Uncommon locations for melanoma and uveal melanoma

2014

Lorenzo AlonsoMedical Oncology

www.foro-osler.com

Please, could you try to figure out some melanoma locations beyond the skin and subcutaneous area?

Sinus

intracardiac

Bronchial mucosa

Small bowel metastases

Genital/anal

subungueal

Toes/ sole

gingiva

Cardiac metastases from melanoma

Right atrium is the most common site.

Clinical scenario

• Melanoma, anemia, abdominal lump

Metastases to small bowel: usually can be resected

Uveal melanoma: pathophysiology

Location % 5-year mts. %10-year mts

Iris 4% 7%

Ciliary body 19% 33%Choroides 15% 25%

Predrag Jovanovic et al.Int J Clin Exp Pathol 2013;6(7):1230-1244

Conjuntival melanoma is related more with its cutaneous counterpart

Ocular melanoma: pathophysiology

Liver: 93% mts Lung: 24% mts.

WHY?Bones: 16% mts

Local treatment

Radiotherapy (plaque) and surgery (enucleation) achieve the same outcome…but not without harm

Uveal melanoma prognosis

Class 1: low grade tumors with low metastatic risk

Class 2: high grade tumors with metastatic risk chracterized by down-regulation of genes on chromosome 3 and up-regulation of genes on chromosome 8q.

Monosomy of chromosome 3 is the most frequent chromosome aberration in uveal melanoma (50%)

BAP1: BCRA-1 associated protein-1 and metastatic development of uveal melanoma

The gene encoding BAP-1 is located on chromosome 3p21.1 and is mutated in 80% of metastatic uveal melanoma. BAP-1 is a enzyme that forms part of a tumor-suppressor complex. BAP-1 mutation is associated to metastatic behaviour

Uveal melanomaTreatment options

• Ipilimumab

• Chemotherapy: nanoparticles(taxanes)

• MAPK pathway: MEK

• Protein kinase C (PKC)

Outcome after compassionate use (USA, Italy):1-year overall survival over 30%.More common dose: 3 mg/KgMedian overall survival 6 months (Italian use)Toxicity experience and response similar to cutaneous

Ipilimumab in metastatic uveal melanoma

Uveal melanoma: rational for treatment

GNAQ and GNA11 are mutated in a mutually exclusive pattern (83% uveal): these mutations are implicated in the stimulus of MAPK pathway via MEK.

GNAQ/GNA11 signals also via PLC(phospholipase C) and PKC (protein kinase C), enzymes implicated in proliferation, invasion,apoptosis via ERK

Cancer Letters 2006;235:1-10

Therapeutic targets

• MEK inhibitors: (no response in wild-type GNAQ/GNA11)– Selumetinib compared with temozolamide; 9 weeks benefit for

selumetinib for PFS– MEK162

• PAK inhibitors: sotrastaurin (AEB071)/ enzastaurin.– G1 cell cycle arrest– Inhibition of PKC in GNAQ-mutant resulted in the inhibition of the

MAPK pathway.

A combination of a MEK and proteinkinase inhibitor could be a perfect therapeutic combination

Conclusions

• 1. Metastases from melanoma can spread to almost every anatomical location.

• 2. Uveal melanoma is the most common primary malignancy of the eye

• 3. GNAQ and GNA11 are mutated in 80% of uveal melanoma in a mutually exclusive pattern

• 4. Ipilimumab achieves a 30% survival in the first year in uveal melanoma

• 5. MEK inhibitors and PAK inhibitors are key for developing targeted therapies.