Molecular genetics and targeted therapeutics in biliary tract carcinoma

Table 1 Epidemiology and clinical features of the primary malignancies of the biliary tract

Type of malignancy	Incidence	Risk factors	Typical presentation	Diagnosis
CC	1-2 per 100000 population[88]	Increasing age[89]		CT or MRI: Mass lesion with contrast uptake during arterial and venous phases[89]
		Hispanic or Asian ethnicity[89]
		PSC[89]
		Helminth infection[89]
		Choledochal cyst[89]
		Thorotrast[89]
		Metabolic syndrome[89,90]
		Hepatobiliary stones[89]
		Viral hepatitis[89,90]
Intrahepatic	10% of CC[89]		Constitutional symptoms (fevers, night sweats, unintended weight loss)[89]	Differentiate from hepatocellular carcinoma via timing of contrast uptake[89]
Extrahepatic	90% of CC[90]		Painless jaundice[89,90]	ERCP with brushing can obtain sample for cytology
				EUS with FNA of lymph nodes can assess for metastasis
GBC	1-2 per 100000 population[91]	Increasing age[92]	Painless jaundice[92]	EUS: Allows for FNA and is considered definitive for staging[92]
		Female gender[92]
		Hispanic, Asian, or Eastern European heritage[92]
		Gallstones[92]	Constitutional symptoms (fevers, night sweats, unintended weight loss)[92]	CT or MRCP: Determines resectability
		Salmonella[92]
		Helicobacter pylori[92]
		PSC[92]
		Heavy metal exposure[92]
		Metabolic syndrome[92]

CC: Cholangiocarcinoma; EUS: Endoscopic ultrasound; ERCP: Endoscopic retrograde cholangiopancreaticography; GBC: Gallbladder carcinoma; MRCP: Magnetic resonance cholangiopancreaticography; PSC: Primary sclerosing cholangitis.

Table 2 Frequency of mutation or abnormal expression of molecular targets in biliary tract carcinoma

Target	Type of alteration	GBC	EHCC	IHCC	Ref.
Growth factors/receptors
EGFR	Point mutation	6%-9%	14%-20%	3%-20%	[29,84]
EGFR	Increased expression	12%	5%-19%	11%-27%	[28,93]
HER2	Increased expression	16%	5%-8%	0%-1%	[28,93]
MET	Increased expression	5%-74%	0%	21%-58%	[93,94]
VEGF	Increased expression	55%-63%	59%	53%	[28,34]
RAS/RAF/MEK pathway
KRAS	Point mutation	0-13%	0%-23%	5%-54%	[29,39,95-99,101]
BRAF	Point mutation	0-33%	0%-2%	0%-21%	[29,39-41,101]
MEK	-	Unknown	Unknown	Unknown	-
PI3K/AKT/mTOR pathway
PI3K/PIK3CA	Point mutation	4%-12%	0	0%-9%	[45,99-101]
AKT	Point mutation	0	0	0-3	[101,102]
mTOR	Increased activation	47%-64%	65%	70%	[50,103]

AKT: Protein kinase B; BRAF: Proto-oncogene BRAF; EGFR: Epithelial growth factor receptor; EHCC: Extrahepatic cholangiocarcinoma; GBC: Gallbladder carcinoma; HER2: Human epidermal growth factor receptor 2; IHCC: Intrahepatic cholangiocarcinoma; KRAS: Kirsten rat sarcoma viral oncogene homolog; MET: Hepatocyte growth factor receptor; MAPK: Mitogen activated protein kinase; MEK: MAPK kinase; mTOR: Mammalian target of rapamycin; PI3K: Phosphoinositide 3-kinase; VEGF: Vascular endothelial growth factor.

Table 3 Clinical trials of targeted therapeutics in biliary tract carcinoma

Targeted therapeutics	Targets	BTC Subtypes	Treatment regimen	TTP (mo)	PFS (mo)	OS (mo)	Ref.
Erlotinib	EGFR	GBC, IHCC, EHCC	Erlotinib	2.6	-	7.5	[60]
Erlotinib	EGFR	GBC, IHCC, EHCC	Erlotinib + GEMOX	-	5.8	9.5	[61]
Erlotinib	EGFR	GBC, IHCC, EHCC	Erlotinib + Bevacizumab	4.4	-	9.9	[62]
Cetuximab	EGFR	GBC, IHCC, EHCC	Cetuximab + GEMOX	-	6.1	11.0	[63]
Panitumumab	EGFR	IHCC, EHCC	Panitumumab + Gemcitabine + Irinotecan	-	9.7	12.9	[64]
Panitumumab	EGFR	IHCC, EHCC	Panitumumab + GEMOX + Capecitabine	-	8.3	10.0	[65]
Lapatinib	HER2, EGFR	GBC, IHCC, EHCC	Lapatinib	-	1.8	5.2	[67]
Lapatinib	HER2, EGFR	GBC, IHCC, EHCC	Lapatinib	-	2.6	5.1	[68]
Bevacizumab	VEGF	GBC, IHCC, EHCC	Bevacizumab + GEMOX	-	7.0	12.7	[71]
Selumetininb	MEK	GBC, IHCC, EHCC	Selumetinib	-	3.7	9.8	[73]
Sorafenib	Multiple TKI	GBC, IHCC, EHCC	Sorafenib	-	2.3	4.4	[76]
Sorafenib	Multiple TKI	GBC, IHCC, EHCC	Sorafenib + Gemcitabine + Cisplatin	-	6.5	14.4	[77]

EGFR: Epidermal growth factor receptor; GEMOX: Gemcitabine + oxaliplatin; HER2: Human epidermal growth factor receptor 2; MEK: Mitogen-activated kinase kinase; PFS: Progression-free survival; OS: Overall survival; TKI: Tyrosine kinase inhibitor; TTP: Time-to-tumor progression; VEGF: Vascular endothelial growth factor.

Table 4 Ongoing clinical trials of targeted therapeutics in cholangiocarcinoma or gallbladder adenocarcinoma

Treatment	Phase	Date of completion	Sponsoring institutions	ClinicalTrials.gov identifier
GEMOX + Erlotinib	II	Dec., 2014	New Mexico Cancer Care Alliance	NCT00832637
Sorafenib + Erlotinib	II	May, 2014	National Cancer Institute	NCT01093222
GEMOX vs GEMOX + Cetuximab	II	Dec., 2014	National Health Research Institutes, Taiwan	NCT01267344
GEMOX + Panitumumab vs GEMOX + Bevacizumab	II	Aug., 2015	Vejle Hospital	NCT01206049
Cisplatin + Gemcitabine + Panitumumab vs Cisplatin + Gemcitabine	II	June, 2014	Hannover Medical School	NCT01320254
GEMOX + Panitumumab vs GEMOX alone	II	March, 2015	Fondazione del Piemonte per l'Oncologia	NCT01389414
Gemcitabine + Capecitabine + Bevacizumab	II	May, 2014	Roswell Park Cancer Institute	NCT01007552
Everolimus	II	June, 2014	Ratchavithi Hospital	NCT01525719
GEMOX + Sorafenib	I/II	Aug., 2014	University of Miami Sylvester Comprehensive Cancer Center	NCT00955721
Gemcitabine + Cisplatin + Sorafenib	II	March, 2014	Memorial Sloan-Kettering Cancer Center	NCT00919061
Gemcitabine + Cisplatin + Selumetinib	I/II	Jan., 2015	AstraZeneca	NCT01242605
Gemcitabine + Cisplatin + Selumetinib	I	Dec., 2014	AstraZeneca	NCT01949870
Trametinib	II	Feb., 2015	GlaxoSmithKline	NCT01943864
Trametinib vs 5-FU + Leucovorin vs Capecitabine	II	July, 2016	National Cancer Institute	NCT02042443
Celecoxib	IV	Dec., 2015	Seoul National University Hospital	NCT01111591
Regorafenib	II	Feb., 2018	University of Pittsburgh	NCT02053376
Regorafenib	II	Oct., 2018	H. Lee Moffitt Cancer Center and Research Institute	NCT02115542
Regorafenib + mGEMOX	I/II	April, 2019	Institut du Cancer de Montpellier-Val d'Aurelle	NCT02386397

5-FU: 5-fluorouracil; GEMOX: Gemcitabine and oxaliplatin.