 (48)
N - Associazione Italiana di Medicina Nucleare ed Imaging Molecolare
Results
Characteristics
Age (group)
Sex
Histologic type
parameters
< 45ys
> 45ys
Male
Female
Follicular
Papillary
PDTC
univariate an.
multivariate an.
.073
.084
.129
.409
.119
.254
T1-T2
T3-T4
N0-N1a
N1b
M negative
M positive
.211
.064
.048
.051
.662
.512
TSH-Tg
undetectable
0.5-5 ng/ml
5-10 ng/ml
>10 ng/ml
.388
.410
Tg-onLT4
undetectable
0.2-2 ng/ml
>2 ng/ml
.404
.469
ATA risk
low
intermediate
high
.410
.949
T stage
N stage
M stage
N - Associazione Italiana di Medicina Nucleare ed Imaging Molecolare
Discussion
N - Associazione Italiana di Medicina Nucleare ed Imaging Molecolare
Discussion
Gandolfi IJC 2014
N - Associazione Italiana di Medicina Nucleare ed Imaging Molecolare
Analysis of the Literature
Authors and year
Characteristics
Results
Xing et al 2005
219 with PTC pts.
Associated significantly with poorer
clinicopathological outcomes
Lupi et al 2007
500 PTC pts.
Associated significantly with poorer
clinicopathological outcomes
Fugazzola et al 2004
Italian cohort of 65 primary thyroid
cancers and 21 benign disorders
Mutation only in PTC patients but
no statistical association with other
clinicopathological parameters.
Trovisco et al 2005
Multicentric 280 patients with 315
tumours
and tumour-like lesions.
No signs of higher aggressiveness
(such as nodal metastasis) in BRAF
mutated PTC.
Li C et al, 2012
Thirty-two studies including 6372
patients were reviewed
Associated with poorer
clincopathological and tall-cell
variant PTC in PTC.
N - Associazione Italiana di Medicina Nucleare ed Imaging Molecolare
Strenght of the study

 Single
Single institution.
institution.

 Single
Single expert
expert pathologist.
pathologist.

 Many
Many clinicopathological
clinicopathological parameters
parameters considered
considered in
in the
the statistical
statistical analysis.
analysis.
Limitations of the study

 Retrospective
Retrospective nature
nature of
of the
the analysis.
analysis.

 Small
Small number
number of
of patients
patients studied.
studied.

 Population
Population heterogeneous
heterogeneous according
according to
to histological
histological subtypes.
subtypes.

 Only
Only 4/46
4/46 (( 9%)
9%) patients
patients with
with distant
distant metastases.
metastases.
N - Associazione Italiana di Medicina Nucleare ed Imaging Molecolare
Conclusion
Correlation
between
preoperative
bRAF mutation analysis and main
clinicopathological parameters:


bRAF
bRAF V600E
V600E mutation
mutation expression
expression occurs
occurs with
with borderline
borderline
significancy
significancy in
in DTC
DTC patients
patients with
with lymph
lymph node
node metastases
metastases ..


No
No other
other predictive
predictive factors
factors (in
(in particular
particular distant
distant metastases)
metastases)
correlated
correlated with
with bRAF
bRAF mutation.
mutation.


bRAF
bRAF mutation
mutation analysis
analysis could
could play
play aa role
role in
in the
the surgical
surgical approach
approach to
to
the
the patients
patients with
with DTC.
DTC.


Larger
Larger prospective
prospective studies
studies are
are needed
needed to
to assess
assess any
any correlation
correlation
between
between bRAF
bRAF mutation
mutation and
and poorer
poorer prognostic
prognostic parameters,
parameters, such
such as
as
distant
distant metastases.
metastases.
N - Associazione Italiana di Medicina Nucleare ed Imaging Molecolare
Thank you
for your
attention
Università Cattolica del Sacro Cuore, Roma