Pancreatic ductal adenocarcinoma: Risk factors, screening, and early detection

Table 1 Selected pancreatic ductal adenocarcinoma genetic risk factors

Risk factor	Gene	Increased PDAC risk	Other associated cancers
Hereditary breast and ovarian cancer syndrome	BRCA1, BRCA2, PALB2	2-3.5	Breast, ovarian, prostate
Lynch syndrome (hereditary non-polyposis colorectal cancer)	MLH1, MSH2, MSH6, PMS2, EPCAM	8.6	Colon, endometrium, ovary, stomach, small intestine, urinary tract, brain, cutaneous sebaceous glands
Familial adenomatous polyposis	APC	4.5-6	Colon, desmoid, duodenum, thyroid, brain, ampullary, hepatoblastoma
Peutz-Jeghers syndrome	STK11/LKB1	132	Esophagus, stomach, small intestine, colon, lung, breast, uterus, ovary
Familial atypical multiple mole melanoma pancreatic carcinoma syndrome	P16INK4A/CDKN2A	47	Melanoma
Hereditary pancreatitis	PRSS1, SPINK1	69
Cystic fibrosis	CFTR	3.5
Ataxia-telangiectasia	ATM	Increased	Leukemia, lymphoma
Non-O blood group		1.3
Familial pancreatic cancer	Unknown	9 (1 FDR) 32 (3 FDRs)

PDAC: Pancreatic ductal adenocarcinomas; FDR: First-degree relative.

Table 2 Selected pancreatic ductal adenocarcinoma modifiable risk factors

Risk factor	Increased PDAC risk
Current cigarette use	1.7-2.2
Current pipe or cigar use	1.5
> 3 alcoholic drinks per day	1.2-1.4
Chronic pancreatitis	13.3
BMI > 40 kg/m2, male	1.5
BMI > 40 kg/m2, female	2.8
Diabetes mellitus, type 1	2.0
Diabetes mellitus, type 2	1.8
Cholecystectomy	1.2
Gastrectomy	1.5
Helicobacter pylori infection	1.4

PDAC: Pancreatic ductal adenocarcinomas; BMI: Body mass index.

Table 3 Pancreatic ductal adenocarcinomas screening efforts and diagnostic yields n (%)

Ref.	Number screened	High-risk group	Initial imaging (if abnormal screening)	Diagnostic yield	Definition of diagnostic yield
Brentnall et al[182]	14	FPC	EUS + ERCP + CT	7 (50)	Dysplasia
Rulyak et al[183]	35	FPC	If symptomatic: EUS + ERCP If asymptomatic: EUS (ERCP)	12 (34.3)	Dysplasia
Kimmey et al[184]	46	FPC	EUS (ERCP)	12 (26)	Dysplasia
Canto et al[185]	38	FPC, PJS	EUS (CT, ERCP, EUS-FNA)	2 (5.3)	PDAC, IPMN
Canto et al[186]	78	FPC, PJS	EUS + CT (ERCP, EUS-FNA)	8 (10.3)	IPMN, PanIN1-2
Poley et al[187]	44	FPC, BRCA, PJS, FAMMM, p53, HP	EUS (CT, MRI)	10 (23)	PDAC, IPMN on imaging
Langer et al[188]	76	FPC, BRCA, FAMMM	EUS + MRCP (EUS)	1 (1.3)	IPMN
Verna et al[181]	51	FPC, PJS, FAMMM, BRCA, HP, HNPCC	EUS and/or MRCP (EUS-FNA, ERCP)	6 (12)1	PDAC, IPMN, multifocal PanIN2-3
Ludwig et al[189]	109	FPC, BRCA	MRCP (EUS)	9 (8.3)	PDAC, IPMN, PanIN2-3, SCA on imaging
Vasen et al[190]	79	p16	MRI/MRCP, EUS if unable	7 (8.9)	PDAC
Al-Sukhni et al[191]	262	FPC, FDR of double-primary cancer, BRCA, PJS, HP, p16	MRI (ERCP, EUS, CT)	3 (1.1)2	PDAC
Schneider et al[33]	72	FPC, BRCA, PALB2, p16	EUS + MRCP (EUS)	4 (5.5)	MD-IMPN, multifocal PanIN23
				9 (12.5)	MD-IMPN, multifocal PanIN2-3, BD-IPMN
Canto et al[174]	216	FPC, BRCA, PJS	CT + MRI/MRCP + EUS (ERCP)	92 (42.6)	Pancreatic lesion

¹Only 41 patients had imaging, resulting in yield of 14.6% (6/41);

²Only 175 patients had imaging, resulting in yield of 1.7% (3/175). PDAC: Pancreatic ductal adenocarcinomas; HNPCC: Lynch syndrome; FAP: Familial adenomatous polyposis; PJS: Peutz-Jeghers syndrome; FAMMM: Familial atypical multiple mole melanoma syndrome; HP: Hereditary pancreatitis; FPC: Familial pancreatic cancer; endoscopic retrograde MRI: Magnetic resonance imaging; CT: Computed tomography; EUS: Endoscopic ultrasonography; ERCP: Endoscopic retrograde cholangiopancreatography; MCN: Mucinous cystic neoplasms ; IPMN: Intraductal mucinous cystic neoplasm; FNA: Fine needle aspirate.

Table 4 Selected highlights

Selected recent advances	Genetic risk factors
	In 2009, the use of gene sequencing identified PALB2, which had previously been implicated in breast cancer, as a susceptibility gene for PDAC[28]
	Expression of the palladin gene has been shown to be upregulated by cohabitance of normal fibroblasts with epithelial cells expressing the K-Ras oncogene. In 2012, it was shown that the palladin gene, which codes for a cytoskeletal protein, promotes mechanisms for metastasis and outgrowth of tumerogenic cells[90]
	Also in 2012, gene sequencing indicated that ATM mutations result in a predisposition to PDAC; LOH was demonstrated in 2 kindreds with PDAC[77]
	Therapy
	For patients with diabetes, treatment with metformin is associated with a lower relative risk of pancreatic cancer[127,136,137]
	A 2011 case report detailing a complete pathological response of a BRCA2-associated pancreatic tumor to gemcitabine plus iniparib showed the potential for PARP inhibitors in the treatment of BRCA2-associated pancreatic cancer[41]. Similar clinical trials are currently underway
Screening	Screening goals
	The goal of PDAC screening is the detection and treatment of (1) resectable PDAC; (2) PanIN-3 lesions; and (3) IPMN with high-grade dysplasia
	Low prevalence and high risk cohort enrichment
	The low absolute risk of PDAC development precludes population-wide screening from a cost-benefit and absolute harm perspective. The opportunity to screen high-risk cohorts will vastly increase the PPV of a screening test
	Screening efforts
	Past screening efforts, using patients cohorts at a high risk of developing PDAC, have demonstrated diagnostic yields from 1.1% to 50%, depending on their definition of yield (Table 3). Current screening modalities may be costly and invasive, and therefore associated with some patient risk. Furthermore, the long-term implications for detection of small and clinically insignificant lesions are uncertain. Further studies are needed to determine appropriate surveillance
Anticipated future advances and screening possibilities	Risk stratification
	Personal, family, genetic and environmental history will allow risk stratification and development of tailored screening and surveillance programs
	Biomarkers
	Ongoing research that suggests a future for gene expression profiling, proteomics, metabolomics, and microRNA as diagnostic PDAC biomarkers
	Targeted therapy
	As with BRCA2-associated tumors and PARP inhibitors, tumor biology will increasingly dictate the subsequent therapy

PDAC: Pancreatic ductal adenocarcinomas; IPMN: Intraductal mucinous cystic neoplasm.