On April 5, 2014 the MRF partnered with Seattle Cancer Care Alliance and Fred Hutchinson Cancer Research Center to provide a free educational event dedicated to melanoma patients and the people who support them.

1. Welcome to the 2014 Melanoma Symposium*
8:30 am – 8:40 am Introduction Dr. David Byrd
8:40 am – 9:40 am Familial Melanoma & Genetic Predisposition Dr. Sancy Leachman
Predisposition
9:40 am – 10:10 am Intra-tumoral Immunotherapy of Dr. Shailender Bhatia
Melanoma: What happens in there,
does not always stay there!
10:10 am – 10:25 am Morning Break
10:25 am – 10:55 am Radiotherapy and Immune Therapy: Dr. Upendra Parvathaneni
An alliance for the future
10:55 am – 11:30 am Questions & Answers with Morning Presenters
11:30 am – 12:30 pm Lunch and Networking
12:30 pm – 1:00 pm Precision Medicine Dr. David Byrd
1:00 pm – 2:45 pm Patient Panel
2:45 pm – 3:15 pm Afternoon Break – Enjoy smoothie samples from SCCA Nutrition
3:15 pm – 3:45 pm Getting Involved Dr. Tim Turnham
3:45 pm – 4:00 pm Closing Remarks Dr. David Byrd
Dr. Kim Margolin
*Speakers/presentations are being filmed. Video will be available online at www.SCCAblog.org.

2. Welcome & Introduction
Thank You to Fred Hutchinson Cancer Research Center

3. Familial Melanoma & Genetic Predisposition
Sancy Leachman, MD, PhD – Keynote Speaker
Chair of the Department of Dermatology
Director of the Knight Cancer Institute Melanoma Program
Oregon Health and Science University

4. Familial Melanoma &
Genetic Predisposition
Sancy Leachman, MD PhD
Oregon Health & Science University

5. Disclosures
• Myriad Genetics

6. Overview
• When is genetic testing helpful?
• Available genetic tests for melanoma
• Current state of DTC genetic testing

7. What Is Familial Melanoma?
Hansen et al, Lancet Oncol., 2004

8. Hereditary Melanoma: An autosomal
dominant cutaneous cancer syndrome
Pancreatic
Melanoma
Pancreatic & Melanoma

9. Background: Inheritance of
Melanoma Risk Is Complex
Population Risk
“Low” Elevation of Risk
Moderately Elevated Risk
High-Risk

10. Genetics of Pigmentation
& Melanoma: Low Penetrance
• Genome-wide association studies (common, low-
penetrance, SNP)
– Agouti signaling protein (ASIP, an MSH antagonist)
– Tyrosinase (Tyr, key enzyme in melanin synthesis)
– Oculocutaneous albinism 2 (OCA2, regulates melanin
synthesis)
– Tyrosinase related protein (TYRP1, regulates melanin
synthesis)
– SLC45A2 (melanocyte differentiation & pigmentation)
Brown et al., Nat Genet 2008; Bishop et al., Nat Genet 2009

11. DNA Repair Genes Associated
with Melanoma: Low Penetrance
• TERT - Telomerase Reverse
Transcriptase
• PARP1
• ATM
• CASP8
Barrett JH, Nat Genet, 2011; 43:1108-1113
Bishop DT, Nat Genet, 2009; 41:920-925
MacGregor S, Nat Genet, 2011; 43:1114-1118

12. ≥3 melanomas in a
family (any degree of
relationship) 12%-41%
≥3 melanomas in an individual 5%-23%
≥3 “cancer events” in a
family (any combination of
melanoma and pancreatic
cancer) ~68%
Which Patients Are Candidates for Genetic
Testing: “Rule of Threes”
*Only 1 criteria needs to be met. Consideration should be given to age at diagnosis, UV exposure,
skin type, and ethnicity, as there may be exceptions to the “Rule of Threes.”
Leachman et al, JAAD 2009

13. MC1R: A Gene That Causes Red Hair
Photo courtesy of Rick Sturm, Australia

14. Effects of MC1R Mutation
• Melanoma risk in the general population
• 2-fold increased risk per R allele
• MC1R mutations make CDKN2A mutations worse
• Penetrance in 15 kindreds with CDKN2A mutation was 50%
with mean age of onset 58 years
• Penetrance was increased to 84% by presence of R allele with
a mean age of onset 38 years.
Palmer et al., Am J. Hum. Genet. 2000; Fargnoli et al., JID, 2009; Box et al., Am. J. Hum. Genet.
2001; Hacker et al., JID 2009

15. Why Test?
Exceptional Lifetime Risk!
*Bishop DT, et al. J Natl Cancer Inst 2002;94:894-903. **Rulyak SJ, et al. Cancer 2003;98(4):798-804.
**Parker JF, et al. Arch Dermatol 2003;139:1019-25.
0
10
20
30
40
50
60
70
80
Melanoma Pancreatic
Melanoma
Pancreatic
76%
17%

16. Can Genetic Testing Improve
Compliance with Prevention Behaviors?

17. Study Design
• 2 large p16
mutation families
• 3 study groups
• Good, balanced
retention
• 5 time points
• Endpoints:
– Photoprotection
– Skin self-exam
– Total body
provider exam
Aspinwall et. Al, CEBP, 2013

18. Photoprotection in Unaffected
Carriers (% Time Utilized)
p < 0.024
Genetic testing improved photoprotective behavior in unaffected carriers

19. TBSEs in the past year at 2 yrs
P = 0.0002
P = 0.635
P = 0.032 P = 0.033
%reportingTBSEinpastyear
Genetic testing alters compliance with TBSEs

20. SSE adherence from baseline to 2 yrs
Genetic testing alters compliance with SSEs

21. What tests are available?

22. Single Gene Testing for Hereditary Melanoma
CDKN2A
Company Price
PreventionGenetics $540
University of Oklahoma $548
GeneDX $660
Center for Human Genetics $675
Emory Genetics $700
Ambry $900
Myriad $900
InVitae $1500

23. Single Gene Testing for Hereditary Melanoma
CDK4
Company Price
PreventionGenetics $680
InVitae $1500 (same price if
bundled with CDKN2A, so
$750/gene if ordering both)

24. Panel Testing for Hereditary Melanoma
Company Price Genes
Yale DNA Lab $561 CDKN2A, CDK4
GeneDX $825 CDKN2A, CDK4
Fulgent $1,450 CDKN2A, CDK4, MC1R,
BRCA1&2 + 8 others
Myriad $4,040 CDKN2A, CDK4,
BRCA1&2 + 21 others
Ambry 4,250 CDKN2A, CDK4,
BRCA1&2 +24 others

25. Example Panel Report - Positive

26. Example Panel Report - Negative

27. Current Status of Direct to
Consumer Genetic Testing

28. Increasing Public Awareness: Google Trends
“23andMe”
“BRCA”
Angeline Jolie double
mastectomy
FDA instructs 23andMe to stop selling tests

29. Reactions to New Technology: Utopian

30. Reactions to New Technology: Utopian

31. Reactions to New Technology: Terror

32. Reactions to New Technology: Terror

33. Rapidly Evolving Landscape
20112013

34. Current Landscape
Company Price What Tested? Results to? Counseling?
23andMe* $99 SNPs Consumer Yes/No
(Informed DNA)
DNA DTC $900
$7,000
Exome @ 80x
Genome @ 30x
Consumer,
raw data
No
Genetic
Testing
Laboratories
$315 SNPs MD Yes
Pathway
Genomics
$399 SNPs MD Yes
Counsyl $600
$1,000
SNPs via PCR
SNPs via exon
seq
MD Yes
*Not currently offering tests

35. Timeline of a Landmark Year: 2010
• Beginning of Myriad litigation culminating in
Supreme Court decision in 2013 against Myriad
stating that a “DNA segment is a product of nature
and not patent-eligible merely because it has been
isolated”
• FDA warns genetic companies doing DTC testing
that tests will be considered medical devices
• Two companies, deCODEme and Navigenics, stop
sales and are acquired by other companies in 2012
• Other companies (Counsyl, Pathways) quickly end
DTC sales

36. 23andMe and the FDA
• Saliva sample ‘spit kits’ submitted for SNP
genotyping
• Time magazine ‘Invention of the Year’ 2008
• 650,000 tests to date
• Affiliation with Google and access to ‘big data’
• FDA’s 2010 take: medical devices, have not
been analytically or clinically validated
• November 2013: FDA stops sales of 23andMe
kits
• Two class-action lawsuits pending for
“misleading advertising”

37. Summary
• When to test: Rule of threes
• Available genetic tests for melanoma:
Single gene and panel tests available
• Current status of DTC genetic testing:
Controlled

38. Future Questions
• What is the future for direct-to-consumer
genetic testing? Is there one? Should
there be one?
• Should DTC testing be considered a
medical device, or something else?
• What will the real legacy of this new,
powerful technology become?

39. Acknowledgements
• Matthew Majerus, M.D.
– OHSU Dermatology Resident, PGY-2

40. Intra-tumoral Immunotherapy of Melanoma:
What happens in there, does not always stay there!
Shailender Bhatia, MD
Assistant Professor, Medical Oncology
Department of Medicine
UW / SCCA / FHCRC

41. Intra-tumoral Immunotherapy:
What happens in there,
does not always stay there
Shailender Bhatia, MD
University Of Washington

42. 1. Establish goals of care
• Durable disease-control (CURE)
• Prolong lifespan
• Preserve/improve Quality-of-life
2. Match desired goals to the safety/efficacy
characteristics of the therapy
• Rate of tumor shrinkage or clinical benefit
• Kinetics of response (rapid vs delayed)
• Duration of response
• Side-effects
• ?Cost
Systemic therapy is the mainstay of
therapy for metastatic disease

43. Until 2011, few standard therapy
options existed.
Treatment of Metastatic Melanoma: An Overview
Bhatia S et al. ONCOLOGY. 2009; 23:6; 488-500
US-FDA approved therapies for metastatic
melanoma.
Dacarbazine (1975)
No proven OS benefit
High-dose IL-2 (1998)

44. Cancer Immunotherapy Works
(Albeit only in a small subset of melanoma patients)
Response
 ORR ~16%
 CR 6%
 Majority of CR’s
are durable.
Likely CURED
Toxicity is
substantial
Retrospective Analysis of 270 patients treated at
the NCI by High-Dose IL-2
[Atkins, MB et al. JCO (1999)]

45. Hodi FS et al. NEJM. 2010
2010: The ceiling was finally broken

46. Ipilimumab: An Example of Response
Maggon et al, 2011

47. However, responses are infrequent, and
complete remissions (CR) rare.

48. Adverse Events from Ipilimumab
[Hodi FS et al. NEJM. 2010]
Immune-related AE Any grade
(%)
Grade 3 or
higher (%)
Any IrAE 60 15
Dermatologic (pruritus,
rash, vitiligo)
43 2
GI (Diarrhea, colitis) 29 8
Endocrine (Hypophysitis,
hypothyroidism, adrenal
insufficiency)
8 2
Hepatic 4 0
Others 5 2

49. True impact of Ipilimumab’s success
story goes far beyond Melanoma
[Topalian S et al. NEJM. 2012; Brahmer J et al. NEJM. 2012]

50. [Wolchok J et al. NEJM. 2013]

51. Near-CRs seen in a large proportion of pts
ORR 40%
N=47; All dose levels included
[Wolchok J et al. NEJM. 2013]

52. Toxicities can be a problem though
• Grade 3/4 treatment-related AEs: 53%
– Elevations in Lipase (13%), AST (13%, ALT (11%)
• Cohort 3 (Nivo 3 + Ipi 3) deemed to have unacceptable
level of toxicity
– 3/6 patients had Gr 3 or 4 lipase elevations lasting
more than 3 weeks.
[Wolchok J et al. NEJM. 2013]

53. Why does immunotherapy not work all
the time?
[Weiner L NEJM 2008 ]

54. Intra-tumoral Immunotherapy
53
• Takes the action into the heart
of the tumor, where it is
needed
• May have a better chance of
overcoming local immune
evasion mechanisms.
• Avoid systemic toxicity

55. Systemic versus Local
Immunotherapy
SYSTEMIC
Potential for ‘Global’ responses
in what is essentially a ‘systemic’
disease.
Systemic toxicities
- Overkill for solitary or oligo-
metastatic disease.
? Adequate intratumoral drug
levels
– limited dose-escalation due to
systemic side-effects.
– penetration into the tumor
microenvironment.
LOCAL
Mostly local toxicities
? Feasibility
– dependent upon location of the
lesions (superficial versus deep;
critical organs)
? Decreased potential for
‘global’ responses

56. Several potential advantages to
intratumoral immunotherapy
• Improve the risk:benefit ratio of otherwise-toxic
drugs.
• Stimulate immune responses against diverse
(including unknown) tumor antigens.
• May overcome the hostile immune-suppressive
tumor microenvironment (TME)
But, can the local benefits spill over into the
systemic circulation?

57. Scientific hypothesis: What happens
there, does not always stay there.

58. How to assess systemic immune
responses from local immunotherapy?
• Regression of distant non-injected lesions.
- Preferably in a different organ type (e.g. visceral
tumor regression from injection of cutaneous tumors)
• Prolonged stable disease or progression-free
interval.
• Anti-tumor immune responses in peripheral blood.

59. Intratumoral Injection of IL-12 plasmid
followed by in vivo Electroporation

60. Interleukin-12 (IL-12)
• Powerful immune stimulant
• Anti-cancer efficacy seen in early clinical trials
• However, systemic administration of IL-12 was
associated with severe toxicities.
- GI, Liver toxicity
- Death.

61. Adil Daud, MD
UCSF
[Daud A et al. J Clin Oncol 2008]

62. Treatment led to Increased
Intratumoral Expression of IL-12 protein
(for up to 5 weeks after only 3 injections on days 1,5, 8)
[Daud A et al. J Clin Oncol 2008]

63. Clinical Efficacy
Distant responses in 4/19 patients – 3 CRs
Disease Control Rate = 10/19 or 53%
[Daud A et al. J Clin Oncol 2008]

64. [Daud A et al. J Clin Oncol 2008]
Development of Vitiligo

65. Phase 2 Study of IL-12 EP in patients
with
Merkel Cell Cancer
And
Melanoma

66. • IL-12 EP is delivered on days 1, 5 and 8 of each cycle.
• Maximum of 4 tumors (or treatment zones) are treated in
each cycle; different set of tumors can be picked for a
new cycle.
• The total daily dose of IL-12 plasmid is 1 mg in 2 mL (0.5
mg/mL); 0.25 mg per each treatment zone.
Study Methods (Contd)

67. The EP applicator (OncoSec Medical Inc) delivers
six pulses at a field strength (E+) of 1300 V/cm and
pulse width of 100 µs.
Study Methods (Contd)

68. Then the show begins.

69. Increased
Intra-tumoral IL-12 protein expression
• 3 patients have paired
baseline and post-
treatment (week 3) tumor
IL-12 protein levels
available (as measured by
a validated ELISA).
– The IL-12 protein level is
increased [25-1000 fold]
post-treatment in 3/3
(100%) patients’ biopsy
samples [Figure].
Figure: Increased IL-12 protein
expression in post-treatment versus
baseline tumor biopsy in 3/3 patients.
[Bhatia S et al. SITC poster. 2012]

70. Impressive response in some patients
Pre-treatment Post-treatment (Day 270)

71. Intriguing evidence of systemic immune
response in another patient
Post-treatment (Day 25)

72. Therapy has been tolerated well with
mostly mild local side effects.
Most common treatment-related AE is transient (lasting ~
3 seconds) pain associated with electroporation.
– No systemic side-effects (such as flu-like
symptoms) have been noted in any patients so far.
[Bhatia S et al. SITC poster. 2012]

73. 002: C2 Wk2 002: C2 Wk6
Mild injection-site discoloration
has been noted in some patients.
[Bhatia S et al. SITC poster. 2012]

74. W420 TIL samples
IFNg response by W420 TIL in presence MCPyV CT44-52 peptide
Oct’11 Jan’12 Feb’12 Sep’12 Oct-Nov’12
No IFNg response by W420 TIL in presence of ST83-91 peptide IFNg response by W420 TIL in presence of ST83-91 peptide
Patient 002:
Suggestion of epitope
spreading

75. IT CD8+ Infiltration (prelim)
Figure: There appears to be increased CD8+ infiltration into
the tumors after therapy (patient 005).
In 1/2 patients, there appears to be increased
CD8+ infiltration into the tumors; rest had
insufficient tumor tissue for comparison.

76. Summary
• Local delivery of IL-12 is feasible via intratumoral
injection of IL-12 plasmid DNA followed by in vivo EP.
• Treatment is tolerated well overall, with transient
grade 1 pain associated with EP.
• No systemic treatment-related AEs occurred so far.
• Preliminary evidence of efficacy has been noted with
regression of injected as well as non-injected tumors
in some (but not all) patients.

77. Intratumoral Immunotherapy of skin
cancers at SCCA.
A phase 2 study of pIL-12 EP in patients with MCC.
{PI: Bhatia}
A phase 2 study of pIL-12 EP in patients with Melanoma.
{PI: Adil Daud, UCSF}
A proof-of-concept trial of intratumoral GLA (synthetic
TLR-4 agonist) in MCC. {PI: Bhatia}
Single 8-Gy Radiation therapy of MCC tumors.
{Led by: Parvathaneni}

78. OncoVEXGMCSF in melanoma
(Oncoloytic HSV-1 expressing GM-CSF)
Talimogene laherparepvec (T-VEC)

79. Phase 2 results with OncoVEXGMCSF
[Senzer NN. JCO 2009]

80. Disease may be too aggressive for
immunotherapy in some patients
003 C1 D1
Pt 003 (SM) - Recurrent MCC – 4 zones treated –
PD after 1 cycle – responded nicely to salvage RT
003 C1 D29

81. 0 50 100 150 200 250 300 350 400
Days from diagnosis
Response to therapy
or stable disease on the CT scan
Progressive disease on the CT scan
41BB
(164 dys without PD)
W787, 56 yo woman
(nurse), 7 cycles of
41BB at 0.12 mg/kg
XRT XRT
Combining local with systemic
immunotherapy

82. Combining local with systemic
immunotherapy

83. Conclusions
• Local intratumoral immunotherapy can result in
clinically meaningful systemic immune responses.
• Toxicity is generally favorable with mostly local AEs.
• Combination of local and systemic immunotherapy
approaches may overcome some limitations of
either approach and deserve further investigation.
What happens in Vegas, does not always stay in Vegas!


84. Acknowledgments
Patients/Families
Kim Margolin John Thompson
Paul Nghiem
Clinicians
Scott Tykodi
Upendra Parvathaneni
David Byrd
Sylvia Lee
Aude Chapuis
Clinical Support Staff
Jeanette Hammond, PA
RNs (Jon, Debbie,
Christine, Sharon)
Marla Teeny (TC)
Research Support Staff
Nichole Real (RC)
RCs (Cassie Oh, Mike
Donahue)
Phase 1 team
Sandy Bergevin, Sarah P
Nghiem Lab
Adil Daud, Rich Heller, OncoSec

85. Kauai, here I come!!

86. Morning Break
10:10 – 10:25 am

87. Radiotherapy and Immune Therapy:
An alliance for the future
Upendra Parvathaneni, MD
Assistant Professor, Radiation Oncology
University of Washington School of Medicine
Radiation Oncologist, Seattle Cancer Care Alliance

88. Radiotherapy and Immunotherapy :
an alliance for the future
Upendra Parvathaneni
Radiation Oncologist, University of Washington
April 2014

89. disclosures
• none

90. Objectives
• Brief introduction to radiotherapy (RT) in melanoma
• Observations of systemic/immunologic effects of RT
• RT interaction with immunotherapy – the new frontier
• Modern RT tools to target tumors

91. RT effects on melanoma

92. Traditional role of RT in melanoma
• Post operative treatment of “high risk” node
positive patients
• To prevent local cancer relapse within the
treated field
• RT was fractionated over 3-6 weeks to allow
normal structures to repair between
treatments
• RT for palliation of metastases

94. Palliative RT for melanoma

95. Dose = energy absorbed in tissues at a specified depth
Units : Gray (100 cGy)
Megavoltage linear accelerator

96. Major types of RT & physical properties
• Photons/Xrays
• Electrons
Depth in tissue
absorbed
dose
Depth in tissue
absorbed
dose

97. RT target = DNA
• maximum effect on dividing cells
that rely on intact DNA during cell
division
• Hence, tumors with dividing cells
responded to RT
• Normal cells are relatively spared,
if allowed to repair

98. Immune system is needed to fight cancer

99. Immunotherapy in Melanoma
• Interferon 2a
• Interleukin -2
• CTLA 4 blockade (ipilumimab)
• Anti PD -1 therapy
• Therapeutic vaccines

100. Systemic/Immunological effects of RT – the new biology
Demaria et al. IJROBP. 2005;63(3):655-66.

101. Immunological effects of RT in melanoma
• Animal modals – eg fewer lung mets in mice
that had RT (25 Gy) to melanoma vs no RT b4
surgery. Perez et al Int J Radiat Biol 2009;85:1126-36
• Clinical data :
- abscopal effects
- vitiligo effects

102. Abscopal effects of RT
• ab = away from (latin) scopus = target, aim (greek)
• Abscopal effect is a phenomenon where localized
irradiation of a tumor causes not only a shrinking of
the irradiated tumor but also a shrinking of tumors
far from the irradiated area.

103. Abscopal effects of RT
• Described in melanoma, renal cell ca,
lymphomas, merkel cell ca, etc…
• First reported in a case of melanoma in 1975 -
treatment with neutrons (14.4 Gy) to groin nodes
regressed pelvic and para aortic lymph nodes. Kingsley
DP Br J Radiology 1975;48:863-66

104. Abscopal effects of RT

105. Abscopal effects
of RT +
ipilumimab
N Engl J Med
2012;366:925-31.
RT: 28.5 Gy in 3 fx
Regression of
untreated
mass in hilum of lung
Regression of
Untreated masses
in liver and spleen

106. RT = 27 Gy in 3 #
3 and 6 months
post RT
Abscopal effects
RT + ipilumimab

107. Immunological effects of RT in melanoma
Note - depigmentation
“vitiligo” effect :
sign of effective immunotherapy
Vitiligo in non irradiated sites
noted in some cases

108. Halo depigmentation – an immunologic effect of RT
note : around treated lesions
compared with RT skin reaction in the rest of the field

109. RT + high dose IL2 immunotherapy
• Pilot study of 7 pts with metastatic melanoma
• 1-3 doses of RT (20-60Gy) + high dose IL-2
• 71% achieved a response - 1 CR and 4 PR
• Median duration of response = 553 days
• Much higher than historically expected
response rates (10-15%)
www.ScienceTranslationalMedicine.org 6 June 2012 Vol 4 Issue 137

110. Discordant effects of RT
• Systemic RT – total body irradiation = immune
suppressive - used to suppress host immunity against foreign graft
during allogeneic bone marrow transplantation
• Local RT = immune stimulatory
• High dose per fraction reqd for immune
stimulatory effects - possible only with newer
techniques

111. Developments in RT technology
allow for the use of
high-dose ablative RT (8-20 Gy)
to target tumors
with limited damage to the
surrounding normal tissue

112. Historical RT = crude techniques
accurate BUT morbid

113. Technological advances : IMRT
multiple beam angles
parts of target are treated by “segments” of a beam
intensity map of each field conforms
with target in 3 dimensions
IMRT = highly conformal
steep dose gradients

114. Proton RT
at UW
Feb 2013

115. Proton RT
at UW
Feb 2013

116. protons vs photons

118. Our 1st H&N proton patient

119. Optic chiasm sparing treatment

120. RT available at UW
• Conventional RT with conformal techniques:
IMRT, SBRT
• Gamma knife
• Protons
• Neutrons

121. Thank you

122. Questions & Answers with Morning Presenters
Dr. Sancy Leachman
Dr. Shailender Bhatia
Dr. Upendra Parvathaneni

123. Lunch & Networking
11:30 am – 12:30 pm

124. Personalized and Precision Medicine in Cancer Care
David Byrd, MD
Director of Surgery, Seattle Cancer Care Alliance
Co-Chair, Northwest Melanoma Symposium

125. Personalized and
Precision Medicine in
Cancer Care
David R Byrd, MD
Director of Surgical Oncology
SCCA
Professor, Department of Surgery
University of Washington

126. IOM Report Sept 10, 2013
Delivering High-Quality Cancer Care:
Charting a New Course for a System in
Crisis
• Crisis is due to:
– Growing demand for cancer care:
• In U.S. 14M have had cancer
• 1.6M new diagnoses/year
– By 2030, expect 2.3M new diagnoses/year
• By 2022, expect 18M cancer survivors
– Increasing complexity of treatment
– Shrinking workforce
– Rising costs
www.iom.edu/qualitycancercare

127. Personalized Medicine
- covers the entire continuum of
quality cancer care
Tesla

128. Diagnosis and Staging of
Cancer
• Histology
• Immunohistochemistry
• Molecular diagnostics:
– Genomics of tumor
– Pharmacogenomics
– Other omics

129. Histologic Diagnosis and
Cancer Staging (TNM)
• Primary tumor organ of origin – Breast,
colon, etc. = T
• Spread to regional lymph nodes = N
• Spread to distant sites/organs = M

130. Melanoma (Tissue level)
Normal skin melanoma
Primary tumor thickness– 1.2 mm,
ulcerated: (T2b)

131. Lymph node metastasis – N1
Lymphocytes
melanoma
cells

132. Metastasis to bone - M1

133. Pathologic Staging
T2b N1 M1 – Stage IV
Provides clinicians and patients with:
- size/local invasion of primary
- extent of spread of disease
- prognostic information

134. Melanoma Survival Curves by
StageSurvivalRate
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Survival Time in Years
0.0 2.5 5.0 7.5 10.0 12.5 15.0 17.5 20.0
Stage I (n=18,370)
Stage II (n=9,269)
Stage III (n=3,307)
Stage IV (n=7,972)
AJCC Cancer Staging Manual, 7th ed, 2009

135. Dr. Michael Kattan
Chairman of Quantitative Health Sciences,
Cleveland Clinic

137. -Apply molecular diagnostics
-Deliver targeted therapy to
actionable mutations in tumor
Precision Medicine

138. The Promise of Precision Medicine in Cancer Care
Morphologic diagnosis and
phenotypic tumor classification
Generic therapeutic regimens with
unpredictable effectiveness
Treatments with unpredictable
adverse effects on patients
Molecular characterization of
tumors and pathways
Targeted therapies tailored to the
molecular profile of the disease
Drug regimens planned around
host genetics that portend toxicity
Advances in Molecular Technologies and Research
Understanding Molecular Biology of Host and Disease
Empiric – population-based Precision Medicine
Courtesy of Dr. Carolyn Compton

139. Precision Medicine Issues
• Technology – evolving rapidly
• Genetic and molecular diagnostics
• Effectiveness of targeted treatment
• Affordability/Costs
• Ethics
• Prevention

140. Personalized Medicine:
Replacing Trial and Error Medicine
Reproduced with Permission from the Personalized Medicine Coalition.

141. Personalized Medicine:
Replacing Trial and Error Medicine
Reproduced with Permission from the Personalized Medicine Coalition.

142. Immunohistochemistry IHC –
Melanoma (Cell level)

143. Precision Medicine
What’s Under the Hood?

144. Genetic Mutations in Cancer
• Germline mutations:
– Present at birth
– Present in all cells
– Can identify predisposition to cancer(s)
• Somatic mutations:
– Acquired during life
– Found in tumors in abundance
– Can be exploited as specific targets for
treatment of cancers

145. BROCA Comprehensive Cancer Panel
(Germline Genetic Testing)

146. Disclosure of Genetic Testing
Results
• Genetic Counseling up front
• Panels of genes may identify other
consequential mutations
– Should the patient be informed of all the
information that will be obtained?
– Who “owns” the management of unintended
genetic results?
• The ethics have not been worked out!
Lolkema et al JCO, 2013

147. Somatic Mutations
Schema of Precision Medicine
MacConaill L E , Garraway L A JCO 2010;28:5219-5228
©2010 by American Society of Clinical Oncology

148. Genetic and Molecular
Diagnostics (Intracellular)
• Sequencing of segments of DNA
coding for mutated proteins – e.g.
EGFR, KRAS, BRAF, ALK
• Gene Panel testing of known or
suspected mutations – UW: OncoplexTM
• Whole exom DNA sequencing

150. Exemplary Oncoproteins and
Targeted Cancer Pathways
Cell surface membrane
DNA
Garraway, et al. JCO 31:1806-1814, 2013
Cell signaling

151. Exemplary Oncoproteins and
Targeted Cancer Pathways
Cell surface membrane
DNA
Garraway, et al. JCO 31:1806-1814, 2013
Cell signaling
Therapeutic targets
In lung carcinoma

152. Exemplary Oncoproteins and
Targeted Cancer Pathways
Cell surface membrane
DNA
Garraway, et al. JCO 31:1806-1814, 2013
Cell signaling
Therapeutic target in
melanoma

153. Exemplary Oncoproteins and
Targeted Cancer Pathways
Cell surface membrane
DNA
Garraway, et al. JCO 31:1806-1814, 2013
Cell signaling
Therapeutic target in
hereditary breast CA

154. Colin Pritchard, UW Lab Medicine
Tier 1: Currently
Actionable
ABL1 ALK BCR BCL2L11 BRAF RET CDK4 CEBPA KIF5B
DDR2 EML4 EGFR ERBB2 FLT3 IDH1 IDH2 JAK2 RARA
KIT KRAS MPL NPM1 NF2 NRAS PDGFRA PML
RICTOR ROS1 TSC1 TSC2
Tier 2: Actionable in
the Near Future
ABL2 AKT1 AKT2 AKT3 ASXL1 ATM AURKA AURKB BAP1
BCOR CBL CBLB CDK6 CDK8 CHEK1 CHEK2 DNMT3A EPHB2
ERBB3 ERBB4 FGFR1 FGFR2 FGFR4 FLT1 FLT4 GATA2 GNA11
GNAQ GRM3 HDAC4 HIF1A HRAS IGF1R JAK3 KDM6A KDR
MAP2K1 MAP2K2 MAPK1 MC1R MCL1 MEN1 MET MLH1 MLL
MRE11A MSH2 MSH6 MYC MYCN NOTCH1 PAX5 PDGFRB PIK3CA
PIK3R1 PMS2 PTEN RAF1 NKX2-1 SMO SRSF2 SUZ12 TET2
TYR VHL MITF ERCC2
Tier 3: Frequently
Mutated
APC BAK1 BCL2 CCND1 CCNE1 CDH1 CDKN2A CREBBP CRLF2
CSF1R CTNNB1 EPHA3 EPHA5 EPHB6 ETV6 EZH2 FBXW7 FGFR3
GAB2 GATA1 GNAS GRIN2A HNF1A IKZF1 IL7R JAK1 MAP2K4
MDM2 MDM4 MUTYH MYCL1 NF1 STK11 NOTCH2 PBRM1 PRPF40B
PTCH1 PTPN11 PTPRD RB1 RPS14 RUNX1 SF1 SF3B1 SMAD2
SMAD3 SMAD4 SMARCA4 SMARCB1 SPRY4 SRC TFG TGFBR2
TP53 TRRAP U2AF1 U2AF65 WT1 ZRSR2
Germline
Pharmacogenomics
ABCB1 ABCC2 ABCC4 ABCG2 C1orf144 COMT CYP1B1 CYP2C19 CYP2C8
CYP2D6 CYP3A4 CYP3A5 DPYD EIF3A ESR1 ESR2 FCGR1A UMPS
FCGR2A FCGR3A GSTP1 GUCY1A2 ITPA LRP2 MAN1B1 MTHFR NQO1
NRP2 SLC19A1 SLC22A2 SLCO1B3 SOD2 SULT1A1 TPMT TYMS UGT1A1
UW-OncoPlex™ v2
Genes Targeted: 194
DNA Sequenced: >850,000 bp
>500X Coverage

156. Next Generation Whole Exom
DNA Sequencing
• Technology is here now
• Costs are expensive but plummeting
• Time to interpret results is long but
decreasing
• The volume of data generated is vast,
especially over time
• Emerging field of computational
biology

157. Treatment for Metastatic
Melanoma 1980’s to 2011
• Node positive melanoma – alpha
interferon only FDA-approved
additional treatment
• Metastatic (distant sites) melanoma –
DTIC (chemo) or Interleukin-2
• Clinical trials

158. Targeted Pathways in Melanoma
Fecher, et al JCO 25:1606, 2007

159. Modeling of Information
Flow in Biological
Networks
Targeted Therapeutics and Cancer: Harder Than We
Thought
Molecular Subtyping
and
ID of RX Targets
Rx-Resistance
via
Redundant
Molecular Pathways
Initial Rx-Response
to
Targeted Rx
B = 15 weeks Rx
(Zelboraf®)
C = 23 weeks Rx
and emergence of
MEK1C1215 mutant
Wagle et al. (2011)
JCO 29, 3085)
Courtesy of Dr. Carolyn Compton - AJCC

160. Emerging Immune and Molecular
Strategies/Therapies in Melanoma
• Targeted therapies:
– Mutated BRAF inhibitors – vemurafenib,
dabrafenib
– C-kit inhibitors – Imatinib (Gleevec)
– MEK inhibitors – trametinib
• Immunotherapy – immune checkpoint
blockers:
– Ipilimumab (Yervoy) - anti-CTLA-4 antibody
– Anti –PD-1 – Nivolumab, Lambrolizumab

161. Pre-Rx
Post-Rx
Immunotherapy for Melanoma

162. The Path Forward

163. The Problem
“…there are known knowns; there are things
we know we know. We also know there are
known unknowns; that is to say we know
there are some things we do not know. But
there are also unknown unknowns -- the
ones we don't know we don't know."
--Donald Rumsfeld
http://www.youtube.com/watch?v=GiPe1OiKQuk
Slide courtesy of Dr. Richard Schilsky

164. What Do We Know?
• Targeted therapy makes clinical sense and is
available now for some cancers
• Targeted therapy doesn’t always work or
effectiveness is short-lived
• Tumors evolve in the patient, spontaneously and
under selection pressure
• Costs of testing and targeted treatment must be
addressed up front.
• Resurgence of promise for immunotherapy

165. What Don’t We Know?
• How to optimally combine agents (dose,
schedule, sequence)
• How to efficiently integrate data sets
• How to quickly convert a lab assay to a clinical
test
• How to navigate regulatory mazes
• How to convey test results to physicians in a
useful format
• How to define how individual tumors behave
• How to present the economic case for targeted
therapy
Courtesy of Dr. Richard Schilsky

166. Costs of Genetic Sequencing
We are rapidly approaching availability
of the $1,000 genome

168. The Patient of the Past

169. The Patient of the Future
DNA Sequence
Barcode on
forehead
Doctor, what do we
do about this?

170. “You want the Truth?
You can’t handle the Truth.”
Jack Nicholson - A few Good Men

171. Linear Growth
Exponential Growth
Technology
Clinical Care
Gap
RateofImprovement Doing One’s Best: 2013

173. Thank you!

174. Patient Panel
1:00 – 2:45 pm

175. Afternoon Break
Enjoy healthy smoothie samples from SCCA Nutrition in the Great Hall!
2:45 – 3:15 pm

176. Getting Involved
Tim Turnham, PhD
Executive Director
Melanoma Research Foundation

177. Getting Involved
April 5, 2014

178. Tell Your Story
181
Melanoma is not widely recognized.
Oh, my friend had that. No, wait it was lymphoma, or was it
mesothelioma, no maybe multiple myeloma….
Melanoma? That’s just skin cancer, right?
The consequence is a cavalier attitude toward risk, toward
early detection, and even around treatment.

179. Tell Your Story:
Primary Prevention
182
UV Radiation is a factor in the majority of cutaneous
melanomas (maybe as high as 75%) in the United States.
•Tanning salons
– More numerous than Starbucks/MacDonalds
– Largely unregulated: bulb intensity, frequency of use, etc.
– Often uses misleading marketing
•Culture of tanning
– “Healthy glow”
– Beauty/fashion/celebrity industries are selling a lie

180. Tell Your Story:
Secondary Prevention
183
Early detection is key!

181. Tell Your Story:
Patient Education
184
What about the patient in North Dakota who doesn’t look for
information on the internet, won’t travel for care, and whose
oncologist sees one or two melanomas a year?
– # of patients in clinical trials
– # of patients treated with Dacarbazine/chemo
CME and general marketing won’t work; key is peer-to-peer
communication.

182. Share Your Strength
185
MRF education and volunteer efforts are built on the absolute
conviction that patients who are well informed and well
supported live longer and better
• Support Groups
• MPIP
• Phone Buddies

183. Become a Lobbyist!
186
•Ongoing “asks”
– Tanning legislation—federal and state
– CDMRP
– NIH/CDC
•Emerging Issues
– Oral Parity
– Specialty Tiering
– Pricing policies (per mg)
•How to get started
– MRF Hill Day
– Virtual Advocacy Program

184. Invest In Better Solutions
•Miles for Melanoma
•Host a fundraiser
•Write a check
•Consider an estate gift
187

185. Do Something!
Commit to doing two things in the next year:
• Send an email to your member of Congress
• Hold a dinner party and tell your story
• Contact local media
• Run in a Miles for Melanoma event
• Speak at a school group
• Write a check to some melanoma effort
• Sign up to volunteer
• Make at least one post on MPIP
• Take patient or caregiver brochures to your dermatologist/oncologist
• Create a fundraising event
• Participate in a clinical trial
• Become a Phone Buddy
188

186. Together we can change the world!
189
Step by step the longest march
Can be won, can be won.
Many stones to build an arch;
Singly none, singly none.
And by union what we will,
can be accomplished still.
Drops of water turn the wheel
sing we on, sing we on.

188. Thank you for joining us at the
2014 Melanoma Symposium!
(Video footage of the symposium will be available
at the end of April at www.sccablog.org.)