Hybrid Capture-Based Genomic Profiling Identifies BRAF V600 and Non-V600 Alterations in Melanoma Samples Negative by Prior Testing

Abstract

Background BRAF and MEK inhibitors are approved for BRAF V600‐mutated advanced melanoma, with response rates of up to 70%. Responses to targeted therapies have also been observed for diverse non‐V600 BRAF alterations. Thus, sensitive, accurate, and broad detection of BRAF alterations is critical to match patients with available targeted therapies. Materials and Methods Pathology reports were reviewed for 385 consecutive melanoma cases with BRAF mutations or rearrangements identified using a hybrid capture‐based next‐generation sequencing comprehensive genomic profiling (CGP) assay during the course of clinical care. Results Records of prior BRAF molecular testing were available for 79 (21%) cases. Of cases with BRAF V600 mutations, 11/57 (19%) with available data were negative by prior BRAF testing. Prior negative BRAF results were also identified in 16/20 (80%) cases with non‐V600 mutations, 2 of which harbored multiple BRAF alterations, and in 2/2 (100%) cases with activating BRAF fusions. Clinical outcomes for a subset of patients are presented. Conclusion CGP identifies diverse activating BRAF alterations in a significant fraction of cases with prior negative testing. Given the proven clinical benefit of BRAF/MEK inhibitors in BRAF‐mutated melanoma, CGP should be considered for patients with metastatic melanoma, particularly if other testing is negative. Implications for Practice Published guidelines for melanoma treatment recommend BRAF mutational analysis, but little guidance is provided as to selection criteria for testing methodologies, or as to clinical implications for non‐V600 alterations. This study found that hybrid capture‐based next‐generation sequencing can detect BRAF alterations in samples from a significant fraction of patients with advanced melanoma with prior negative BRAF results. This study highlights the need for oncologists and pathologists to be critically aware of coverage and sensitivity limitations of various assays, particularly regarding non‐V600E alterations, of which many are potentially targetable.

Clinical genomic profiling in the management of patients with soft tissue and bone sarcoma

“…Strikingly, in the ultrarare (11, 0.15%) cases that harbored very high TMB (≥100 mut/Mb), a UV signature was usually present (77.8%, 7/9 evaluable), which suggests either an anatomic origin with exposure to solar radiation or sampling of a metastatic site with UV exposure. Interestingly, these cases also harbored frequent NF1 mutations (45.5%, 5/11) and thus, the co-occurrence of NF1 alterations and a UV signature may suggest an alternate diagnosis of desmoplastic melanoma (S100+, melanA/HMB45-negative) or radiation-associated MPNST 50 .

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L’héliodermie péricicatricielle du mélanome primitif cutané comme marqueur clinique prédictif de réponse à l’immunothérapie par anti-PD-1

“…Ainsi, la principale difficulté de ce travail était d'évaluer de manière fiable les grades de Ceci pourrait s'expliquer par le fait que cette mutation est réputée non UV-induite, associée à un TMB plus faible, et à une moins bonne réponse à l'immunothérapie. [9,10] Avec l'avènement des thérapies ciblées et de l'immunothérapie en contexte adjuvant et néoadjuvant, le choix du meilleur traitement de première ligne va se poser pour de plus en plus de patients mutés BRAF. [11][12][13][14] Le traitement choisi doit répondre à deux exigences : un minimum de toxicité et un maximum d'efficacité.…”

Next generation sequencing for personalized therapy: About a class III BRAF N581K mutation associated to NRAS Q61L mutation in malignant melanoma: Case report

“…L.Boussemart et al, in 2018 [ 26 ], tested in the interest of using Hybrid Capture-Based Genomic profiling, to identify BRAF alterations initially negative by prior BRAF classical testing. They concluded that this method should be considered, particularly in patients with initial negative result with classical methods, because of the capacity to identify more alterations in one sample, allowing personal care.…”