The incidence of melanoma has recently been increasing. BRAF mutations have been found in 40–60% of melanomas. The increased activity of BRAF V600E leads to the activation of downstream signaling through the mitogen-activated protein kinase (MAPK) pathway, which plays a key role as a regulator of cell growth, differentiation, and survival. The use of BRAF inhibitors in metastatic melanoma with BRAF mutation ensures clinical improvement of the disease. Vemurafenib and dabrafenib are two selective BRAF inhibitors approved by the Food and Drug Administration (FDA). Both drugs are well tolerated and successfully used in clinical practice. However, some adverse reactions have been reported in patients in the course of treatment. Cutaneous side effects are the most common adverse events among them with a broad spectrum. Both the case reports and several original clinical trials reported cutaneous reactions during the treatment with BRAF inhibitors. In this review, the common cutaneous side effects of BRAF inhibitors in the treatment of metastatic melanoma with BRAF V600E mutation were reviewed.
Melanoma is a lethal type of skin cancer that is derived from melanocytes. The incidence of melanoma has been increasing in recent decades and the mortality is approximately 10% [
Until recently, dacarbazine and interleukin-2 were the only agents approved by the Food and Drug Administration (FDA) for the standard treatment of metastatic melanoma [
The mitogen-activated protein kinase (MAPK) is an important signaling pathway that plays a key role as a regulator of cell growth, differentiation, and survival. When an extracellular ligand binds to specific plasma membrane receptor tyrosine kinase, a series of phosphorylation including RAS, RAF, MEK, and ERK mediates the growth signals to the nucleus to promote cell proliferation, differentiation, and survival [
The mutation of the MAPK pathway is the critical point at the pathogenesis of melanoma. BRAF mutations were found in approximately 40–60% of cutaneous melanomas and V600E is the most common type of these mutations. It was shown that valine is substituted by glutamic acid at position 600 in 90% of BRAF mutant melanomas [
After the discovery of BRAF mutations, clinical trials of targeted therapies of advanced melanoma show significant improvement. The selective inhibitors of mutant BRAF kinase have become the key component of the treatment of metastatic disease. Vemurafenib and dabrafenib are two BRAF inhibitors (BRAFi) that have been licensed by FDA for the treatment of metastatic melanoma with mutant BRAF V600 [
Vemurafenib was the first selective tyrosine kinase inhibitor that demonstrated antitumor activity by blocking the activation of MAPK kinase pathway [
Dermatologic reactions related to the treatment of BRAFi in advanced melanoma are well known common side effects. The rate of cutaneous adverse events associated with vemurafenib was 92% to 95% of patients in the BRAF inhibitor melanoma (BRIM) studies [
Percentage of common (>5%) cutaneous adverse events with vemurafenib treatment.
Adverse events | Percentage (%) |
---|---|
Verrucous papilloma/wart | 22.2 [ |
Rash |
64–71 [ |
Photosensitivity | 22.2 [ |
Hand-foot skin reaction (PPD) | 5.6 [ |
Hair growth modification | 45 [ |
Actinic keratosis | 40 [ |
Alopecia | 11.1 [ |
Pruritus | 29 [ |
Xerosis | 11.1 [ |
Milia | 26.7 [ |
cSCC and KA | 22.2 [ |
Panniculitis | 14 [ |
Keratosis pilaris | 16.7 [ |
Cheilitis | 14 [ |
BCC | 13.3 [ |
Nipple hyperkeratosis | 12 [ |
Nevi changes | 5.6 [ |
PPD: palmar-plantar dysesthesia; cSCC: cutaneous squamous cell carcinoma; KA: keratoacanthoma; BCC: basal cell carcinoma.
Indicated numbers beside the percentages denote the related references.
Percentage of common (>5%) cutaneous adverse events with dabrafenib treatment.
Adverse events | Percentage (%) |
---|---|
Actinic keratosis | 10.7 [ |
Hyperkeratosis | 27 [ |
Pruritus | 5.35 [ |
Photosensitivity | 2.67 [ |
Panniculitis | 33.3 [ |
Keratosis pilaris | 33.3 [ |
Alopecia | 28.8 [ |
Skin papilloma | 15 [ |
Palmar-plantar dysesthesia | 20.32 [ |
Rash | 18.72 [ |
Dry skin | 10.7 [ |
Seborrheic keratosis | 8.56 [ |
Hair texture abnormal | 6.42 [ |
cSCC | 1.6 [ |
cSCC: cutaneous squamous cell carcinoma.
Indicated numbers beside the percentages denote the related references.
Skin rash was one of the most commonly reported AEs [
Boussemart et al. reported grade 1 xerosis in 33% of patients with a median time of 57 days. Xerosis could provoke mild pruritus [
Anforth et al. reported acneiform eruptions in 3% of patients who were treated with BRAFi longer than 52 weeks. These lesions were seen at areas such as face, trunk, and upper limbs [
Boussemart et al. described grade 1 or 2 erythematous hyperkeratotic follicular papules on the arms and thighs that were usually associated with bilateral nipple hyperkeratosis. The incidence of these eruptions was 55% of patients with a mean time to onset of 32 days. The histopathological examination of the skin biopsy revealed pilar dystrophy and folliculitis [
Grade 1 and 2 hand-foot skin reactions were observed with the mean time to onset of 61 days in 60% of patients in the study by Boussemart et al. Hyperkeratotic, yellowish, and painful plaques were localized on the soles [
Boussemart et al. reported that, three weeks after the drug initiation, one patient developed greasy, scaly papules on the back with gingival lesions that indicated Darier’s disease with distinctive histopathological findings [
Cutaneous granulomatous eruption is a very rare side effect due to BRAFi therapy. Park et al. reported two cases of granulomatous reactions during BRAFi treatment. The first patient developed multiple erythematous and violaceous papules and erythematous indurated plaque after two months of dabrafenib and trametinib (MEK inhibitor) initiation. The lesions occurred on the areas of the metastatic subcutaneous disease. While the first biopsy revealed granulomatous inflammation with no melanoma cells, the second biopsy revealed granulomatous inflammation surrounding melanoma cells. It was speculated that the cause of the reaction was an immune response or activation against melanoma cells and indicated a positive therapeutic sign. The eruption resolved completely with clobetasol ointment use within two weeks. The second patient developed multiple erythematous, violaceous papules on his extremities after five months of vemurafenib treatment. The biopsy revealed granulomatous dermatitis with focal necrosis. The lesions disappeared spontaneously after the cessation of treatment and did not appear again after the resume of vemurafenib [
Garrido et al. reported that a patient developed erythematous nonpruritic plaques on his trunk and arm during dabrafenib and trametinib (MEK inhibitor) treatment. The histopathological findings of the first biopsy revealed granulomatous inflammation, admixed with melanophages. The second biopsy demonstrated granulomatous reaction. Atypical cells were not seen in either biopsy. The lesions improved spontaneously within few weeks [
Boussemart et al. described that 14% of patients developed panniculitis on the lower extremities. Lesions occurred with the mean time to onset of 78 days [
Hair growth changes were observed in patients during BRAFi treatment such as cymotrichous, alopecia, or slower and thinner scalp hair growth [
Photosensitivity reaction was one of the most reported adverse events related to BRAFi. The photosensitivity incidence was 52% in the BRIM 2 study, 7% with grade 2, and 1% with grade 3 in the BRIM 1 study of patients treated with vemurafenib [
Both benign and malignant skin lesions occurred as side effects during BRAFi treatment. Cutaneous squamous cell carcinoma (cSCC) and keratoacanthoma (KA) were seen more frequently.
The incidence rate of cSCC or KA development was 22.2%–26% in Sanlorenzo et al.’s study and the BRIM 2 study, respectively [
The underlying mechanism of cutaneous neoplasia was paradoxical activation of the MAPK pathway in sun-damaged skin cells with preexisting RAS mutations. BRAFi activated CRAF signaling in wild-type cells that induce ERK signaling, which promoted the development of cSCC [
Basal cell carcinoma was also observed in patients during treatment with both vemurafenib (13.3%) and dabrafenib (4%) [
Actinic keratoses (AKs) were well-described lesions in patients during BRAFi treatment. Sanlorenzo et al. reported AKs in 44.4% of patients during vemurafenib treatment and 66.7% of patients during dabrafenib treatment [
Changes in melanocytic lesions were seen in patients with advanced melanoma during treatment with BRAF inhibitors [
Zimmer et al. analyzed 22 cutaneous melanocytic lesions in 19 patients with metastatic melanoma, undergoing treatment with selective BRAF inhibitors. Seven invasive and five in situ melanomas developed in 11 patients with a mean time of eight weeks. None of these 12 new primary melanomas harbored the BRAF V600 mutation. Five of these new melanomas appeared on sun-exposed areas. Nine of ten preexisting nevi were classified as dysplastic nevi and one lesion was classified as a common nevus. The mean time of change was 17.5 weeks [
Anforth et al. reported a patient who developed eruptive nevi during the treatment of a new selective BRAF inhibitor LGX818. Multiple lesions occurred on the back, chest, and leg, two months after the treatment. The histopathological examination revealed pigmented compound nevus [
Sanlorenzo et al. observed warts in the course of BRAFi treatment in 22.2% of patients [
Mattei et al. reported 26.7% of patients developed milia and one patient developed infundibular occlusion cysts [
Garrido et al. described a patient that developed multiple nodular lesions on his back during vemurafenib treatment for advanced melanoma. The lesions occurred after four months of treatment. The biopsy was performed and histopathological findings revealed primary, cutaneous small/medium CD4 T-cell lymphoma. The authors believed that the activation of immunity that was induced by vemurafenib was the cause of this situation [
BRAF inhibitors have a crucial role in patients with inoperable metastatic melanoma. They have significant benefits in the prognosis, but some cutaneous adverse reactions can occur in their clinical use. The combination therapies with MEK inhibitors reduce the side effects that occur with monotherapy alone. The patients undergoing BRAFi treatment should be examined in the course of the treatment periodically by selective dermatologic working groups. Early diagnosis and treatment of these cutaneous side effects can improve the patient’s quality of life.
The authors declare that there is no conflict of interests regarding the publication of this paper.