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Research Letter |

Dermoscopic Evaluation of Melanocytic Nevi Changes With Combined Mitogen-Activated Protein Kinase Pathway Inhibitors Therapy for Melanoma ONLINE FIRST

Marie Perier-Muzet, MD1; Amélie Boespflug, MD1; Nicolas Poulalhon, MD2; Julie Caramel, PhD1; Anne-Laure Breton, MD2; Luc Thomas, MD, PhD2; Stephane Dalle, MD, PhD2
[+] Author Affiliations
1Cancer Research Center of Lyon, Lyon, France
2Department of Dermatology, Centre Hospitalier Lyon-Sud, Hospices Civils de Lyon, Lyon, France
JAMA Dermatol. Published online July 27, 2016. doi:10.1001/jamadermatol.2016.2426
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This observational study investigates nevi changes after combined BRAF inhibitor and mitogen-activated protein kinase pathway inhibitor therapy in patients with metastatic melanoma.

Previous studies1,2 have described the changes that occur in nevi and the induction of new melanomas during treatment with the BRAF inhibitor (BRAFi) vemurafenib in a cohort of patients with metastatic melanoma. These findings were later confirmed by others3 for the second approved BRAFi, dabrafenib mesylate. These changes are not completely understood but are probably due to the paradoxical activation of the mitogen-activated protein kinase (MAPK) signaling pathway in NRAS-mutated or wild-type BRAF melanocytes, notably via the heterodimerization of BRAF and CRAF, as demonstrated by proximity ligation assay on de novo melanomas in patients receiving BRAFi.4 Since then, mitogen-activated kinase kinase (MEK) inhibitors (MEKi) have been routinely administered in combination with BRAFi, owing to the improvement of progression-free survival rates compared with BRAFi alone. As expected with their mechanism of onset through the RAS-MEK pathway, the incidence of induced cutaneous squamous cell carcinomas was shown to be significantly lower with the combined treatment, whereas nevi changes have so far only been reported in isolated case-reports.5,6 We conducted an observational study of digital dermoscopy follow-up in a small cohort of patients treated with combination BRAFi and MEKi therapy to more precisely describe early dermoscopic modifications occurring to the nevi.

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Figure 1.
Dermoscopic Modifications Arising in Nevi During the Treatment Course

Patients received a combination of a BRAF inhibitor (BRAFi) and mitogen-activated kinase kinase inhibitor (MEKi). A, Evolution of the various dermoscopic criteria over the time with combined BRAFi-MEKi therapy. B, A comparison of the evolution of global pigmentation (main modified criterion) in patients receiving combination therapy with previously described global pigmentation during vemurafenib as monotherapy.

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Figure 2.
Evolution of 3 Melanocytic Lesions in 3 Patients

A, Changes in lesion 37 from patient 4 show global hypopigmentation after 6 months of combined BRAF inhibitor (BRAFi) and mitogen-activated kinase kinase inhibitor (MEKi) therapy. B, Dermoscopic changes in lesion number 12 from patient 7, after 3 months of combination therapy. C, Hyperpigmented changes in lesion 27 from patient 13 after cessation of cobimetinib fumarate therapy and 3 months of BRAFi monotherapy (dabrafenib mesylate), leading to a surgical excision (a 0.22-mm superficial spreading melanoma was diagnosed).

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