BRAF inhibitors in BRAF V600E-mutated ameloblastoma: systematic review of rare cases in the literature

Abstract

Background Ameloblastoma in 66% of the cases harbor a somatic mutation of the “mitogen-activated protein kinase” signaling pathway (BRAF V600E). In V600E mutations, BRAF is in the permanent “on” state and relays the growth-promoting signals independently of the EGFR pathway. Therefore, mutant BRAF represents a target for handful of new drugs. Methods We conducted a literature search, with the search terms “Vemurafenib, Dabrafenib, Ameloblastoma, and BRAF.” These included seven case reports with nine patients who underwent monotherapy with Dabrafenib or Vemurafenib or combination therapy with Dabrafenib and Trametinib. Results The patients age ranges from 10 years up to 86 years. The distribution of women and men is 4:5. Patients with an initial diagnosis of ameloblastoma, as well as recurrences or metastasized ameloblastoma were treated. Indications cover neoadjuvant therapy up to the use in metastasized patients in an irresectable state. Results ranging from “only” tumor size reduction to restitutio ad integrum. Conclusion We see the use of BRAF Inhibitors to reduce tumor size with consecutive surgical treatment as a reasonable option for therapy. However, we are aware that at present the data are based only on case reports with the longest follow-up of just 38 months. We encourage further clinical trials in the use of BRAF Inhibitors for selecting ameloblastoma patients in a multi-center setting.

Efficiency of B-RAF-/MEK-inhibitors in B-RAF mutated Ameloblastoma: Case report and review of literature

“…Similar case studies presented remarkable downsizing of the BRAF -mutated ameloblastoma or metastatic ameloblastoma after receiving therapies with different doses of BRAF -inhibitors or combined BRAF - MEK -inhibitors [ [11] , [12] , [13] ]. Even a case of metastasized ameloblastoma responding remarkably well to BRAF/MEK inhibitor therapy has been documented ion the literature and underscores the clinical utility of neoadjuvant therapy [ 14 ].…”

It was not possible to detect BRAF V600E mutation in circulating cell‐free DNA from patients with ameloblastoma: A diagnostic accuracy study

“…2,5,6 Patients with ameloblastoma that displays BRAF mutations are potentially eligible for targeted therapy using MAPK pathway (BRAF, MEK, ERK) inhibitors. 7 For this reason, assessment of the BRAF V600E mutation in ameloblastomas might play a pivotal role in tumor management and could therefore soon become a routine test in clinical practice. 8 Molecular tests, such as DNA sequencing and polymerase chain reaction (PCR)-based assays, and immunohistochemistry are currently available for the detection of BRAF V600E mutation in tumor tissue.…”

Does BRAF mutation status and related clinicopathological factors affect the recurrence rate of ameloblastoma? A systematic review, meta‐analysis and metaregression

“…The role of BRAFv600e in ameloblastoma has gained clinical interest with the emergence of targeted therapy in the neoadjuvant setting 11–13 . Initial results from trials using targeted towards the BRAF gene have shown promising results in such selected cases of ameloblastoma, but there is currently a lack of prospective clinical trials evaluating the efficacy of targeted therapy in this disease 14 . While it is therefore plausible that the patients with BRAF‐v600e mutation positive ameloblastoma have a higher recurrence rate, these patients may benefit from combined surgical and targeted therapy against BRAF .…”

“…[11][12][13] Initial results from trials using targeted towards the BRAF gene have shown promising results in such selected cases of ameloblastoma, but there is currently a lack of prospective clinical trials evaluating the efficacy of targeted therapy in this disease. 14 While it is therefore plausible that the patients with BRAF-v600e mutation positive ameloblastoma have a higher recurrence rate, these patients may benefit from combined surgical and targeted therapy against BRAF. The lack of widespread availability of targeted therapy limits routine diagnostic testing for this variant mutation in routine clinical practice.…”