Emerging Trends in Diagnostics and Therapeutics

ATA Corporate Leadership Council

Kathryn Schuff, MD, MCR

Opportunities in Clinical Thyroid Disease 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

Therapeutic Areas

Hypothyroidism• Subclinical

hypothyroidism• Hypothyroidism• Hypothyroidism in

pregnancy

Hyperthyroidism• Subclinical/overt

hyperthyroidism• Graves opthalmopathy

Opportunities in Clinical Thyroid Disease

Molecular Diagnostics• Evaluation of thyroid

nodules• Thyroid Ca risk stratification• Thyroid Ca tumor marker

surveillance

Imaging• Thyroid Ca imaging

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’

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 5.02.5 10.0

Theoretical optimal TSH range

High-normal TSH Mildly elevated TSH

Mild Hypothyroidism

Hypothyroidism

Questions in the Treatment of HypothyroidismDiagnostics 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 HypothyroidismDiagnostics 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?

Lee EJ. Clin Endocrinol 2011;75:844

BRAF testing + U/S + cytology improves DA

• 991 nodules–60% benign–22% indeterm–17% malignant

The Evolving Evaluation of the Nodule: First DNA, then RNA, next proteomics?

Reference

• Focus on 497 indeterminate nodules • DNA Mutation panel: BRAF, RAS, RET/PTC, PAX8/PPARγ

• Improves identification ‘benign’ subset of nodules • If negative:

The Evolving Evaluation of the Nodule: First DNA, then RNA, next proteomics?

Alexander EK. N Engl J Med 2012;367:8

• 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

Cytologic diagnosis: NPV:

AUS/FLUS 95%

FN/SFN 94%

SMC 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

Affirma gene classifier improves classification of indeterminant nodules

Shen R. Thyroid 2012;22:9

• 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

The Evolving Evaluation of the Nodule: First DNA, then RNA, next proteomics?

The Evolving Evaluation of the Nodule: First DNA, then RNA, next proteomics?

Optimizing RAI for Multinodular GoiterUse of Modified release rhTSH

Graf H. JCEM 2011;96:1368

• 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

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

Staging T1-3, N0-1, M0 T1N0-1,T2-3N0, M0

Definition of successful ablation

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

• 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

Schvartz C. J Clin Endocrinol Metab 2012;97:1526

HR CI P-valueUnivariate OS 1.92 1.20 - 3.07 0.007

DFS 1.86 1.27 – 2.74 0.002

Multivariate 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

• 1298 low risk thyroid cancer patients

• 10.3 years median f/u

• 987 adjunctive RAI, 387 no RAI

What is optimal surveillance for low risk thyroid cancer?

Han JM. Thyroid 2012;22:784Rosario PW. Thyroid 2012; 22: 482

Klubo-Gwiezdzinska JK. Clin Endocrinol 2011;74:111

# patients 278 1010 203

Definition of initial remission

12 mo stim Tg undetectable

12 mo stim Tg undetectable

6-12 mo stim Tg <2

Duration of f/u 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%

NPV of second stim Tg

100% at 2 year 100% at 5 year

Recurrence details

½ of stim Tg+ had no clinical

recurrence

Only ½ of recurrences found

by stim Tg+

1/3 of stim Tg + had no clinical

recurrence

• 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

What is optimal surveillance for low risk thyroid cancer?

<< PrevNext >>From:Biologics. 2012; 6: 257–265.

Published online 2012 August 8. doi: 10.2147/BTT.S24465Copyright/License ►Request permission to reuse

Figure 1Click on image to zoom

Molecular pathways targeted by multikinase inhibitors in refractory thyroid cancer.Notes: Rearranged during transfection is the receptor for members of the glial cell line-derived neurotrophic factor family of extracellular signaling molecules or ligands. The complex of the glial cell line-derived neurotrophic factor family of ligands with the coreceptor glial cell line-derived neurotrophic factor family receptor α brings together two molecules of rearranged during transfection, triggering transautophosphorylation of specific tyrosine residues within the tyrosine kinase domain of each rearranged during transfection molecule. Rearranged during transfection can increase proliferation and survival through several pathways such as Ras/extracellular signal-related kinase and phosphatidylinositol 3′ kinase. Both vascular endothelial growth factor-2 and epidermal growth factor pathways can also induce proliferation, invasion, and survival by activation of both Ras/extracellular signal-related kinase and phosphatidylinositol 3′ kinase pathways. Marked in red are the targets inhibited by multikinase inhibitors.Abbreviations: EGFR, epidermal growth factor; ERK, extracellular signal-regulated kinase; GFL, glial cell line-derived neurotrophic factor family of ligands; GFRα, glial cell line-derived neurotrophic factor family α coreceptor; MAPK, mitogen-activated protein kinase; MEK, mitogen-activated protein kinase kinase; PI3K, phosphatidylinositol 3′ kinase; RET, rearranged during transfection; VEGF-A, vascular endothelial growth factor A; VEGFR2, vascular endothelial growth factor receptor-2.

TKI du jour

Perez CA, Biologics: Targets and Therapy 2012;6

<< PrevNext >>From:Biologics. 2012; 6: 257–265.

Published online 2012 August 8. doi: 10.2147/BTT.S24465Copyright/License ►Request permission to reuse

Figure 1Click on image to zoom

Molecular pathways targeted by multikinase inhibitors in refractory thyroid cancer.Notes: Rearranged during transfection is the receptor for members of the glial cell line-derived neurotrophic factor family of extracellular signaling molecules or ligands. The complex of the glial cell line-derived neurotrophic factor family of ligands with the coreceptor glial cell line-derived neurotrophic factor family receptor α brings together two molecules of rearranged during transfection, triggering transautophosphorylation of specific tyrosine residues within the tyrosine kinase domain of each rearranged during transfection molecule. Rearranged during transfection can increase proliferation and survival through several pathways such as Ras/extracellular signal-related kinase and phosphatidylinositol 3′ kinase. Both vascular endothelial growth factor-2 and epidermal growth factor pathways can also induce proliferation, invasion, and survival by activation of both Ras/extracellular signal-related kinase and phosphatidylinositol 3′ kinase pathways. Marked in red are the targets inhibited by multikinase inhibitors.Abbreviations: EGFR, epidermal growth factor; ERK, extracellular signal-regulated kinase; GFL, glial cell line-derived neurotrophic factor family of ligands; GFRα, glial cell line-derived neurotrophic factor family α coreceptor; MAPK, mitogen-activated protein kinase; MEK, mitogen-activated protein kinase kinase; PI3K, phosphatidylinositol 3′ kinase; RET, rearranged during transfection; VEGF-A, vascular endothelial growth factor A; VEGFR2, vascular endothelial growth factor receptor-2.

TKI du jour – Emerging concepts and issues

Perez CA, Biologics: Targets and Therapy 2012;6

• 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…