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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 • • • • 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…