NeuroEndocrine Tumors Overview

Simron Singh, MD
Odette Cancer Centre Sunnybrook Health Sciences Centre Toronto, Ontario

The scientific information discussed in this program may include data/information on investigational uses of compounds/drugs that have not yet been approved by regulatory authorities. The opinions expressed in this program are those of the faculty and do not necessarily represent the views of Novartis Oncology.

NET in 2011: Presentation Overview

Epidemiology Clinical Presentation Nomenclature Biomarkers

Neuroendocrine Tumours (NET): The Facts

Over 60% of NET are advanced at the time of diagnosis1 The median survival for patients with advanced NET is 33 months1 Limited evidence for chemotherapy and other therapies High unmet need for evidence-based treatment options for patients with metastatic NET

1Yao

JC, et al. J Clin Oncol. 2008:26:3063-3072.

Diagnostic Challenges in NET

Heterogeneous group of tumours Wide variety of clinical presentations Late presentation Different terminology and classifications Histologic diagnosis may be difficult Variety of therapeutic options/approaches

Classification of NET
Functional versus non-functional Classification by site of origin
Nearly identical characteristics on routine histologic evaluation, but different responses to therapeutic agents

Classification by tumor stage: TNM

AJCC ENETS

Histologic classification
Well differentiated, poorly differentiated Tumours with a high grade (grade 3), a mitotic count >20 per10 high powered fields, or a Ki-67 proliferation index of >20% represent highly aggressive malignancies

Molecular Classification
MEN 1 & 2, Tuberosis Sclerosis, Von Hippel Lindau disease

NET in 2011: Presentation Overview

Epidemiology Clinical Presentation Nomenclature Biomarkers

Introduction to Neuroendocrine Tumours

NET are relatively rare, thus many physicians are not familiar with them The natural history of NET is poorly understood The use of dozens of terms for similar diseases arising in different organs has caused a great deal of confusion

The Overall Incidence of NET Is Increasing Rapidly Compared with All Malignant Neoplasms
6.00 600 5.25 5.00 4.00 3.00 2.00 500 400 Incidence of all malignant neoplasms per 100,000

Incidence of NET per 100,000

300 200 100 0 74 76 78 80 82 84 86 88 90 92 94 96 98 00 02 04 Year

1.00 0

Incidence of all malignant neoplasms Incidence of neuroendocrine tumours

The incidence and prevalence of NET has increased approximately 500% over the past 30 years, which may be partially due to improved diagnosis
Source: US SEER database. Adapted with permission from: Yao JC, et al. J Clin Oncol. 2008:26:3063-3072.

US and European Incidence of NET

6.0 Incidence rates per 100,000 Men Women 4.0

2.0

0.0 Country: USA1

(SEER)

Sweden2

Netherlands2

Norway3

Switzerland2
(Vaud)

Italy2
(Tuscany)

Study Period:

2000-2004

1983-1998

1989-1996

1993-2004

1974-1997

1985-1991

1Yao

3Hauso

J, et al. J Clin Oncol. 2008;26:3063-3072. 2Taal BG, et al. Neuroendocrinology. 2004;80(suppl 1):3-7. O, et al. Cancer. 2008;113:2655-2664.

Incidence of NET Is Increasing*

1.40 1.20 NET Site Lung Colon Small intestine 1.00 0.80 0.60 0.40 0.20 0 Rectum Pancreas

Incidence per 100,000

Year
*Approximate 5-fold increase between 1975 and 2004 Approximate 7-fold increase also evident in Norwegian registry SEER = Surveillance, Epidemiology, and End Results (for malignant NET)
Yao JC, et al. J Clin Oncol. 2008;26:3063-3072.

NET Are the Second Most Prevalent Type of Gastrointestinal Malignancy

1,200, 000

1,100, 000 2 times more prevalent than pancreatic cancer 100, 000

Colorectal1

GEP-NET2

Stomach1

Pancreas1

Esophagus1

Hepatobiliary1

Prevalence in SEER Database

GEP = gastroenteropancreatic
1National 2Modlin

Cancer Institute. SEER Cancer Statistics Review, 1975-2004. http://seer.cancer.gov/csr/1975_2004; IM, Lye KD, Kidd M. Cancer. 2003;97(4):934-959.

NET Epidemiology Summary

The incidence has increased dramatically over the last 30 years Gastroenteropancreatic NET are now the second most prevalent GI malignancy Location of primary tumours influences treatment strategy and outcome

NET in 2011: Presentation Overview

Epidemiology Clinical Presentation Nomenclature Biomarkers

Clinical Presentation of NET

NET may functional and non-functional NET exhibit a wide spectrum of clinical behaviors, and the majority are malignant NET secrete bioactive peptides and amines and are sometimes associated with carcinoid syndrome or other functional syndromes
Gastrinoma Insulinoma Vipoma Glucagonoma

Initial clinical symptoms are often not specific

Diffuse symptoms such as flushing, diarrhea, and cramps are often mistakenly attributed to other pathologies

Vinik A, et al. Pancreas. 2009;38(8):876-889.

Nonspecific Symptoms Often Lead to a Delayed Diagnosis

Presents to primary care
Vague abdominal symptoms
May be diagnosed as IBS May be referred to specialists for evaluation when symptoms do not resolve

Referred to multiple specialists

Symptoms become worse or patient consults for another reason
Diagnosis remains unclear

Seen by gastroenterologist or other specialist who orders imaging

Surgeon, pathologist perform biopsy or resection

Biopsy provides diagnosis of NET
Patient is referred to surgical oncologist, medical oncologist, or endocrinologist Treatment depends on stage, histology, symptoms

A referral leads to a scan or patient scanned for another reason

Liver metastasis or primary lesion is visualized May be an incidental finding

Estimated time to diagnosis: 5 to 7 years1

1Modlin

IM, et al. J Natl Cancer Inst. 2008;100(18):1282-1289.

33-Month Median Survival for Patients with Metastatic NET

Tumours with well- and moderately differentiated histology1
1.0 0.8 0.6 0.4 0.2 0 0 12 24 36 48 60 72 84 96 108 120

Survival probability

5-year survival rate in metastatic NET is similar to that in other metastatic cancers
Poorly differentiated NET: 4%1 Well/moderately differentiated NET: 35%1 Lung: 4%2 Colorectal, breast, and prostate: 11%, 23%, and 31%, respectively2

Time (months)
Median survival Stage Localized Regional Distant CI = confidence interval
1Yao

65% of patients with advanced NET will not be alive in 5 years

Month 223 111 33

95% CI 208-238 104-118 31-35

J, et al. J Clin Oncol. 2008;26:3063-3072; 2Jemal A, et al. CA Cancer J Clin. 2010;60:277-300.

The GI Tract Is the Most Common Primary Location of NET (US SEER Data)
Percent distribution (%)
17.2 Rectum Jejunum/ileum Pancreas Stomach Colon Duodenum Cecum Appendix Liver

Lung

13.4

27%

6.4

Digestive system

6.0 4.0 3.8 3.2

15%
Other/ Unknown

58%

3.0 0.8

Yao JC, et al. J Clin Oncol. 2008;26:3063-3072.

The Pancreas Is the Most Common Primary Location of NET Breakdown (Middle East & Asia Pacific Region)

Bile duct and gallbladder 3% Omentum/abdominal lining 1% Rectum 1% Ovary 1% Lung 1%

Liver 4% Stomach 6%

Hwang T, et al. Presented at: 8th Annual ENETS Conference; March 9-11, 2011; Lisbon, Portugal. Abstract C48.

Correlation of Primary Tumour Site with Survival

Known prognostic factors include: Location of primary tumour Extent of disease Tumour stage Degree of differentiation/ proliferative index (PI) Tumour grade Patient age Performance status
Survival probability
0.8 1.0

Distant Metastases
Colon Lung Pancreas Rectum Small bowel

0.6

0.4

0.2

12 24 36 48 60 72 84 96 108 120

Time (months)

65% of patients with advanced NET will not be alive in 5 years

Yao JC, et al. J Clin Oncol. 2008;26:3063-3072.

NET Are Often Advanced at the Time of Diagnosis

50%

27%

Distant metastases

23%

Regional spread

Localized
Source: US SEER Database. Yao JC, et al. J Clin Oncol. 2008;26:3063-3072.

Metastatic

Metastatic Well-Differentiated Neuroendocrine Neoplasms: Prognosis

1.0 No Risk Factors 0.9 0.8

Survival rates %

0.7 0.6 0.5 0.4 0.3 3 Risk Factors 0.2 0.1 0.0 0 1 2 3 4 5 6

1 Risk Factor

Prognostic factors (MV analysis): Age >65 years

2 Risk Factors

Number of liver metastases (>10) Tumour progression (100% if Ki67 >10%) Primary not removed

10

Years after metastases

MV = mean variance
Durante C, et al. Endocr Rel Cancer. 2009;16:585-597.

NET Clinical Presentation Summary

Symptoms are often absent or vague
Approximately 40% of pNET1 and 90% of GI NET2 are nonfunctioning

More than half of NET are metastatic at diagnosis 65% of patients with advanced NET will no longer be alive in 5 years

1Modlin

IM, et al. Lancet Oncol. 2008;9:61-72.

2Modlin

IM, et al. Gastroenterology. 2005;128:1717-51.

NET in 2011: Presentation Overview

Epidemiology Clinical Presentation Nomenclature Biomarkers

NET Vary by Primary Tumour Site

Generally characterized by their ability to produce peptides that may lead to associated syndromes (functional vs nonfunctional)1,2 Historically classified based on embryonic origin3
Foregut tumours Midgut tumours Hindgut tumours
Foregut Thymus Esophagus Lung Stomach Pancreas Duodenum Midgut Appendix Ileum Cecum Ascending colon Hindgut Distal large bowel Rectum

Today, primary tumour location is recommended for NET classification4

1Modlin 3NCCN.

IM, et al. Lancet Oncol. 2008;9:61-72. 2Modlin IM, et al. Gastroenterology. 2005;128:1717-1751. In: Practice Guidelines in Oncology. V.1.2008. 4Klimstra DS, et al. Am J Surg Pathol. 2010;34:300-313.

Confusion Caused by the Term Carcinoid

Oberndorfer coined the term karzinoide in 19071
This term implies that these tumours are benign; this is an unfortunate misnomer for the majority of NET
NET have malignant potential and metastasize, generally to the liver

Referring to any NET, the term carcinoid should only be used in reference to carcinoid syndrome
Symptoms of carcinoid syndrome include flushing, abdominal cramps, and diarrhea2 Most cases are associated with tumours of the intestines, which frequently metastasize to live2

1Klppel

G, et al. Endocr Pathol. 2007;18:141-144. 2Bhattacharyya S, et al. Nat Rev Clin Oncol. 2009;6:429-433.

WHO Classifications of Neuroendocrine Neoplasms of the GEP System

WHO 1980 WHO 2000 Well-differentiated endocrine tumour (WDET) Well-differentiated endocrine carcinoma (WDEC) Poorly differentiated endocrine carinoma/small-cell carcinoma (PDEC) II. Mucocarcinoid III. Mixed forms carcinoidadenocarcinoma IV. Pseudotumour lesions Mixed exocrine-endocrine carcinoma (MEEC) WHO 2010 Neuroendocrine tumours Grade 1 Grade 2

I. Carcinoid

Neuroendocrine carcinoma Grade 3 Mixed adenoneuroendocrine carcinoma (MANEC) Hyperplastic and preneoplastic lesions

Tumour-like lesions (TLL)

Bosman FT, et al. WHO Classification of Tumours of the Digestive System. Lyon, France: IARC Press; 2010.

Staging of NET According to Tumour-Node-Metastasis (TNM)

The European Neuroendocrine Tumour Society (ENETS) and American Joint Committee on Cancer (AJCC) have developed TNM staging systems Staging systems are developed for the following tumour locations:
Gastric, duodenum/ampulla/proximal jejunum, pancreas1 Lower jejunum and ileum, appendix, and colon and rectum2

1Rindi

G, et al. Virchows Arch. 2006;449:395-401; 2Rindi G, et al. Virchows Arch. 2007;451:757-762.

ENETS/AJCC TNM Staging Systems

ENET/AJCC Classification Criteria GI NET Stage includes tumour location, size, lymph node involvement/distant metastasis Stage I Stage IIa Stage IIb Stage IIIa Stage IIIb Stage IV T1 T2 T3 T4 Any T Any T N0 N0 N0 N0 N1 Any N M0 M0 M0 M0 M0 M1

ENETS = European Neuroendocrine Tumour Society AJCC = American Joint Committee on Cancer
1Rindi 3American

G, et al. Virchows Arch. 2006;449:395-401. 2Rindi G, et al. Virchows Arch. 2007;451:757-762. Joint Committee On Cancer. AJCC Cancer Staging System. 7th ed.

Correlation of Tumour Stage and Cumulative Survival (ENETS TNM Staging Proposal)
1.0 0.8 0.6 0.4
Stage IV I vs II I vs III I vs IV II vs III II vs IV III vs IV P = .227 P = .048 P<.001 P = .171 P<.001 P = .004 Stage I Stage II Cumulative survival

Stage III

0.2 0.0 0 50 100 150 200 250

Survival time (months)
202 cases: gastric (48), duodenal (23), pancreatic (131) Pape UF, et al. Cancer. 2008;113:256-265.

ENET/AJCC Grading System

ENET/AJCC Grade
G1 G2 G3

Mitotic count (10 HPF)*

<2 2-20 >20

Ki-67 index (%)**

2 3-20 >20

*10 HPF (high power field) = 2 mm2, at least 40 fields (at 40 magnification) evaluated in areas of highest mitotic density. ** MIB1 antibody; % of 2,000 tumour cells in areas of highest nuclear labeling.
1Rindi

3American

G, et al. Virchows Arch. 2006;449:395-401. 2Rindi G, et al. Virchows Arch. 2007;451:757-762. Joint Committee On Cancer. AJCC Cancer Staging System. 7th ed.

Metastatic GEP-NET: Correlation Between Mitotic Count and Ki-67 Index

100 90 80
Mitoses/10 HPF

70 60 50 40 30 20 10 0 0 10 20 30 40 50
Ki-67 R Sq Linear = 0.813

60

70

80

90 100

Strosberg J, et al. Human Pathology. 2009;40:1262-1268.

Correlation of Tumour Grade and Cumulative Survival (ENETS Grading Proposal)

1.0 G1
Cumulative survival

0.8 0.6 0.4 0.2 0.0 0 50 G3 100 150 Time (months) 200
G1 vs G2 G1 vs G3 G2 vs G3

G2
Grade1 G1 P = .040 P<.001 P<.001 G2 G3 Mitotic count (10 HPF)2 <2 2-20 >20 Ki-67 index (%)3 2 3-20 >20

250

1ENETS 210

grading system. HPF = 2 mm2 at least 40 fields (40 magnification) evaluated in areas of highest mitotic density. 3Percentage of 2,000 tumour cells in areas of highest nuclear labeling with MIB1 antibody. Pape UF, et al. Cancer. 2008;113:256-265.

Nomenclature Summary
Neuroendocrine tumours originate from a wide variety of different cell types that can secrete their own peptide hormone
Site = Pancreas vs intestine
Organ of origin should be determined Nomenclature could be simplified by using location of origin

Classification = Give a name to the disease

WHO classification is based on morphology and clinical pathological information (and is independent from presence and type of hormone secretion)

Staging = Measure the extent of the disease

TNM staging for ENETS and AJCC is same for GI NET but differ for pNET (ENETS has proved preliminary clinical effectiveness while AJCC needs confirmation)

Grading = Measure the pace of NET growth

Mitosis count or Ki67 with cut-off at 5% and 20% discern prognosis between diseases

NET in 2011: Presentation Overview

Epidemiology Clinical Presentation Nomenclature Biomarkers

Biomarkers in NET
CgA is the best available biomarker for diagnosis of NET
Elevated CgA may correlate with tumour progression CgA is elevated 80% to 100% of the time

NSE is also expressed in NET

Not as commonly used as CgA Also elevated in pNET and poorly differentiated NEC SSTR CgA NSE

5-HIAA

5-HT Gastrin Insulin Glucagon

5-HIAA reflects serotonin levels

Elevated serotonin levels over time lead to comorbidities such as cardiac disease

VIP Other biomarkers are available, however, few have achieved widespread acceptance New biomarkers in NET are needed to provide better diagnostic and prognostic information
CgA = Chromogranin A; 5-HIAA = 5-hydroxy-3-indoleacetic acid, 5-HT = serotonin, NSE = neuron-specific enolase, VIP = vasoactive intestinal peptide; SSTR = somatostatin receptor Vinik A, et al. Pancreas. 2009;38:876-889.

Correlation of Baseline CgA Levels with Survival

1.0 Chromogranin A g/l <100 n=6 100-1000 n = 16 >1000 n = 16

0.8

Cumulative survival

0.6

0.4

0.2
P = .02

0.0 0 20 40 60 80 100

Survival time (months)

Korse C, et al. Neuroendocrinology. 2009;89:296-301.

CgA and NSE: Prognostic Biomarkers

Nonelevated CgA Everolimus, n Median PFS, mos HR (95% CI)* P value Placebo, n Median PFS, mos HR (95% CI)* P value 97 4.9 1.33 (0.98, 1.82) .035 121 11.2 1.2 (0.82, 1.76) .173 103 4.3 138 5.36 2.01 (1.43, 2.84) <.001 Elevated CgA 84 8.5 Nonelevated NSE 155 13.86 2.03 (1.33, 3.09) <.001 56 2.83 Elevated NSE 48 8.11

Elevated baseline CgA were associated with shorter PFS in patients who received everolimus or placebo, suggesting that these biomarkers are prognostic for outcome Everolimus improved PFS vs placebo regardless of patients baseline CgA levels
PFS = progression-free survival * Obtained from unstratified Cox model. Obtained from unstratified 1-sided log-rank test. berg K, et al. Presented at: 8th Annual ENETS Conference; March 9-11, 2011; Lisbon, Portugal. Abstract C81.

CgA and NSE: Predictive Biomarkers*

CgA
100
Median PFS (months) Early response (n/N = 16/33) = 13.3 No early response (n/N = 26/38) = 7.5 Censored observations

NSE
100
Median PFS (months) Early response (n/N = 17/28) = 8.6 No early response (n/N = 10/11) = 2.9 Censored observations

80

80

PFS (%)

40

PFS (%)

60

HR = 0.25 95% CI: 0.13-0.51 P = .00004

60

HR = 0.25 95% CI: 0.10-0.58 P = .00062

40

20

20

0 0 3 6 9 12 15 18 Time since study start (months)

26 12 19 5 12 1 5 1 3 0

0 21 24 0 3 6 9 12 15 18 Time since study start (months)

16 2 9 0 6 0 3 0 1 0

21

24

Patients at Risk Resp. 33 29 Nonresp. 38 26

2 0

0 0

28 11

23 5

0 0

0 0

*Data from RADIANT-1 clinical trial. An early CgA or NSE response was defined as normalization or 30% decrease at week 4. Yao JC, et al. J Clin Oncol. 2010;28(1):69-76.

CgA Diagnosis and Monitoring Summary

Early diagnosis is critical to improving the management of NET CgA is the best available biomarker for the diagnosis and monitoring of NET Other more specific biomarkers are available to further assist in the monitoring and diagnosis of NET Additional biomarkers are still needed to help stratify patient risk and predict treatment response

NET in 2011: Conclusions

Incidence of NET is increasing NET include a diverse family of malignancies with varying behaviors, although some commonalities exist Poor survival outcomes for patients with distant metastases
65% of patients will not be alive 5 years after diagnosis

Advances in standardizing nomenclature, classification, and staging systems are essential to guide care and improve patient outcomes Biomarkers available today, CgA and NSE, may provide important prognostic information There remains a high clinical unmet need for therapies to effectively treat patients with advance NET Quality data from phase III randomized trials are emerging and is transforming the treatment landscape for patients with advanced NET