Mutant BRAF inhibitors: their cutaneous manifestations and the mechanisms leading to epidermal hyperproliferation and malignancy

This thesis addresses the important topic of the cutaneous side effects of type 1 BRAF inhibitors (BRAFi). These agents are now widely utilized in therapy for treatment of American Joint Committee on Cancer (AJCC) stage IV mutant BRAF metastatic melanoma. For this reason knowledge of the side effects of BRAFi therapy is of paramount importance. This research project was designed to firstly identify and formally diagnose the cutaneous side effects present in patients taking BRAFi. Attempts were then made to identify the mechanisms at play, focusing mainly on the role of the Mitogen Activate Protein Kinase (MAPK) pathway. Finally, in order to improve the patients’ quality of life, different preventative and treatment options were investigated

Mutant BRAF inhibitors: their cutaneous manifestations and the mechanisms leading to epidermal hyperproliferation and malignancy

This thesis addresses the important topic of the cutaneous side effects of type 1 BRAF inhibitors (BRAFi). These agents are now widely utilized in therapy for treatment of American Joint Committee on Cancer (AJCC) stage IV mutant BRAF metastatic melanoma. For this reason knowledge of the side effects of BRAFi therapy is of paramount importance. This research project was designed to firstly identify and formally diagnose the cutaneous side effects present in patients taking BRAFi. Attempts were then made to identify the mechanisms at play, focusing mainly on the role of the Mitogen Activate Protein Kinase (MAPK) pathway. Finally, in order to improve the patients’ quality of life, different preventative and treatment options were investigated

Acneiform eruption in a patient with metastatic melanoma after ceasing combination dabrafenib/trametinib therapy

BRAF inhibitors (BRAFi) and MEK inhibitors (MEKi) increase survival in BRAF mutant metastatic melanoma patients; however, they induce a well-known spectrum of cutaneous side effects during treatment. Whereas the BRAFi dabrafenib induces cutaneous squamous cell carcinomas and verrucal keratosis, the MEKi trametinib frequently induces acneiform eruptions that are reversible after drug discontinuation. Furthermore, when dabrafenib and trametinib are used in combination, there are fewer cutaneous toxicities. We report a patient with BRAF mutant metastatic melanoma treated with the BRAFi/MEKi combination therapy who developed an acneiform eruption after treatment discontinuation rather than during active therapy. Moreover, the eruption resolved when the combination treatment was reintroduced and recurred after increasing the dose of trametinib. The eruption may be explained by the longer half-life of trametinib (4.5 days) compared with dabrafenib (5.2 h). This is the first case reported with this particular side effect induced after stopping the treatment and could become more frequent as the BRAFi/MEKi combination of drugs is more frequently prescribed.3 page(s