Current concepts in ameloblastoma-targeted therapies in B-raf proto-oncogene serine/threonine kinase V600E mutation: Systematic review

Table 1 Presence of B-raf proto-oncogene serine/threonine kinase and B-raf proto-oncogene serine/threonine kinase V600E and the relation with additional mutations

BRAF type	Ameloblastoma			Histological pattern	Mutations	Additional mutation	Anatomic location
	Type	Cases with expression	Total cases	Histological pattern (cases)	Gene (cases/total)	Gene (cases)	Site (cases)
BRAF WT	Ameloblastoma	39	521	Follicular (15)	NRAS Q161R (2/15)		Mandible (9)
							Maxilla (1)
					G606E (1/15)		NS (5)
					L584P, V590G (1/15)
				Plexiform (14)	HRASQ161R (2/14)		Mandible (10)
					FGFR2 p.C382R (2/14)		Maxilla (1)
							NS (3)
				Mixed (4)			Mandible (4)
				NS (6)	FGFR2 (4/12)	PTEN, TP53 (1)	NS (6)
					KRAS (1/12)
	Unicystic ameloblastoma	10	81	Luminal/intraluminal (6)			Mandible (4)
							Maxilla (2)
				NS (4)			Mandible (1)
							NS (3)
	Ameloblastic carcinoma	7	13	Without cell variant (5)			Mandible (3)
							Maxilla (2)
				NS (2)			NS (2)
	Metastasizing ameloblastoma	0	2
BRAF V600E	Ameloblastoma	297	521	Follicular (121)			Mandible (91)
					JAK3 P132T (3/121)
					SMARCB1 (1/121
					PIK3CA (1/121)
					CTNNB1 (1/121)
					SMO (1/121)
					SMO (1/121)	FGFR2 (1)	Maxilla (4)
							Left frontal bone (1)
					G606E (2/121)		NS (25)
				Plexiform (65)	JAK3 P132T (1/65)		Mandible (38)
					SMARCB1 (1/65)
					PIK3CA (1/65)
					PIK3CA (1/65)		Maxilla (2)
					BRAF 597R (1/65)	SMO (1)
							NS (25)
				No follicular (20)			Mandíbula (20)
				No plexiform (15)			NS (15)
				Granular-cell (4)			Mandible (4)
				Mixted (10)			Mandible (4)
							NS (6)
				Without cell variant (1)			Mandible (1)
				Desmoplastic (2)			Mandible (1)
							Maxilla (1)
				NS (59)	FGF21 (23)		Mandible (4)
					FGFR11 (24)		Maxilla (1)
							NS (45)
							Cavernus sinus (1)
							Coronoid process (1)
	Unicistyc ameloblastoma	63	81	Luminal/Intraluminal (21)			Mandible (19)
							Maxilla (2)
				Mural (20)			Mandible (20)
				NS (22)			Mandible (12)
							Maxilla (1)
							NS (9)
	Peripheral ameloblastoma	5	6	NS (5)			NS (5)
	Ameloblastic carcinoma	3	13	Without cell variant (3)			Mandible (3)
	Metastasizing	1	2	Follicular (1)			Mandible (1)
	NS			Acanthomatous (7)			Mandible (7)
				Granular cells (2)			Mandible (2)
				NS (2)	PIK3CA, CDKN2A (1)		Mandible (1)
					PIK3CA, PTEN (1)		Mandible (1)
				NS (2)	CDKN2A (1)		Mandible (1)
					CTNNB1 (1)		Mandible (1)
No mutations	Metastasizing Ameloblastoma	1	2	Plexiform (1)			Infratemporal fosa (1)
	Ameloblastic Carcinoma	3	13	NS (3)			NS (3)
	Unicistyc Ameloblastoma	1	81				NS (1)

¹Expressed without mutation. NS: No specified; BRAF: B-raf proto-oncogene serine/threonine kinase; BRAF WT: B-raf proto-oncogene serine/threonine kinase Wild-type.

Table 2 Targeted therapies to B-raf proto-oncogene serine/threonine kinase V600E in ameloblastomas

Ref.	Age	Evolu-tion tumor (yr)	Gender	Tumor	Locali-zation	Primary tumor/ recur-rent	Pre-vious treat-ments	Size	Course of the disea-ses	Muta-tion detected	Treat-ment	Evolu-tion	Follow-up
Kaye et al[27]	40	30	M	MA	Left jaw, bilateral neck mass, pulmo-nary metas-tases	Recurrent	Surgical resection and radiot-herapy	NS	Three recur-rences (13, 9, 7 yr), surgical resection (two recur-rences), RT (last recurrence), neck bilateral and lung metas-tasis. (imaging diagnosis CT)	BRAF V600E (gene profile and IHC)	BRAF/MEK inhibition (Dabra-fenib 150 mg twice daily + Trame-tinib 2 mg once daily)	Decrease of the tumor size and metas-tases in the first four days	20 wk (tumor response to treatment, without toxicity)
Faden et al[26]	83	16	F	AM	Right jaw	Recurrent	Conser-vative surgery	3.79 cm × 5.87 cm × 5.62 cm	Two recur-rences, difficult to nutrition, not suitable for surgery	BRAF V600E	Dabra-fenib 75 mg twice daily	Decrease of the tumor size	12 wk (tumor response to treatment)
Fernandes et al[29]	29	12	F	AM	Ramus and left jaw	Recurrent	Surgical resection and radiot-herapy	1.3 cm × 0.9 cm (residual tumor)	Tumor recur-rence by conser-vative surgery for 16 yr, metas-tases in cavernous sinus and tumorl extention to orbit	BRAF V600E (PCR allele-specific)	Vemurafenib 960 PO twice daily and analgesic treatment	Decrease of the tumor size with sympto-matology (anorexy, nausea and fatigue)	11 wk, asympto=matic with treatment tolerance
Tan et al[28]	85	NS	M	AM	Left jaw	Primary	Surgical resection	4 cm (CT Scan)	Tumor recur-rence with patho-logical fracture	BRAF V600E (PCR allele-specific)	Dabrafenib 150 mg PO twice daily	Decrea-sed of tumor size with develo-pment of actinic keratosis on face, back and scalp and thic-kening voice	16 wk, notable decrease of tumor size

NS: No specified; PO: Oral administration; BRAF: B-raf proto-oncogene serine/threonine kinase; IHC: Immunohistochemical; CT: Chemotherapy; MA: Metastatic ameloblastomas; AM: Ameloblastomas.