TUMORI NEUROENDOCRINI: HIGHLIGHTS 2017 - PowerPoint Presentation

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TUMORI NEUROENDOCRINI:

HIGHLIGHTS 2017

Mauro

Cives

Riunione nazionale COMU

2-3 Febbraio 2018

Torino, Centro Congressi Torino Incontra

Dipartimento di Scienze

Biomediche

e

Oncologia Umana

Unità di Oncologia Medica

Direttore: Prof. Franco

Silvestris

Università degli Studi di Bari “Aldo Moro”

Epidemiology

/

classification of

NETs

Updated

information on the incidence and

prevalence

of NETs

New

grading system for pNETs (WHO 2017)

New staging systems for pNETs

(mENETS) and SB NETs

(AJCC 2017)

Biology of NETsDefinition of

the genomic

landscape

of

pNETs

Treatment of

NETs

Telotristat etiprate

in the palliation

of carcinoid

syndrome

PRRT for the treatment of SB NETs progressing on SSAs

Immunotherapy?PRESENTATION OUTLINE

THE INCIDENCE AND PREVALENCE OF NETs ARE STEADILY INCREASING

Dasari

A et al,

JAMA

Oncol

2017

;

Halperin

DM et al, Lancet Oncol

2017THE INCIDENCE OF

NETs IS RISING

CARCINOID SYNDROME IS DIAGNOSED IN 19% OF PATIENTS WITH NEWLY DIAGNOSED NET

2017 WHO CLASSIFICATION OF

pNETs

Grading

Tumor Differentiation

Mitotic index

Ki-67 index

Genetic features

NET G1

Well differentiated

<2/10 HPF

<3%

Frequent mutations of:

MEN1

, DAXX/ATRX, mTOR pathway genes

NET G2

Well differentiated

2-20/10 HPF

3-20%

NET G3Well differentiated

>20/10 HPF

>20%

NEC G3

Poorly differentiated>20/10 HPF

>20%

Frequent mutations of: RB1, TP53

WELL DIFFERENTIATED TUMORPOORLY DIFFERENTIATED TUMORLloyd RV et al. WHO/IARC Classification of

tumours

, 4

th

Ed.

NEW STAGING SYSTEMS FOR

pNETs

: THE

mENETS

CLASSIFICATION

Luo

G et al, J

Clin

Oncol

2017

AJCC CLASSIFICATION

ENETS CLASSIFICATIONmENETS

CLASSIFICATION

Epidemiology

/

classification of

NETs

Updated information on the incidence

and

prevalence of

NETs

New grading system for

pNETs (WHO 2017)New staging systems

for pNETs

(mENETS) and SB NETs

(AJCC 2017)Biology of NETs

Definition

of the

genomic landscape

of pNETs

Treatment

of

NETsTelotristat

etiprate in the

palliation of

carcinoid

syndromePRRT for the treatment of SB NETs progressing

on SSAsImmunotherapy?

PRESENTATION OUTLINE

SOMATIC DRIVER MUTATIONS IN PANCREATIC NETs

Scarpa

A et al, Nature 2017

THE GENOMIC LANDSCAPE OF PANCREATIC NETs

Scarpa

A et al, Nature 2017

Epidemiology

/

classification of

NETs

Updated information on the incidence

and

prevalence of

NETs

New grading system for

pNETs (WHO 2017)New staging systems

for pNETs

(mENETS) and SB NETs

(AJCC 2017)Biology of NETs

Definition

of

the genomic

landscape of

pNETs

Treatment of

NETs

Telotristat etiprate

for the

palliation

of carcinoid syndromePRRT for the treatment of SB NETs

progressing on SSAsImmunotherapy?

PRESENTATION OUTLINE

TELOTRISTAT FOR THE PALLIATION OF CARCINOID SYNDROME

Kulke

M et al, J

Clin

Oncol

2017

TELOTRISTAT ETIPRATE INHIBITS THE PRODUCTION OF SEROTONIN

TELOTRISTAT ETIPRATE SIGNIFICANTLY REDUCES THE FREQUENCY OF BOWEL MOVEMENTS IN PATIENTS WITH CS

PRRT IN PATIENTS WITH ADVANCED MIDGUT NETs

Strosberg

J et al, NEJM 2017

PRRT SIGNIFICANTLY PROLONGS PFS AND OS IN PATIENTS WITH ADVANCED MIDGUT

NETs

THE SURVIVAL BENEFIT IS CONSISTENT ACROSS PRE-SPECIFIED SUBGROUPS

PD-L1 EXPRESSION IN SB NETs

Characteristics

n

of patients (

n

=102)

%

Age at diagnosis (years)

Median

Range

6027-95

Sex

MaleFemale

52505149

Carcinoid

syndrome

YesNo

23

79

2377

Tumor locationDuodenum

Jejunum

IleumRight colon

Unknown

102861310

28413Tumor size (cm)

Median

Range

1.9

0.3-8

TNM stage (AJCC classification)

I

IIA

IIB

IIIA

IIIB

IV

Unknown

2

5

4

0

33

55

3

2

5

4

0

32

54

3

Tumor grade (WHO 2010)

G1

G2

94

8

92

8

Follow-up (months)

Median

Range

61

1-182

BASELINE CHARACTERISTICS

IHC I

IHC II

IHC III

PD-L1 cut-off

positivity

(clone 28-8

Abcam

):

≥1% or ≥5%

of

tumor

cells

≥50%

of

tumor

cells

40/102, 39%

(95%

CI

, 30-49%)

14/102, 14%

(95%

CI

, 8-22%)

p

<0.0001

PROGNOSTIC ROLE OF PD-L1 IN STAGE IV SB NETs

p

=0.87

p

=0.38

p

=0.82

p

=0.96

PD-L1

≥1% cut-off

PD-L1≥50% cut-offOVERALL SURVIVAL

CANCER-SPECIFIC SURVIVAL

IMMUNE INFILTRATION IN SB NETs

Li= 0

Li= >50

Li= >100

Li=500

Tumor

Significant

association

between

PD-L1

expression

by

tumor

cells and immune infiltration

density (p=0.001)

PD-L1 EXPRESSION AND LLS PRESENCE: ANY BIOLOGICAL SIGNIFICANCE?

CD27

LYMPH NODE-LIKE STRUCTURES IN

SI-NETs

miRNA

PROFILING

UNSUPERVISED HIERARCHICAL ANALYSIS

Immune

infiltration

very

low

Immune

infiltration

very

high

IMMUNE-RELATED

miRNAs

ARE OVEREXPRESSD IN LLS+ SI-NETs

DIFFERENTIALLY EXPRESSED

miRNA

IN

SI-NETs

BASED ON LLS PRESENCE

miR181a-3p

miR376c-5p

miR499a-5pmiR-577

IMMUNE MICROENVIRONMENT AND RESPONSE TO CANCER IMMUNOTHERAPY

Teng

MWL et al. Cancer Res

2015;

Cives

M et al. submitted

Adaptive

immune

resistance

33%

Immunological ignorance

27%Tolerance

33%Intrinsic

induction7%TYPE I TUMOR MICROENVIRONMENT IS THOUGHT TO BE THE GROUP RESPONDING BETTER TO IMMUNOTHERAPY

THE IMMUNE MICROENVIRONMENT IN SB

NETs

KEYNOTE-028: PEMBROLIZUMAB FOR PD-L1

+

ADVANCED NETs

Courtesy of

Mehnert

JM et al, presented at ESMO 2017

ENGINEERING T CELLS TO TREAT CANCER

Maude SL et al. Blood 2015

Ectodomain

Antigen

recognition

Usually

an Ab

single-chain

variable fragment

Endodomain Intracellular signaling

Costimulatory

domains (usually

CD28 and 4-1BB) Stimulatory

domain (usually the CD3zeta chain

of the

T-cell receptor

)Output

T cell proliferation

Cytokine production Tumor cell killing

ACKNOWLEDGEMENTS

Franco

Silvestris

,

MD

Paola

Cafforio

,

PhD

Ester

D’Oronzo, MDClaudia Felici, PhDDominga Lovero

, PhDFrancesco Mannavola

, MDRaffaele Palmirotta, MD

Anna Passarelli, MDEleonora Pellè, MDDavide Quaresmini, MDStefania Stucci, MDMarco

Tucci, MD,

PhD