Is immunohistochemistry of BRAF V600E useful as a screening tool and during progression disease of melanoma patients?

Abstract

BackgroundIn clinical practice the gold standard method to assess BRAF status in patients with metastatic melanoma is based on molecular assays. Recently, a mutation-specific monoclonal antibody (VE1), which detects the BRAF V600E mutated protein, has been developed. With this study we aimed to confirm the clinical value of the VE1 Ventana® antibody, as today a univocal validated and accredited immunohistochemical procedure does not exist, to preliminary detect BRAF status in our routine diagnostic procedures. Moreover, we explored the biological meaning of BRAF immunohistochemical labeling both as a predictor marker of response to target therapy and, for the first time, as a player of acquired tumor drug resistance.MethodsWe analyzed a retrospective series of 64 metastatic melanoma samples, previously investigated for molecular BRAF status, using a fully automatized immunohistochemical method. We correlated the data to the clinicopathologic characteristics of patients and their clinical outcome.ResultsThe sensitivity and the specificity of the Ventana® VE1 antibody were 89.2 and 96.2% respectively, while the positive predictive value and negative predictive value were 97.1 and 86.2%, respectively. For six mutated patients the histological sample before treatment and when disease progressed was available. The immunohistochemical BRAF V600E expression in the specimens when disease progressed was less intense and more heterogeneous compared to the basal expression. Multivariate analysis revealed that a less intense grade of positive expression is an independent predictor of a less aggressive stage at diagnosis (p = 0.0413).ConclusionsOur findings encourage the introduction of immunohistochemistry as a rapid screening tool for the assessment of BRAF status in melanoma patients in routine diagnostic procedures and prepare the ground for other studies to highlight the role of immunohistochemical BRAF V600E expression in patients at the time of progression.

BRAF V600 mutation detection in melanoma: a comparison of two laboratory testing methods

“…This is consistent with literature reports that younger age and reduced Breslow thickness are associated with the BRAF V600E mutation 54. A number of studies have shown that superficial spreading melanomas (SSM) have a higher rate of BRAF V600 mutation than other melanoma subtypes 22 55.…”

Distant metastasis due to heavily pigmented epithelioid melanoma with underlying BRAF V600E, NOTCH1, ERBB3, and PTEN mutations

“…In the case presented, NGS identified a BRAF V600E mutation in the tumor, consistent with recent evidence describing the BRAF V600E immunostain as highly reliable and correlative with sequencing . In tandem with loss of p16, this BRAF driver mutation was recently described in a heavily pigmented epithelioid melanoma in a 28‐year‐old man .…”

Concordance in BRAF V600E status over time in malignant melanoma and corresponding metastases

“…Owing to limited access to patient treatment information in our study, it is beyond the scope of this article to further address this issue. However, BRAF V600E expression status before and after treatment was evaluated in a few patients by Schirosi et al, 36 who showed that the intensity of BRAF V600E IHC staining was lower and more heterogeneous after treatment with a BRAF inhibitor. Wilmott et al 37 showed that, even though protein expression varied between patients, there was no correlation between the level of mutant BRAF protein expression and the response to BRAF inhibitors or survival in treated patients.…”