OHSU Presentation Template

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Emerging Trends in
Diagnostics and Therapeutics
ATA Corporate Leadership Council
Kathryn Schuff, MD, MCR
Opportunities in Clinical Thyroid Disease
Therapeutic Areas
Hypothyroidism
• Subclinical
hypothyroidism
• Hypothyroidism
• Hypothyroidism in
pregnancy
Hyperthyroidism
• Subclinical/overt
hyperthyroidism
• Graves opthalmopathy
Thyroid hormone responsive
diseases
Thyroid Nodules
• Thyroid nodule suppression
• Thyroid nodule ablation
Thyroid Cancer
• Thyroid remnant ablation
• RAI for thyroid cancer therapy
• Advanced thyroid cancer
Opportunities in Clinical Thyroid Disease
Diagnostic Areas
Genetics
• Genetic risk of AITD, CA
• Newborn screening
• Genetic variants predicting
response to LT4
Thyroid hormone
assessment
• Newborn screening
• T4, T3 assessments
• Thyroid hormone
‘bioassay’
Molecular Diagnostics
• Evaluation of thyroid
nodules
• Thyroid Ca risk stratification
• Thyroid Ca tumor marker
surveillance
Imaging
• Thyroid Ca imaging
Subclinical Hypothyroidism
Yes, that TSH is abnormal… But does it matter?
Impact of SCH: Nonalcoholic Fatty Liver Disease
• NAFLD is a common disorder: 20% of US
• Manifests as: Steatosis
Nonalcoholic steatohepatitis (NASH)
Progression to cirrhosis in 20%
Hepatocellular Carcinoma
• “Hepatic manifestation of metabolic syndrome”
• Cross-sectional case-control study
• 2324 hypothyroid - age/gender matched
• NAFLD defined by u/s, excl ETOH, Hep B/C
Chung Ge, J Hepatol 2012;57:150
NAFLD not simply due to worsened
metabolic syndrome – stratified analysis
Chung Ge, J Hepatol 2012;57:150
‘Dose-response’ in NAFLD
•
•
•
•
Increasing risk of NAFLD with higher TSH
Clinical implications not yet clear– RCT needed
May influence overall decision to treat SCH
?Target for TH analogues
Subclinical Hypothyroidism Clinical Trial Design
• RCTs of endogenous SCH: Difficult recruitment
– Lots of patients, but unwilling to be randomized
– Normalization of TSH/‘Regression to mean’
• Experimentally-induced SCH
–
–
–
–
Randomize LT4 treated to desired target ranges
Lots of LT4 treated patients
Interested in seeing what effects there are
Randomized, parallel arm study targeting:
TSH Range (mU/L)
Lower normal
limit
Proposed upper
normal limit
Current upper
normal limit
Consensus threshold
for treatment
0.28
2.5
5.0
10.0
Theoretical optimal
TSH range
High-normal TSH
Mildly elevated TSH
Mild Hypothyroidism
Hypothyroidism
Questions in the Treatment of Hypothyroidism
Diagnostics and Therapeutics
• Why are patients so unhappy with levothyroxine?
• Can we test for polymorphisms that predict
response to LT4 vs. T3 therapy?
• Do we need a thyroid hormone bioassay (other
than TSH)?
• Do patients gain (more) weight on LT4 therapy?
• Why don’t we yet have a sustained release
preparation of 16:1 LT4/LT3 + ‘other thyroid stuff’?
• What is the ‘other thyroid stuff’? T1AM?
Questions in the Treatment of Hypothyroidism
Diagnostics and Therapeutics
• Is there opportunity to modulate the process of
AITD?
• What does isolated hypothyroxinemia mean for
pregnant and nonpregnant patients?
• Do TPO+ pregnant women benefit from LT4?
• At what level of TSH and for what outcomes do
pregnant women benefit from LT4?
• Its’ so simple – why can’t we ensure iodine
sufficiency?
Thyroid responsive
diseases
Thyroid Hormone Analogues - Hyperlipidemia
•
•
•
•
•
•
•
•
168 patients, 12 wk
Eprotirome + statin
No change in TSH
T4 ↓ 22-34%
FT4 ↓ 12-21% WNL
LDL ↓ 12-32%
TG ↓ 16-33%
Lp(a) ↓ 10-43%
Further development halted
due to cartilage defects in
preclinical studies
Ladenson P. N Engl J Med 2010;11:906
Thyroid Hormone Analogues –
X-linked Adrenoleukodystrophy
• X-ALD: Genetic loss of the
ABCD1 gene results in LCFA
accumulation, neurologic damage
• Three other ABCD genes
• Sobetirome activates ABCD2
• Novel paradigm: Pharmacologic
approach to genetic
complementation
• Phase I dose escalation trial
imminent launch at OHSU
Genin J Steroid Biochem Mol Biol 2009;116:39
Thyroid Nodules
The Evolving Evaluation of the Nodule:
First DNA, then RNA, next proteomics?
BRAF testing + U/S + cytology improves DA
• 991 nodules
–60% benign
–22% indeterm
–17% malignant
Lee EJ. Clin Endocrinol 2011;75:844
The Evolving Evaluation of the Nodule:
First DNA, then RNA, next proteomics?
•
•
•
•
Focus on 497 indeterminate nodules
DNA Mutation panel: BRAF, RAS, RET/PTC, PAX8/PPARγ
Improves identification ‘benign’ subset of nodules
If negative:
Reference
The Evolving Evaluation of the Nodule:
First DNA, then RNA, next proteomics?
•
•
•
•
•
•
•
Focus on 265 nodules indeterminate FNA
85 malignant, 180 benign on final histology
Affirma gene expression classifier analysis
RNA microarray – 162 genes
Training set, validation set
Correctly identified 78 of 85 malignancies
6 of 7 FN showed low yield on FNA
– Generalization issue
Alexander EK. N Engl J Med 2012;367:8
Affirma gene classifier improves
classification of indeterminant nodules
Cytologic diagnosis:
AUS/FLUS
FN/SFN
SMC
NPV:
95%
94%
85%
Allows observation of nodules with AUS/FLUS or
FN/SFN + ‘Benign’ gene classifier
(risk of Ca similar to benign cytology)
DNA+RNA: Addition of BRAF testing does not
improve operating characteristics
The Evolving Evaluation of the Nodule:
First DNA, then RNA, next proteomics?
• Evaluation of panel of miRNAs defines
miRNA signature
• Training set of 60 FNA “AUS”
• Validation set of 68 FNA
• Good performance in PTC, but difficulty
with FTC/FAs
Shen R. Thyroid 2012;22:9
The Evolving Evaluation of the Nodule:
First DNA, then RNA, next proteomics?
Optimizing RAI for Multinodular Goiter
Use of Modified release rhTSH
• 95 pts MNG – avg size 96 ml (32 – 242 ml)
• Randomized placebo vs. 0.01 mg vs. 0.03 mg
• Treated with RAI
• Outcome: change in thyroid volume at 6 mo
Responder: 28% or greater ↓ in volume
• Secondary: trachea cross-sectional area,
TFTs, thyroid sx, EKG
Graf H. JCEM 2011;96:1368
Improved reduction in thyroid volume
with 0.03 mg MRrhTSH than lower dose
or RAI alone
• More ‘responders’ (64%
vs. 25% placebo)
• More hyperthyroid
symptoms, but tolerated
(18-26% vs. 3%)
• More neck pain
(18% vs. 10%)
• More hypothyroidism
(24% vs. 6%)
Graf H. JCEM 2011;96:1368
Thyroid Cancer
Adjunctive RAI for Low Risk Thyroid Ca:
30 mCi vs. 100 mCi
# evaluable patients
421
684
T1-3, N0-1, M0
T1N0-1,T2-3N0, M0
6-9 mo rhTSH or
THW scan <0.1%
8 mo neck u/s, rhTSH
Tg <1 ng/mL or -scan
Ablation rate: 30 vs. 100 mCi
85.0 vs. 88.9%
87.1 vs. 86.7%
Ablation rate: rhTSH vs. THW
87.1 vs. 86.7%
91.7 vs. 92.9%
Citation: NEJM 2012, Vol. 366
Mallick, p. 674
Schlumberger, p. 1663
Staging
Definition of successful
ablation
• Equivalence of low dose, high dose RAI and
method of preparation rhTSH, THW
• Short-term risks: Sialoadenitis, -cytopenias
• Long-term risks: Secondary malignancies
No impact of RAI in low risk thyroid Ca
HR
CI
P-value
OS
1.92
1.20 - 3.07
0.007
DFS
1.86
1.27 – 2.74
0.002
OS
0.69
0.37 – 1.29
0.243
DFS
0.73
0.43 – 1.25
0.259
Propensity
OS
0.75
0.4 – 1.38
0.352
stratified
DFS
1.11
0.73 – 1.70
0.48
Univariate
Multivariate
• 1298 low risk thyroid cancer patients
• 10.3 years median f/u
• 987 adjunctive RAI, 387 no RAI
Schvartz C. J Clin Endocrinol Metab 2012;97:1526
What is optimal surveillance for low risk
thyroid cancer?
# patients
278
1010
203
12 mo stim Tg
undetectable
12 mo stim Tg
undetectable
6-12 mo stim Tg
<2
6.3 years
7 years
8.5 years
Clinical
recurrence
2%
1.3%
3.9% at 5 yr
NPV of 12 mo
stim Tg
98%
98%
96%
Definition of
initial remission
Duration of f/u
NPV of second
stim Tg
100% at 2 year
Recurrence
details
½ of stim Tg+
had no clinical
recurrence
100% at 5 year
Only ½ of
recurrences found
by stim Tg+
1/3 of stim Tg +
had no clinical
recurrence
Han JM. Thyroid 2012;22:784
Rosario PW. Thyroid 2012; 22: 482
Klubo-Gwiezdzinska JK. Clin Endocrinol 2011;74:111
What is optimal surveillance for low risk
thyroid cancer?
• Undetectable rhTSH stimulated Tg predicts low risk
of clinical recurrence
• Improved NPV by repeat rhTSH stim Tg at 2 or 5 yr
• About half of +stim Tg are not clinical recurrences
• Some clinical recurrences not detected by stim Tg
• Not clear that stim Tg improves detection of
recurrences
• Same limitations will apply to ultrasensitive Tg
assays
TKI du jour
Perez CA, Biologics: Targets and Therapy 2012;6
TKI du jour – Emerging concepts and issues
Perez CA, Biologics: Targets and Therapy 2012;6
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Stratification by mutational status
Combination therapy
Difficulty of RCTs competing with off-label use
Outcomes for ‘static’ therapy – RECIST vs. clinical
benefit
Ferengi Rules of Acquisition
#9: Opportunity plus instinct equals profit…
#58: There is no substitute for success…
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