BI04 Erupting and spontaneously vanishing moles in a new cohort of patients on BRAF inhibitor monotherapy
Authors: Selvendran Subothini Sara , Cernova Jeva , Harwood Catherine 
Published: June 2024

Abstract
When introduced for advanced BRAF-V600E-positive melanoma in 2011, BRAF inhibitor monotherapy cutaneous adverse effects included development of cutaneous squamous cell carcinoma (cSCC), eruptive melanocytic naevi (EMN) and melanoma. These risks became significantly less common when combination BRAF inhibitor/MEK inhibitor therapy became standard of care. However, in recent years BRAF inhibitor monotherapy is once again being used for other BRAF-V600E-positive malignancies. We report the first case of florid EMN developing on encorafenib BRAF inhibitor monotherapy for colorectal cancer, which dramatically regressed upon its withdrawal. A 62-year-old female patient with BRAF-V600E metastatic colorectal cancer was started on dual cetuximab (epidermal growth factor receptor inhibitor) and encorafenib therapy. Within 2–3 months &gt; 40 new darkly pigmented melanocytic naevi had developed on her palms, soles, face and trunk. None were clinically or dermoscopically suspicious for melanoma. Treatment was continued given the initial partial response of the colorectal tumour. However, by 6 months this had progressed; cetuximab and encorafenib were stopped and chemotherapy started with FOLFIRI (folinic acid, fluorouracil and irinotecan). Within 2–3 months of encorafenib withdrawal, the EMN were involuting. Twelve months after stopping encorafenib, there had been almost complete involution of all EMN while pre-existing naevi remained stable. Excisional biopsy of a regressing lesion confirmed a benign melanocytic naevus with no dysplasia. Encorafenib is a highly selective RAF kinase inhibitor, which blocks the activated downstream mitogen-activated protein kinase (MAPK)-signalling pathway in BRAF-V600E mutant cells. However, in BRAF-wildtype melanocytes, BRAF-inhibitor monotherapy can cause paradoxical activation of MAPK signalling, promoting melanocytic hyperproliferation and development of new melanocytic naevi, EMN and primary melanomas. It is postulated that with ongoing BRAF inhibitor exposure, EMN become dependent upon activated MAPK signalling. This view is supported by reports of BRAF inhibitor monotherapy-associated EMN that subsequently undergo involution when MEK inhibitors are started. However, to our knowledge, there are no reports of spontaneous involution of EMN when BRAF inhibitor monotherapy alone is stopped, as in our case. This may not have been evident in historic cohorts of patients with advanced melanoma who had poor survival rates once BRAF inhibitor resistance developed. We hypothesize that EMN involution reflects reversal rather than blockade of MAPK pathway activation. In summary, we report the first case of EMN associated with BRAF inhibitor monotherapy to demonstrate complete involution upon treatment withdrawal. Given increasing use of BRAF inhibitor monotherapy as part of treatment regimens for patients with BRAF-V600E-positive cancers other than melanoma, this is likely to become a more common problem in the future. These risks will potentially extend to invasive cSCC and melanoma and highlight the central importance of supportive dermato-oncology expertise in ensuring clinician and patient awareness and appropriate ongoing skin surveillance.