Rossella Elisei. Department of Endocrinology, University Hospital, Pisa, Italy

Transcription

1 Rossella Elisei Department of Endocrinology, University Hospital, Pisa, Italy

2 THYROID CANCER IS RARE TUMOR AND REPRESENTS ONLY 3.8% OF ALL HUMAN TUMORS All human cancer Thyroid cancer MOST FREQUENT CANCER AMONG ALL ENDOCRINE TUMORS!!!

3 MALIGNANT THYROID TUMORS Thyroid Follicular Cells Parafollicular cells (C cells) Non epithelial thyroid cells Differentiated thyroid carcinoma Papillary Carcinoma Follicular Carcinoma Mixed papillary and follicular Insular Poorly differentiated Undifferentiated or Anaplastic Medullary Carcinoma Lymphomas, sarcomas

4 % THYROID CANCER HISTOTYPE (Department of Endocrinology, Pisa) PAPILLARY FOLLICULAR MEDULLARY UNKNOWN ANAPLASTIC LYMPHOMA

5 THYROID CANCER INCIDENCE IS STILL GROWING National Cancer Institute s Surveillance, Epidemiology, and End Results (SEER) program.

6 Trend incidence of papillary thyroid cancer by size in USA ( ) Davies L and Welch G, JAMA, May 10, 2006

7 In the 80s: neck ultrasound More and more thyroid nodules!!!

8 Thyroid nodule prevalence Age (yrs) Palpation Autopsy or Neck ultrasound (Mazzaferri et al. 1993)

9 AUTOPTIC PREVALENCE 3,5-35,6% OF HUMAN THYROID GLANDS IN PERSONS DYING OF NON THYROID DISEASES OCCULT CARCINOMA: 1 cm MOSTLY PAPILLARY NO SEX DIFFERENCE NO AGE DIFFERENCE (40-90 yrs)

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11 DISTRIBUTION OF DIFFERENTIATED THYROID CANCER ACCORDING TO AGE AND SEX Subjects (Department of Endocrinology, Pisa) Years of age Males Females

12 Thyroid Cancer in Childhood RARE DISEASE 1.4% of all newly diagnosed childhood malignancies INCIDENCE 7% of all pediatric head and neck tumors / / YEAR for age < 16 yrs RARELY BEFORE 10 yrs INCIDENCE PEAK: yrs M : F = 6 : 1 M : F = 1 : 1 M : F = 2 : 5 age 5 9 yrs age yrs age yrs ISTOTYPE: PAPILLARY >> FOLLICULAR >> MEDULLARY Harach HR, Williams ED Br J Cancer 1995

13 EVIDENCE OF METASTASES AT FIRST WBS % Age 10 yrs Age > 10 yrs p=0.01 RESIDUE LYMPH NODE LUNG

14 Risk factors Radiazioni ionizzanti Apporto di iodio Fattori geografici Fattori etnici Familiarità Patologia tiroidea preesistente Fattori ormonali e riproduttivi Dieta, farmaci, fumo?

15 RADIATION AND THYROID CANCER The Chernobyl Experience

16 Thyroid cancer in Belarus before and after the Chernobyl accident Age Fold of increase > Total

17 Cases per ,3 0,3 0,2 0, , , Incidence per in Belarus Children (0-14) Adolescents (15-18) Adults (19-34) ,3 1,4 0, ,9 1, ,4 3,5 4 2,9 0, ,8 3,2 1, , ,8 3 4,2 3,1 2,6 2, , ,4 2,6 6, ,9 9,5 2, ,7 5,7 1,7 11, , ,9 0 Adolescents Young adults Children Cardis E et al, J. Radiol Prot 26: , 2006

18 Estimated risk of developing thyroid cancer after radiation dose of 1 Gy, by level of soil iodine and potassium iodide supplementation at the time of Chernobyl accident Consumption of potassium iodide No Yes * Lowest risk **Highest risk Highest two tertiles of soil iodine 3.5 (1.8 to 7.0) OR at 1 Gy (95% CI) 1.1 (0.3 to 3.6)** Lowest tertiles of soil iodine 10.8 (5.6 to 20.8)* 3.3 (1.0 to 10.6) From Cardis E et al, J Natl Cancer Inst, 97: , 2005

19 THYROID TUMORIGENESIS: MOLECULAR EVENTS Normal follicular cell BRAF RET/PTC TRK MET RAS PAX8-PPAR RAS FA PTC BRAF + FTC PDC ATC

20 THE CANCER GENOME ATLAS RESEARCH NETWORK: CELL, 2014

21 WHOLE EXOME GENE ANALYSIS IN >400 TISSUE PAIRS (dtc/normal)

22 % Survival Kaplan-Meier survival analysis Follow-up (mesi) BRAFp=0.015 BRAF+ Elisei R et al, JCE&M 2008

23 Survival of thyroid carcinoma patients with (n=35) and without (n=72) ras mutation Modified from Garcia-Rostan et al J Clin Oncol 2003

24 BRAF V600E and TERT Promoter Mutations Cooperatively Identify the Most Aggressive PTC With Highest Recurrence Xing et al, JCO, 2014

25 4187 DIFFERENTIATED THYROID CANCER (PTC and FTC) OVERALL SURVIVAL AT 35 YEARS FOLLOW UP (Department of Endocrinology, University of Pisa, Italy) % survival Follow up (years) 94.5 % Prevalence: In 2013, there were an estimated 637,115 people living with thyroid cancer in the USA.

26 Distant metastases at diagnosis represent a poor prognostic factor for survival National Cancer Institute s Surveillance, Epidemiology, and End Results (SEER) program.

27 % Survival Distant Metastasis and Advanced Age at diagnosis are the two bad prognostic factors for survival in papillary and follicular thyroid cancer Distant Metastases Yes No Follow up (years) p=< % Survival Age at diagnosis < 40 yr yr > 60 yr p=< Follow up (years) Elisei R et al, JCE&M, 2010

28 SURVIVAL 50 % SURVIVAL vs HISTOTYPE (n=1150) ATC YEARS PTC FTC MTC

29 THYROID TUMORIGENESIS: MOLECULAR EVENTS Normal follicular cell BRAF RET/PTC TRK MET RAS PAX8-PPAR RAS FA PTC BRAF + FTC PDC ATC

30 Landa et al, JCO 2016

31 Fig.1a Fig.1b AFTER Anaplastic thyroid cancer: primary tumor 1-2% of all thyroid cancer

32 Anaplastic thyroid carcinoma

33 Cancer, 2005 ATC IS STILL A RAPIDLY LETHAL DISEASE

34 THYROID GLAND: 2 CELLULAR TYPES Colloid Blood vessel Parafollicular cells Follicular cells FOLLICULAR CELLS: 99% C CELL or PARAFOLLICULAR CELLS: 1%

35 % LYMPH NODES METASTASES AT DIAGNOSIS IS THE MOST IMPORTANT NEGATIVE PROGNOSTIC FACTOR (MAYO CLINIC SERIES) Distant mets Gharib H et al, Mayo Clin Proc 67:934, 1992 SURVIVAL (years) Intrathyroidal Lymph node mets. Extrathyroidal invasion

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37 PREVALENCE OF DIFFFERENT FORMS OF MEDULLARY THYROID CARCINOMA MTC SPORADIC 75% FAMILIAL 25% MEN 2A MEN 2B FMTC

38 CODON SPECIFIC AGE RELATED PROGRESSION IN MEN 2 exon 10 exon 11 exon 13 exon 14 exon 15 exon 16 Earliest age of manifestation (yr) MTC (95%) PCC (50%) Cys 609 (1%) 5 19 Cys 611 (3%) 7 30 Cys 618 (7%) Cys 620 (7%) 6 22 Cys 630 (1%) 1 32 Cys 634 (68%) Glu 768 (1%) Leu 790 (5%) Tyr 791 (2%) Val 804 (2%) phpt (10-30%) Ser 891 (2%) Met 918 (3%) adapted from Machens and Dralle 2006+ATA guidelines 201

39 Human. Mol. Genet , 1993 Localisation of the gene for multiple endocrine neoplasia type 2A to a 480 kb region in chromosome band 10q11.2 Sara E. Mole+, Lois M. Mulligan, Catherine S. Healey, Bruce A.J. Ponder and Alan Tunnacliffe* 10q11.2 RET AND MEN II!

40 RET PROTONCOGENE: TYROSINE KINASE RECEPTOR

41 GENETIC SCREENING FOR GERMLINE RET MUTATIONS IN SIBLINGS OF PATIENTS WITH MEN II SYNDROMES IDENTIFICATION OF SUBJECTS WITH RET MUTATION (gene carriers) NON CARRIERS FREE FROM FOLLOW UP: no other tests CARRIERS EVALUATION OF SERUM CALCITONIN TO PERFORM AN EARLY OR EVEN PROPHYLACTIC THYROIDECTOMY

42 THYROID CARCINOMA HAVE DIFFERENT BIOLOGICAL BEHAVIOURS GOOD TUMORS CURABLE 90% OF WD-PTC 70% OF WD-FTC 50% OF MTC INTERMEDIATE 15-20% OF WD-DTC LOOSING THE WD FEATURES BAD TUMORS LETHAL 80% OF PDTC 100% OF ATC 30% OF MTC

43 LENVATINIB: PROFILE OF INHIBITION OF TK RECEPTORS a 51

44 Progression-Free Survival Schlumberger M et al. N Engl J Med Median PFS, months (95% CI) Lenvatinib 18.3 (15.1 NE) Placebo 3.6 ( ) HR (99% CI): 0.21 ( ) Log-rank test: P < Progression events, 86% Progression events, 41%

45 Vandetanib (Caprelsa) selectively targets VEGFR, EGFR and RET tyrosine kinase activity N O O F HN Adapted from Wedge SR et al. Cancer Res 2002;62: N N Br Kinase IC 50 (mm) VEGFR-2 (KDR) 0.04 VEGFR-3 (Flt-4) 0.11 RET 0.13 EGFR 0.50 VEGFR-1 (Flt-1), >1 PDGFR-b, Tie-2, FGFR1 MEK, CDK2 >10 c-kit, erbb2, FAK, >20 PDK1 AKT >100 IGF-1R >200

46 Vandetanib in patients with locally advanced or metastatic medullary thyroid cancer: a randomized, double-blind phase III trial (ZETA) Progression-free survival Number of patients Vandetanib 300 mg Placebo Significant increase of progression free survival Time (months) Vandetanib 300 mg Placebo Wells S. et al, J Clin Oncol, 2011

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