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Published on: June 7, 2019
Multiple BRAF Wild-Type Melanomas During Dabrafenib Treatment for Metastatic BRAF-Mutant Melanoma
Cristina Carrera1, Joan A Puig-Butillè2, Gemma Tell-Marti2
1Melanoma Unit, Department of Dermatology, Hospital Clínic, Institut d'Investigacions Biomèdiques August Pi i Sunyer, University of Barcelona, Barcelona, Spain2Centro de Investigación Biomédica en Red en Enfermedades Raras, Instituto de Salud Carlos III, B.
Importance:
BRAF inhibitors have become the standard of care in metastatic BRAF-mutant melanomas. Compared with chemotherapies, BRAF inhibitors improve overall and disease-free survival and speed the recovery of symptomatic patients with metastatic disease. The most worrisome finding is the possible development of resistance to new malignant tumors.
Observations:
A patient in her 30s developed massive BRAFV600E melanoma metastasis during her 30th week of pregnancy. After emergency cesarean delivery, oral dabrafenib treatment was initiated, and a partial radiologic response was confirmed within 1 month. At dermatologic digital follow-up aided by confocal microscopy 8 weeks after initiation of dabrafenib treatment, 4 melanomas were detected. Unfortunately, within the next month, the melanoma rapidly progressed. The 4 new melanomas were wild-type BRAFmelanomas, whereas the new metastasis carried a different BRAF mutation (S467L).
Conclusions And Relevance:
Cutaneous malignant tumors are the most frequent adverse events of BRAF inhibitors; therefore, strict dermatologic surveillance in a referral center aided by digital follow-up is mandatory, especially when multiple nevi are present and these drugs are used in an adjuvant setting. In view of our findings, the pathogenesis of the development of new melanomas seems to be different from therapy resistance. Whether paradoxical RAF activation could explain these BRAF wild-type secondary malignant tumors is still unknown.
Insights
BRAF inhibitors effectively treat melanoma but can lead to new tumors. These new melanomas may arise from different mutations, suggesting a distinct pathogenesis from drug resistance.
Area of Science:
- Oncology
- Dermatology
- Genetics
Background:
- BRAF inhibitors are standard treatment for metastatic BRAF-mutant melanoma, improving survival rates.
- While effective, BRAF inhibitors are associated with adverse events, including secondary cutaneous malignant tumors.
Observation:
- A pregnant patient with BRAFV600E melanoma developed new wild-type BRAF melanomas and a distinct BRAF-mutated metastasis during dabrafenib treatment.
- The patient experienced rapid progression of these new melanomas despite initial response to BRAF inhibitor therapy.
Findings:
- New melanomas developing during BRAF inhibitor therapy can be BRAF wild-type, indicating a different origin than acquired resistance.
- The secondary metastasis harbored a novel BRAF mutation (S467L), distinct from the primary tumor's BRAFV600E mutation.
Implications:
- Strict dermatologic surveillance, including digital follow-up, is crucial for patients on BRAF inhibitors, especially those with multiple nevi.
- The development of BRAF wild-type melanomas may involve mechanisms beyond direct therapy resistance, potentially including paradoxical RAF activation.
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