Diagnostic and therapeutic biomarkers in pancreaticobiliary malignancy

Table 1 Diagnostic serum markers for pancreatic ductal adenocarcinoma and cholangiocarcinoma

	Diagnostic markers	Countries	CCA or PDACpatients, n	Sensitivity (%)	Specificity (%)
Pancreatic cancer	miRNA-10b, -30c, -106b, -155, and -212[120]	United States	77	73-100	83-100
	Index 1: (miR-145, miR-150, miR-223, miR-636)	Denmark	409	Index 1: 77 Index 2: 80	Index 1: 66 Index 2: 82
	Index 2: (miR-26b, miR-34a, miR-122, miR-126, miR-145, miR-150, miR-223, miR-505, miR-636, miR-885.5p)[121]
	miR-21, miR-210, miR-155, and miR-196[122]	United States	49	64	89
CCA	CYFRA 21-1[18,24,30]	United Kingdom, Italy	30	17-76	79-95
	MMP-7[24,123,124]	Thailand, Italy	120	53-78	72.5-92
	Combo	Italy	24	92	96
	(CEA, CA 19-9, MMP-7, CYFRA 21-1)[24]
	Combo	United Kingdom	6	45	96
	(CYFRA 21-1, CA 19-9)[30]
	IL-6[35,125-127]	United States, Thailand	207	71.1-100	90-92
	SSP411[37]	China	35	90	83.3
	miR-21[128]	United States	23	95	100
	miR-150[129]	China	15	80.6	58.1
	1miR-192[130]	Japan	51	74	72
	MUC5AC[131,132]	Thailand	348	62.6-71	90-96.9
	Combo	China	30	90	90
	(AFP, CEA, CA 19-9, CA 125)[133]

All markers identified with ELISA, except for

¹Western blot. All cases of cholangiocarcinoma are histologically-proven. Control patients for CCA include those with benign liver diseases, HCC and healthy controls. Combo: Combination; PDAC: Pancreatic ductal adenocarcinoma; CCA: Cholangiocarcinoma; CYFRA 21-1: Cytokeratin 19 fragment; MMP-7: Matrix metalloproteinase-7; CEA: Carcinoembryonic antigen; CA 19-9: Cancer antigen 19-9; IL-6: Interleukin-6; SSP411: Sperm-specific protein 411; MUC5AC: Mucin 5AC; AFP: Alpha-fetoprotein; ELISA: Enzyme-linked immunosorbent assay; HCC: Hepatocellular carcinoma.

Table 2 Tissue-based diagnostic biomarkers for cholangiocarcinoma

	Diagnostic marker	Countries	Total patients, n	CCA patients, n	Sensitivity (%)	Specificity (%)
PSC-associated strictures	Brush Cytology[21,76,134-140]	United States, The Netherlands, Sweden, Norway	828	138	7-73	89-100
	FISH polysomy[21,73,136,137,140]	United States	387	89	22-50	88-100
	FISH polysomy or trisomy[21,73,136,140]	United States	373	75	60-88	57-87
	Kras[141,142]	Norway, United States	180	74	29-47	96-100
	p53[142]	Norway	48	33	31	100
	Cytology + CA19-9[135]	United States	333	44	87.5	97.3
	Cytology + DNA aneuploidy + CA19-9 + CEA[138]	Sweden	20	7	88-100	80-85
	Cytology + p53 + KRAS[76]	The Netherlands	23	10	100	79
	FISH + KRAS[141]	United States	14	14	50-68	96
Indeterminate strictures	Brush Cytology[75,78,79,136,140,143-150]	United States, Germany, France, Italy	640	199	5.8-80	92-100
	FISH Polysomy[75,78,79,136,137,140]	United States, Italy	386	165	31-80	97-100.0
	FISH Polysomy or trisomy[75,136,140]	United States	147	88	49-64	79.6-100
	Biopsy[144,145,147,150-153]	United States, Japan, France	347	65	30-88	97-100
	FNA[145,154]	United States	133	30	25-61.6	100.0
	Cytology + biopsy[144,150]	France, Austria	258	28	63-86	97-100
	Cytology + FNA + biopsy[145]	United States	133	30	47-52	100
	Cytology + KRAS[155]	Belgium	142	12	55	100

Some studies included all biliary tract cancers (cholangiocarcinoma, gallbladder, pancreatic and ampullary), but sensitivity and specificity values were similar, so data is merged. Endobiliary sampling technique for cytology and FISH: ERCP or PTC brushing; Biopsy technique: Standard forceps, mini-forceps or transpapillary biopsy. FISH: Fluorescent in situ hybridization; PTC: Percutaneous transhepatic cholangiography; CCA: Cholangiocarcinoma; PSC: Primary sclerosing cholangitis; p53: Tumor protein p53; KRAS: Kirsten rat sarcoma viral oncogene homolog; CEA: Carcinoembryonic antigen; CA 19-9: Cancer antigen 19-9; FNA: Fine-needle aspiration.

Table 3 Prognostic markers in pancreatic ductal adenocarcinoma and cholangiocarcinoma

	Marker	Country	Total patients,n	Marker positive PDAC	Type of dysregulation	Prognostic value, OS months	HR or P value for OS
Pancreatic cancer	SPARC	United States[81]	299	200	Up-regulated	+SPARC: 15 -SPARC: 30	1.89
		Germany[83]	58	58	Up-regulated	+SPARC: 7.6 -SPARC: 10.2	2.23
		Germany[84]	160	95	Up-regulated	+SPARC: 17.9 -SPARC: 30.2	P = 0.006
		Japan[85]	104	104	Up-regulated	Decreased survival	2.92
		Sweden[82]	88	68	Up-regulated	+SPARC: 11.5 -SPARC: 25.3	2.12
	Marker	Country	Total Patients, n	CCA patients, n	Type of dysregulation	Prognostic value	HR (95%CI) or P value for OS
CCA	1miR-192[130]	Japan	83	51	Up-regulated	Increased LN mets; shorter survival	2.076 (1.004-4.291) P < 0.05 mets
	miR-675-5p[88]	China	72	63	Up-regulated	Shorter survival	2.562 (1.295-4.929)
	miR-652-3p, miR-338-3p[88]	China	72	63	Down-regulated	Increased survival	0.477 (0.247-0.922); 0.498 (0.257-0.966)
	miR-151-3p and miR-126[156]	United States	32	32	Up-regulated and down-regulated, respectively	Increased survival	0.201 (0.043-0.928)
	1miR-21[46]	Thailand, China	41	32	Up-regulated	Increased LN mets; shorter survival	P < 0.05 OS P = 0.037 mets
	miR-214[157]	China	14	14	Down-regulated	Increased mets	P < 0.05 mets
	miR-373[90]	China	48	48	Down-regulated	Shorter survival	P < 0.05 OS
	Group 1: miR-21, miR-31, miR-223 Group 2: miR-122, miR-145, miR- 146a, miR-200c, miR-221, and miR-222[44]	Greece	179	21	Group 1: Up-regulated Group 2: Down-regulated	None	-
	CYFRA 21-1[18,30]	United Kingdom, Japan	195	137	Up-regulated	Shorter survival	P = 0.001[30] P < 0.01[18]
	EGFR[93,94]	Japan	373	338	Up-regulated	Shorter survival	5.655 (2.72–11.74)[93] 2.67 (1.52-4.69)[94]

¹Liver fluke-associated CCA. PDAC: Pancreatic ductal adenocarcinoma; CCA: Cholangiocarcinoma; mets: Metastases; OS: Overall survival; SPARC: Secreted protein acidic and rich in cysteine; CYFRA 21-1: Cytokeratin 19 fragment; EGFR: Epidermal growth factor receptor; LN: Lymph node.

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.