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Hot Topics in Thyroidology Paul W. Ladenson, MD Illinois AACE Annual Meeting Maywood, IL October 14, 2017

Hot Thyroid Topics Aims Consider new evidence related to detection and treatment of subclinical hypothyroidism Be aware of several novel therapeutic approaches to hyperthyroid Graves disease Review new molecular diagnostic options for differential diagnosis of cytologically indeterminate thyroid nodules Balance benefits and risks of chemotherapy for metastatic non-iodine avid thyroid cancers

Hot Thyroid Topics Disclosures Dr. Ladenson serves on the ABIM Specialty Board in Endocrinology, Diabetes, & Metabolism Dr. Ladenson is an advisor to Veracyte

Hot Thyroid Topics Case 1: 87 yo woman with TSH 7.4 mu/l Mother of cardiologist with fatigue, cold intolerance and memory lapses TSH 7.4 miu/l Frail but mentally sharp elderly woman with no palpable thyroid Repeat TSH 7.2 miu/l LDL-cholesterol 84 mg/dl (on atorvastatin) TPO and Thyroglobulin antibodies negative

Subclinical Hypothyroidism Potential Indications for Therapy Quality of life, neurocognitive deficits, and mood disorders Prevent progression to overt hypothyroidism, esp. in antithyroid antibody-positive patients Cardiovascular risks, including ischemic heart disease and heart failure [Maternal and fetal consequences in pregnancy]

Subclinical Hypothyroidism in the Elderly PRCT Assessing Levothyroxine Therapy Stott DJ, et al. N Engl J Med. 2017;376:2534-2544

Subclinical Hypothyroidism in the Elderly PRCT Assessing Levothyroxine Therapy Double-blind RCT in 737 adults >65 with TSH 4.6-19.9 miu/l and normal FT4 1 0 Outcomes: Hypothyroid Symptoms score & Tiredness QOL score at 1 year L-T4 (median 50 μg) reduced TSH 6.4 mu/l to 3.6 mu/l No differences in Hypothyroid Symptoms score or Tiredness score No beneficial effects seen on 2 o outcomes, incl. other QOL; cognition; BP, Wt, BMI, & Waist circ., daily living activities, and fatal & non-fatal CV events. Stott DJ, et al. N Engl J Med. 2017;376:2534-2544

Subclinical Hypothyroidism Potential Indications for Therapy? Quality of life, neurocognitive deficits, and mood disorders Prevent progression to overt hypothyroidism, esp. in antithyroid antibody-positive patients Cardiovascular risks, including ischemic heart disease and heart failure Maternal and fetal consequences in pregnancy

Subclinical Hypothyroidism Spontaneous Resolution is Common 40/107 SCH patients normalized TSH w/o therapy Age 63; 32F:8M 3/40 had goiter 15/40 symptomatic 24/40 had TPO Ab Diez, J. J. et al. J Clin Endocrinol Metab 2005;90:4124

Subclinical Hypothyroidism Potential Indications for Therapy? Quality of life, neurocognitive deficits, and mood disorders? Prevent progression to overt hypothyroidism, esp. in antithyroid antibody-positive patients Cardiovascular risks, including ischemic heart disease and heart failure Maternal and fetal consequences in pregnancy

Subclinical Hypothyroidism & Cardiovascular Events Incident Cardiovascular Events Prospective Studies Atomic Bomb Surv. 2004 Effect of Mild Hypothyroidism Yes Comment All cause mortality; Middle aged men Busselton study 2005 Yes Mean age 50 Whickham survey 1977 No 20 year F/U Rotterdam study 2000 No 5 year F/U CV Health Study 2006 No >age 65 Health Aging Study 2005 No Mean age 75; CHF risk Leiden Plus 2004 No Age >85

Mild Hypothyroidism Coronary Heart Disease Events CHD Events Rodondi N, et al. JAMA. 2010;304:1365 1374.

Mild Hypothyroidism Coronary Heart Disease Mortality CHD Mortality Rodondi N, et al. JAMA. 2010;304:1365 1374.

Ischemic Heart Disease Events in Patients with Subclinical Hypothyroidism + Levothyroxine Investigated association of L-T4 treatment of SCH with IHD morbidity and mortality. UK GP Research Database to identify new SCH cases (TSH 5-10 miu/l w/ nl. FT4) in 2001 and capture outcomes through March 2009. HRs adjusted for IHD risk factors, baseline TSH, and L-T4 initiation of as a time-dependent covariate Results: SCH identified in 3093 individuals 40-70 yrs and 1642 >70 yrs, with L-T4 therapy in 53% and 50%, respectively, for median f/u 7.6 yrs Razvi S, et al. Arch Intern Med. April 23, 2012

Cumulative Fatal & Nonfatal IHD Events Ischemic Heart Disease Events in Patients with Subclinical Hypothyroidism + Levothyroxine Patients 40-70 Years Old Untreated L-T4 treated Adjusted HR, 0.61; 95% CI, 0.39-0.95 P = 0.02 Razvi S, et al. Arch Intern Med. April 23, 2012

Cumulative Fatal & Nonfatal IHD Events Ischemic Heart Disease Events in Patients with Subclinical Hypothyroidism + Levothyroxine Patients >70 Years Old L-T4 treated Untreated Adjusted HR, 0.99; 95% CI, 0.59-1.33 Adjusted HR, P 0.61; = 0.56 95% CI, 0.39-0.95 Razvi S, et al. Arch Intern Med. April 23, 2012

Subclinical Hypothyroidism Potential Harms of Detection & Rx False-positive results (i.e., spontaneous reversibility) Psychological effects of disease labeling Cost Overtreatment

Treatment of Hypothyroidism Suboptimal Therapy Is Common 30% Excessive Thyroxine Therapy 20% 10% 14% 21% 22% 18% Inadequate Thyroxine Therapy 10% 20% 18% 18% 27% 15% 30% Ross, 1990 Parle, 1993 Canaris, 2000 Hallowell, 2002

Hot Thyroid Topics Case 2: 34 yo woman with hyperthyroidism Yoga instructor with unexplained weight loss, heat intolerance, tremor, and palpitations Diffuse goiter 3 X normal FT4 4.6 ng/dl, T3 525 ng/ml, TSH<0.02 mu/l TSI 260% Discussed alternatives of MTZ, RAI, & surgery Chose MTZ, but developed rash and arthralgias after 3 weeks Now unenthusiastic about the alternatives

Hot Thyroid Topics Novel Treatments for Graves Disease Transoral thyroidectomy Arterial embolization Small molecule TSH receptor inhibitor

Novel Graves Disease Treatments Transoral Endoscopic/Robot-Assisted Thyroidectomy

Novel Graves Disease Treatments Transoral Endoscopic/Robot-Assisted Thyroidectomy Feasibility initially demonstrated in animal and cadaveric studies, and subsequently in patients Done with either endoscopic or robotic gear Initial rates of conversion-to-open, RLN injury, and operative time fall with experience Broadest use with unilateral nodule surgery Other disadvantages of surgery remain: hospitalization, gen. anesthesia, cost, lifelong L-T4. A work in progress

Novel Graves Disease Treatments Thyroid Arterial Embolization

Novel Graves Disease Treatments Thyroid Arterial Embolization Reported follow-up in 12 of 15 patients who undewrwent partial thyroid arterial embolization for hyperthyroidism, which was well tolerated. Transiently higher FT4 and 3 days after embolization followed at 12 weeks by normal serum levels of ft3, ft4 and TSH in 9 (75%) and persistent hyperthyroidism in 3 (25%). Mean goiter reduction to 32% of original volume One year after embolization 7/12 patients required thyreostatic drugs. Brzozowski K, etal. Eur J Radiol. 2012 Jun;81(6):1192-6

Novel Graves Disease Treatments Thyroid Arterial Embolization Limited experience Cosmetic advantage vs. surgery Reported long-term euthyroidism rate: 42-91% One ophthalmopathy exacerbation report CVA risk? Not read for prime time

Novel Graves Disease Treatments Small Molecule TSH Receptor Inhibitor Neumann S, et al. Endocrinol 2014; 155: 310 314.

Novel Graves Disease Treatments Small Molecule TSH Receptor Inhibitor Research to date limited to in vitro and animal models Challenge of avoiding gonadotropin receptor interactions A successful agent would require extended use and probably simultaneous levothyroxine therapy A long way from the clinic

Hot Thyroid Topics Case 3: 28 yo woman with thyroid nodule Physician s wife undergoing ovarian sonogram was offered a gratis thyroid sonogram by radiologist. 1.6 cm isoechoic nodule without suspicious features FNAB: atypia of undetermined significance with nuclear atypia

Bethesda Thyroid Cytopathology Criteria Diagnostic Category Cancer Risk Usual Management Benign 0-3% Observation Atypia of undetermined significance (ACUS) Follicular neoplasm (or suspicious for ) Suspicious for malignancy 5-15% Repeat FNA 15-30% Surgery (unilat. or bilat.) 60-75% Surgery (bilat.) Malignant 97-99% Surgery (bilat.) Nondiagnostic (unsatisfactory)? Repeat FNA with sono. guidance

Negative Predictive Value for Cancer Thyroid Nodule Assessment Cytological Categories NPV Molecular testing

Strategies for Molecular Genetic Testing Rationale Mutation Analysis and/or mirna* Rule in cancer by finding one of the mutations known to be associated with malignancy Gene Expression and Genomic Sequencing Classifiers Rule out cancer by identifying a pattern of 142 genes expression characteristic of benign nodules General characteristics Tests available Higher specificity, lower sensitivity Quest Mutation Panel ThyroSeq2* (CBL Path) mirinform* (Interpace) RosettaGX* Reveal Higher sensitivity, lower specificity Afirma GEC (Veracyte)

Molecular Testing for Selected Cancer Mutations All Known Mutations MAP Kinase Signaling Pathway Mitogenic Signal/Receptor Tyrosine Kinases Ras B-Raf Kinase MEK MAPK/ERK Cell Growth/Proliferation/Division

Molecular Testing for Selected Mutations Multiple Thyroid Cancer Mutations 806 thyroid nodule FNA samples from 5 centers Sought 17 DNA point mutations and rearrangements, including RET/PTC, RAS, BRAF, and PAX8/PPAR-gamma mutations Correlated mutations with cytology and surgical pathology in 109 who went to surgery In 17 (2%) of the nodules, mutations were found; and all of these were thyroid cancers. For Bethesda III (AUS) & IV (FN/SFN), the NPV of not detecting any mutations was 84%. Beaudenon-Huibregtse S, et al. Thyroid. 2014;24:1479-87

Molecular Testing Gene Expression Classification Differential expression of alternative splicing RNA using Affymetrix exon arrays Goal: predict which cytologically indeterminate nodules are benign with <5% false negatives

Gene Expression Classifier Validation Study Methods 4812 samples from 3,789 patients with nodules >1 cm biopsied at 49 U.S. sites (99% w/ sonography) Among cytologically indeterminate nodules confirmed and subcategorized by path experts, 210 patients had Bethesda 3 or 4 cytology Surgery with a histopathological diagnosis Adequate mrna for GEC testing Unequivocal nodule FNAB-Surg correlation Alexander EK, et al. NEJM 2012:367:705-715

Gene Expression Classified Validation Study Results by Indeterminate Subcategory N 47 129 81 55 55 Alexander EK, et al. NEJM 2012:367:705-715 41

NPV for Cancer Impact of Molecular Testing Approaches Clinical Perspective 100% 80% 97% 84% 95% 60% 67% 40% 20% 0% Benign Cytology Indeterminate Cytology Indeterminate + Cancer Gene Mutation Analysis Indeterminate + Gene Expression Profiling

Evolution of Gene Classifier Gene Expression Classifier (GEC) mrna microarrays Classifier developed with machine learning Genomic Sequencing Classifier (GSC) mrna transcriptome sequencing Ensemble of multiple classifiers developed with machine-learning

Information Provided by RNA Sequencing GENE EXPRESSION SEQUENCE VARIANTS AUUCGA UACAGU CGUAAC MITOCHONDRIAL GENOME LOSS OF HETEROZYGOSITY Normal One copy from each parental chromosome Loss-Of-Heterozygosity (LOH) One copy from each parental chromosome 44

GSC Validation with Blinded Residual Samples 1. Alexander EK, et al. NEJM 2012. 45

Genomic Sequencing Classifier (GSC) SC Improves Specificity 1 All (*n=190) Hürthle (n=26) Non-Hürthle (n=164) GEC Sensitivity Specificity B-Call 88.9% [75.9-96.3] 50.3% [41.9-58.7] 41.1% Sensitivity Specificity B-Call 88.9% [51.8-99.7] 11.8% [1.46-36.4] 11.5% Sensitivity Specificity B-Call 88.9% [73.9-96.9] 55.5% [46.4-64.3] 45.7% GSC Sensitivity Specificity B-Call 91.1% [78.8-97.5] 68.3% [60-75.7] 54.2% Sensitivity Specificity B-Call 88.9% [51.8-99.7] 58.8% [32.9-81.6] 42.3% Sensitivity Specificity B-Call 91.7% [77.5-98.2] 69.5% [60.8-77.4] 56.1% GAIN 18% GAIN 47% GAIN 14% * One sample excluded by follicular content index classifier 1. p=0.0028 2. p=0.012 46

Performance of Original GEC vs GSC in Bethesda III/IV Nodules CYTOLOGICALLY INDETERMINATE (n=100) Afirma GEC GSC Benign (54) (42) Afirma GEC GSC Suspicious (46) (58) Afirma GEC 1 Sensitivity 90% Specificity 52% Afirma GSC 91% 68% 47 1. Alexander EK, et al. NEJM 2012.

Case 4: 64 yo man with thyroid cancer In 2008, 5.6 cm tall cell variant PTC with tracheal invasion, and 18/23 positive cervical nodes Treated with thyroidectomy, neck dissection, and postoperative 131-I In 2009, thyroglobulin 12 ng/ml with TSH 0.05 mu/l Cervical sonography: negative Chest CT: bilateral numerous <0.7 cm lung nodules rtsh-stimulated 123-I whole body scan negative (with rise in thyroglobulin to 65 ng/ml) 12-mon f/u chest CT: lung nodules up to 1.1 cm? Chemotherapy

Chemotherapy for Differentiated Thyroid Cancer Lenvatinib Phase III Trial Schlumberger M et al. N Engl J Med 2015;372:621-630.

Re-differentiating Chemotherapy for Non-iodine Avid Metastatic Disease Thyroid cancers often lose iodine-concentrating ability due to decreased expression of thyrocyte specific genes, e.g., TSH-R, TPO, and Tg. Previous studies of other agents to circumvent this problem, e.g., lithium and retinoic acid, have shown minimal if any effectiveness. In BRAF-mutated mice with thyroid cancer, MAPK pathway antagonists increase expression of the sodium iodide symporter and uptake of iodine Recent study of the MEK1 & MEK2 inhibitor selumetinib (AZD6244)

Re-differentiating Chemotherapy for Non-iodine Avid Metastatic Disease Selumetinib used in 20 patients with minimally or noniodine avid metastatic papillary thyroid cancers Ho AL, et al. N Engl J Med 2013;368:623-632

Re-differentiating Chemotherapy for Non-iodine Avid Metastatic Disease Selumetinib increased 124 I uptake in 12 (60%), incl. 4/9 patients with BRAF & 5/5 NRAS mutant tumors 8 reached the dosimetry threshold for 131 I therapy 5 had partial responses and 3 had stable disease All 8 patients had decreased Tg at 2 mos. (m=-89%)

Chemotherapy for Differentiated Thyroid Cancer Adverse Events During Treatment Adverse Event Axitinib Motesanib Sorafenib Sunitinib Fatigue 50% 46% 80% 79% Diarrhea 48% 59% 73% 56% Nausea 33% 28% 30% 10 Weight loss 25% 40% 50% Hypertension 28% 56% 30% 42% Rash 15% <10% 70% - - - Pain - - - - - - 57% - - - Hand-Foot Syndrome 15% - - - 83% 53% AE Grade >3 63% 62% 70%?

Chemotherapy for Differentiated Thyroid Cancer Tyrosine Kinase Inhibitor Pros & Cons Several agents have been shown to stop disease progression often and produce partial responses sometimes Lenvatinib prolongs overall survival Selumetinib can restore iodine-avidity in 60% of selected patients Minor to moderate constitutional, GI, and dermatologic side effects are common Lenvatinib therapy is associated with 1-2% mortality

Case 4: 64 yo man with thyroid cancer In 2008, 5.6 cm tall cell variant PTC with tracheal invasion, and 18/23 positive cervical nodes Treated with thyroidectomy, neck dissection, and postoperative 131-I Non-iodine avid lung nodules up to 1.1 cm In asymptomatic patient Doubling time longer than one year with none threatening bronchial obstruction Chemotherapy withheld and repeat CT planned in 6 months

Hot Thyroid Topics Conclusions Evidence supporting treatment (and detection) of subclinical hypothyroidism is not strong, except for CV risk reduction in 40-70 yo s. Novel therapeutic approaches to hyperthyroid Graves disease aren t yet ready for prime time.

Hot Thyroid Topics Conclusions New molecular diagnostic options for differential diagnosis of cytologically indeterminate thyroid nodules can avoid surgery in the majority of Bethesda 3 and 4 patients. TKI chemotherapies for thyroid cancer offer hope of restaining disease, but also have high morbidity