title: Cutaneous toxicities of BRAF inhibitors: clinical and pathological challenges and call to action.
abstract: Somatic mutations in the BRAF gene have been identified as the most frequent and relevant to develop targeted molecular therapies in melanoma. Recently, seminal clinical trials have provided indisputable evidence that BRAF inhibitors improve response rate, progression free and overall survival in BRAFV600 mutated metastatic melanoma patients, thus representing the novel standard of care. Dermatological "off target" effects of these so-called 'targeted therapies' have to be considered, however, and among them the most intriguing are cutaneous adverse reactions. Skin toxicity is of relevance for at least three reasons: (1) it worsens the patient's quality of life and may be difficult to manage, (2) its heterogeneous clinical presentation differs from the clinico-pathological pictures observed in patients who do not receive BRAF inhibitors, and; (3) onset of skin cancer represents a model of carcinogenesis which may help to better understand the potential visceral tumorigenesis induced by BRAF inhibitors. This manuscript summarizes and critically reviews the state of the art of skin toxicity associated with BRAF inhibitors. Special attention will be paid to clinical presentation and histopathological findings, as well as related challenges for clinicians, pathologists, and basic scientists.
authors.affiliation: Medical Oncology Unit, Papa Giovanni XXIII Hospital, Bergamo, Italy. Electronic address: mariomandala@tin.it.
authors.forename: Mario
authors.initials: M
authors.lastname: Mandalà
authors.forename: Daniela
authors.initials: D
authors.lastname: Massi
authors.forename: Vincenzo
authors.initials: V
authors.lastname: De Giorgi
mesh_terms: D000970:Antineoplastic Agents / Q000009:adverse effects* / Q000627:therapeutic use; D002294:Carcinoma, Squamous Cell / Q000139:chemically induced / Q000175:diagnosis; D006801:Humans; D008545:Melanoma / Q000150:complications* / Q000188:drug therapy; D047428:Protein Kinase Inhibitors / Q000009:adverse effects* / Q000627:therapeutic use; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors; D012106:Research; D012867:Skin / Q000187:drug effects / Q000473:pathology; D012871:Skin Diseases / Q000139:chemically induced* / Q000175:diagnosis / Q000628:therapy
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D048493:Proto-Oncogene Proteins B-raf
keywords: BRAF inhibitors; Clinical; Histopathology; Management; Melanoma; Skin toxicity