Effectiveness Treatment of a BRAF-ZKSCAN5 Fusion Gene Melanoma Case with Dabrafenib/Trametinib

Several genetic mutations have been reported in malignant melanoma that are targets for therapy, the most important of which are BRAF mutations, which are driver genes for tumor cell growth and are generally expressed in the V600 region [1]. This gene mutation is known to be found in cancers other than melanoma, such as biliary tract and lung cancer, and the benefit of molecularly targeted therapies has also been reported [2, 3]. The most common of these mutations is in the V600E region, but several other mutations have been reported in recent years [4]. In this study, we report a case of melanoma expressing the BRAF-ZKSCAN fusion gene that was successfully treated with dabrafenib/trametinib.

With the development of cancer genome research, has identified various melanoma driver genes have been identified [5]. We report a case of melanoma expressing the BRAF-ZKSCAN5 fusion gene that was treated with dabrafenib/trametinib. The patient was a 71-year-old female. She underwent extended resection and axillary lymph node dissection for abdominal malignant melanoma in the abdomen with axillary lymph node metastasis (pT4aN3M0, STAGE IIIC) and received peginterferon-α as postoperative adjuvant therapy (Fig. 1). Lung and mediastinal lymph node metastases were detected 2 months after surgery, and she was treated with nivolumab. Her metastatic lesions remained stable for 2 years, but then increased in number 2 years after the initial treatment. The combination of treatment with ipilimumab and nivolumab was started as second-line therapy. Although the patient achieved a complete response at the first posttreatment evaluation, she developed bullous pemphigoid with a mucocutaneous rash after the second administration, and the ipilimumab/nivolumab treatment was discontinued. After remission of the bullous pemphigoid, treatment with pembrolizumab was started. No tumor relapse was observed during the first year of treatment, but cervical lymph node metastases appeared and gradually increased. At that time, the other lesions continued to shrink. Therefore, radiotherapy (electron beam, 66 Gy) was applied to the cervical lymph node, leading to a partial response (Fig. 2). At 4 months after the completion of radiotherapy, the tumor was enlarged (Fig. 3). Next-generation sequencing with FoundationOne^® CDx detected the gene for the BRAF-ZKSCAN5 fusion protein, leading to treatment with dabrafenib/trametinib. At 1-month posttreatment, the tumor had stopped growing and the long diameter was reduced by 22.2% (Fig. 4). The patient developed grade 3 adverse events of nausea, fatigue, and diarrhea, which caused movement difficulties and forced the discontinuation of treatment 6 weeks. A chronology was created from a timeline of events that occurred with this patient (Table 1).

BRAF mutations, involving the driver gene for tumor cell growth, are usually observed in the V600 region [6]. In this case, a fusion gene related to BRAF was expressed. The efficacy of BRAF/MEK inhibitors in such cases is well established [7]. In addition, the efficacy of the BRAF/MEK inhibitor for brain metastases from melanoma was also reported in BRAFi naive patients with an overall response rate of 67.3%, median overall survival of 20.0 months, and median progression-free survival of 7.5 months compared to previous treatment modalities [8]. Although there are some case reports of BRAF fusion genes in various tumors other than melanoma, no BRAF-targeted therapies for melanoma have been reported [9, 10]. Previous basic research on melanoma cells reported that the efficacy of BRAF inhibitors is specific to the fusion gene type [11]. In another case report, a MEK inhibitor was administered to a case of malignant melanoma expressing the GOLGA4-RAF1 fusion gene, and efficacy was achieved [12]. Similarly, in our case, the efficacy of dabrafenib/trametinib was observed during short-term administration in our case, and the results suggest that the BRAF-ZKSCAN5 fusion gene is a potential target gene for the treatment of melanoma. Although many variations of BRAF fusion genes are known, the effects of molecularly targeted therapeutics on each fusion gene remain unclear. As cancer genomic testing becomes more widespread in the future, it is expected that multiple such genes will be detected. This case report may provide evidence for treatment options for cases with BRAF fusion gene detection, which is expected to be detected in large numbers by next-generation sequencing in the future. It is important to accumulate such reports while conducting basic research to deepen our understanding of the effects of drugs on each target molecule. The CARE Checklist has been completed by the authors for this case report, available online at https://doi.org/10.1159/000533822.

We would like to thank Editage (www.editage.com) for English language editing.

Written informed consent was obtained from the patient for publication of the details of their medical case and any accompanying images. In addition, the administration of dabrafenib/trametinib in this case was reviewed and approved review by the Ethics Committee of Nagoya City University Hospital (approval #2021-33).

Kato H. has received speakers’ bureau from Novartis Pharma K.K.

The authors received no funding from any source for the preparation of this article.

Kato H. wrote the case report. Kato H., Kano S., Yasui Y., Nojiri Y., Yoshimitsu M., and Nakamura M. contributed to the clinical management of this patient. Morita A. contributed to critical review of the manuscript for important intellectual content.