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5th Annual Mid-Winter
Neuroendocrine Tumor Conference
WELCOME
Overview of neuroendocrine tumors and
adrenocortical carcinoma
Stephen Leong, MD, MMedSci
Neuroendocrine Tumors and Adrenal
Cancers
Stephen Leong MD
Associate Professor, SOM
University of Colorado Cancer Center
Sat Feb 4 2017
Learning Objectives
• Know the difference of Neuroendocrine Tumor vs Neuroendocrine
Cancer
• What is the “Grade” of Neuroendocrine Tumor?
• What is the “Stage” of NET?
Tumor vs Cancer
• Tumor and cancer are often used interchangeable but that is not
correct.
• Not all cancers are tumors. Not all tumors are cancer.
• A tumor is the Latin word for ”swelling”. Therefore tumor is
defined as a “swelling or abnormal mass of tissue – it may solid or
fluid.”
Tumor vs Cancer
• A cancer is a term for a group of diseases in
which abnormal cells divide without control and
can invade nearby tissues. Cancer cells can
also spread to other parts of the body through
the blood and lymph system.
What is the Neuroendocrine System?
• The neuroendocrine system is made up of a network of cells that
are distributed throughout the body.
• The word neuroendocrine refers to 2 qualities of these cells: they
have a similar structure to nerve cells (neurons) and produce
hormones like endocrine cells.
• The neuroendocrine system is formed by the
– diffuse neuroendocrine system and the
– endocrine system.
Diffuse Neuroendocrine System
• Neuroendocrine cells in the digestive system regulate intestinal movements and the
release of digestive enzymes.
• Neuroendocrine cells in the respiratory system are believed to play a role in the
developmental stages of the respiratory organs. They also regulate respiratory
function.
• There are small neuroendocrine organs, known as paraganglia, along the spinal
column. They include the adrenal medulla inside the adrenal gland and paraganglia
outside the adrenal gland. They produce the hormones epinephrine and
norepinephrine. These hormones control blood pressure and heart rate.
• Neuroendocrine cells are also found in non-neuroendocrine glands and are
scattered in the skin, thymus, prostate and other tissues.
Neuroendocrine Tumors
• Gastrointestinal and pancreatic neuroendocrine tumor and carcinomas
(GEP)
– Well differentiated NET/NEC, poorly differentiated
• Lung neuroendocrine tumor and carcinomas
– Carcinoid, atypical carcinoid, small cell and large cell
• Merkel cell carcinoma
• NET of endocrine system
– Pituitary adenoma, thyroid medullary, thymus, parathyroid,
pheochromocytoma/paraganglioma, adrenal tumors
Classification of NET
• In 2010, the World Health Organization (WHO) updated its
classification of NET based on tumor site of origin, clinical
syndrome, and differentiation.
• The grade of a tumor refers to its biologic aggressiveness.
– Low-grade tumors are characterized by low proliferative indices
and are considered indolent in nature.
– High-grade tumors tend to be poorly differentiated, have high
proliferative indices, and are thus very aggressive.
Klimstra et al, Pancreas Aug 2010
Differentiation
• NET can also be classified based on differentiation, which refers
to the extent to which cancerous, or neoplastic, cells resemble
normal cells.
• Well-differentiated NET are usually of low or intermediate grade;
• Poorly differentiated NET are usually high grade.
Neuroendocrine Tumor
GRADE
Low
Well differentiated G1
Carcinoid
Intermediate
Well differentiated G2
Carcinoid
Atypical Carcinoid
High
Well differentiated G3
Poorly Differentiated
Small Cell
Large Cell
NET GRADING
Staging
•
•
•
•
Reflects of the extent of disease and is based on TMN criteria
T – size of the tumor and the extent of local invasion
N – Nodal involvement
M – Evidence of metastases
• Each organ has its own specific TMN classification
TMN STAGING – SMALL BOWEL
Why is this important?
• The Grade, Differentiation and Stage contributes the prognosis of
one’s carcinoid.
• It also contributes to one’s management decision of one’s NET.
• These are not the only factors we need to consider for the
management of one’s cancer: symptoms, clinical history etc..
Gastrointestinal NET
• Estimated to represent 55% of all NET
• 8,000 people/yr in the United States are diagnosed with a
neuroendocrine tumor that starts in the gastrointestinal tract: small
intestine (45%), rectum (20%), appendix (16%), colon (11%) and
gastric (7%)
• Generally they are well-differentiated
Pancreatic NET
•
•
•
•
•
1,000 people/yr in the US have pancreatic NET
Represent about 3% of all pancreatic cancers
Vast majority are well-diffentiated
50-75% are non-functioning
25% functioning tumors: insulin; gastrin, glucagonoma, vasoactive
intestinal peptide (VIP)
Presentations
• Early stage GEP-NET do not usually have symptoms
• Clinical symptoms may be general, or they may correlate with the
location of the tumor and be organ related.
• Symptoms of the carcinoid syndrome (eg, flushing and diarrhea)
typically occur in patients with metastatic carcinoid tumors of the small
bowel.
• Rarely, the carcinoid syndrome is observed in non-metastatic tumors,
which can release hormones directly into the systemic circulation (eg,
lungs, ovaries).
LUNG NET
• Bronchial neuroendocrine tumors (NETs) account for approximately 1
to 2 percent of all lung malignancies in adults and roughly 20 to 30
percent of all NETs
• Well differentiated: Carcinoid, atypical carcinoid
• Poorly differentiated NET: Small Cell, Large Cell
• Most patients with a bronchial NET have a centrally-located tumor and
are symptomatic from the tumor mass with coughing, hemoptysis,
wheezing, or a recurrent post-obstructive pneumonia.
• Peripheral lesions present most often as an asymptomatic solitary
pulmonary nodule
ADRENAL GLAND
Adrenal Cortex Tumors
• Adrenal tumors are common
• The majority (85%) of adrenocortical tumors are benign, nonfunctioning
adenomas that are discovered incidentally on abdominal imaging
studies
• Benign, hormone-secreting adenomas (15%)- Cushing's syndrome,
primary aldosteronism, or much less commonly, virilization.
• Adrenocortical carcinomas (ACCs) are rare (200-300 pts), often
aggressive tumors that may be functional and cause Cushing's
syndrome and/or virilization, or nonfunctional and present as an
abdominal mass or an incidental finding
Adrenal Cancer Staging
The European Network for The Study of Adrenal Tumors
(ENSAT) with estimated five-year disease-specific survival rates:
●Stage I – Confined to the adrenal gland without local invasion
or distant metastases; greatest tumor dimension ≤5 cm
(T1N0M0): 82 percent
●Stage II – Same as stage I but with tumor size >5 cm without
risk factors (T2N0M0): 61 percent
●Stage III – Tumor of any size with at least one of the following
factors: tumor infiltration in surrounding tissues (T3), tumor
invasion into tumor thrombus in the vena cava or renal vein (T4),
positive lymph nodes (N1) but no distant metastases: 50 percent
●Stage IV – Distant metastases: 13 percent
European Network for The Study of Adrenal Tumors
Pheochromocytoma / Paraganglioma
Pheochromocytoma
• NET of the chromaffin cells
• Location
– 90% occurred in the adrenal medulla
– 10% are outside of the adrenal gland. They are known as
paraganglioma or extra-adrenal pheochromocytomas
• 90% are benign; 10% are malignant
• Symptoms include high blood pressure, headaches, excessive
sweating, and/or heart palpitations.
Paraganglioma
• 97% are benign; 3% are malignant
• Presentation:
– Most are asymptomatic or present as a painless mass.
– 1-3% of cases is secretion of hormones (catecholamines)
A Dazzle of Zebras
Nuclear Medicine imaging and
therapeutics
Erik Mittra, MD, PhD
Theranostics: Ga68 imaging and
Lu177 therapy for NET
Erik Mittra, MD, PhD
Clinical Associate Professor
Radiology / Nuclear Medicine
MIPS
MIPS
Molecular Imaging Program
Molecular
at Stanford
Imaging Program at Stanford
Stanford
Stanford
School of Medicine, Department
School ofofMedicine,
Radiology
Department of Radiology
Outline
1.
2.
3.
4.
5.
6.
MIPS
Theranostics
Imaging of NETs
Therapy of NETs (Lutathera, PRRT)
NETTER-1 trial results
Practical aspects
Future directions
Molecular Imaging Program at Stanford
Stanford
School of Medicine, Department of Radiology
Outline
1.
2.
3.
4.
5.
6.
MIPS
Theranostics
Imaging of NETs
Therapy of NETs (Lutathera, PRRT)
NETTER-1 trial results
Practical aspects
Future directions
Molecular Imaging Program at Stanford
Stanford
School of Medicine, Department of Radiology
Thera(g)nostics: Therapy + Diagnosis
MIPS
Molecular Imaging Program at Stanford
systems.hanyang.ac.kr
Stanford
School of Medicine, Department of Radiology
Targeted Molecular Imaging and Therapy
THERANOSTICS
The Key-Lock
Schematic Representation
of a Drug for Principle
Imaging and Targeted Therapy
pharmacokinetic/biodistribution modifier
Target
Lock
Target
• Antigens
(e.g. CD20, HER2)
• GPCRs
• Transporters
Ligand
Key
Molecular Address
• Antibodies, minibodies,
Affibodies, SHALs, Aptamers
• Regulatory peptides and
analogs thereof
• Amino Acids
Chelator
Linker
68Ga, 90Y, 177Lu
Reporting Unit
•
• 64Cu, 68Ga
• Gd3+
Cytotoxic Unit
•
•
MIPS
Molecular Imaging Program at Stanford
99mTc, 111In, 67Ga
Courtesy Richard Baum, Helmut Mäcke (modified)
90Y, 177Lu, 213Bi
105Rh, 67Cu, 186,188Re
Stanford
School of Medicine, Department of Radiology
Outline
1.
2.
3.
4.
5.
6.
MIPS
Theranostics
Imaging of NETs
Therapy of NETs (Lutathera, PRRT)
NETTER-1 trial results
Practical aspects
Future directions
Molecular Imaging Program at Stanford
Stanford
School of Medicine, Department of Radiology
Imaging of NETs
•
•
•
•
•
•
•
CT
MRI
Ultrasound
Endoscopy
OctreoScan
Ga68-PET/CT
18F-FDG PET/CT
MIPS
Molecular Imaging Program at Stanford
Stanford
School of Medicine, Department of Radiology
Imaging of NETs
•
•
•
•
•
•
•
CT
MRI
Ultrasound
Endoscopy
OctreoScan
Ga68-PET/CT
18F-FDG PET/CT
MIPS
Molecular Imaging Program at Stanford
Stanford
School of Medicine, Department of Radiology
Imaging of NETs
•
•
•
•
•
•
•
CT
MRI
Ultrasound
Endoscopy
OctreoScan
Ga68-PET/CT
18F-FDG PET/CT
MIPS
Molecular Imaging Program at Stanford
Stanford
School of Medicine, Department of Radiology
Imaging of NETs
•
•
•
•
•
•
•
CT
MRI
Ultrasound
Endoscopy
OctreoScan
Ga68-PET/CT
18F-FDG PET/CT
MIPS
Molecular Imaging Program at Stanford
Stanford
School of Medicine, Department of Radiology
Imaging of NETs
•
•
•
•
•
•
•
CT
MRI
Ultrasound
Endoscopy
OctreoScan
Ga68-PET/CT
18F-FDG PET/CT
MIPS
Molecular Imaging Program at Stanford
Stanford
School of Medicine, Department of Radiology
Somatostatin and NETs
MIPS
Molecular Imaging Program at Stanford
Stanford
School of Medicine, Department of Radiology
Types of Radiation
Beta
MIPS
Molecular Imaging Program at Stanford
Alpha
Stanford
School of Medicine, Department of Radiology
Gamma cameras (Anger)
MIPS
Molecular Imaging Program at Stanford
Stanford
School of Medicine, Department of Radiology
Inside a gamma camera
MIPS
Molecular Imaging Program at Stanford
Stanford
School of Medicine, Department of Radiology
OctreoScan Imaging of NETs
MIPS
Molecular Imaging Program at Stanford
Stanford
School of Medicine, Department of Radiology
Somatostatin and NETs
MIPS
Molecular Imaging Program at Stanford
Stanford
School of Medicine, Department of Radiology
MIPS
Molecular Imaging Program at Stanford
Stanford
School of Medicine, Department of Radiology
Positron Emission Tomography/CT
MIPS
Molecular Imaging Program at Stanford
Stanford
School of Medicine, Department of Radiology
OctreoScan vs Ga68-DOTA-TATE PET
MIPS
Molecular Imaging Program at Stanford
111In
Octreoscan®
(4 hours)
111In
Octreoscan®
(24 hours)
Stanford
School of Medicine, Department of Radiology
OctreoScan vs Ga68-DOTA-TATE PET
MIPS
Molecular Imaging Program at Stanford
111In
Octreoscan®
(4 hours)
111In
Octreoscan®
(24 hours)
68Ga
DOTATATE
(1 hour)
Stanford
School of Medicine, Department of Radiology
OctreoScan vs Ga68-DOTA-TATE PET
111In
MIPS
Molecular Imaging Program at Stanford
Octreoscan®
(24 hours)
Images courtesy of Andrei Iagaru, MD
Stanford
School of Medicine, Department of Radiology
OctreoScan vs Ga68-DOTA-TATE PET
111In
MIPS
Molecular Imaging Program at Stanford
Octreoscan®
(24 hours)
68Ga
DOTATATE
(1 hour)
Images courtesy of Andrei Iagaru, MD
Stanford
School of Medicine, Department of Radiology
Outline
1.
2.
3.
4.
5.
6.
MIPS
Theranostics
Imaging of NETs
Therapy of NETs (Lutathera, PRRT)
NETTER-1 trial results
Practical aspects
Future directions
Molecular Imaging Program at Stanford
Stanford
School of Medicine, Department of Radiology
Peptide Receptor Radionuclide Therapy
(PRRT)
• PRRT started with [111In]-DTPA0-octreotide (1990s)
• Next: [90Y]-DOTA0-Tyr3-octreotide (mid 2000s)
• Most recent: [177Lutetium]-DOTA0-Tyr3-octreotate
(Lutathera®) (late 2000s)
MIPS
Molecular Imaging Program at Stanford
ENJM (2012). 39 (S1): S103-S112
Stanford
School of Medicine, Department of Radiology
Physical Properties of Radionuclides
Used for PRRT
MIPS
Isotope
t1/2
(days)
Energy
(keV)
Path length
(mm)
Gamma
(keV)
177Lutetium
6.7
133
2
113 (6.6%)
208 (11%)
90Yttrium
2.7
935
12
-
Molecular Imaging Program at Stanford
Stanford
School of Medicine, Department of Radiology
Lutathera® Mechanism of Action
Intravenous
injection
MIPS
Molecular Imaging Program at Stanford
Concentration Lutathera
into sites of
binds to
NET
somatostatin
receptor type
2 (sstr2)
overexpresse
d by NETs
Lutathera is
Lutathera
internalized in delivers
the NET cell
radiation
within the
cancer cell
Radiation
induces DNA
strand breaks
causing
tumor cell
death
Stanford
59 of Medicine, Department of Radiology
School
Outline
1.
2.
3.
4.
5.
6.
MIPS
Theranostics
Imaging of NETs
Therapy of NETs (Lutathera, PRRT)
NETTER-1 trial results
Practical aspects
Future directions
Molecular Imaging Program at Stanford
Stanford
School of Medicine, Department of Radiology
NETTER-1
MIPS
Molecular Imaging Program at Stanford
Stanford
School of Medicine, Department of Radiology
NETTER-1 Sites
MIPS
Molecular Imaging Program at Stanford
Stanford
School of Medicine, Department of Radiology
NETTER-1 US Sites
MIPS
Molecular Imaging Program at Stanford
Stanford
School of Medicine, Department of Radiology
NETTER-1 Study Design
MIPS
Molecular Imaging Program at Stanford
Stanford
School of Medicine, Department of Radiology
NETTER-1 Objectives
MIPS
Molecular Imaging Program at Stanford
Stanford
School of Medicine, Department of Radiology
NETTER-1 Eligibility Criteria
MIPS
Molecular Imaging Program at Stanford
Stanford
School of Medicine, Department of Radiology
NETTER-1 Progression Free Survival
MIPS
Molecular Imaging Program at Stanford
Stanford
School of Medicine, Department of Radiology
NETTER-1 Results
MIPS
Molecular Imaging Program at Stanford
Stanford
School of Medicine, Department of Radiology
NETTER-1 Overall Survival
MIPS
Molecular Imaging Program at Stanford
Stanford
School of Medicine, Department of Radiology
NETTER-1 Adverse Events
MIPS
Molecular Imaging Program at Stanford
Stanford
School of Medicine, Department of Radiology
Global Health Status (EORTC QLQ-C30)
†
†
*
*
In mean, during the study, global health status was :
§improved in 28% of the patients in Lutathera arm (Lu) vs. 15% in the Octreotide LAR arm (Oct)
§worsened in 18% of the patients in Lutathera arm (Lu) vs. 26% in the Octreotide LAR arm (Oct)
* Statistically significant difference between the arms
† ≥ 10% change from baseline
71
Diarrhea (EORTC QLQ-C30)
*
In mean, during the study, diarrhea:
§
§
improved in 39% of the patients in Lutathera arm (Lu) vs. 23% in the Octreotide LAR arm
(Oct)
worsened in 19% of the patients in Lutathera arm (Lu) vs. 23% in the Octreotide LAR arm
(Oct)
* Statistically significant difference between the arms.
72
Pain
In mean, during the study, pain:
§
§
improved in 41% of the patients in Lutathera arm (Lu) vs. 28% in the Octreotide LAR arm
(Oct)
worsened in 17% of the patients in Lutathera arm (Lu) vs. 25% in the Octreotide LAR arm
(Oct)
73
Flushing/sweats
In mean, during the study, flushing/sweats:
§
§
improved in 42% of the patients in Lutathera arm (Lu) vs. 38% in the Octreotide LAR arm
(Oct)
worsened in 22% of the patients in Lutathera arm (Lu) vs. 19% in the Octreotide LAR arm
(Oct)
* Statistically significant difference between the arms.
74
NETTER-1
Summary and Conclusions
•
Final analysis : In this first prospective randomized study in patients with progressive
metastatic midgut NETs, 177Lu-Dotatate was superior to Octreotide 60 mg in terms of:
− PFS (Not Reached vs 8.4 months, p<0.0001)
− ORR (18% vs 3%, p=0.0008)
•
•
•
•
Interim analysis suggests increased OS (14 vs 26 deaths), to be confirmed by final
analysis
177Lu-Dotatate
demonstrates a favorable safety profile, with no clinically relevant
findings especially regarding hematological and renal and parameters
Consistent benefits seen across prognostic subgroups
Preliminary QOL analysis suggests evidence of benefit in key domains that are
pertinent to midgut NETs, including global health and diarrhea. No clear evidence of
benefit in flushing/sweats vs. high-dose octreotide.
19
Outline
1.
2.
3.
4.
5.
6.
MIPS
Theranostics
Imaging of NETs
Therapy of NETs (Lutathera, PRRT)
NETTER-1 trial results
Practical aspects
Future directions
Molecular Imaging Program at Stanford
Stanford
School of Medicine, Department of Radiology
Practical Considerations
MIPS
Molecular Imaging Program at Stanford
Photos by Paulo Castaneda
Stanford
School of Medicine, Department of Radiology
Practical Considerations
MIPS
Molecular Imaging Program at Stanford
Photos by Paulo Castaneda
Stanford
School of Medicine, Department of Radiology
Practical Considerations
MIPS
Molecular Imaging Program at Stanford
Photos by Paulo Castaneda
Stanford
School of Medicine, Department of Radiology
Practical Considerations
MIPS
Molecular Imaging Program at Stanford
Photos by Paulo Castaneda
Stanford
School of Medicine, Department of Radiology
PRRT Administration
•
•
•
•
•
Requires team effort between NM and oncology, and nursing
Location?
Lutathera infused i.v. over 30 minutes
Amino acids infused i.v. over 4-6 hours
Anti-nausea medication and titration of AAs are very
important
MIPS
Molecular Imaging Program at Stanford
Stanford
School of Medicine, Department of Radiology
Radiation/Release Considerations
• Limited emitted exposure
– 2 mR/hr @ 1m at end of first day
– 1 mR/hr @ 1m the next morning
• Excreted exposure may be more significant
• Routine precautions if patient goes home though not as strict
as I-131
• And if patient cannot go home? Admission or hotel?
MIPS
Molecular Imaging Program at Stanford
Stanford
School of Medicine, Department of Radiology
Patient selection issues
• Pathology
– Grade, Ki-67, functional/non-functional
• Receptor density
– OctreoScan or Ga68-DOTATATE PET
• Kidney function
– Serum creatinine, creatine clearance, MAG3
• Other
– Hemoglobin, platelets, bilirubin, albumin
MIPS
Molecular Imaging Program at Stanford
Stanford
School of Medicine, Department of Radiology
Outline
1.
2.
3.
4.
5.
6.
MIPS
Theranostics
Imaging of NETs
Therapy of NETs (Lutathera, PRRT)
NETTER-1 trial results
Practical aspects
Future directions
Molecular Imaging Program at Stanford
Stanford
School of Medicine, Department of Radiology
Future Directions of PRRT
•
•
•
•
DUO-PRRT, TANDEM-PRRT
Repeat-PRRT
Intra-arterial PRRT
Combined PRRT:
–
–
–
–
TACE, SIRT, RFA
Chemotherapy (e.g. Capecitabine, Doxorubicin, Evorolimus)
Kinase inhibitors (e.g. Sunitinib, Sorafenib)
Antibodies (e.g. Bevacizumab)
• Improved peptides (e.g. antagonists)
• Improved dosimetry and radioprotection
MIPS
Molecular Imaging Program at Stanford
Stanford
School of Medicine, Department of Radiology
Acknowledgements
MIPS
•
•
•
•
•
•
•
•
Patients (you!)
Pam Kunz, MD
Other Stanford MDs
Other NETTER-1 sites
Technologists
Research coordinators
Nurses
AAA
Molecular Imaging Program at Stanford
Stanford
School of Medicine, Department of Radiology
-- Thank you –
Questions?
MIPS
MIPS
Molecular Imaging Program
Molecular
at Stanford
Imaging Program at Stanford
Stanford
Stanford
School of Medicine, Department
School ofofMedicine,
Radiology
Department of Radiology
Hereditary cancer syndromes associated with NETs
and ACC and what to expect at a Medical Genetics visit
Lisen Axell, MS
Cathy Klein, MD
Hereditary Cancer Syndromes
Associated with Neuroendocrine
Tumors
What Happens at a Medical
Genetics Visit
Lisen Axell, Genetic Counselor
Catherine Klein, MD
Overview
• Genetics of Cancer
• Inherited Cancer syndromes with neuroendocrine tumors
• MEN
• Hereditary pheochromocytoma/paraganglioma
• Li-Fraumeni
• Von Hippel-Lindau
• Others
• The Hereditary Cancer Clinic, Cancer Risk Assessments and Genetic Testing
• Inheritance and implications for family members
DAD
MOM
Common Diseases
• Cancer
• Heart disease
• Diabetes
• Hypertension
• Stroke
• Alzheimer's
• Arthritis
• Osteoporosis
Common Risk Factors for Disease
• Age
• Family history
• Ethnicity
• Lifestyle
• Diet
• Alcohol
• Smoking
What is Cancer?
All cancer is genetic,
BUT
most cancer is NOT
inherited
Cancer Risk Based on Family History
Sporadic
70%
Familial
25%
Hereditary
5%
Inherited Cancer
Dx 55
Dx 35
43 Dx 45
Dx 65
• Cancer in young individuals (less than age 50)
• Many generations affected with the same type or related
cancer on the same side of the family
• Two primary cancers or two related cancers in same
individual
Is the Cancer in My Family Hereditary?
• Cancers diagnosed younger than average
• Multiple family members with similar or related cancers, e.g.
Parathyroid and Pheochromocytoma
• Rare cancers, e.g. paraganglioma
• People diagnosed with cancer more than once
• Multiple generations affected by related cancers
What are some of the hereditary
syndromes we look for?
Neuroendocrine tumors with
hereditary syndromes
Joakim Crona, and Britt Skogseid Eur J
Endocrinol 2016;174:R275-R290
Petr Sem Oncol 2016; 43:582-90
Pheochromocytoma/Paraganglioma
• Paraganglioma: NET that arise outside the adrenal from paraganglia (cells that can
secrete catecholamines)
• Sympathetic PG usually secrete CA and arise in the thorax, abd, pelvis
• Parasympathetic PG usually don’t secrete CA and arise in the neck and base of skull
• Pheochromocytomas: paraganglioma arising in the adrenal gland
• Both can secrete CA and cause HT, HA, sweating and fast heart rate
Pheochromocytoma/Paraganglioma
Underlying germline mutation common
• Apparently sporadic: 11% may have germline mutation
•
•
•
•
No family history of PPGL
No syndromic features
No bilateral disease
No metastatic disease
• More common (50%) with
• bilateral or multifocal disease
• diagnosis before the age of 45
• extra adrenal location (paraganglioma)
Pheochromocytoma/Paraganglioma
Most are sporadic
1/3 are associated
with an inherited
syndrome
Guidelines
recommend genetic
testing be considered
for all cases
Pheochromocytoma/Paraganglioma
Genetics
SDHB 10%
SDHD 8%
SDHA 1%
VHL 7%
no mutation 61%
RET 6%
NF1 3%
MAX 1%
TMEN127d 1%
Paraganglioma syndromes
Gene
Pheochro
mocytoma
Paragangliom
a (thoracoabdominal
Paragangliom
a (head and
neck)
Multi- Malignant
focal
Renal
other
Cell
Carcino
ma
SDHD
Paternally
inherited
10-25%
20-25%
85%
5560%
~4%
SDHAF2
Paternally
inherited
0
0
100%
0
0
0
SDHC
0
Rare
?
0
Rare
GIST
SDHB
20-25%
50%
20-30%
1520%
2025%
~30%
~14%
SDHA
Rare
Rare
Rare
Rare
Rare
0
GIST
Pituitary
adenom
a
~8%
GIST
Pituitary
adenom
a
GIST
Pituitary
adenom
a
Screening Pheo’s or paragangliomas
SDHB
Age to begin screening (years)
5-10
24-hour urinary fractionated
metanephrines and catecholamines
Annually
Physical exam and blood pressure
MRI-CT of abdomen, thorax, and
pelvis
MRI-CT of skull base and neck
Periodic MIBG scintigraphy
Screening for renal cell carcinoma
SDHC
SDHD
VHL
Every 6-12
months
Annually
Annually
Annually
after age 11
Annually
5-10
5-10
Every 6-12
months
Every 6-12
months
Annually
Annually
Every 6–24
Month
Every 1–4
years
Every 1–
4 years
Every 2-4 years Every 6-36
months
Every 2-4 years Every 1-4
years
Consider
5
Every 6-36
months
Every 1-4
years
Abdominal
u/s or MRI
annually after
16
MEN2
8-20
Multiple Endocrine Neoplasia 2
MEN2
• Autosomal dominant condition, very high penetrance. 1:30,000
• Subdivided into
• MEN2A: Medullary thyroid cancer (MTC), pheo and 1o hyperpara
•
•
•
•
MEN2A (peak MTC age in 30’s)
MEN2A with cutaneous lichen amyloidosis (CLA)
MEN2A with Hirschsprung disease (HD)
FMTC variant
• MEN2B: MTC, pheo,
• Peak incidence of MTC 20s
• Virtually all will get medullary thyroid cancer, as early as 9
months of age
• 1 hyperpara: multiglandular, usually mild
• Pheos occur in about 50%, generally are found later than MTC
• Many are bilateral
• Uncommonly malignant
RET Mutations in MEN2
•
•
•
•
•
•
Genetic mistake causing MEN2 is the RET oncogene
Specific mutation can impact prognosis
Age of onset of MTC
Risk for pheo
Risk for primary hyperparathyroidism
Risk of Hirschsprung disease (colon disease)
Managing MEN2 patients:
• Remove thyroid before cancer is diagnosed
• In highest risk group: surgery by age 1
• Less high: monitoring starts at age 5, surgery by age 11
• Monitor with US of the neck, physical exam and serum calcitonin
• Screening for pheo
• Age 11 in high-risk, others by about age 16
• Plasma and urine testing
• Screening for hyperparathyroidism
• Usually mild
• Average age at diagnosis: 33
• Begin screening at age 11 for high risk patients
Von Hippel-Lindau
• Rare, autosomal dominant condition. 1:36,000
• Can show up in children, adolescents, adults
• Average age: 26
• Diagnosis is established by finding a genetic mutation in VHL
•
•
•
•
Testing should be considered for anyone with 2 of the tumors listed
Anyone with Pheo/para, CNS hemangioblastoma, ELST
Anyone with CCRC younger than age 40
>1 pancreatic serous cystadenoma or neuroendocrine tumor
• We are learning more about what effect different mutations have on the clinical picture
• Surveillance protocols begin at age 1
• www.VHL.org is a good source
Von Hippel-Lindau syndrome (VHL)
• Retinal and CNS
hemangioblastomas,
• Pheochromocytomas
• Paragangliomas
• Renal clear cell carcinomas
• Renal cysts
• Pancreatic neuroendocrine
tumors
• Pancreatic cysts
• Endolymphatic sac tumors
Pheochromocytoma/Paraganglioma
Neurofibromatosis type 1
• Neurofibromas
• Multiple café au lait
spots,
• Axillary and inguinal
freckling,
• Lisch nodules,
• Bony abnormalities,
• CNS gliomas,
• Macrocephaly
• Cognitive defects
Pheochromocytoma/Paraganglioma
MEN2
MEN1
• Rare autosomal dominant condition. 2/100,000
• Condition is defined as 2 or more of the primary MEN1 tumors
• Only one tumor necessary if the syndrome is known to be in the family
• MEN1 gene mutations are found in about 75% of families
• Other tumors appear more commonly
•
•
•
•
Duodenal gastrinomas
Bronchial carcinoids
ACC
Lipomas
Multiple Endocrine Neoplasia type 1:
MEN1
• The three P’s
• Parathyroid glands(95%)
• the anterior pituitary (20-40%)
• the endocrine calls of the
pancreas and duodenum(40-80%)
• Neuroendocrine tumors of the
foregut are also common (brochial,
thymic and gastric tumors)
• Rare cases of adrenocortical
carcinomas
• 90% penetrance by age 40
• Due to mutations in the MEN1 gene
Thymic/Brochial carcinoid
• Part of MEN1 syndrome with a penetrance of less than 10%
Adrenocortical cancer (ACC)
• RARE: 4-12:1,000,000
• Can be a functioning or
nonfunctioning tumor.
• May produce more than 1
hormone.
Adrenocortical tumors (ACC)
Genetics
Childhood ACC
• LiFraumeni syndrome
• Beckwith-Wiedemann syndrome
Adult ACC
• 4-6% due to LiFraumeni
syndrome
• 3.2% Lynch syndrome
• 1-2% MEN1
• Possible in Familial
Adenomatous Polyposis
• In patients with MEN1 1.4%
developed ACC
No mutation
LiFraumeni
Lynch
MEN1
ACC: Li-Fraumeni Syndrome
ACC: Li-Fraumeni
• Rare autosomal dominant condition
• Germline mutations in TP53
• Many cancer types, many in children
• In kids, the most common are osteosarcoma and ACC
• In adults: breast cancer, sarcomas, ACC brain tumors
• Important issues:
• When to do genetic testing in kids
• Cancer surveillance:
•
•
•
•
Whole body MRI increasingly recommended
Early breast cancer screening (about age 20-25) with MRI
Colonoscopy starting at about age 25
Careful attention to general health
Small intestinal NET
• No known underlying germline gene mutations
Neuroendocrine tumors with
hereditary syndromes
Joakim Crona, and Britt Skogseid Eur J
Endocrinol 2016;174:R275-R290
If I Have a Personal and/or Family
History of Cancer, How May a
Medical Genetics Appointment Play a
Role?
Who Do We See?
•Individuals with cancer
•Making surgical and/or treatment decisions
•Concerns for additional cancers
•Individuals with previous diagnosis of cancer
•Individuals with no cancer, but + family hx
•Assessing risk for cancer(s)
•Making screening/surgical decisions
What do we discuss?
•Likelihood:
•developing cancer based on family history
•inherited cancer syndrome
•detectable mutation
•Medical management recommendations
•Recommendations for at risk family members
•Discussion of genetic testing and if patient
wants to pursue testing
The Complexities of Genetic Testing
GENPET
Pheos/
Paraganglio
ma
Thyroid
ACC
Parathyroid
• Each cancer site is
associated with
numerous hereditary
cancer syndromes
• Testing options may
include single gene,
cancer-specific panel,
or large, multi-cancer
panel
Genetic Testing vs. Genomic Tumor
Profiling
Genetic testing
Done on blood or
saliva
Inherited from parent
Cancer Predisposition
– may inform risk for
cancer and risk to
other family members
May impact cancer
screening
recommendations
Occasionally
used in
cancer
treatment
decisions
Genomic tumor
profiling
Done on tumor
block
Not inherited
Malignant
transformation of
initially normal
cells
May be used in
cancer treatment
decisions
Genetic Testing - Why Know??????
Cancer Risk Based on Family History
Sporadic
70%
Familial
25%
Hereditary
5%
Classification: Who Needs What?
Family
History
Sporadic
Risk: Average
General population screening
recommendations
Familial
Risk: Moderate
Personalized screening
recommendations
Inherited
Risk: High
Genetic evaluation/testing
Personalized screening and risk
reduction recommendations
Benefits of Genetic Testing – What if Testing is
Positive?
• Helps identify cause of cancer
• Determines other cancer risks
• MOST cancer syndromes associated with multiple
cancer risks
• changes screening recommendations
• Identify family members at risk
Implications for family members
Autosomal Dominant
Most Hereditary Cancer syndromes are
NOT associated with 100% Cancer Risk
Family History
Lifestyle
Cancer Risk
Environment
Genes
What if Genetic Testing is Negative or is NOT
Done?
• If a mutation has NOT yet been identified and
testing is negative = Uninformative
Or….
• If testing is not done
=screening recommendations are based off of the
family history
• If there is a known mutation in the family and
testing is negative = True Negative
Myths about Inherited Cancer
• “Even if I have the mutation, I
can’t do anything about it.”
•Early detection and risk
reduction can change outcome.
• “Cancer runs in my family, so I •Only a 50% risk to inherit a
know I have the mutation.”
family mutation.
• “I‘ve already had cancer, so shy •There may be risk for other
is knowing whether or not I
cancers.
have the genetic mutation
important
Exception: SDHD mutations
• Maternally
imprinted
• Children on women
may be carriers of
the SDHD mutation
but will not develop
tumors
• Only children who
inherit the SDHD
mutation from their
father are at risk to
develop tumors
Insurance
• No clinical criteria for genetic testing
• No insurance criteria for genetic testing for neuroendocrine tumors.
Clinical recommendation
• Laboratories do insurance preverification prior to testing
• Will notify of total out of pocket expense
• For individuals for whom insurance doesn’t cover genetic testing,
Invitae offers $475 out-of pocket option
Invitae
• Genetic testing for up to 14 genes associated with hereditary paragangliomapheochromocytoma syndrome (PGL/PCC).
GENES TESTED:
• Primary Panel:
MAX, NF1, RET, SDHA, SDHAF2, SDHB, SDHC, SDHA, SDHD, TMEM127, VHL,
• Add-on preliminary-evidence genes:
EGLN1, FH, KIF1B, MEN1
Ambry
• PGLFirst, a comprehensive non-syndromic hereditary PGL/PCC panel.
• Genes on this panel include MAX, SDHA, SDHAF2, SDHB, SDHC, SDHD,
TMEM127.
• PGLNext is a comprehensive syndromic and non-syndromic hereditary
PGL/PCC panel of 12 genes.
• Genes on this panel include FH, MAX, MEN1, NF1, RET, SDHA, SDHAF2, SDHB,
SDHC, SDHD, TMEM127, VHL.
GINA – Prohibits:
Genetic Information Non-Discrimination
Act (2008)
• Use of genetic information in
setting eligibility or premiums
• Health insurers from
requesting a genetic test
• Use of genetic information in
employment decisions
• Employers from requesting
genetic information
We can’t
change
our genes….
But ......
we can
potentially
change the
outcome!!!
For more information about the
Risk Assessment Program
at University of Colorado Cancer Center
or to set up an appointment,
call 720-848-1030.
Hormones and endocrine tumors
Lauren Fishbein, MD, PhD, MTR
Hormones and
Neuroendocrine
Tumors
Lauren Fishbein MD, PhD, MTR
Assistant Professor of Medicine at the University of Colorado
Division of Endocrinology, Metabolism and Diabetes
Division of Biomedical Informatics and Personalized Medicine
Neuroendocrine Tumor and ACC patient conference
February 4, 2017
Overview
• What are endocrine glands?
• What is a hormone?
• Hormones in neuroendocrine tumors and
adrenocortical carcinoma
Endocrine Glands
Master Gland
• Organs in our body that
make hormones
Metabolism
Energy
BP/HR
Immune Gland
Gut/GI tract
Energy
BP
Metabolism
Skin
Food breakdown and metabolism
Signals for energy usage and stores
Lung
Female hormones
https://s-media-cache-ak0.pinimg.com/736x/5e/eb/a4/5eeba4d996ec972d35980896fe5bb654.jpg
Male hormones
What is a hormone?
• Any thoughts?
What is a hormone?
• Hormones are chemical messengers in the body
• Send messages about a particular function from one cell to another
Pancreas
Hormone
Liver
Receptor
Can you name some hormones?
Common examples
• Thyroid hormone
• Estrogen
• Progesterone
• Testosterone
• FSH
Hormones made by NETs and ACC
PNETS
Pheo/Para
Insulin
Glucagon
Somatostatin
Gastrin
Vasoactive intestinal polypeptide (VIP)
GI-NETs
Serotonin
Gastrin
Glucagon
Adrenaline (metanephrines/catecholamines)
Lung NETs
Serotonin
ACTH
ACC
Cortisol
Aldosterone
Androgen (Testosterone)
Pancreatic Neuroendocrine Tumors (PNETs)
• 25-50% of PNETs are “functional”
• Overtime hormone profiles can change
Pancreas
http://biocrine.com/wp-content/uploads/2011/09/DAD2.png
http://quasargroupconsulting.com/anatomy/pancreaseCells.gif
Pancreas Hormones –
Pancreas messengers
Releases enzymes to
help breakdown food
http://quasargroupconsulting.com/anatomy/pancreaseCells.gif
Insulin
Blood
sugar
Blood
sugar
Pancreas
Insulin
Blood
sugar
Blood
sugar
Blood
sugar
Blood
sugar
Liver
Receptor
Muscle
• Insulinoma– low blood sugar, confusion, vision changes,
unusual behavior, rapid heart beat, sweating, shakiness,
amnesia, eating every few hours, waking up at night to eat
to avoid symptoms.
Glucagon
Blood
sugar
Liver
Pancreas
Glucagon
Receptor
Blood
sugar
• Glucagonoma – blood sugar too high causing diabetes,
weight loss, blood clots and a specific rash called
necrolytic migratory erythema.
Blood
Blood
sugar
sugar
Somatostatin
Pancreas
Pancreas
Somatostatin
insulin
glucagon
Receptor
Nerve
Decrease
acid
Slow
motility
• Somatostatinoma – results in dysregulation of many
endocrine hormones. Lowers insulin leading to
diabetes. Slows GI motility which can lead to gallstones,
intolerance to fat in the diet and leads to fatty diarrhea.
Secrete
pituitary
hormones
Pituitary picture from https://s-media-cache-ak0.pinimg.com/236x/3d/45/12/3d4512b044af3b0e5877a78499114d4e.jpg
Vasoactive Intestinal Polypeptide
(VIP)
Pancreas
Energy
Liver
VIP
glycogen
Receptor
bicarb
• VIPoma – causes huge amounts of very watery diarrhea
leading to dehydration, low potassium and chloride
Pancreas
Stomach and Small Intestine
Gastrin
Pancreas
Stomach
Acid
Small intestine
• Gastrinoma – Zollinger Ellison Syndrome – causes peptic
ulcer disease and diarrhea
Hormones made by NETs and ACC
PNETS
Pheo/Para
Insulin
Glucagon
Somatostatin
Gastrin
Vasoactive intestinal polypeptide (VIP)
GI-NETs
Serotonin
Gastrin
Glucagon
Adrenaline (metanephrines/catecholamines)
Lung NETs
Serotonin
ACTH
ACC
Cortisol
Aldosterone
Androgen (Testosterone)
GI-NETS
• About 10% of patients with carcinoid (bowel NETs) will have carcinoid
syndrome
• Neuroendocrine cells make serotonin that cannot be broken down
properly
Serotonin
• Neurotransmitter (message signal from a nerve) plays a
role in mood regulation, pain perception, GI function.
serotonin
Nerve ending
Too much serotonin
https://pearlpoint.org/sites/default/files/styles/large/public/carcinoid_syndrome.png?itok=fIdBQO4s
Somatostatin
Pancreas
Somatostatin
Receptor
Slow
motility
Somatostatin analogs help control carcinoid syndrome
Decreases diarrhea and flushing
Pituitary picture from https://s-media-cache-ak0.pinimg.com/236x/3d/45/12/3d4512b044af3b0e5877a78499114d4e.jpg
Hormones made by NETs and ACC
PNETS
Pheo/Para
Insulin
Glucagon
Somatostatin
Gastrin
Vasoactive intestinal polypeptide (VIP)
GI-NETs
Serotonin
Gastrin
Glucagon
Adrenaline (metanephrines/catecholamines)
Lung NETs
Serotonin
ACTH
ACC
Cortisol
Aldosterone
Androgen (Testosterone)
Adrenal gland
http://cf.ydcdn.net/1.0.1.66/images/main/A5adrenalgland.jpg
Pheochromocytoma and Paraganglioma
• The majority are “functional”
• Exception being the head and neck
paragangliomas which rarely make hormones
Adrenaline
(metanephrines
catecholamines)
Flight or flight response
• Pheochromocytoma – leads to high blood pressure, rapid
heart rate, sweating, headache, anxiety, tremors, increased
blood sugar
Adrenaline
(metanephrines
catecholamines)
Nerve signaling
• Paraganglioma – leads to high blood pressure, rapid heart
rate, sweating, headache, anxiety, tremors, increased blood
sugar
https://classconnection.s3.amazonaws.com/839/flashcards/464839/png/screen_shot_2012-01-18_at_2.18.07_pm1326932318702.png
Adrenal gland
http://cf.ydcdn.net/1.0.1.66/images/main/A5adrenalgland.jpg
Aldosterone
Cortisol
Androgens (Testosterone)
androgen
cortisol
aldosterone
Salt/water balance
Control BP
Steroid hormone
Controls immune system,
BP, metabolism, bone health, …
Male physical
characteristics
A malignant neuroendocrine tumor in the adrenal cortex is called adrenocortical carcinoma
Adrenocortical carcinoma
The majority of ACCs are “functional”
Aldosterone
Salt/water balance
Control BP
Cortisol
Steroid in body
Controls immune system,
BP, metabolism, bone health, …
Androgens
Male physical
characteristics
• Aldosterone over producing – can lead to high BP and low potassium
• Cortisol over producing – can lead to high BP, weight gain in a certain
pattern, low potassium, easy bruising
• Androgen over producing – can lead to male pattern hair growth in
women
Hormones made by NETs and ACC
PNETS
Pheo/Para
Insulin
Glucagon
Somatostatin
Gastrin
Vasoactive intestinal polypeptide (VIP)
GI-NETs
Serotonin
Gastrin
Glucagon
Adrenaline (metanephrines/catecholamines)
Lung NETs
Serotonin
ACTH
ACC
Cortisol
Aldosterone
Androgen (Testosterone)
Lung neuroendocrine tumors
(bronchial carcinoids)
Rarely functional but can be
Lung
serotonin
ACTH
= neuroendocrine cells in the lung
Carcinoid
syndrome
cortisol
Hormones made by NETs and ACC
PNETS
Pheo/Para
Insulin
Glucagon
Somatostatin
Gastrin
Vasoactive intestinal polypeptide (VIP)
GI-NETs
Serotonin
Gastrin
Glucagon
Adrenaline (metanephrines/catecholamines)
Lung NETs
Serotonin
ACTH
ACC
Cortisol
Aldosterone
Androgen (Testosterone)
Medullary thyroid carcinoma
Merkel cell carcinoma (skin)
Thymoma
Ovarian NET
Neuroendocrine Tumors
and Hormones
Gut/GI tract
Skin
Lung
https://s-media-cache-ak0.pinimg.com/736x/5e/eb/a4/5eeba4d996ec972d35980896fe5bb654.jpg
University of Colorado precision medicine initiative
Biobank initiative
Kathleen Barnes, PhD
Personalized Medicine:
It’s about the patient…not the disease
Kathleen Barnes, PhD
Director Colorado Center for Personalized Medicine
February 4, 2017
What is Personalized Medicine?
Personalized medicine is a young but rapidly advancing field
of healthcare that is informed by each person's unique
clinical, genetic, genomic, and environmental information
One size doesn’t fit all
Percentage of the patient
population for which a particular
drug in a class is effective, on
average
Nature 30 April 2015
“The right dose of the right drug for the right
patient at the right time”
Personalized medicine is integrating patient health record data with “omics”
data (i.e., genetic information) to make predictions about how a patient will
respond to therapy, and to make decisions about the most effective treatment
Responds to normal dose
Responds to lower dose
Responds to higher dose
Responds to alternative medication
How does it work?
How do we make Personalized Medicine work in the
clinical setting?
CYP2D6
Tamoxifen and
Antidepressants
poor metabolizer
CYP2C19
Plavix
poor metabolizer
CYP2C19
Plavix
Rapid metabolizer
CYP2C9
Coumadin
slow metabolizer
SLCO1B1
Statin myopathy
CYP2C9
Coumadin
ultra slow metabolizer
VKORC1
Coumadin dose
IL28
Hepatitis C
therapy
The Vanderbilt way: a 250-gene variant chip, $42/panel (16 cents/variant)
Personalized medicine’s greatest strides have been in cancer
Center for Cancer Research
What are the advantages?
• Detection, Prediction & Prevention: development of biomarkers
to clarify specific patient populations has benefits beyond guiding/
tailoring treatments to match patient populations, including:
• Earlier, more sensitive, specific diagnosis promotes curative vs.
disease modifying intervention
• Accurate monitoring of the disease state
• Efficiency: Tailoring treatment to patients improves the efficacy/
side effect proposition inherent in any therapeutic intervention (i.e.,
HER2 & breast Ca treatment)
• Reducing healthcare costs
• Improving the efficiency of clinical development (i.e., by enabling
specific patient population selection, a smaller sample can be
powered to show requisite benefit reducing trial costs and time)
What have we built so far?
If you sequenced the genes of the 1.65 million Americans who are going
to be diagnosed with cancer this year just once, and then you add
clinical and imaging data from their electronic health records, you'd have
4 exabytes of data. That is the equivalent of all of the data that's in the
Library of Congress. Five exabytes represents the digitization of all
human words every spoken.
Eric Dishman, PMI Director
What to do with all of these data???!!!
A river of data
You are here
• State-of-the art instrumentation/robotics
• Scalable to accommodate 500,000 samples/yr
*
*Clinical Pharmacogenetics Implementation Consortium
Courtesy of A Monte
Population Ancestry Information Resource (PAIR)
• Create a CCPM ‘deliverable’ of non-clinical data to all biobank participants
leveraging ancestry data from the MEGA chip
“An individual patient’s ailments represent a particular
point in time at the convergence of ancestries,
environment, and exposures, like the tips of growing and
changing trees whose branches intermingle through time
but stay mostly out of sight”
Antolin et al. 1 Evolution 66-6: 1991–2006
Research at University of Colorado in neuroendocrine tumors
and adrenocortical carcinoma
Katja Kiseljak-Vassiliades, DO
Research at University of Colorado in
neuroendocrine tumors and adrenocortical
carcinoma
Katja Kiseljak-Vassiliades, D.O.
Assistant Professor
Division of Endocrinology
The Key Points of Medical Science
To prevent
To diagnose
To treat
Disease
Benign vs Malignant Tumor
Characteristics
Benign
Malignant
Morphology and
Differentiation
Structure similar to tissue Structure often atypical
origin
different than tissue of origin
Local invasion
No Invasion
Cohesive growth
Capsule often present
Rate and pattern of
growth
Metastasis
Damage to human body
Prognosis
Slow, progressive
expansion
Slow to rapid growth; erratic
growth rate
No metastasis
Frequent metastasis (definitive
criteria for malignancy)
Relatively smaller
Good
Local Invasion
Infiltrative growth
Usually no capsule
Relatively bigger
Bad
Goals and Tasks of Diagnostic Medicine
• Determine: Nature and name of disease (neoplasm)
• Determine: grading and staging
• Report: molecular changes and biomarkers
Benign vs Malignant Tumor
Characteristics
Benign
Malignant
Morphology and
Differentiation
Structure similar to tissue Structure often atypical
origin
different than tissue of origin
Local invasion
No Invasion
Cohesive growth
Capsule often present
Rate and pattern of
growth
Metastasis
Damage to human body
Prognosis
Slow, progressive
expansion
Slow to rapid growth; erratic
growth rate
No metastasis
Frequent metastasis (definitive
criteria for malignancy)
Relatively smaller
Good
Local Invasion
Infiltrative growth
Usually no capsule
Relatively bigger
Bad
Terms for Neoplasm
• Neoplasm — the new growth
• Tumor — the term was originally applied to the swelling
caused by inflammation, but by long precedent, the term
is now equated to neoplasm
• Cancer — the common term for all malignant tumors
• Dysplasia — recognizable morphologic changes in cells
that indicate the presence of genetic mutations
beginning the development of a neoplasm
Where does the cancer start?
New tumor growth starts with a MUTATION
…..but what is really a mutation?
DNA
•
•
•
•
•
DNA looks like a twisted ladder.
The rungs of the ladder are made from
four types of “blocks” called bases
which pair up.
The bases are abbreviated as the letters
A, T, C and G
It takes about 3 billion pairs of As, Ts, Cs
and Gs to write the human genome.
The sequence of the blocks matter
because it makes up the instructions for
how the body functions
Understanding DNA
• Try reading this:
odaytayisebruaryfayourthfay
• It’s difficult unless you know the code:
Today is february fourth
Same is true for DNA
Slide courtesy of Lauren Fishbein
Understanding DNA
• If you know the “genetic code,” you can decipher DNA sequence.
• We break up the sequence into three letter “words.”
ATTCAGGGTCTAATGATCGTG
ATT CAG GGT CTA ATG ATC GTG
• The three letter words go together to make “sentences”, or genes
• Each gene tells the cell how to make a specific protein
• Genes make a message called RNA which is then translated into a protein
• Proteins are the building blocks of the human body
• Tens of thousands of proteins are needed to build a human
Slide courtesy of Lauren Fishbein
http://www.genome.gov/Pages/Education/AllAbouttheHumanGenomeProject/GuidetoYourGenome07.pdf
Understanding Variation in DNA
• All of us have slight variations in our DNA sequence which have
little or no impact on our health.
Variant
• Think of it as the American vs British way of spelling a word:
Theater vs Theatre or Labor vs Labour
They mean the same thing despite slight variation
• But sometimes a variation in our DNA can change the meaning.
In other words, it causes the formation of a damaged protein
which will not work properly.
Mutation
• Think of it as this example:
State vs Slate or Eat vs Seat
Single letter variation makes completely different
meaning
Slide courtesy of Lauren Fishbein
How does CHEMO work?
-chemo
targets cancer cells
as well normal cells of the body
http://www.lymphoma.ca/lymphoma/patient-journey/treatment/general-chemotherapy-treatment
Traditional model of cancer treatment
If tumor
still present
or comes
back
BENEFIT
Same therapy
NO BENEFIT
ADVERSE EFFECTS
Cancer research in 21st century
http://precisionmedicine.ucsf.edu/elements-precision-medicine
Goals of cancer treatment in 21st century
Same therapy
BENEFIT NO BENEFIT ADVERSE EFFECTS
Challenges in NET and ACC research
• Limited or no human cell cultures
• No animals models
• Research funding is difficult to obtain especially
for rare cancers
UC research projects
• Clinical Research
• Database and tumor tissue collection
• Retrospective studies (to identify new clinical markers of disease)
• Clinical trials (growing)
• Laboratory and genetic studies
• New research model development
• Identifying new pathways to target in tumors in cells and mice
• High-throughput studies with newly identified inhibitors in collaboration with
School of Pharmacy
New Research Models
• Development of human PDX (patient derived xenograft) models in
mice
• Development of new human cell line
• Projecting to develop new 3D cell lines which resembele tumor
function but easier to use than mice
ACC001
Identifying new pathways to target in tumors in
cells and mice
High throughput screening
Summary
• There is a wide spectrum of neoplasia
• In the new era of precision medicine and bioinformatics there are
new and exciting discoveries in human tumors
• At UC we are interested in NET and ACC, where research and progress
is needed by:
• Developing new cell lines
• Generating new animal models
• Studying new pathways that are abnormal in people with NET and
ACC tumors with the goal of translating our laboratory research
into clinical trials