Diagnostic and therapeutic biomarkers in pancreaticobiliary malignancy

Table 4 Theranostic markers in pancreatic ductal adenocarcinoma and cholangiocarcinoma

	Marker (drug)	Countries	Patients with + marker	Staining	Median survival (mo)	HR
Pancreatic cancer	SPARC[2] (nab-paclitaxel/ gemcitabine)	United States	67	36	+SPARC: 17.8 -SPARC: 8.1	P = 0.0431
	hENT1 (Gemncitabine)	Canada[96]	21	Low hENT1: 12	Low: 4	1
				High hENT1: 9	High: 13
		Italy[158]	83	Low hENT1: 27	Low: 8.5	4.21
				Inter: 28	Inter:15.7
				High hENT1: 26	High: 25.7
		United States[97]	91	Low hENT1: 39	2	0.51
				High hENT1: 34
		Belgium[98]	45	Low hENT1: 26	Low: 13.3	4.31 (HR for death)
				High hENT1: 19	High: 18.7	P = 0.0001 (OS)
		Japan[159]	40	Low hENT1: 26	Low: 8	P = 0.011 (OS)
				High hENT1: 14	High:25
		Japan[160]	55	Low hENT1: 16	Low: 11.8	3.15 (OS)
				High hENT1: 39	High: 24.9
		Belgium	243	Low hENT1: 142	2	0.34
		France[86]		High hENT1: 92
		Worldwide multicenter[99]	177	Low hENT1: 118	Low: 6.1	1.147
				High hENT1: 59	High: 5.2
		England[161]	176	Low hENT1: 77	Low: 17.1	0.6
				High hENT1: 99	High: 26.2
	Marker	Countries	CCA patients	% mutated	Type of mutation	Potential theranostic value
CCA	EGFR[94,105,109,112]	United States, South Korea, Japan, Italy	400	1-81	G719S kinase activation	EGFR inhibitors
	VEGF[108,162]	South Korea	272	41.7-56.8	Up-regulation	Anti-VEGF therapies
	Kras[109,111,142,163-166]	United States, Germany, China, Norway, Japan	197	7.4-45	Substitution	U0126 (MEK inhibitor)
	BRAF[109,110,164,167]	United States, Germany, China	222	0-22	Activating missense	BRAF inhibitors
	ErbB2 (HER2/neu)[94,112]	South Korea, Italy	284	4-5.1	Up-regulation	Anti-ErbB2 therapies
	IDH1/2[109,114,115,168]	United States	576	10-22.31	Gain of function	α-KG-mimics reverse methylation
	miR-21, miR-200b[40]; miR-29b, miR-205, miR-221[117]	United States, Japan	1	1	Up-regulated	Increased sensitivity to gemcitabine
	miR-494[92]	United States	43	1	Down-regulated	Up-regulation decreases tumor growth
	Panel: CDO1, DCLK1, ZSCAN18 and SFRP1[169]	Norway	39	87	Promoter methylation	Anti-methylation therapy
	Panel: CDO1, CNRIP1, SEPT9, and VIM[170]		30	85
	SFRP1[169,171-173]	Norway, United Kingdom, South Korea, Thailand	255	59-83.6	Promoter methylation	Tumor suppression with gene therapy (RNAi)

¹Not reported;

²Results graphed. OS: Overall survival; PDAC: Pancreatic ductal adenocarcinoma; CCA: Cholangiocarcinoma; Kras: Kirsten rat sarcoma viral oncogene homolog; MEK: Mitogen-activated protein kinase/ERK kinase; EGFR: Epidermal growth factor receptor; ErbB2: Erythroblastosis oncogene B 2; VEGF: Vascular endothelial growth factor; CDO1: Cysteine dioxygenase type 1; DCLK1: Doublecortin-like kinase 1; ZSCAN18: Zinc finger and SCAN domain containing 18; SFRP1: Secreted frizzled-related protein 1; CNRIP1: Cannabinoid receptor interacting protein 1; SEPT9: Septin 9; VIM: Vimentin; IDH1/2: Isocitrate dehydrogenase 1/2; α-KG: Alpha-ketoglutarate.