Relevance of detection of RAF fusion transcripts in pan-negative melanoma in routine practice
Guillaume Delzenne1,2, Marie Boileau1,2, Philippe Jamme1,2
1Service de Dermatologie, Hôpital C. Huriez, CHU de Lille.
Abstract:
Pan-negative melanomas account for 30% of melanomas. In case of immunotherapy failure, therapeutic options are limited. Oncogene fusions represent a target of interest in many solid cancers. In melanoma, the frequency of oncogene fusion is not well documented and not routinely investigated. We conducted a single-center retrospective study. The objective was to determine the frequency of oncogene fusion detected by RNA sequencing, in patients with advanced or metastatic pan-negative melanoma. In parallel, an extended molecular alteration search was performed using extended targeted next-generation sequencing. We identified 59 patients with advanced pan-negative melanoma between January 2021 and January 2023. It was a cutaneous melanoma in 71.1% of the cases, a mucous melanoma in 15.2% of the cases. We identified nine patients with a RAF fusion, including seven BRAF gene fusion and two RAF1 fusion. Of the other molecular alterations, NF1 mutation was the most frequent molecular alteration identified. Among the nine patients with RAF fusions, all the patients initially received treatment with anti-PD1 ± anti-CTLA4 immunotherapy. After immunotherapy failure, five patients benefited from second-line targeted therapy (two with BRAF and MEK inhibitors combination, three MEK inhibitors alone). The response rate was 20%. In a population of pan-negative melanoma, we detected 15.2% of RAF fusion. Fusion detection allowed the introduction of a second line of targeted therapy, in the absence of a validated therapeutic option in 55.5% of cases. This study suggests the relevance of detecting RAF fusion in a selected population.
Insights
Pan-negative melanoma patients often lack treatment options after immunotherapy failure. This study found RAF fusions in 15.2% of these patients, enabling targeted therapy and improving outcomes.
Area of Science:
- Oncology
- Genetics
- Molecular Biology
Background:
- Pan-negative melanoma represents 30% of melanoma cases.
- Limited therapeutic options exist for patients with pan-negative melanoma who fail immunotherapy.
- Oncogene fusions are emerging therapeutic targets in solid cancers, but their role in melanoma is understudied.
Purpose of the Study:
- To determine the frequency of oncogene fusions using RNA sequencing in advanced or metastatic pan-negative melanoma.
- To investigate the utility of extended targeted next-generation sequencing for identifying molecular alterations.
- To evaluate the impact of detecting RAF fusions on subsequent treatment strategies.
Main Methods:
- Single-center retrospective study of 59 patients with advanced pan-negative melanoma (Jan 2021-Jan 2023).
- RNA sequencing was employed to detect oncogene fusions.
- Extended targeted next-generation sequencing was used for comprehensive molecular profiling.
Main Results:
- RAF fusions were identified in 15.2% of patients (9/59), including BRAF and RAF1 fusions.
- NF1 mutations were the most frequent other molecular alteration found.
- Five patients with RAF fusions received second-line targeted therapy after immunotherapy failure, with a 20% response rate.
Conclusions:
- RAF fusion detection is relevant in pan-negative melanoma, identifying a targetable alteration.
- Fusion detection facilitated the introduction of second-line targeted therapy in 55.5% of fusion-positive cases.
- This highlights the importance of investigating oncogene fusions in advanced pan-negative melanoma.
