Prognostic significance of BRAF and NRAS mutations in melanoma: a German study from routine care

Abstract

BackgroundHotspot mutations of the oncogenes BRAF and NRAS are the most common genetic alterations in cutaneous melanoma. Specific inhibitors of BRAF and MEK have shown significant survival benefits in large phase III trials. However, the prognostic significance of BRAF and NRAS mutations outside of clinical trials remains unclear.MethodsThe mutational status of BRAF (exon 15) and NRAS (exon 2 and 3) was determined in melanoma samples of 217 patients with pyrosequencing and Sanger sequencing. The genotypes were correlated with clinical outcomes and pathologic features of the primary tumors. Time to disease progression was calculated with the cumulative incidence function. Survival analyses were performed with Kaplan-Meier estimates and Cox proportional hazards regression analysis. Relative survival was calculated with the Ederer-II method. Treatment with BRAF and MEK inhibitors and immune checkpoint blockade (ICB) was allowed.ResultsMutations in BRAF and NRAS were identified in 40.1 and 24.4% of cases, respectively. Concurrent mutations in both genes were detected in further 2.3%. The remaining 33.2% were wild type for the investigated exons (WT). BRAF mutations were significantly associated with younger age at first diagnosis (p < 0.001) and truncal localization of the culprit primary (p = 0.002). The nodular subtype was most common in the NRAS cohort. In addition, NRAS-mutant melanoma patients showed a higher frequency of nodal relapse (p = 0.013) and development of metastatic disease (p = 0.021). The time to loco-regional nodal relapse was shortest in NRAS-mutant melanoma (p = 0.002). Presence of NRAS mutation was an independent risk factor for disease progression in multivariate analysis (HR 2.01; 95% CI 1.02 – 3.98). BRAF-mutant melanoma patients showed a tendency for better overall and relative survival. Genotype was not a consistent risk factor in multivariate analysis. Instead, positive sentinel lymph node status (HR 2.65; 95% CI 1.15 – 6.10) and treatment with ICB in stage IV disease (HR 0.17; 95% CI 0.06–0.48) were significant multivariate risk factors.ConclusionsNRAS-mutant tumors tended to behave more aggressively particularly in early stages of the disease in this high-risk melanoma population. Treatment with immune checkpoint blockade improved survival in stage IV disease in a real-world setting.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-017-3529-5) contains supplementary material, which is available to authorized users.

BRAF V600E mutation as a prognostic factor in cutaneous melanoma patients

“…Some data support that BRAF V600 mutation is an independent favorable prognostic factor (Heppt et al, ). In a recent German trial on 217 melanoma patients (most of them [96%] were Stage I–III patients) BRAF mutation was identified in 40.1% of the samples (Heppt et al, ). BRAF mutation was found to be significantly associated with young age at initial diagnosis, low mitotic activity and seldom acral lentiginous histologic subtype and truncal lesion.…”

“…Many studies have investigated the association between BRAF mutation and clinicopathological features in melanoma (Akslen et al, ; Ellerhorst et al, ; Heppt et al, ; Hugdahl et al, ; Inumaru et al, ; Maldonado et al, ; Mann et al, ; Meckbach et al, ; Moreau et al, ; Picard et al, ; Shinozaki et al, ). Most of these studies concluded that BRAF mutation was in association with younger age at diagnosis (Heppt et al, ; Hugdahl et al, ; Meckbach et al, ), truncal lesion (Heppt et al, ; Hugdahl et al, ), and the superficially spreading melanoma histotype (Heppt et al, ; Meckbach et al, ), we agree with these findings.…”

“…Many studies have investigated the association between BRAF mutation and clinicopathological features in melanoma (Akslen et al, ; Ellerhorst et al, ; Heppt et al, ; Hugdahl et al, ; Inumaru et al, ; Maldonado et al, ; Mann et al, ; Meckbach et al, ; Moreau et al, ; Picard et al, ; Shinozaki et al, ). Most of these studies concluded that BRAF mutation was in association with younger age at diagnosis (Heppt et al, ; Hugdahl et al, ; Meckbach et al, ), truncal lesion (Heppt et al, ; Hugdahl et al, ), and the superficially spreading melanoma histotype (Heppt et al, ; Meckbach et al, ), we agree with these findings. Regarding major prognostic indicators, precious studies demonstrated BRAF‐mutant melanomas were correlated with increased tumor thickness (Ellerhorst et al, ; Hugdahl et al, ), higher mitotic count (Ellerhorst et al, ; Hugdahl et al, ; Long et al, ; Meckbach et al, ) and presence of ulceration (Akslen et al, ; Ellerhorst et al, ; Hugdahl et al, ).…”

“…Along with these findings, prognostic value of BRAF mutation in cutaneous melanomas has also been discussed and conflicting results ensued (Akslen et al, ; Ardekani et al, ; Edlunch‐Rose et al, ; Ellerhorst et al, ; Heppt et al, ; Hugdahl et al, ; Inumaru et al, ; Long et al, ; Maldonado et al, ; Mann et al, ; Meckbach et al, ; Menzies et al, ; Moreau et al, ; Picard et al, ; Shinozaki et al, ). We found that BRAF V600E mutation had favorable prognostic impact on both disease‐free and OS for both the entire cohort and the individual stages except the local disease (Stage I–II).…”

“…In literature, controversy exists for the prognostic role of BRAF V600 in nonmetastatic cutaneous melanoma patients (Akslen et al, ; Ellerhorst et al, ; Heppt et al, ; Inumaru et al, ; Maldonado et al, ; Mann et al, ; Meckbach et al, ; Moreau et al, ; Picard et al, ; Shinozaki et al, ). Some data support that BRAF V600 mutation is an independent favorable prognostic factor (Heppt et al, ). In a recent German trial on 217 melanoma patients (most of them [96%] were Stage I–III patients) BRAF mutation was identified in 40.1% of the samples (Heppt et al, ).…”