Rossella Elisei

Department of Endocrinology, University Hospital, Pisa, Italy

Rare adult solid ca

ncers

All humancancer

Thyroid cancer

THYROID CANCER IS RARE TUMOR AND REPRESENTS ONLY 3.8% OF ALL HUMAN TUMORS

MOST FREQUENT CANCER AMONG ALL ENDOCRINE TUMORS !!!

Rare adult solid ca

ncers

Thyroid Follicular Cells

Parafollicular cells(C cells)

MALIGNANT THYROID TUMORS

Differentiated thyroid carcinomaPapillary CarcinomaFollicular CarcinomaMixed papillary and follicular

InsularPoorly differentiatedUndifferentiated or Anaplastic

Medullary Carcinoma

Lymphomas, sarcomasNon epithelial thyroid cellsRare adult solid ca

ncers

70

%

PAPILLARY FOLLICULAR ANAPLASTIC LYMPHOMA0

10

20

30

40

50

60

MEDULLARY UNKNOWN

THYROID CANCER HISTOTYPE(Department of Endocrinology, Pisa)

Rare adult solid ca

ncers

THYROID CANCER INCIDENCE IS STILL GROWING

National Cancer Institute’s Surveillance, Epidemiology,and End Results (SEER) program.Rare adult s

olid cance

rs

Trend incidence of papillary thyroid cancer by size in USA (1988-2002)

Davies L and Welch G, JAMA, May 10, 2006Rare adult solid ca

ncers

In the ’80s: neck ultrasound

More and more thyroid nodules !!!

Rare adult solid ca

ncers

70

0

10

20

30

40

50

60

0 10 20 30 40 50 60 70 80 90

Age (yrs)

Autopsy or

Neck ultrasound

Palpation

(Mazzaferri et al. 1993)

Thyroid nodule prevalence

Rare adult solid ca

ncers

AUTOPTIC PREVALENCE

3,5-35,6% OF HUMAN THYROID GLANDS IN PERSONS DYING OF NON THYROID DISEASES

NO SEX DIFFERENCE

MOSTLY PAPILLARY

NO AGE DIFFERENCE (40-90 yrs)

OCCULT CARCINOMA: ≤1 cm

Rare adult solid ca

ncers

Rare adult solid ca

ncers

1-10 11-20 21-30 31-40 41-50 51-60 61-70 71-80 81-90

DISTRIBUTION OF DIFFERENTIATED THYROID CANCER ACCORDING TO AGE AND SEX

Years of age

Subje

cts

(Department of Endocrinology, Pisa)

0

20

40

60

80

100

120

140

160

180

200

MalesFemales

Rare adult solid ca

ncers

RARE DISEASE

1.4% of all newly diagnosed childhood malignancies

7% of all pediatric head and neck tumors

INCIDENCE 0.02 – 0.3 / 100.000 / YEAR for age < 16 yrs

RARELY BEFORE 10 yrs

ISTOTYPE: PAPILLARY >> FOLLICULAR >> MEDULLARY

INCIDENCE PEAK: 15 – 19 yrs

M : F = 6 : 1 age 5 – 9 yrs

M : F = 1 : 1 age 10 – 14 yrs

M : F = 2 : 5 age 15 – 19 yrs

Harach HR, Williams ED Br J Cancer 1995

Thyroid Cancer in Childhood

Rare adult solid ca

ncers

EVIDENCE OF METASTASES AT FIRST WBS

%p=0.01

Age ≤ 10 yrs Age > 10 yrs

0

5

10

15

20

25

30

35

40

45

50

RESIDUE

LYMPH NODE

LUNG

Rare adult solid ca

ncers

Radiazioni ionizzantiApporto di iodio

Patologia tiroidea preesistente

Fattori ormonali e riproduttivi

Fattori etnici

Dieta, farmaci, fumo ?

Risk factors

Fattori geografici

Familiarità

Rare adult solid ca

ncers

RADIATION AND THYROID CANCER

The Chernobyl ExperienceRare adult solid ca

ncers

Thyroid cancer in Belarus before and after the Chernobyl accident

Age 1971-1985 1986-2000 Fold ofincrease

0-14 8 703 87.8

15-18 21 267 12.7

>19 1465 6719 4.6

Total 1494 7689 5.1

Rare adult solid ca

ncers

Incidence per 100 000 in Belarus

2,3

2,9

3,4 3,5

43,8

3,1

0,3 0,3 0,2

3

4,2

1,4

2,1

3,4

4,9

5,7 5,7

0

0,7

1,7

2,5

2,61,2

11,3

5,6

1,00,8

9.7

3,8

2,9

9,5

6,6

1,4

3,2

0,80,4

6,9

1,9

0,1

2,6

0

2

4

6

8

10

12

1986

1987

1988

1989

1990

1991

1992

1993

1994

1995

1996

1997

1998

1999

2000

2001

2002

Ca

se

s p

er

10

0 0

00

Children (0 -14)

Adolescents (15 - 18)

Adults (19 - 34)

Adolescents

Children

Young adults

Cardis E et al, J. Radiol Prot 26: 127-140, 2006Rare adult solid ca

ncers

Consumption of potassium iodide

OR at 1 Gy (95% CI)

Highest two tertilesof soil iodine

Lowest tertilesof soil iodine

No

Yes

3.5 (1.8 to 7.0)

1.1 (0.3 to 3.6)**

10.8 (5.6 to 20.8)*

3.3 (1.0 to 10.6)

* Lowest risk

**Highest risk

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

From Cardis E et al, J Natl Cancer Inst, 97: 724-32, 2005 Rare adult solid ca

ncers

FA

FTC PDC ATC

PTC

BRAFRET/PTCTRKMET

RAS

PAX8-PPARRAS

Normal follicular

cell

BRAF +

THYROID TUMORIGENESIS: MOLECULAR EVENTS

Rare adult solid ca

ncers

THE CANCER GENOME ATLAS RESEARCH NETWORK: CELL, 2014

Rare adult solid ca

ncers

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

Rare adult solid ca

ncers

Follow-up (mesi)0 50 100 150 200 250

50

60

70

80

90

100

BRAF+

BRAF-

p=0.015%

Su

rviv

al

Kaplan-Meier survival analysis

Elisei R et al, JCE&M 2008Rare adult solid ca

ncers

Modified from Garcia-Rostan et al J Clin Oncol 2003

Survival of thyroid carcinoma patients with (n=35) and without (n=72) ras mutation

Rare adult solid ca

ncers

BRAF V600E and TERT Promoter Mutations CooperativelyIdentify the Most Aggressive PTC With Highest Recurrence

Xing et al, JCO, 2014

Rare adult solid ca

ncers

50

60

70

80

90

100

Follow up (years)

0 5 1510 20 3025 35

% s

urv

ival

94.5 %

4187 DIFFERENTIATED THYROID CANCER (PTC and FTC)OVERALL SURVIVAL AT 35 YEARS FOLLOW UP

(Department of Endocrinology, University of Pisa, Italy)

Prevalence: In 2013, there were an estimated 637,115 people living with thyroid cancer in the USA.Rare adult s

olid cance

rs

Distant metastases at diagnosis represent a poor prognostic factor for survival

National Cancer Institute’s Surveillance, Epidemiology,and End Results (SEER) program.Rare adult s

olid cance

rs

Follow up (years)

0

20

40

60

80

100

5 10 15 20 25 30

0

Distant Metastases

% S

urv

ival p=<0.0001

No

Yes

Follow up (years)

50

60

70

80

90

100

% S

urv

ival

5 10 15 20 25 30

0

41 - 60 yr> 60 yr

< 40 yr

Age at diagnosis

p=<0.0001

Distant Metastasis and Advanced Age at diagnosis are the two bad prognostic factors for survival in

papillary and follicular thyroid cancer

Elisei R et al, JCE&M, 2010Rare adult solid ca

ncers

SURVIVAL%

PTC

FTC

MTC

ATC

YEARS

0

50

100

0 2 5 10 15 20

SURVIVAL vs HISTOTYPE (n=1150)

Rare adult solid ca

ncers

FA

FTC PDC ATC

PTC

BRAFRET/PTCTRKMET

RAS

PAX8-PPARRAS

Normal follicular

cell

BRAF +

THYROID TUMORIGENESIS: MOLECULAR EVENTS

Rare adult solid ca

ncers

Landa et al, JCO 2016Rare adult solid ca

ncers

Anaplastic thyroid cancer: primary tumor

1-2% of all thyroid cancer

Fig.1a Fig.1bAFTER

Rare adult solid ca

ncers

Anaplastic thyroid carcinoma

Rare adult solid ca

ncers

Cancer, 2005

ATC IS STILL A RAPIDLY LETHAL DISEASERare adult solid ca

ncers

THYROID GLAND: 2 CELLULAR TYPES

FOLLICULAR CELLS: 99%C CELL or PARAFOLLICULAR CELLS: 1%

Parafollicular cells

Follicular cells

Colloid

Blood

vessel

Rare adult solid ca

ncers

LYMPH NODES METASTASES AT DIAGNOSISIS THE MOST IMPORTANT NEGATIVE PROGNOSTIC FACTOR

(MAYO CLINIC SERIES)

%

0

20

40

60

80

100

0 1 2 3 4 5 6 7 8 9 10111213 1415161718 1920212223 2425262728 2930313233

Lymph node mets.

Extrathyroidal invasion

Distant mets.

Intrathyroidal

SURVIVAL (years)

Gharib H et al, Mayo Clin Proc 67:934, 1992Rare adult solid ca

ncers

Rare adult solid ca

ncers

PREVALENCE OF DIFFFERENT FORMS OF MEDULLARY THYROID CARCINOMA

MTC

FAMILIAL 25%

SPORADIC 75%

MEN 2A

MEN 2B

FMTC

Rare adult solid ca

ncers

exon 13

exon 10exon 11

exon 14

exon 16

exon 15

Cys 609 (1%) 5 19Cys 611 (3%) 7 30Cys 618 (7%) 7 29 41Cys 620 (7%) 6 22

Cys 630 (1%) 1 32

Cys 634 (68%) 1.1 9 10

Glu 768 (1%) 22 59Leu 790 (5%) 10 28Tyr 791 (2%) 21 38 38

Val 804 (2%) 6-12 28-33

Ser 891 (2%) 13 52 10Met 918 (3%) 0.75 8

Earliest age of manifestation (yr)

MTC(95%)

PCC(50%)

phPT(10-30%)

adapted from Machens and Dralle 2006+ATA guidelines 2015

CODON SPECIFIC AGE RELATED PROGRESSION IN MEN 2

Rare adult solid ca

ncers

10q11.2RET AND MEN II!

Human. Mol. Genet.247-252, 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*

Rare adult solid ca

ncers

RET PROTONCOGENE: TYROSINE KINASE RECEPTOR

Rare adult solid ca

ncers

GENETIC SCREENING FOR GERMLINE RET MUTATIONS IN SIBLINGS OF

PATIENTS WITH MEN II SYNDROMES

IDENTIFICATION OF SUBJECTS WITH RET MUTATION

(gene carriers)

NONCARRIERS

FREE FROM FOLLOW UP: no other tests

CARRIERS

EVALUATION OF SERUM CALCITONIN TO PERFORM AN

EARLY OR EVEN PROPHYLACTIC

THYROIDECTOMYRare adult solid ca

ncers

GOOD TUMORS

90% OF WD-PTC70% OF WD-FTC50% OF MTC

CURABLE

15-20% OF WD-DTCLOOSING

THE WD FEATURES

INTERMEDIATE

BAD TUMORS

80% OF PDTC100% OF ATC30% OF MTC

LETHAL

THYROID CARCINOMAHAVE DIFFERENT

BIOLOGICAL BEHAVIOURS

Rare adult solid ca

ncers

LENVATINIB: PROFILE OF INHIBITION OF TK RECEPTORS

a 51

Rare adult solid ca

ncers

Progression-Free Survival

Median PFS, months (95% CI)

Lenvatinib 18.3 (15.1–NE)

Placebo 3.6 (2.2–3.7)

HR (99% CI): 0.21 (0.14–0.31)Log-rank test: P < 0.001

Progression events, 41%

Progression events, 86%

Schlumberger M et al. N Engl J Med 2015.Rare adult solid ca

ncers

N

HN

NO

O

F Br

N

Adapted from Wedge SR et al. Cancer Res 2002;62:4645–4655

Vandetanib (Caprelsa) selectively targets VEGFR, EGFR and RET tyrosine kinase activity

Kinase IC50 (mM)

VEGFR-2 (KDR) 0.04

VEGFR-3 (Flt-4) 0.11RET 0.13

EGFR 0.50

VEGFR-1 (Flt-1), PDGFR-b, Tie-2, FGFR1

>1

MEK, CDK2 >10

c-kit, erbB2, FAK, PDK1

>20

AKT >100

IGF-1R >200

Rare adult solid ca

ncers

Vandetanib in patients with locally advanced or metastatic medullary thyroid cancer:

a randomized, double-blind phase III trial (ZETA)

Time (months)

0

Pro

gre

ss

ion

-fre

e s

urv

iva

l

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

6 12 18 24 30 36

Number of patients

231 196 169 140 40 1 0

100 71 57 45 13 0 0

Vandetanib 300 mg

Placebo

Vandetanib 300 mg

Placebo

Significant increase of progression free survival

Wells S. et al, J Clin Oncol, 2011Rare adult solid ca

ncers

Rare adult solid ca

ncers