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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

www.mghcme.org

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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