Significant increase in melanoma incidence

The incidence of melanoma continues to rise steadily for more than 30 years. This increase is largely at the expense of melanomas with a good prognosis, so mortality and/or life expectancy are not dependent on these data.

The growth in incidence in the last decade, both in situ melanoma and invasive melanoma, is 2.6% per year, with in situ melanoma growing by 9.5% per year.
This increase represents one of the fastest growth rates among neoplastic processes, according to data from the American Epidemiology Center. However, there are some researchers who suggest that this is due more to improved diagnostics and surveillance campaigns than to the actual increase in cases.

Advances in melanoma diagnosis

Non-invasive examinations are achieving greater accuracy in early diagnosis, with a significant reduction in the number of biopsies required to diagnose melanoma. There is a meta-analysis that supports this hypothesis: dermoscopy achieves a sensitivity of 90% compared to 74% for plain vision.

Therefore, in a non-specialized clinic 30 nevi need to be removed to detect a melanoma, whereas in expert hands only 9 are removed.

Recently, new applications of dermoscopy have been investigated: in particular, the correlation of some particular dermoscopic signs and the mutational status of the BRAF gene. The presence of ulceration and irregular peripheral striae correlated with BRAF mutations, while thickened vessels are predictors of wild-type melanoma.

The foundations are now being laid for the use of refractance focal microscopy (RCM) in the early diagnosis of melanoma. It is proving useful in lesions located in the head and neck, and the number of nevi removed to detect melanoma after viewing with RCM is only 2.4, with 97% sensitivity and 72% specificity for the diagnosis of melanoma.

Advances in melanoma treatment

Recent Nobel Laureates in Medicine, James P. Allison and Tasuku Honjo, have highlighted the momentous discovery of cancer treatment by regulating the negative immune response, and melanoma is one of the tumors that is benefiting most from this technique.
The revolution has come through personalized or precision oncology, with new treatments for metastatic melanoma, which have increased the immune response or blocked proliferation. For this reason, they are giving excellent results in the control of the disease.

Ipilimumab is an IG1-type monoclonal antibody developed to inhibit CTLA-4 activity and allow T-cell activity and proliferation. Clinical trials with ipilimumab have shown high efficacy with survivors of more than 3 years.

Another treatment is the use of anti-PD-1 antibodies which, like CTLA-4, regulate a different point of the immune response and cause activation of effector T cells in the vicinity of the tumor. These are humanized IgG4 monoclonal antibodies approved to treat metastatic melanomas with unresectable disease. They achieve an improvement in survival at the cost of increased toxicities that force treatment to be discontinued in 21% of cases.

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The origin of the BRAF gene mutation

The mutation in the BRAF gene appears in 50% of melanomas, through the substitution of glutamic acid for valine at position 600 (p.V600E), and appears in dysplastic and acquired nevi. However, these nevi do not undergo malignant transformation, because the cell cycle is contained by the cell inhibitor p16.
The V600E mutation is not the classic UVB mutation, and has been shown to occur in areas of intermittent sun exposure rather than chronic exposure, in sun-damaged skin and in non-sun-exposed locations such as acral or mucosal. This suggests that the origin of the mutations are not physical or chemical causes, but complex genetic interactions. These alterations are lethal without genetic repair.

The most effective treatments

The two main BRAF inhibitors are vemurafenib and dabrafenib, and they have demonstrated excellent antitumor efficacy in patients with disseminated metastatic melanomas expressing BRAF mutation. They have shown positive results in survival, which doubles that achieved with dacarbazine. Among the multiple toxicities that dermatologists can see in these therapies, the most common are the appearance of keratoacanthomas and epidermoid carcinomas.

Other treatments such as Trametinib, Binimetinib, Selumetinib, belong to the group of MEK-1 and MEK-2 inhibitors. They are administered orally and have shown good efficacy, but also multiple adverse effects in various organs.

The study of therapies by meta-analysis shows that the use of BRAF inhibitors (either alone or in combination with MEK inhibitors) and anti-PD-1 monoclonal antibodies (alone or in combination with anti-CTLA-4) are the most effective treatments for patients with metastatic melanomas in relation to progression-free survival, with the following considerations:

  1. BRAF inhibitors are only effective in those patients with BRAF-mutated melanomas.
  2. BRAF inhibitors, in combination with MEK inhibitors, are the most effective regimen in patients with BRAF-mutated melanoma, at least in terms of disease-free survival.
  3. Anti-PD monoclonal antibodies are the least toxic regimen, but the combination with immune checkpoint inhibitors has the highest toxicity.

In conclusion, immune-based treatments and molecular targets are showing very promising results, achieving a radical change in the survival of patients with metastatic melanoma and converting, in many cases, a lethal disease into a chronic disease.