understanding true risk factors and associations for skin … · 2021. 3. 29. · ak treatment: •...
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"Risky Business”
Understanding True Risk Factors
and Associations for Skin Cancer
Shawn Demehri, MD, PhD
Director, High Risk Skin Cancer Clinics
Massachusetts General Hospital
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Disclosures
I am a co-inventor on a filed patent for the use of calcipotriol plus
5-fluorouracil for the treatment of precancerous skin lesions
(PCT/US2015/049434)
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Skin Cancer Risk
❑ Keratinocyte carcinoma:
Basal cell carcinoma (BCC)
Squamous cell carcinoma (SCC)
❑ Melanoma
❑ Other primary cutaneous malignancies:Merkel cell carcinoma
Adnexal carcinomas
Dermal sarcoma
Kaposi sarcoma
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What are the determinants of “high risk” in
the skin cancer field?
❖ High risk cancer
❖ High risk patient
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❖ High risk cancerA primary skin cancer with high-risk features, which denote
an increased risk for local recurrence and metastasis.
Squamous cell carcinoma (SCC):• Tumor diameter of at least 2 cm
• Poorly differentiated histological findings
• Perineural invasion of at least 0.1 mm nerves
• Lymphovascular invasion
• Invasion beyond subcutaneous fat
• Bone invasion
What are the determinants of “high risk” in
the skin cancer field?
Thompson, AK, et al. JAMA dermatology, (2016)
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What are the determinants of “high risk” in
the skin cancer field?
❖ High risk patientA patient is considered high risk due to the increased
likelihood of developing new skin cancers over time.
High risk categories:• Patients with a history of 4 or more skin cancers
• Patients with immunosuppression
• Patients with genetic mutations that predispose them to skin cancer
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Amplified risk of new keratinocyte carcinoma in
patients with a history of skin cancer
Wehner, MR, et al. JAMA dermatology, (2015)
KC: keratinocyte carcinoma
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Amplified risk of new SCC in patients with a
history of SCC
Tokez, S, et al. JAMA dermatology, (2020)
Netherlands Cancer Registry
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Amplified risk of new SCC in patients with a
history of SCC
Tokez, S, et al. JAMA dermatology, (2020)
Netherlands Cancer Registry
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Patients with specific propensity to multiple
new SCCs on lower legs
Tallon, B, et al. Australas J Dermatol, (2013)
❖ Multiple lower leg SCCs UV exposure cannot explain the specific susceptibility to
SCCs on lower legs. Other cancer promoting factors need
to be investigated.
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Markedly increased risk of new skin cancer
in immunosuppressed patients
❖ Immunosuppressed patientsAcquired or inherited immunosuppression leads to a
dramatic increase in the risk of keratinocyte carcinoma.
Causes of immunosuppression:• Organ transplantation (iatrogenic immunosuppression)
• Chronic lymphocytic leukemia (acquired immunosuppression)
• HIV/AIDS (acquired immunosuppression)
• Ulcerative colitis and other inflammatory diseases that require
long-term systemic immunosuppression
• Epidermodysplasia Verruciformis (inherited error of immunity)
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Markedly increased risk of new skin cancer
in immunosuppressed patients
❖ Organ Transplant recipientsImmunosuppressive treatment leads to over 100-fold
increase in the risk of SCC.
0.1 1 10 10
0
1000
1000
0
MelanomaBasal cell carcinoma
Squamous cell carcinoma
Standardized Incidence Ratio (compared to general population)
Mittal, A, et al. American journal of transplantation, (2017)
Grulich, AE, et al. Lancet, (2007)
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Markedly increased risk of new AK-SCC in
immunosuppressed patients
❖ AK-SCC spectrum lesions
1 cm
Squamous cell
carcinoma in situ
(SCCIS)
Squamous cell
carcinoma
(SCC)
Actinic keratosis
(AK)
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What defines SCC risk in organ transplant
recipients?
❖ Risk of developing multiple new SCCs over time
❖ Risk of developing a high-risk SCC
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45yo female
Organ transplant recipients are at risk of
developing multiple SCCs over time
Immunosuppressive meds:
• Block TCR signaling (e.g.,
calcineurin inhibitors, tacrolimus and
cyclosporine)
• Inhibit T cell proliferation (e.g.,
azathioprine, mycophenolate
mofetil)
• Inhibit cytokine signaling in T cells
(e.g., prednisone)
• Suppress mTOR signaling (e.g.,
sirolimus)
• Block T cell co-stimulation axis
(e.g., Belatacept)
Systemic immunosuppression increases the risk of AK and SCC.
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Belatacept
Cyclosporine
Imuran
AzathioprinePrograf
Prednisone
CellCept
TacrolimusMycophenolate mofetil
MyforticSirolimus
Rapamune
Everolimus
Afinitor
Impact of immunosuppressive medications
on SCC risk
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Cyclosporine increases SCC risk beyond
immunosuppression
Wu, X, et al. Nature, (2010)
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Azathioprine increases SCC risk beyond
immunosuppression
Inman, GJ, et al. Nature communications, (2018)
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Organ transplant recipients are at risk of
developing high-risk SCC
Unresectable SCC treatment options:
• Radiation
• Chemotherapy (e.g., capecitabine)
• Targeted therapy (e.g., cetuximab)
• Immunotherapy (e.g., cemiplimab)
• Experimental drugs in trial
Systemic immunosuppression increases the risk of aggressive SCC
development with limited therapeutic options for advanced disease
2 months
67yo male
s/p lung transplant
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Organ transplant recipients are at risk of
developing high-risk SCC
Unresectable SCC treatment options:
• Radiation
• Chemotherapy (e.g., capecitabine)
• Targeted therapy (e.g., cetuximab)
• Immunotherapy (e.g., cemiplimab)
• Experimental drugs in trial
Systemic immunosuppression increases the risk of aggressive SCC
development with limited therapeutic options for advanced disease
67yo male
s/p lung transplant
s/p WLE and lymph node resectionarrows point to in-transit metastasis
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Markedly increased risk of skin cancer in
patients with genetic predispositions
Hereditary mutations can increase the risk of skin cancer
Genetic mutations with increased skin cancer risk:• Xeroderma pigmentosum (increased risk of SCC, BCC, melanoma)
• Epidermodysplasia verruciformis (increased risk of SCC)
• Recessive dystrophic epidermolysis bullosa (increased risk of SCC)
• Basal cell nevus syndrome (Gorlin syndrome; increased risk of BCC)
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Skin cancer prevention is key to optimal
care for high-risk patients
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Treatment modalities for skin cancer
prevention in high-risk patients
UV protection
AK treatment:• Cryotherapy
• Topical 5-fluorouracil (5-FU)
• Photodynamic therapy
• Topical imiquimod
• Topical calcipotriol plus 5-fluorouracil (5-FU)
Skin cancer screening for early detection and treatment
Nicotinamide (500mg BID)
Acitretin (up to 25mg qdaily)
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Topical Immunotherapy (clinical trial outcome)
Week 8
Shawn Demehri, Calcipotriol final analysis 20MAY15 M.Wallendorf
Drug
Perc
ent
Reduction W
eek 8
Location = LUELocation = RUE
Location = FaceLocation = Scalp
A BA B
-100
-50
0
50
100
-100
-50
0
50
100
SCALP FACE
RUE LUEP < 0.0001 P < 0.0001
P < 0.0001 P < 0.0001
% R
ed
uctio
n in
AK
No
.
Cunningham, TJ, et al. JCI, (2017)
Treatment regimen: BID x 4 days
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Vaselin
e+
5-F
UC
alc
ipotr
iol+
5-F
UAK @ day 5 (after treatment)
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AK @ day 5 (after treatment)C
alc
ipotr
iol+
5-F
U
CD4
CD8
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27
Calcipotriol + 5-FU Vaseline + 5-FU P value
Type of lesionParticipants With ≥1
Lesion, n (%)
Participants With ≥1
Lesion, n (%)
Year 1
SCC 1 of 32 (3) 4 of 40 (10) 0.25
Year 2
SCC 2 of 31 (6) 7 of 40 (18) 0.17
Year 3
SCC 2 of 30 (7) 11 of 40 (28) 0.027
SCC prevention on face/scalp after
calcipotriol plus 5-FU treatment
Rosenberg , AR, et al. JCI Insight, (2019)
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Can immunotherapy prevent skin cancer in
high-risk patients?
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Patient Case
• 17yo XP female arrived from Dominican Republic and presented to High Risk Skin Cancer Clinic at MGH (4/14/16)
• PMHx: spindle cell melanoma and multiple SCC
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PE:
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Patient Case
• Referred to Oncology
– Pembrolizumab started (11/30/16) x 1yr with
CR
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Pembrolizumab
www.cancer.gov
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Induce immunogenic
cell death in tumor
Therapeutic Strategy to prevent SCC in our
XP patientCALCIPOTRIOL 5-FU
Increase cytokine
expression in tumor
Induce T cell immunity
against tumor cells
Optimal antitumor
immune response to
prevent SCC
PD1/PDL1 axis blockade
and potentiation of T cell
immunityPEMBROLIZUMAB
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Tumor Incidence
-230
-18
8
-153
-11
8-9
7-6
9
-41 0
-51
Time from ICB therapy start (days)
8 months before ICB
8
69
3
43
70
10
51
40
18
22
03
25
22
87
31
5
75
37
13
43
41
34
41
51
85
52
60
26
30
65
8
72
17
42
78
4
26 months after ICB
…
Invasive SCC
SCCIS
Calcipotriol plus 5-FU
Pem
bro
lizum
ab s
tart
date
Pembrolizumab
Ameri , AH, et al. BJD, (2019)
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• In the skin cancer field, high-risk patients aredefined as patients who are at risk of developingmultiple new skin cancers over time in additionto the risk of developing of an aggressivecancer.
• The burden of disease in this population ismainly determined by the many surgeries theyendure for skin caner treatments.
• Novel strategies for optimal skin cancerprevention in high-risk populations are urgentlyneeded.
Conclusions
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Demehri Lab
Dr. Lynn CorneliusDr. Wayne YokoyamaDr. Abby RosenbergMary TabacchiDr. Michael WallendorfDr. Ilana RosmanDr. Andras Schaffer
Washington University
Acknowledgement
Cincinnati Children's Hospital
Dr. Rafi KopanAhu Turkoz
Trevor CunninghamKenneth NgoDr. Jean-Pierre ElianeDr. Sara Moradi TuchayiSindhu ManivasagamHengameh Mirzaalian
MGH
High Risk Skin Cancer Clinic Patients
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