Upfront rational therapy in BRAF V600E mutated pediatric ameloblastoma promotes ad integrum mandibular regeneration

Abstract

Ameloblastoma is a neoplasm arising in the craniofacial skeleton. Proliferating odontogenic epithelial cells comprise this benign, yet locally invasive tumor, often causing severe disfiguration. High recurrence rate entails ablative surgical resection, which is the current standard of care, resulting in subsequent critical size osteocutaneous defects. The high incidence of BRAF mutations in ameloblastoma, most notably the BRAF V600E mutation, enabled the use of BRAF inhibiting agent in a neoadjuvant setting. In this investigator-initiated, open-label study, three consecutive pediatric patients, with confirmed BRAF V600E ameloblastoma deemed marginally resectable, were treated with BRAF inhibiting agents, prior to undergoing surgery. The use of upfront BRAF inhibitor treatment resulted in substantial tumor regression, allowing for non-mutilating complete surgical removal, ad integrum bone regeneration and organ preservation. All patients showed a marked radiologic and clinical response to medical treatment, enabling successful conservative surgery. Microscopically, all patients showed evidence of minimal residual tumor with extensive tumor necrosis, fibrosis and generation of new bone. At a median follow-up of 31 months, all patients remained free of disease. Face preservation therapy was achieved in pediatric patients presenting with BRAF V600E mutated ameloblastoma. Our study demonstrates the translational potential of targeted therapy as a neoadjuvant agent. Patient-specific organ preservation therapy should be considered as the new standard of care in ameloblastoma, mainly for children and adolescents.

Ameloblastoma: An Updated Narrative Review of an Enigmatic Tumor

“…Most patients show a marked radiologic and clinical response to medical treatment, enabling successful conservative surgery. Face preservation therapy could be achieved in pediatric patients presenting with BRAF V600E mutated ameloblastoma [52].…”

Genomic profiling and precision medicine in complex ameloblastoma

“…Tan et al report on a case of unresectable, recurrent ameloblastoma treated with neoadjuvant dabrafenib with a strong clinical response that reduced the tumor size enough to make it resectable 27 . Hirschorn and Dawes et al describe its use in the neoadjuvant setting for unicystic ameloblastoma allowing them to reduce the magnitude and morbidity of surgery in the pediatric population 19,24 …”

“…The identification of these potential targets for treatment is well documented 12,16–18 . In addition, the use of precision medicine for complex ameloblastoma shows demonstrable treatment response 15,19–29 …”

Ameloblastoma in a Three-Year-Old Child with Hurler Syndrome (Mucopolysaccharidosis Type I)

“…Mutations of the BRAF (V600E) and MEK genes have been frequently observed as well, together with those of FGFR-2 and SMO [43,44]. Targeted therapies, such as vemurafenib and dabrafenib (inhibitors of BRAF gene), trametinib (inhibitor of MEK gene), cyclopamine (inhibitor of SMO gene), ponatinib and regorafenib (inhibitors of FGFR2 gene), seem to be an encouraging upcoming option [42,43,45]. Hence, a weighted risk/benefit assessment of pediatric ameloblastoma surgical resection needs to be further defined.…”