Successful (neo)adjuvant BRAF-targeted therapy in a patient with locally advanced BRAF V600E mutant melanoma1

(Updated follow up and new data for neo/adjuvant targeted therapy)

Teofila Seremet1, Danielle Lienard2, Mariano Suppa2, Anne-Laure Trepant3, Sandrine Rorive3, Erwin Woff4, Nicolas Cuylits2, Yanina Jansen1, Max Schreuer1, Véronique Del Marmol2, Bart Neyns1

  1. Department of Medical Oncology, Universitair Ziekenhuis Brussel, VUB, Brussels, Belgium
  2. Department of Dermatology, Hôpital Erasme, ULB, Brussels, Belgium
  3. Department of Pathology, Hôpital Erasme, ULB, Brussels, Belgium
  4. Department of Nuclear Medicine, Hôpital Erasme, ULB, Brussels, Belgium

The treatment of locally advanced metastasized melanoma is challenging because there is no level 1 evidence to guide clinical decision-making. Moreover the treatment options available fail to improve overall survival and are associated with considerable morbidity.

Case report

A 62-year old Caucasian female patient presented to the dermatology department with a large pigmented lesion accompanied by multiple satellite and in-transit pigmented smaller lesions on the medial side of the left ankle.

The physical examination revealed a pigmented skin tumor with an irregular border, and a diameter of 3 by 2.5 cm. The primary lesion was surrounded by approximately 25 satellite and “in transit” epidermotropic lesions with a diameter between 1 and 6 mm. Four lesions were located at more than 5 cm from the primary lesion (Fig 1C). No distant metastases were found at further clinical examination. A biopsy of two of the “in transit” lesions revealed proliferation of large atypical melanocytic tumor cells in the superficial dermis (Fig 1A). These cells were positive for Melan-A (Fig 1B) and S-100 by immunohistochemistry establishing the diagnosis of melanoma (data not shown). The BRAF V600 mutation status was assessed by qPCR on the same biopsy samples after macrodissection of the regions rich in tumor cells, and found to be positive for the V600E mutation. Increased 18F-FDG-uptake by the tumoral lesions was documented on whole-body [18F] fluorodeoxyglucose positron emission tomography (FDG-PET)/computed tomography (CT) (Fig 1D, E). There was no evidence of CNS metastases on MRI of the brain. The diagnosis was AJCC stage IIIB melanoma.

Following multidisciplinary consultation, the patient was started on 960 mg twice daily vemurafenib, which was stopped and resumed at 720 mg twice daily, and finally substituted with the combination dabrafenib and trametinib in order to reduce the persisting side effects. Successive clinical examinations had revealed a progressive reduction in the thickness of the melanoma lesions. After about five months of therapy, surgery was performed and the histopathological analysis showed an almost complete regression of tumor cells. The treatment with dabrafenib/trametinib was continued only three months after surgery and stopped at patient’s request.

The patient remains currently in complete remission at 36 months after diagnosis and treatment onset (Figure 2).

Our results were among the first to be published in order to pave the way for changing the standards of care in the treatment of locally advanced melanoma. The recent data from the phase II COMBI-Neo trial showed a major improvement in the 6-months relapse-free survival for the arm receiving neo/adjuvant treatment. This led to the decision of stopping the trial and reopening it as a single arm study in order that all patients would benefit from the treatment. These very encouraging results suggest that neo/adjuvant BRAF-targeted therapy can become the new standard of care for BRAF mutant patients.

  1. Seremet T, Lienard D, Suppa M, Trepant AL, Rorive S, Woff E, Cuylits N, Jansen Y,      Schreuer M, Del Marmol V, Neyns BSuccessful (neo)adjuvant BRAF-targeted therapy in a patient with locally advanced BRAF V600E mutant melanoma, Melanoma Res. 2015 Apr;25(2):180-3
  2. Amaria RN, Prieto P, Tetzlaff M, et al. Treatment with neoadjuvant + adjuvant dabrafenib and trametinib (D+T) is associated with improved relapse-free survival (RFS) versus standard of care (SOC) therapy in patients with high-risk resectable BRAF-mutant melanoma. Presented at: Society for Melanoma Research Annual Meeting; Boston, Massachusetts, November 6-9, 2016 - See more at: http://www.onclive.com/conference-coverage/smr-2016/perioperative-dabrafenibtrametinib-improves-rfs-in-stage-iii-melanoma#sthash.o7dm0Ecv.dpuf

Figure 1 (click on Figure 1 to view document). Timeline of patient clinical course.

Clinical, 18F-FDG PET/CT and histopathological images are shown at different time points. The 18F-FDG PET/CT scan revealed no distant metastases (not shown) while the lesion showed an increased 18F-FDG uptake (D, E). This lesion was confirmed as melanoma by the hematoxylin-eosin (A) and MelanA (B) staining before the initiation of treatment (C). Adverse events (including their grade) present during various time periods are described in the rectangles along the horizontal axis (in orange covering the vemurafenib treatment and in blue the Dabrafenib/Trametinib treatment). After 13 weeks of treatment the lesion became flat albeit the pigmentation did not change significantly (F), however the18F-FDG PET/CT showed no 18F-FDG uptake in the region of the lesion (G, H). The lesion was removed by surgery 5 weeks later and the corresponding hematoxylin-eosin image points out to an almost complete regression of the melanoma (I). The thickness of the macrophage band for the main lesion was of 1.1mm. Interestingly, higher magnification shows abundant vascularization and hyperplastic vessels at this level (J).

Figure 2. Clinical picture of the left ankle at 36 months of follow up.