The Past, Present and Future of Uveal Melanoma - 2019 CURE OM Symposium

All Rights Reserved, Duke Medicine 2007
Eyes on a Cure: Patients & Caregiver Symposium
April 5-7, 2019
Uveal Melanoma: Past, Present and Future
Miguel A. Materin, M.D.
Professor of Ophthalmology
Professor of Radiation Oncology
Director, Ophthalmic Oncology

YOU ARE NOT ALONE!!!!

Disclosure:
Castle Biosciences (Advisor/Consultant)
Ideaya Biosciences (Advisor/Consultant)

• Collaborative Ocular Melanoma Study Group: Accuracy of diagnosis of choroidal melanomas in the Collaborative Ocular Melanoma Study. COMS Report No. 1. Arch Ophthalmol 108:1268-1273,
1990.
• Collaborative Ocular Melanoma Study Group: Complications of enucleation surgery. COMS Report No. 2. In: Proceedings of the Symposium on Retina and Vitreous (Rudolph M. Franklin, ed.).
New Orleans Academy of Ophthalmology. Kugler Publications, New York, 1993; pp. 181-190.
• Collaborative Ocular Melanoma Study Group: Design and methods of a clinical trial for a rare condition: The Collaborative Ocular Melanoma Study. COMS Report No. 3. Controlled Clin Trials
14:362-391, 1993.
• Collaborative Ocular Melanoma Study Group: Mortality in patients with small choroidal melanoma. COMS Report No. 4. Arch Ophthalmol 115:886-893, 1997.
• Collaborative Ocular Melanoma Study Group: Factors predictive of growth and treatment of small choroidal melanoma. COMS Report No. 5. Arch Ophthalmol 115:1537-1544, 1997.
• Collaborative Ocular Melanoma Study Group: Histopathologic characteristics of uveal melanomas in eyes enucleated from the Collaborative Ocular Melanoma Study. COMS Report No. 6. Am J
Ophthalmol 125:745-766, 1998.
• Collaborative Ocular Melanoma Study Group: Sociodemographic and clinical predictors of participation in two randomized trials: Findings from the Collaborative Ocular Melanoma Study. COMS
Report No. 7. Controlled Clin Trials 22:526-537, 2001.
• Grossniklaus HE, Albert DM, Green WR, Conway BP, Hovland KR for the Collaborative Ocular Melanoma Study Group: Clear cell differentiation in choroidal melanoma. COMS Report No. 8. Arch
Ophthalmol 115:894-898, 1997.
• Collaborative Ocular Melanoma Study Group: The Collaborative Ocular Melanoma Study (COMS) randomized trial of pre-enucleation radiation of large choroidal melanoma. I: Characteristics of
patients enrolled and not enrolled. COMS Report No. 9. Am J Ophthalmol 125:767-778,1998.
• Collaborative Ocular Melanoma Study Group: The Collaborative Ocular Melanoma Study (COMS) randomized trial of pre-enucleation radiation of large choroidal melanoma. II. Initial mortality
findings. COMS Report No. 10. Am J Ophthalmol 125:779-796,1998.
• Collaborative Ocular Melanoma Study Group: The Collaborative Ocular Melanoma Study (COMS) randomized trial of pre-enucleation radiation of large choroidal melanoma. III. Local
complications and observations following enucleation. COMS Report No. 11. Am J Ophthalmol 126:362-372, 1998.
• Collaborative Ocular Melanoma Study Group: Echography (ultrasound) procedures for the Collaborative Ocular Melanoma Study. COMS Report No. 12. J Ophth Nurs Technol Part I, 18(4):143-
149, Part II, 18(5):219-232, 1999.
• Collaborative Ocular Melanoma Study Group: Consistency of observations from echograms made centrally in the Collaborative Ocular Melanoma Study. COMS Report No. 13. Ophthalmic
Epidemiol 9:11-27, 2002.
• Collaborative Ocular Melanoma Study Group: Cause-specific mortality coding: Methods in the Collaborative Ocular Melanoma Study. COMS Report No. 14. Control Clin Trials 22: 248-262, 2001.
Uveal Melanoma: C.O.M.S.

• Collaborative Ocular Melanoma Study Group: Assessment of metastatic disease status at death in 435 patients with large choroidal melanoma in the Collaborative Ocular Melanoma Study.
COMS Report No. 15. Arch Ophthalmol 119:670-676, 2001.
• Collaborative Ocular Melanoma Study Group: Collaborative Ocular Melanoma Study (COMS) randomized trial of I-125 brachytherapy for medium choroidal melanoma. I. Visual acuity after 3
years. COMS Report No. 16. Ophthalmology 108(2):348-366, 2001.
• Collaborative Ocular Melanoma Study Group: The COMS randomized trial of iodine 125 brachytherapy for choroidal melanoma. II. Characteristics of patients enrolled and not enrolled. COMS
Report No. 17. Arch Ophthalmol 119: 951-965, 2001.
• Collaborative Ocular Melanoma Study Group: The COMS randomized trial of iodine 125 brachytherapy for choroidal melanoma. III. Initial mortality findings. COMS Report No. 18. Arch Ophthalmol
119: 969-982, 2001.
• Collaborative Ocular Melanoma Study Group: The COMS randomized trial of iodine 125 brachytherapy for choroidal melanoma. Local treatment failure and enucleation in the first 5 years after
brachytherapy. COMS Report No. 19. Ophthalmology 198:2197-2206, 2002.
• Collaborative Ocular Melanoma Study Group: Trends in size and treatment of recently diagnosed choroidal melanoma, 1987-1997. Findings from patients evaluated at Collaborative Ocular
Melanoma Study centers. COMS Report No. 20. Arch Ophthalmol 121:1156-1162, 2003.
• Collaborative Ocular Melanoma Study Group: Comparison of clinical, echographic, and histologic measurements from eyes with medium-sized choroidal melanoma in the Collaborative Ocular
Melanoma Study. COMS Report No. 21. Arch Opthalmol 121:1163-1171, 2003.
• Collaborative Ocular Melanoma Study Group: Ten-year follow-up of fellow eyes of patients enrolled in Collaborative Ocular Melanoma Study (COMS) randomized trials. COMS Report No. 22.
Ophthalmology 111:996-976, 2004.
• Diener-West M, Reynolds SM, Agugliaro DJ, Caldwell R, Cumming K, Earle JD, Green DL, Hawkins BS, Hayman I, Jaiyesimi I, Kirkwood JM, Koh W-J, Robertson DM, Shaw JM, Thoma J.
Screening for metastasis from choroidal melanoma: Experience of the Collaborative Ocular Melanoma Study. Collaborative Ocular Melanoma Study Report No. 23. Am J Clin Oncol 22:2438-
2444, 2004.
• Collaborative Ocular Melanoma Study Group: The Collaborative Ocular Melanoma Study (COMS) randomized trial of pre-enucleation radiation of large choroidal melanoma. IV. Ten-year mortality
findings and prognostic factors. COMS Report No. 24. Am J Ophthalmol 138:936-951, 2004.
• Collaborative Ocular Melanoma Study Group: Second Primary Cancers After Enrollment in the COMS Trials for Treatment of Choroidal Melanoma. COMS Report No. 25. Arch Ophthalmol
123:601-604, 2005.
• Collaborative Ocular Melanoma Study Group. Development of metastatic disease after enrollment in the COMS trials for treatment of choroidal melanoma. Collaborative Ocular Melanoma Study
Group Report No. 26.Arch Ophthalmol 123:1639-1643, 2005.
• Collaborative Ocular Melanoma Study Group. Incidence of cataract and outcomes after cataract surgery in the first 5 years after 125I brachytherapy in the COMS. COMS Report No. 27.
Ophthalmology 2007.
• Collaborative Ocular Melanoma Study Group. The COMS randomized trial of iodine 125 brachytherapy for choroidal melanoma. V. Twelve-year mortality rates and prognostic factors. COMS
Report No. 28. Arch Ophthalmol 124:1684-1693, 2006.
Uveal Melanoma: C.O.M.S.
High diagnostic accuracy: medium and large size tumors
Medium size tumors: enucleation is not better than brachytherapy
Large size tumors: previous radiation has no benefit before enucleation

Cutaneous Melanoma

NCCN Guidelines for Patients®, translations of the NCCN clinical guidelines, are meant to help patients with
cancer talk with their physicians about the best treatment options for their disease.
The National Comprehensive Cancer Network® (NCCN®) is a not-for-profit alliance of 28 leading cancer
centers devoted to patient care, research, and education. NCCN is dedicated to improving and facilitating
quality, effective, efficient, and accessible cancer care so patients can live better lives.
NCCN Resources
NCCN offers a variety of resources to patients and their caregivers, including NCCN Guidelines for
Patients®, patient and payment assistance information, and clinical trial enrollment information.

• Workup and staging, tumor size, primary treatment
• Risk of distant metastases, systemic imaging based on risk
• Treatment of tumor recurrence/metastases
• Risk factors for development of uveal melanoma
• Clinical trials
• Others

• Ophthalmology. 2012 Aug;119(8):1596-603. doi:
10.1016/j.ophtha.2012.02.017. Epub 2012 Apr 21.
Collaborative Ocular Oncology Group report number 1: prospective
validation of a multi-gene prognostic assay in uveal melanoma.
• Collaborative Ocular Oncology Group 2: In progress (enrolling
phase) 28 centers
Uveal Melanoma: MULTICENTER COLLABORATION

• Most common primary intraocular malignancy
in adults (3%-5% of all melanomas)
• 5-7 new cases per million per year
• Median age at diagnosis: 55-60 years
• Caucasian
• Metastases to liver and lungs
Uveal Melanoma
• Incidence of noncutaneous melanomas in the U.S. 2005 American Cancer Society.
• Trends in incidence, survival, and management of uveal melanoma: a population-based study of 7,516 patients from the Surveillance, Epidemiology, and End Results
database (1973-2012). Clin Ophthalmol. 2016 Oct 25;10:2113-2119

• Males
• Non-Hispanic whites
• Low incidence in Asians and African Americans
• In Europe incidence increases with latitude
o 2 per million (Spain and Italy)
o 8 per million (Denmark and Norway)
Uveal Melanoma: Epidemiology
Virgili G, Gatta G, Ciccolallo L, et al. Incidence of uveal melanoma in Europe. Ophthalmology. 2007;114(12):2309–2315

• Light eyes
• Fair skin
• Ocular melanocytosis
• BAP1 mutations
• Role of sun exposure: controversial
• Welding?
Uveal Melanoma: Risk Factors

• Posterior choroidal melanomas: might be associated with adenine-to-
cytosine mutations
• Ciliochoroidal melanomas: might be associated with adenine-to-thymine
mutations and light eye color
Uveal Melanoma: Risk Factors
de Lange MJ, Razzaq L, Versluis M, et al. Distribution of GNAQ and GNA11 mutation signatures in uveal melanoma points to a light dependent mutation mechanism.
PLoS One. 2015;10(9):e0138002.

Uveal Melanoma
• Choroid: 85%-90%
• Ciliary Body: 5%-10%
• Iris: 3%-5%

Uveal Melanoma
• Blurred vision
• Flashes/floaters
• No symptoms
• Pain
• Red eye
• Others

15 year-old girl

Radiation Retinopathy

Small Choroidal Melanoma vs Large Choroidal Nevus

Choroidal Melanocytic Lesions

#1. Cytogenetic analysis
#2. Cytology
#3. Cell line
Fine Needle Aspiration Biopsy

Metastasis
by
Category
% at 1 Yr % at 3 Yrs % at 5 Yrs
% at 10
Yrs
% at 15
Yrs
% at 20
Yrs
T1 1% 4% 8% 15% 20% 25%
T2 1% 7% 14% 25% 32% 40%
T3 3% 19% 31% 49% 60% 62%
T4 11% 32% 51% 63% 68% 68%
American Joint Cancer Committee, 7th Edition Classification in 7731
Patients Is Predictive of Melanoma Metastasis

Choroidal Melanoma: Prognosis
Class 1B
SF3B1
6p+ 8q+
Class 1A
EIF1AX
6p+
Class 2
BAP1
M3 8q+
Higher risk
Intermediate risk
Lower risk

• More than 80% of uveal melanomas carry somatic mutations in
either GNAQ or GNA11
• Mutation of either gene is necessary but not sufficient for
malignant transformation
• Downstream effectors of are potential targets
for therapy
Gαq and Gα11
The New England Journal of Medicine (Editorial) Dec. 2010

Signaling Pathway in Uveal Melanoma
• Wild type for BRAF and NRAS
(cutaneous melanoma)
• Point mutation in G protein alpha
subunit
o GNAQ and GNA11 genes
Carvajal et al. Uveal melanoma: epidemiology, etiology,
and treatment of primary disease.
Clinical Ophthalmology 2017:11 279–289

Immunotherapy
T-cell therapy
Proliferation
inhibitors
MEKi PI3Ki PKCi
Epigenetic
modulators
HDACi
DNMTi
EZH2i
Uveal Melanoma
Clin Cancer Res. 2016 Mar 1;
22(5): 1234–1242.
NIHMSID: NIHMS735478
PRAME as an independent
biomarker for metastasis in
uveal melanoma
Matthew G. Field,1 Christina L.
Decatur,1 Stefan Kurtenbach,1
Gülçin Gezgin,2 Pieter A. van der
Velden,2 Martine J. Jager,2 Kaleigh
N. Kozak,1 and J. William Harbour1

• 20 year-old male
• Blurry vision OS
• OD: 20/20
• OS: 20/400
• MGGF ocular tumor with
liver metastases
Melan A (+)

27
Choroidal Melanoma: Epitheliod Cell Type
Gene Expression Profile: Class 2

Melanoma cell line: DNA sequencing
RPE
Melanoma
BAP 1
(+) Lung nodules
BAP 1
(+) Mother
MGGF died liver mets from
ocular tumor
Wild type: B-RAF
N-RAS

11/15/2017
37 year-old female
20/40 OD
20/20 OS (wnl)
PGF: colon cancer
PGM: uterine cancer
MGF: lung cancer

More info:
• On 11/15/2017 (day of presentation): 32 weeks pregnant
• Twins
• Scheduled C-section around Christmas (38 weeks)
• Patient is from Huntersville, NC

Results:
• FNAB: abnormal pigmented spindle cells and epithelioid cells,
compatible with clinical impression of melanoma
• Pathology: uveal melanoma (choroid, CB and TM), mixed cell
type
• GEP: Class 2; PRAME +
• Had uneventful C-section as originally planned

HUMAN INTEREST (PEOPLE.COM)
Mom of 4 Diagnosed with Rare Cancer Loses Eye
Weeks Before Giving Birth to Twins
North Carolina mother with rare eye cancer gives birth to
healthy twins (ABC7 NEWS)

Case Report
• 2013, 53 year-old white male
• Asymptomatic
• VA: 20/25 OD; 20/20 OS
• Pigmented choroidal mass superior to optic
disc
• 6.5 x 6.5 x 3 mm
• (+) Sub-retinal fluid, (+) orange pigmentation

Small Choroidal Melanoma in a patient with Oculo-Dermal Melanocytosis
- FNAB for GEP: Class 1A
- I 125 plaque

Pre-treatment 2 years post-treatment

2 years post-treatment

2 years post-treatment 2017

Choroidal Melanoma #2: 10x10x3.5

Choroidal Melanoma #2: 10x10x3.5
• FNAB for GEP
• I 125 plaque (#2)
CLASS 2

Choroidal Melanoma x 2
• #1: Class 1A, good prognosis (2013)
• #2: Class 2, poor prognosis (2017)
First tumor located superior to the optic nerve, before treatment (A) and after
treatment (B). Wide-view showing the first (treated) tumor superior to the optic
nerve (black arrow) and the second tumor along the distal inferotemporal arcade at
diagnosis (white arrow) (C). External photo demonstrating episcleral pigmentation
typical of ocular melanocytosis (D).

• Enucleation
• Radiation
o Radioactive plaque
o Proton Beam
o Others
• Transpupillary Thermotherapy
• Tumor resection
Choroidal Melanoma: Treatment
Goals
1. Life
2. Eye
3. Vision

Choroidal Melanoma Treatment: Enucleation

Choroidal Melanoma: Radioactive Plaque
S L I D E 11
Eye Physics
Bebig
COMS

Transpupillary Thermotherapy (TTT) as Primary Treatment
Choroidal Melanoma
Adjuvant Treatment to Brachytherapy

Choroidal Melanoma: Stereotactic Body Radiation Therapy

03/2018

01/2019

Thank you…

The Past, Present and Future of Uveal Melanoma - 2019 CURE OM Symposium

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The Past, Present and Future of Uveal Melanoma - 2019 CURE OM Symposium