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Bea lehming memorial lectures cacs - washington dc 11-15-2014
1. Advanced Pancreatic and GI
Neuroendocrine Cancer
Presented at:
The Bea Lehming
Memorial Lectures
November 15, 2014
Washington, DC
Presenters
M. Sue OâDorisio, M.D., Ph.D.
Professor of Pediatric Oncology
PI, Iowa Neuroendocrine Tumor
SPORE
Thomas M. OâDorisio, M.D.
Professor of Medicine
Director, Carcinoid &
Neuroendocrine Tumor Program
2. Why should patients learn about
genetics?
⢠Understand my disease
⢠Obtain genetic counseling if needed
⢠Converse with my doctors
⢠Obtain help from my insurance carrier
⢠Have fun educating my family
⢠Advocate for myself and my children
3. Objectives of todayâs talk
⢠Show chromosomes and genes involved in
carcinoids and neuroendocrine tumors
⢠Demonstrate how NET genetics travel in
families
⢠Discuss how 68Ga-DOTATOC imaging and 90Y-DOTATOC
therapy target genes
5. Neuroendocrine Tumors in Kids?
⢠More common than Medulloblastoma
⢠Nearly as common as Neuroblastoma
Navalkele, OâDorisio, Zamba, Lynch Ped Blood Cancer, 2011
12. Can one chromosome make a difference?
Tumor
suppressor
gene
STF gene
TS gene
CC gene
X Chromosome
Y Chromosome
Testis Specific
Protein gene
13. What happens if a cell loses part or all of
a chromosome?
⢠Can lose a small piece, an arm, or entire
chromosome
⢠Can be first step in development of NET
14. Chromosomes Related to NETs
Neuroendocrine
Tumor Type
Chromosome
involved
Lung Losses of 11q
Midgut Deletions of 18q
Pancreatic Losses of 1 and 11q
Gains of 9q
Gut and Pancreatic Losses of Xq26
Methylation of Xq25
Insulinoma Losses of 22q
16. Where are genes located?
⢠Stored on chromosomes in nucleus of cell
⢠Chromosome breakage results in loss of as
many as 5,000 genes
17. How many genes are on one
chromosome?
⢠Depends on the size of the chromosome
⢠Y chromosome is smallest with 200 genes
⢠X chromosome has about 2000 genes
⢠Chromosome 1 has more than 5000 genes
18. What are genes?
⢠Pieces of DNA
⢠We have over 40,000 genes in every cell
⢠Blueprint for proteins
⢠Somatostatin receptor gene makes a protein with
the same name
⢠Ki67 gene makes a protein with the same name
⢠Serotonin gene makes a protein with the same
name
21. How do I know if I should have
genetic testing?
⢠If I have a first degree relative (parent,
sibling, child) with the same tumor type
⢠If I have traits associated with NF1, VHL,
MEN
⢠If I have an extra $20,000 for whole genome
sequencing
23. Which genes take a hit in NETs?
Tumor Type Gene
⢠Lung NET drs, MEN-1
⢠Gastric NET β-catenin, VMAT
⢠Ileal NET DADI
⢠Pancreatic NET NF1, TSC2
⢠Colon NET MUC1, Ki-67
⢠Appendiceal NET MUC1, Ki-67
24. How we use genes to diagnose
and treat NET?
⢠Measure the gene product in blood:
chromogranin A, glucagon, Neurokinin A
⢠Stain the gene product with an antibody (sst2,
Ki-67, NSE)
⢠Target gene product with a radioactive tag
(sst2, dopamine, VMAT, OXTR) for diagnosis
and therapy: Theranostics!
26. Molecularly targeted PET
using 68Ga-DOTATOC
Somatostatin Receptor Modified Somatostatin
ďś High receptor expression
ďś Native peptide sequence known
ďś High affinity/specificity/avidity for target
ďś Synthetically feasible (<50 residues)
Ga-68
Linker
(DOTA)
Vector
(TOC)
Target
Concept & design by M Schultz
27. Small Bowel NET identified by
OctreoScan in 16 yo female
Anterior Posterior
28. Initial Treatment based on
Octreoscan and CT
⢠Surgical removal of small bowel primary
⢠Removal of 8 regional nodes (5+)
⢠Wedge resection of 2 right lobe liver lesions
identified by CT/OctreoScan
⢠Sandostatin-LAR initiated
29. Restaging 16 yo with small bowel NET
using 68Ga-DOTATOC PET and MRI
PET
PET/CT PET
⢠C7 vertebral lesion on low resolution CT
⢠Lesion positive on 68Ga-DOTATOC PET
⢠Lesion confirmed as C7 on MRI
Low res CT
30. Restaging 16 yo with small bowel NET
using 68Ga-DOTATOC PET and MRI
PET Low res CT
PET/CT PET
34. Genetics in NETs: Summary
⢠Chromosome losses and gene mutations can
cause cancer, including neuroendocrine tumor
⢠We are just beginning to understand genetic
causes of NET
⢠We can exploit genetic signatures to make the
diagnosis and to predict prognosis in NETs
⢠Future NET treatment strategies will target
multiple genes at once to cure NETs
38. Figure 2: US Prevalence of gastroenteropancreatic neuroendocrine tumors
The number of patients in the United States with neuroendocrine tumors now outnumbers the combined prevalence
of stomach and pancreatic cancer according to SEER (adapted from Yao).
1,141,407
103,312
65,836
32,353 28,664
21,427
10000000
1000000
100000
10000
Colon and Rectum Neuroendocrine Stomach Pancreas Esophagus Hepatobiliary
39. Y
In memory of Stephen Qualman, Pathology
The Ohio State University Childrenâs Hospital
2008
Y = Somatostatin receptor subtype 2
Hypervascular
45. Well-Differentiated Endocrine Carcinoma, Ileum
Tumor cells
invading
muscularis
propria
Serotonin
tumor cell
nests
Solcia E, Kloppel G, Sobin LH. Histological
Typing of Endocrine Tumours, 2nd ed, 2000.
46. Ki67
⢠Is a antibody that recognizes an antigen Mr, 345 and
395 kDa
Encoded by single gene (chromosome 10)
Expression tightly associated with cell
cycle
Excellent indicator of tumor proliferation
⢠MIBI is an monoclonal antibody raised against a Ki67
c DNA fragment and perpetuated in E. Coli
⢠Ki67 is also a antibody, but recognizes a different
epitope of the Ki-67 fragment than MIBI
Histopathology 1993; 22: 355-360.
48. Kaplan-Meier Curve
Overall survival in 31
patients according to
degree of differentiation:
(A) Log Rank (p<0.001)
and Ki67 score
(B) Log Rank (p<0.001)
A.
J. Endocrinol. Invest. 2008;31:216-223.
B.
50. Pancreastatin Predicts Survival in
Neuroendocrine Tumors
Scott K. Sherman, MD, Jessica E. Maxwell, MD, MBA,
M. Sue OâDorisio, MD, PhD, Thomas M. OâDorisio, MD, and
James R. Howe, MD
Ann Surg Oncol (2014) 21:2971-2980
DOI 10.1245/s10434-014-3728-0
51. Overall Survival
5 yr. OS=79.3% 10 yr. OS=57.4%
Median not
reached
SEER 88 mos.
10 yr. OS=52.9%
Median 126 mos.
SEER 42 mos.
5 yr. OS=79.9%
SK Sherman et al. Ann. Surg. Oncol. 21:2971, 2014
52. Overall Survival-M1 Disease
5 yr.
OS=71.0%
10 yr. OS=50.9%
Median not reached
SEER 56 mos.
10 yr. OS=45.6%
Median 90 mos.
SEER 24 mos.
5 yr.
OS=75.8%
54. Somatostatin and its Congeners
Ala-Gly-Cys-Lys-Asn-Phe-
Cys-Ser-Thr-Phe-
Phe
Trp
Lys
Phe-Cys- Tyr
Trp
Lys
Thr -Cys- Thr
-OL
D
D
D
Nal-Cys-
Trp
Lys
Thr -Cys- Val
-NH2
D
Somatostatin
Modified Octreotide Lanreotide
Tyr
Thr
Dawn A. Wray
s
s
s
s
s
s
56. Sandostatin and Gastroenteropancreatic
Endocrine Tumor â Therapeutic
Characteristics
M.J. Dunne, R. Elton, T. Fletcher,
P. Hofkur, J. Shui
Chapter 14; pp. 93-117. Im: Sandostatin in
the Treatment of GEP Endocrine Tumors
(ed: T.M. OâDorisio)
pp. 1-146, 1987. SPRINGER VERLAG
(Berlin, Heideberg, N.Y.)
57. OCTREOTIDE
Registration for Europe (1988) and U.S. (1989) was
determined from a TOTAL of 173 subjects submitted
by 38 investigators (from Europe) and 40 investigators
(from U.S.)
TUMOR U.S. Europe TOTAL
Carcinoid 47 38 85
VIPoma 12 13 25
Glucagonoma 9 7 16
Gastrinoma 14 12 26
Insulinoma 3 12 15
GRF-oma 4 - 4
PP-oma 2 - 2_
173
M. J. Duane, R. Elton, et al
59. Carcinoid Response to Octreotide (n = 74)
M. Dunne, R. Elton, et al. FDA Registration, 1989
60. First VIPoma Patient (H.T.) Treated in U.S.
P. Maton, T.M. OâDorisioâŚ.R.T. Jensen. N Engl J Med 1985; 312:17-21
61. First VIPoma Patient (H.T.) Treated in U.S.
P. Maton, T.M. OâDorisioâŚ.R.T. Jensen. N Engl J Med 1985; 312:17-21
62. Placebo-Controlled, Double-blind,
Prospective, Randomized study on the effect
of Octreotide â LAR in the control in patients
with metastatic neuroendocrine mid-gut
tumors: A Report from the PROMID Study
Group
Anja Rinkie, Hans-Helge MuellerâŚ.Rudolf Arnold
J.Clin Onc.;2009, 27(28): 4656-4663
ď§ 85 patients (well-differentiated midguts);ki-67 < 2%
ď§ Placebo versus Sandostatin-LAR 30 mg monthly
ď§ Median time to tumor progression (TTP)
6 months = placebo
14.3 mo Octreotide-LAR (29.4 mo; Liver < 10%)
(Non-Crossover)
63. Lanreotide in Metastatic Enteropancreatic
Neuroendocrine Tumors (CLARINET Study
Group)
M. E. Caplin, M. Pavel, J.B. Cwikta.... P. Rusznieswski
N.E.J.M., 2014; 371:224-233
ď§ 107 Patients (well-differentiated midgut &
hindgut) ki-67<10%
ď§ Placebo versus Lanreotide Depot 120mg
monthly
ď§ Median time to progressive (TTP)
18 months = Placebo
LAN-DEP median not reached
(Cross-over Study)
65. Everolimus for Advanced
Pancreatic Neuroendocrine
Tumors
J.C. Yao, M. Shah, T. Ito⌠K. Oberg
(NEJM 2011; 364:514-522)
ď§ 410 patients; Grade 1 or 2; RECIST 1.1
progression
ď§ Placebo versus 10mg daily Everolimus &
Octreotide
ď§ Median progression-free survival (PFS):
4-6 month = placebo
11 month = Everolimus
(Cross-Over Study)
66. Sunitinib Malate For the Treatment of
Pancreatic Neuroendocrine Tumors
E. Raymond, L. Dahan, J.L. Raoul⌠P. Ruszniewski
(NEJM 211; 364:501-513)
ď§ 171 Patients; Grade 1 or 2; RECIST 1.1
Progression
ď§ Placebo versus 37.5 mg daily Sunitinib &
Octreotide
ď§ Median progression-free survival (PFS):
5.5 month = placebo 11.4 month = Sunitinib
(Non-cross over study)
67. Theranostics
âMolecular targeting of VECTORS
which can be used for both therapies
and diagnosis, when modified
accordinglyâŚ
(it) embodies both molecular and
personalized medicine.â
Rosch, F, Baum R.P. Generator-based PET
radiopharmaceuticals for molecular imaging of tumours:
On the way to THERANOSTICS. Dalton Trans 2011;
40:6104-11.
68. DOTA-DPhe1-Tyr3-Octreotide (DOTA-TOC)
Theranostic Application
D
Isotope-DOTA- Phe-Cys-s
Tyr
s
Trp
D
Lys
Thr -Cys- Thr -OL
(SMS 204-090)
Isotope (Radiometal):
⢠Ga68-DOTA-TOC-PET: sensitive; quantifiable
⢠Y90-DOTA-TOC: hard beta; 7-9 mm range âkillâ
⢠Lu177-DOTA-TOC: soft beta; 3-5 mm range âkillâ
69. Current Targeting Paradigm
One Receptor â One Ligand
Somatostatin Receptor
Subtype 2
ďś High receptor expression
ďś Native peptide sequence known
ďś High affinity/specificity/avidity for target
ďś Synthetically feasible (<50 residues)
Ga-68
Linker
(DOTA)
Vector
(TOC)
Target
Concept & design by M Schultz
Modified Somatostatin
70. GA-68 DOTATOC Imaging at the
University of Iowa
Y Menda, M Schultz, L Watkins, D
Bushnell, T OâDorisio, M Graham, L
Ponto, J Sunderland, M Sue
OâDorisio
FDA IND held by M. Sue OâDorisio and
Yusuf Menda
76. Outcome of Peptide Receptor
Radionuclide Therapy (PRRT) in
Patients with Metastatic Low Grade
Neuroendocrine Tumors
N. Sharma, E.S., B.G. Naraev Engelman, D.L.
Bushnell, T.M. OâDorisio, T.R. Halfdanarson
PANCREAS 2012; 41(2):347 (Abs)
77. Methods
⢠108 Metastatic Neuroendocrine tumors:
Small Bowel (Mid Gut, 44%)
Pancreas (PNET 28%)
Lung (Foregut 5%)
⢠Peptide Receptor Radio-Nuclide Therapy
(PRRNT), 72% Basel, 26% Iowa
⢠86% y90-DOTA-TOC and 13% Lu177 DOTATOC
⢠ALL followed up for 10 years in NETC
B.G. Nareav, PANCREAS 2012
78. Site
OS from
Diagnosis (years)
OS from PRRT
#1 (months)
TTP from PRRT
#1 (months)
All sites 9.9 40.6 39.6
SNETs 13.7 96.7 60.3
PNETs 5.7 39.4 63.1
Lung 2.7 22.7 4.5
Unknown
Primary
4.1 20.7 24.1
Other 7.2 52.0 26.6
P<0.0001 P=0.1 P<0.0001
OS: Median overall survival TP: Median Time to Progression
79. Conclusion
âPRRNT appears to be a valuable
treatment option for mNETs,
especially SBNETs, and its role
earlier in the disease course
warrants investigationâ
B.G. Nareav, PANCREAS 2012
80. Neuroendocrine Tumor Faculty
Thomas M OâDorisio, MD, Director
James R Howe, MD, co-Director
Nuclear Medicine
David Bushnell, MD
Yusuf Menda, MD
Michael Schultz, PhD
Michael Graham, MD
Internal Medicine
Daniel Berg, MD
Joseph Dillon, MD
Henning Gerke, MD
Daniel Vaena, MD
Interventional Radioology
Schilang Sun, MD
Surgery
Mark Iannatoni, MD
Joel Shilyansky, MD
Pediatrics
M Sue OâDorisio, MD, PhD