Uveal melanoma and uncommon locations


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Concepts about bases for the treatment of uveal melnoma and some uncommon location of cutaneous melanoma

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Uveal melanoma and uncommon locations

  1. 1. Uncommon locations for melanoma and uveal melanoma 2014 Lorenzo Alonso Medical Oncology www.foro-osler.com
  2. 2. Sinus gingiva intracardiac Bronchial mucosa Small bowel metastases Genital/anal subungueal Toes/ sole Please, could you try to figure out some melanoma locations beyond the skin and subcutaneous area?
  3. 3. Cardiac metastases from melanoma Right atrium is the most common site.
  4. 4. Clinical scenario • Melanoma, anemia, abdominal lump Metastases to small bowel: usually can be resected
  5. 5. Uveal melanoma: pathophysiology Location Iris % 5-year mts. %10-year mts 4% 7% Ciliary body 19% 33% Choroides 15% 25% Conjuntival melanoma is related more with its cutaneous counterpart Predrag Jovanovic et al. Int J Clin Exp Pathol 2013;6(7):12301244
  6. 6. Ocular melanoma: pathophysiology Liver: 93% mts Lung: 24% mts. WHY? Bones: 16% mts
  7. 7. Local treatment Radiotherapy (plaque) and surgery (enucleation) achieve the same outcome…but not without harm
  8. 8. Uveal melanoma prognosis Monosomy of chromosome 3 is the most frequent chromosome aberration in uveal melanoma (50%) 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.
  9. 9. 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
  10. 10. Uveal melanoma Treatment options • • • • Ipilimumab Chemotherapy: nanoparticles(taxanes) MAPK pathway: MEK Protein kinase C (PKC)
  11. 11. Ipilimumab in metastatic uveal melanoma Outcome after compassionate use (USA, Italy): 1-year overall survival over 30%. More common dose: 3 mg/Kg Median overall survival 6 months (Italian use) Toxicity experience and response similar to cutaneous
  12. 12. 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
  13. 13. 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
  14. 14. 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.