Melanoma

Question 1

What is melanoma? Epidemiology? Mutations?

Answer 1

It is a malignant tumor of melanocytes. 5th most common cancer in men and the seventh in women. Treated with a combination of surgery, chemotherapy, targeted therapies, and immune-based therapies.

5 year survival rates for patients with metastatic disease, unfortunately, are below 10%.
It has been classified according to pathologic and clinical characteristics such as histology and anatomic site of origin. Subsets of melanoma can be further defined at the molecular level by recurrent ‘driver’ mutations leading to constitutive activation of signaling proteins. -

With melanoma there are mutations and hyper-activated pathways. Mutations in BRAF, GNA11, GNAQ, KIT, MEK1, and NRAS can be found in approximately 70% of all melanomas. In addition, mutations in CTNNB1 have also been described in melanoma.

Question 2

BRAF mutation?

Answer 2

Somatic mutations in BRAF have been found in 50% of malignant melanomas, especially melanomas derived from skin without chronic sun-induced damage. The most prevalent breath mutations are missense mutations, at valine 600.
Approximately 80-90% of V600 mutations are V600E (val to glu) while 5-12% are V600k (val to lys).

While BRAF inhibitor therapy is associated with clinical benefit in most patients with BRAF V600E- mutated melanoma, resistance to treatment and tumor progression occurs in nearly all patients, usually in the first year.

Question 3

Targeted therapy and immune checkpoint inhibitors?

Answer 3

Vemurafenib : used in late stage melanoma targets BRAF V600.

Dabrafenib : used in BRAF V600 melanoma but also NSCLC and thyroid cancer.

Nivolumab or pembrolizumab : ICI anti PD1, used in combination with dabrafenib.

Atezolizumab : ICI anti PD1.