Thyroid Tumor Management in the Era of Precision Oncology. Bryan Haugen, MD Former Fellow

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1 Thyroid Tumor Management in the Era of Precision Oncology Bryan Haugen, MD Former Fellow

2 Outline/Timeline Disclosures Led Afirma GEC study Writing group Thyroseqv3 study Rosetta Genomics research support

3 Two Conundrums SEER Before FNAB 90-95% unnecessary thyroid surgeries After FNAB 50% unnecessary thyroid surgeries 75-80% indeterminate FNA led to unnecessary surgeries results_merged/topic_graph_trends.pdf

4 Western J Med 134:198, 1981

5 Management of Patients with Thyroid Nodules Modified from Nishino M. Cancer Cytopathology 2015

6 Bethesda Cytopathology Classification FNA Benign 2.5% (1-10) Monitor Malignant 99% (94-100) Surgery (prognostic MM) Nondiagnostic Risk of malignancy Median (range) Repeat biopsy Indeterminate Suspicious 70% (53-97) Surgery (prognostic MM) Neoplasm 25% (14-34)(25-40)** Surgery, MM or scintigraphy AUS/FLUS 14% (6-48)(10-30)** Repeat biopsy or MM MM Molecular Markers Baloch ZW, Diag Cytopath 36:425, 2008 Lanman R, Thyroid, 2011 Bongiovanni, Acta Cytologica 2012 Pustaszeri M, Acta Cytologica 2016 Cibas E, Thyroid 2017**

7 Algorithm incorporating molecular testing Mayson SE and Haugen BR Endo Clinics NA, submitted

8

9 2003

10 Statistical Definitions gold standard (histopathology) Positive Negative Test result Positive True positive False positive (type I error) Negative False Negative (type II error) True negative PPV NPV Sensitivity Specificity Cytology benign: 93-98% sensitivity, 90-98% NPV Cytology malignant: % specificity, % PPV Sangalli, Cytopath, 2006; Alexander, Cancer 2007; Theoharis, Thyroid 2009 ; Renshaw, Cancer Cytopath, 2010

11 Which patient(s) with indeterminate cytology should I send for surgery? BRAFV600E: High specificity (100%) and PPV (100%) Cytology malignant: % specificity, % PPV Which patient(s) with indeterminate cytology can avoid surgery? BRAFV600E: Low sensitivity (32%) and NPV (73%) Cytology benign: 93-98% sensitivity, 90-98% NPV Rossi M, J Clin Endo Metab, 2012

12 Comparative Performance of Commercial Molecular Tests First Generation Sensitivity Specificity 167 RNA GEC (Afirma GEC) 1 * 92% 52% 7-gene panel (Thyroseq) 2 61% 98% BRAF, HRAS, KRAS, NRAS, RET/PTC, PAX8-PPAR *- blinded, prospective, multi-center trial 1 Alexander EK, et al, NEJM 2012; 2 Nikiforov Y, JCEM 2011

13 Comparative Performance of Commercial Molecular Tests First Generation Sensitivity Specificity 167 RNA GEC (Afirma GEC) 1 * 92% 52% 7-gene panel (Thyroseq) 2 61% 98% Second Generation 19-gene panel (Thyroseqv2) 3 91% 93% 8-gene panel/mirna GEC 4 89% 85% (ThyGenX/ThyramiR) 24 mirna GEC (Reveal) 5 85% 72% *- blinded, prospective, multi-center trial 1 Alexander EK, et al, NEJM 2012; 2 Nikiforov Y, JCEM 2011; 3 Nikiforova MN, JCEM 2013; 4 Labourier E, JCEM 2015; 5 Lithwick-Yanai G, J Clin Path 2016

14 Third Generation Testing Afirma Genomic Sequencing Classifier (GSC) RNA sequencing (gene expression and mutations) 12 classifiers, genes (1115 core genes) BRAFV600E, RET/PTC1, RET/PTC3 Hurthle lesions classifier 191 Indeterminate FNA (III-IV) Sensitivity 91% Specificity 68% 24% malignancy rate NPV 96% PPV 47% Xpression Atlas Patel KN, 3 rd World Congress on Thyroid Cancer (WCTC), Boston, MA, July 27-30, 2017 Patel KN, JAMA Surgery 2018

15 Cancer genes: point mutations, indels, fusions, CNA, gene expression

16 CCNY CHEK2 CHGA CITED1 CREB3L2 CTNNB1 DICER1 EIF1AX EML4 EP300 ERBB4 ERC1 ETV6 EZH1 EZR IGF2BP3 IRF2BP2 KIAA1217 KIAA1598 KIF5B KLK1 KRAS KRT20 KRT7 KTN1 LOC LTK MACF1 MEN1 MET MKRN1 NCOA4 NF2 NRAS NTRK1 NTRK3 OFD1 PAX8 PCM1 PGK1 PICALM PIK3CA POR PPARG PRKAR1A PTEN PTH RAF1 RBPMS RET RNF213 ROS1 SLC26A11 SLC5A5 SND1 SPECC1L SQSTM1 SS18 SSBP2 STK11 STRN SYN2 TBL1XR1 TERT TFG THADA TP53 TPM3 TPR TRA2A TRIM24 TRIM27 TRIM33 TSC2 TSHR UACA VCL VHL WARS ZBTB8A ZC3HAV1 FAM114A2 FAM193A FARSB FGFR2 FKBP15 GFPT1 GLIS3 GNAS GOLGA5 GORASP2 GTF2IRD1 HOOK3 HRAS IDH1 IDH2 AGGF1 AGK AKAP1 AKAP9 AKT1 ALK APC BANP BCL2L11 BRAF C7orf10 CALCA CCDC149 CCDC30 CCDC6 Cancer genes: point mutations, indels, fusions, CNA, gene expression

17 Third Generation Testing Thyroseqv3 Genomic Classifier (GC) 112 genes Prospective, double-blinded, multicenter Each alteration gets a score of 0-2 for risk of malignancy Total score: 0-1 benign or >2 high cancer probability Score % >2 41 Score of 1 is currently negative 247 Indeterminate FNA (III-IV) Sensitivity 94% 28% malignancy rate Specificity 82% NPV 97% PPV 66% Steward DL, 87 th Annual Meeting of the American Thyroid Association Victoria, BC, October 18-22, 2017 Steward DL, et al, JAMA Oncology 2018

18 Comparative Performance of Commercial Molecular Tests First Generation Sensitivity Specificity 167 RNA GEC (Afirma GEC) 1 * 92% 52% 7-gene panel (Thyroseq) 2 61% 98% Second Generation 19-gene panel (Thyroseqv2) 3 91% 93% 8-gene panel/mirna GEC 4 89% 85% (ThyGenX/ThyramiR) 24 mirna GEC (Reveal) 5 85% 72% Third Generation 112-gene panel (Thyroseqv3 GC) 6 * 94% 82% RNAseq panel (Afirma GSC) 7 * 91% 68% *- blinded, prospective, multi-center trial 1 Alexander EK, et al, NEJM 2012; 2 Nikiforov Y, JCEM 2011; 3 Nikiforova MN, JCEM 2013; 4 Labourier E, JCEM 2015; 5 Lithwick-Yanai G, J Clin Path 2016; 6 Patel KN, JAMA Surgery 2018; 7 Steward DL, JAMA Oncology 2018

19 Third Generation Testing Thyroseqv3 Genomic Classifier (GC) 112 genes 99% NPV 95% NPV 99% NPV 95% NPV 83% PPV 84% PPV 40% PPV 40% PPV Steward DL, et al, JAMA Oncology 2018

20 45 % 40 Malignancy Rates UC-SOM ,019 FNA Bethesda III (AUS/FLUS) 231 (11.4%) Bethesda IV (SFN/FN) 80 (4.0%) Malignancy 24.5% 25.5% Range 8-38% 3 yr ave 21-30% Range 0-42% 3 yr ave 24-34% AUS/FLUS SFN/FN Deaver KE, Clin Endo 2018

21 Third Generation Testing Thyroseqv3 Genomic Classifier (GC) 60% negative UC-SOM 97% NPV 98% NPV 65% PPV 57% PPV Steward DL, et al, JAMA Oncology 2018

22 2013

23 2016 Molecular Prognosis Survival 30 PTC deaths 15 TERT+BRAF 30 other deaths 2 TERT+BRAF Adjusted RR 9.34 ( )

24 Molecular Prognosis Metanalyses Tumor Biology, 2017 Clinicopathologic features Recurrence Survival (Clin Endo) Thyroid, 2017 BRAF poor predictor TERT mixed BRAF+TERT strong Clin Endo, 2017

25 2018 Haugen BR, Thyroid 1997

26 Giordano, Getz, et al, Cell, 2014 BRAF mutations 60% RAS mutations 13% RET rearrangements 6.3% TERT promoter mutations 9.4% TP53 mutations 0.7%

27 2016 Precision Oncology BRAFV600E 33-45% RAS 24-28% RET 0-6% Pax8-PPARγ* 0-4% ALK 0-4% TERT 40-73% TP %

28 Pax8-PPARγ directed therapy 40 patients with progressive DTC 1 patient (2.5%) with Pax8-PPARγ fusion Giordano TJ, JCEM 2018

29 Genetics Testing of Advanced Thyroid Cancer MSK-IMPACT (n=149) FoundationOne (n=630) Zehir A, Nat Med 2017 NGS panels of cancer associated genes genes genes 229 genes are included in all versions of both panels Detect somatic and germline base substitutions, short insertions or deletions (indels), copy number alterations (CNAs), and selected promoter mutations and structural rearrangements 539x sequencing depth Normal tissue sequenced 613x sequencing depth Normal tissue NOT sequenced Pozdeyev N, Clin Cancer Research, 2018

30 MSK-IMPACT and Foundation One thyroid cancer cohorts Tumor type MSK-IMPACT Foundation One Total PTC Pediatric PTC FTC HCTC ATC Total PTC (51% TERT mutation, 10% TP53 mutation) Pozdeyev N, Clin Cancer Research, 2018

31 468 advanced PTC (51% TERT mutation, 10% TP53 mutation) Pozdeyev N, Clin Cancer Research, 2018 Tumor suppressor 16% MAPK 84% CDKN2A 8% CDKN2B 5% Top Genetic Alterations BRAF (73%) TERT (51%) TP53 (10%)

32 196 ATC (66% TP53 mutation, 54% TERT mutation) Pozdeyev N, Clin Cancer Research, 2018 Tumor suppressor 74% MAPK 70% CDKN2A 22% CDKN2B 13% Top Genetic Alterations TP53 (66%) TERT (54%) BRAF (41%)

33 Genetic Evolution of Thyroid Cancer Drivers of PTC, not progression Gene PTC 1 (n=496) Adv PTC 3 (n=468) PDTC 2 (n=84) ATC 2 (n=33) ATC 3 (n=196) BRAFV600E 62% 73% 33% 45% 41% RET 6.3% 7% 6% 0% 1% PAX8-PPAR 1% ND 4% 0% ND ALK 0.8% 1% 4% 0% 1% 1 Giordano TJ, Cell Landa I, JCI Pozdeyev N, Clin Cancer Res 2018

34 Genetic Evolution of Thyroid Cancer Progression to advanced DTC/PDTC, not ATC Gene PTC 1 (n=496) Adv PTC 3 (n=468) PDTC 2 (n=84) ATC 2 (n=33) ATC 3 (n=196) RAS 13% 10% 28% 24% 26% RBM10 0% 6% 10% 3% 3% EIF1AX 1.5% ND 11% 9% ND Progression to PDTC and ATC Gene PTC 1 (n=496) Adv PTC 3 (n=468) PDTC 2 (n=84) ATC 2 (n=33) ATC 3 (n=196) TP53 0.7% 10% 8% 73% 66% TERT 9.4% 51% 40% 73% 54% PTEN 0.5% 2% 4% 15% 11% CDKN2A 0% 8% 0% 8% 22% 1 Giordano TJ, Cell Landa I, JCI Pozdeyev N, Clin Cancer Res 2018

35 2017

36 Coming to a clinic near you. 48 yo female 3 cm PTC Neck US no abn LN or invasion Molecular testing: RET/PTC1 only Discussion: Active surveillance vs lobectomy Agreed plan: Active surveillance Oncogene duet 48 yo female 3 cm PTC Neck US no abn LN or invasion Molecular testing: BRAFV600E TERT promoter mutation RBM10 mutation Discussion: Recommend Tx/LND dissection + RAI Agreed plan: Above

37 Potential Pathway Targets in advanced PTC and ATC Spindle Assembly Checkpoint??? PD-1/PD-L1 MMR APOBEC Lenvatinib Pozdeyev N, Clin Cancer Research, 2018

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39 Precision Medicine in Thyroid Nodule and Cancer Care Molecular Diagnostics Third generation testing (high NPV, good PPV) Individual gene mutations, alterations Precision Oncology Using genetics to help guide therapy and prognosis Prognosis: TERT + BRAF, RBM10, TP53, PTEN, CDKN2A Treatment: BRAFV600E, ALK, RET, NTRK, PD-L1, KDR/VEGFR, TP53

40 Acknowledgements University ofcolorado Nikita Pozdeyev Dan Bowles Kelsi Deaver Sarah Mayson Janice Kerr Rebecca Schweppe Jena French Stephanie Davis Carrie Marshall Bev McLaughlin Foundation Medicine Laurie Gay Molecular Diagnostics Yuri Nikiforov Marina Nikiforova Dave Steward Zubair Baloch Susan Mandel Pax8-PPARγ Ron Koenig Tom Giordano Steve Sherman Manisha Shah Elaine Caoili Mary Rossick Kern and Jerome H Kern Endowment