BRAF inhibitor therapy-associated melanocytic lesions lack the BRAF V600E mutation and show increased levels of cyclin D1 expression.

Newly appearing or changing melanocytic lesions (MLs) are a recently reported toxicity of BRAF inhibitor (BRAFi) therapy. Morphologically, MLs associated with BRAFi therapy (BRAFi-MLs) may demonstrate alarming features of melanoma with an epithelioid cell phenotype with notable cytologic atypia. We sought to characterize the clinicopathological and molecular features of BRAFi-MLs. A retrospective review over a 4-year period revealed 20 patients in which 44 MLs (including 11 control nevi) were characterized by histopathology, review of clinical medical records, and immunohistochemical (IHC) studies (with anti-BRAF V600E, anti-BAP1, anti-cyclin D1, and anti-p16); the percentage of IHC+ cells was scored. Of the 20 patients, 3 (15%) whose BRAFi-MLs were biopsied had a second primary cutaneous melanoma. Of the 44 BRAFi-MLs tested, 37 (100%) of 37 MLs available for BRAF V600E testing lacked expression in contrast to 1 (9%) of 11 control nevi (lesions not associated with targeted therapy). A significantly higher level of cyclin D1 expression (>50% IHC+ cells) was more commonly seen in BRAFi-MLs (44%) than in control nevi (9%). No difference in p16 expression in melanocytes was seen between the 2 groups. BRAF mutation status distinctly differs between BRAFi-MLs from melanomas and nevi biopsied in patients who do not receive BRAFi therapy. Morphologically, BRAFi-MLs demonstrate a greater degree of atypia than do control nevi. Furthermore, BRAFi-MLs with coexisting cutaneous keratinocyte toxicity developed during fewer days of targeted therapy. Paradoxical activation of the MAPK pathway in BRAF(WT) melanocytes may account for ~15% to 21% of patients developing a second new primary melanoma within a year of starting BRAFi therapy; thus, close clinical surveillance is warranted.

Mudaliar K ，Tetzlaff MT ，Duvic M ，Ciurea A ，Hymes S ，Milton DR ，Tsai KY ，Prieto VG ，Torres-Cabala CA ，Curry JL ... -  《-》

Combination with γ-secretase inhibitor prolongs treatment efficacy of BRAF inhibitor in BRAF-mutated melanoma cells.

Oncogenic triggering of the MAPK pathway in melanocytes results in senescence, and senescence escape is considered as one critical step for melanocytic transformation. In melanoma, induction of a senescent-like state by BRAF-inhibitors (BRAFi) in a fraction of treated cells - instead of killing - contributes to the repression of tumor growth, but may also provide a source for relapse. Here, we demonstrate that NOTCH activation in melanocytes is not only growth-promoting but it also protects these cells against oncogene-induced senescence. In turn, treatment of melanoma cells with an inhibitor of the NOTCH-activating enzyme γ-secretase led to induction of a senescent-like status in a fraction of the cells but overall achieved only a moderate inhibition of melanoma cell growth. However, combination of γ-secretase inhibitor (GSI) with BRAFi markedly increased the treatment efficacy particularly in long-term culture. Moreover, even melanoma cells starting to regrow after continuous BRAFi treatment - the major problem of BRAFi therapy in patients - can still be affected by the combination treatment. Thus, combining GSI with BRAFi increases the therapeutic efficacy by, at least partially, prolonging the senescent-like state of treated cells.

Zhu G ，Yi X ，Haferkamp S ，Hesbacher S ，Li C ，Goebeler M ，Gao T ，Houben R ，Schrama D ... -  《-》

Histopathologic characteristics of therapy-associated cutaneous neoplasms with vemurafenib, a selective BRAF kinase inhibitor, used in the treatment of melanoma.

Activating mutations in BRAF have been observed in up to 60% of melanomas, indicating a pivotal role for kinase deregulation in tumor progression. Vemurafenib is a specific inhibitor of BRAF for treatment of melanomas with activating BRAF V600E mutations and has been a major advancement in melanoma treatment. Treatment with vemurafenib, and to a lesser extent, sorafenib, a relatively non-specific inhibitor of BRAF, has been associated with cutaneous squamous cell carcinoma (SCC). Clinical and microscopic characteristics of cutaneous neoplasms were evaluated following vemurafenib administration. Twenty-four of 47 (51%) patients receiving vemurafenib at our institution developed 146 total cutaneous neoplasms, with 75% developing multiple lesions. The median number of lesions in affected patients was three. Body distribution included head/neck (29%), chest/back (21%), upper (23%) and lower extremities (27%). Lesions were biopsied and pathologically showed multiple types of epidermal tumors including, but not limited to, verrucous keratoses with/without partial thickness dysplasia, actinic keratoses and well-differentiated and invasive SCCs with/without keratoacanthomatous features. We describe the histopathologic findings of skin lesions potentially associated with vemurafenib. Additional investigation is necessary to further elucidate cutaneous neoplasms associated with vemurafenib; however, frequent dermatologic evaluation is warranted in all patients receiving BRAF inhibitors.

Sufficool KE ，Hepper DM ，Linette GP ，Hurst EA ，Lu D ，Lind AC ，Cornelius LA ... -  《-》

Clinical significance of BRAF V600E mutational status in capsular nevi of sentinel lymph nodes in patients with primary cutaneous melanoma.

Capsular nevi (CN) are clusters of benign melanocytes situated in the capsule of lymph nodes and occur in up to 20% of lympadenectomy specimens. The molecular profile of CN in relation to prognostic parameters in patients with primary cutaneous melanoma (PCM) has not been previously investigated. We assessed BRAF V600E mutation by immunohistochemistry (IHC) in the CN of sentinel lymph nodes (SLN) in PCM patients and correlated the findings with demographic characteristics, PCM histopathologic and molecular features, and clinical outcome parameters. Seventy-eight cases of CN involving SLN of PCM patients were evaluated for BRAF V600E mutation by IHC. The results were correlated with patient demographics, PCM histopathologic and molecular features, and outcome measures. Thirty-six (46%) of 78 CN cases expressed BRAF V600E mutation by IHC. Nineteen (53%) of those BRAF-positive CN cases were from patients with at least American Joint Committee on Cancer stage II melanoma, whereas 62% of BRAF-negative CN cases (26/42) were from patients with stage I melanoma (P = .013). Twelve (33%) of the 36 BRAF-positive CN cases had metastatic melanoma involving lymph nodes, compared with 14% (6/42) of BRAF-negative CN cases (P = .061). CN mutation status was not associated with patient demographics, histopathologic or molecular features of the PCM, or survival outcomes. A high percentage of CN identified in the SLN of patients with PCM harbor BRAF V600E mutation. Positive mutation was associated with adverse clinicopathological parameters, specifically increased tumor stage and lymph node metastasis. These findings suggest that BRAF V600E mutation in CN of SLN may be useful as an adverse predictive biomarker in patients with melanoma.

Siroy AE ，Aung PP ，Torres-Cabala CA ，Tetzlaff MT ，Nagarajan P ，Milton DR ，Curry JL ，Ivan D ，Prieto VG ... -  《-》

Changes in tumor morphology and cyclin-dependent kinase inhibitor expression in metastatic melanoma treated with selective second-generation BRAF inhibitor.

Curry JL ，Falchook GS ，Hwu WJ ，Torres-Cabala CA ，Duvic M ，Tetzlaff MT ，Prieto VG ... -  《-》