Abstract
Purpose of Review
Pancreatic cancer remains one of the most lethal of malignancies with 5-year survival of only 8%. A number of reasons account for the high fatality rate including few known modifiable risk factors, no effective screening tools, and lack of early diagnostic symptoms. Therefore, in this review, we aim to summarize existing evidence from major studies concerning (1) risk factors for risk assessment and risk stratification, and (2) screening modalities and early detection markers to better understand the ways to prevent pancreatic cancer or identify it at earlier stages. Improvements in primary and secondary prevention of pancreatic cancer are critical to reduce the morbidity and mortality of this deadly disease.
Recent Findings
We searched the published literature and identified studies of pancreatic cancer risk published prior to September 30, 2018, with an emphasis on manuscripts publicized during the last 5–10 years. Known and suspected risk factors include familial and genetic risk, smoking, obesity, alcohol, poor diet including sugary sweetened beverages, diabetes, and periodontal disease. Recent advances have identified potential early detection markers (e.g., ctDNA, circulating cancer cells, metabolites, and miRNA).
Summary
Currently, pancreatic cancer has few known and suspected risk factors, and risk assessment tools have limited utility given their modest discriminatory power. Although emerging evidence suggests blood-based biomarkers may be useful as early detection markers, findings need to be confirmed in prospective studies. Due to the rarity of disease, future studies should consider a two-tiered approach in which risk assessment is used to identify high-risk individuals for screening, and then effective imaging and biomarkers in pathways known to affect pancreatic cancer risk are employed; these combination approaches may reduce false positives and mortality compared with just risk assessment or screening alone.
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Introduction
Pancreatic cancer remains one of the most lethal of malignancies. An estimated 232,306 cases of pancreatic cancer occur globally each year, and 227,023 die from the disease [1]. Since 2004, incidence rates have increased by 1.5% per year in the USA [2]. This is extremely alarming given that half of the individuals diagnosed with pancreatic cancer die within 6 months and that the 5-year survival for pancreatic cancer is 8% [3]. While the 5-year survival rate improves to 37.4% in patients presenting with stage 1 or localized disease, only 10% of patients are identified at this early stage [4]. The majority of patients (53%) are diagnosed with distant, metastatic cancer, and have a 5-year survival of 2.9% [5]. A number of reasons exist for the late diagnosis and high fatality rate, including few known modifiable risk factors, no effective screening tools, and lack of early diagnostic symptoms unique to pancreas cancer. Thus, approaches to prevent disease or identify it at earlier stages (e.g., stage 1a) are critical to reduce the morbidity and mortality of this deadly disease. Therefore, in this review, we aim to review the recent literature with regard to the (1) identification for risk factors for risk assessment and risk stratification (Table 1 and Fig. 1) and (2) identification of screening modalities and early detection markers.
Risk estimates for studies examining arsenic and cadmium exposure with pancreatic cancer risk. The meta-analyses included are Ojajarvi, 2000 (92 occupational studies); Chen, 2015: (five published studies and one de novo study). The black squares and horizontal lines correspond to the study-specific relative risks and 95% confidence intervals. The area of the black squares is proportional to the inverse of the sum of the between-studies variance and the study-specific variance. The red boxes represent studies in which the exposure was occupational exposure to arsenic or cadmium
Risk Factors for Pancreatic Cancer
Familial and Genetic Risk
Genetic variation, both familial and sporadic, plays an important role in pancreatic cancer. Family history of any cancer has been associated with a 15–30% higher pancreatic cancer risk [6, 7]; risk is stronger when considering only a family history of pancreatic cancer, with risk ratios of 1.68 for any relative, 3.88 for at least two first-degree relatives, and up to fivefold for when an individual has an affected sibling [6, 8]. A meta-analysis consisting of seven case-control studies and two cohort studies reported an association between having a family history of pancreatic cancer and pancreatic cancer risk (summary RR = 1.80, 95% CI 1.48–2.12). Increased risks were observed when considering the number of first degree relatives affected (summary RR = 4.6, 95% CI 0.5, 16.4; summary RR = 6.4, 95% CI 1.8–16.4; summary RR = 32.0, 95% CI 10.2–74.7, for one relative, two relatives, or three relatives affected, respectively) [9].
The associations between family history and pancreatic cancer risk suggest that there are genes of varying penetrance that influence the pancreatic carcinogenesis. Several genes have been implicated in pancreatic cancer risk (e.g., BRCA1, BRCA2, PALB2, ATM, CDKN2A, APC, MLH1, MSH2, MSH6, PMS2, PRSS1, and STK11), as well as the ABO genotype [10•]. A recent meta-analysis conducted with the largest pancreatic cancer GWAS that included up to 11,537 cases and 17,107 controls observed several new genome-wide significant loci. Specifically, SNPs located on the NOC2L gene were statistically significantly associated with pancreatic cancer risk (OR = 1.26, 95% CI 1.19–1.35, P = 8.36 × 10−14) [11•]. Additionally, genetic syndromes have been shown to be associated with a 4–40% increased pancreatic cancer risk such as familial atypical multiple mole melanoma, Peutz-Jeghers syndrome, hereditary pancreatitis, hereditary nonpolyposis colon cancer, and multiple endocrine neoplasia type 1 syndrome [12]. However, family history and/or genetic predisposition is reported to account for only 5–10% of all pancreatic cancer cases in the US; estimates have remained stable over the last few decades [10•, 13, 14].
Lifestyle Factors
Smoking
Tobacco use is one of the strongest and most consistent lifestyle risk factors for pancreatic cancer with an estimated population attributable fraction of 11–32% [15•]. Nicotine derivatives in cigarette smoke can promote carcinogenesis of the pancreas by inducing cellular damage, formation of DNA adducts, or interfering with physiological pathways [16]. Two recent case-control studies [17, 18], a pooled analysis of 12 case-control studies from Panc4 consortium [19], as well as a large meta-analysis of 30 case-control and 12 cohort studies [20], reported a twofold higher pancreatic cancer risk for current compared with never smokers, and the risk increased up to threefold with > 35 cigarettes per day.
Overall and Central Obesity
The World Cancer Research Fund (WCRF) and American Institute for Cancer Research (AICR) estimate that healthy weight is the second most important factor, besides not smoking, for cancer prevention; excess weight is estimated to be attributable for up to 15% of all pancreatic cancer cases [21]. Excess body fat has been implicated in pancreatic cancer risk due to modification of insulin, hormonal, and inflammation pathways [22,23,24,25]. Prior research has shown that overall obesity, as measured by BMI, and central obesity, as measured by waist circumference or waist-to-hip ratio, are positively associated with pancreatic cancer incidence [26, 27, 28•]. In four pooled analyses [26, 27, 28•, 29], a significant 8–14% higher pancreatic cancer risk and mortality were observed for a 5 kg/m2 increase in BMI at baseline (usually measured in mid to late adulthood) and a 55% higher risk when examining > 35 compared with 18.5–24.9 kg/m2). A slightly stronger 18–20% higher pancreatic cancer risk was observed for a 5 kg/m2 increment in BMI at younger ages (usually retrospectively assessed for ages 18–21) [28•, 29]. In only one [28•] of three pooled analyses [26, 28•, 29] was waist circumference positively associated with pancreatic cancer; however, all three pooled analyses reported statistically significant positive associations for waist-to-hip ratio [26, 28•, 29]. In 2018, the expert panel of the WCRF/AICR report stated that there was convincing evidence that greater body fatness is associated with higher pancreatic cancer risk [30•].
Alcohol
Heavy alcohol drinking has been hypothesized to be associated with higher pancreatic cancer risk. Alcohol may promote carcinogenesis through several mechanisms, such as the creation of acetaldehyde, an alcohol metabolism byproduct; upregulation of immunosuppressive and inflammatory pathways; activation of phase I cytochrome P450 biotransformation enzymes; and folate depletion that can interfere with DNA processes [31,32,33,34]. Most case-control studies have observed no association with alcohol intake [35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54], while a number of case-control studies found positive [55,56,57,58,59,60] and inverse [61,62,63] associations. Additionally, inconsistent associations have been reported with pancreatic cancer risk from 12 prospective studies [64,65,66,67,68,69,70, 71•, 72•, 73•, 74, 75]. In a pooled analysis of 14 prospective cohort studies, a 22% (95% CI 3–45%) higher pancreatic cancer risk was observed for alcohol intake > 30 g(g) (equivalent to > two drinks per day) compared with 0 g/day [71•]; whereas no statistically significant association was noted in PanScan or PanC4 case-control consortia for that contrast [72•, 73•]. Yet, a 60% increased risk was noted for those consuming more than nine drinks compared with < one drink/day in PanC4 [72•]. Based on this evidence, the WCRF/AICR expert panel concluded that the current data on alcohol intake were too inconsistent to reach a judgment [30•].
Diet
Dietary factors have long been hypothesized to be associated with pancreatic cancer risk due to the large geographic variation in incidence rates worldwide [76]. To date, most research, including consortia studies, has focused on individual foods and nutrients including fruits and vegetables [77], dairy products [78], sugar-sweetened beverages [79], fats, meats, and protein (all individual studies cited in WCRF/AICR 2018 report) [80]. In 2018, an expert panel for the WCRF/AICR stated the evidence was suggestive for a positive association between consumption of red meat, processed meat, foods containing saturated fatty acids, and foods containing fructose and pancreatic cancer risk [30•]. However, as pancreatic cancer is believed to be a disease of multifactorial origins, it is also critical to understand risk in the context of multiple, simultaneous dietary, and lifestyle factors. Few studies have examined associations between dietary and lifestyle patterns and indices, which capture multiple exposures simultaneously, and pancreatic cancer risk. In studies examining data-driven dietary patterns (e.g., prudent pattern) identified within their own cohorts; results have been inconsistent [48, 81,82,83,84,85], whereas indices that are a priori (e.g., Alternative Healthy Eating Index) have been associated with lower pancreatic cancer risk for those who adhered to a healthier dietary and lifestyle [86,87,88,89]. Yet, case-control studies pose the potential for information and selection biases, or and cohort studies had limited case numbers and statistical power [81, 82, 85, 86].
Physical Activity
Physical activity, through reducing insulin resistance, adiposity, DNA damage, and inflammation, has been posited to lower pancreatic cancer risk [90]. Prior case-control [91, 92] and a cohort study [93], as well as two large meta-analyses [90, 94], have suggested that physical activity is inversely associated with pancreatic cancer risk with risk estimates ranging from 7 to 35% lower risk when comparing high to low levels of physical activity, while several prospective cohort studies have found nonsignificant or no association [95,96,97,98]. Some studies have suggested that risk may be limited to leisure-time physical activity only [91, 94•]. The WCRF in 2018 stated that the evidence of a protective effect of physical activity on pancreatic cancer risk is too limited and inconsistent to draw a conclusion [30•].
Reproductive Factors
Due to suggested hormonal effects on pancreatic carcinogenesis in rat and human tissue models [99,100,101,102], reproductive and hormonal factors have been hypothesized to play a role in pancreatic cancer risk. Results have been inconsistent when examining age at menarche, oral contraceptive use, parity, age at first birth, menopausal status, and hormone replacement therapy (HRT) use as possible risk factors of pancreatic cancer. Although individual studies have reported null [103, 104], inverse [105], and positive associations with increasing parity [106], a meta-analysis of six cohorts and five case-control studies reported a 21% higher pancreatic cancer risk for highest vs. lowest categories of age at first birth [107]. Overall, there was no association with hormone use [104,105,106] and age at menopause [103, 108]. However, one cohort study observed a protective effect of older age of menopause on pancreatic cancer risk (HR = 0.35 (95% CI 0.18–0.68) comparing menopause at > 55 to < 45 years) [104], and for women who have had a hysterectomy (OR=0.78; 95% CI 0.67–0.91) in the Panc4 case-control consortium [109]. Overall, there is conflicting evidence of reproductive factors and pancreatic cancer risk in women that warrants further research.
Medical History
Pancreatitis
Pancreatitis, the acute or chronic inflammation of the pancreas [110], has been implicated in pancreatic cancer incidence. Specifically, a twofold higher risk has been observed in patients diagnosed with acute pancreatitis [110, 111], while a meta-analysis of six cohort studies and one case-control reported a 13-fold higher pancreatic cancer risk in those diagnosed with chronic pancreatitis [112].
Diabetes and Metformin
Type 2 diabetes mellitus, a disease that can occur when the body develops insulin resistance or not enough is produced, has been associated with an excess pancreatic cancer risk; however, it has also been posited that diabetes may be a consequence or early manifestation of pancreatic cancer. Two meta-analyses and one pooled analysis observed a 50–90% higher pancreatic cancer risk in patients who have a history of diabetes [113,114,115]; risk was similar even for individuals who had diabetes for up to 20 years prior to diagnosis [114]. Medications, like metformin, used to treat type II diabetes, has been hypothesized to have been protective due to its hypoglycemic and hypoinsulinemic effects [116], but results have been heterogeneous. A case-control and nested case-control study have observed a non-significant positive association between metformin use and pancreatic cancer risk [116, 117] while a meta-analysis of 10 cohort studies and three case-control studies observed an inverse association for metformin use in individuals with type 2 diabetes (summary RR = 0.63, 95% CI 0.46, 0.86) [118].
Statins
Statins are traditionally used for the treatment and prevention of cardiovascular disease and have been studied in relation to cancer due to their possible anti-neoplastic properties [119]. One case-control and one cohort studies observed no association with statin use and pancreatic cancer risk [119, 120], while a 34% (95% CI 8–53%) lower risk was observed in a case-control study; the statistically significant inverse association was limited to men (ORmen = 0.50; 95% CI 0.32–0.79; ORwomen = 0.86; 95% CI 0.52–1.43) [121]. Two meta-analyses observed a suggestive (summary RR = 0.89, 95% CI 0.74, 1.07) [122] and statistically significant protective effect of statin use on pancreatic cancer risk (pooled OR = 0.70; 95% CI 0.60–0.82) [123].
Hepatitis B, Hepatitis C, and Helicobacter pylori (H. pylori) Infection
Hepatitis B, hepatitis C, and H. pylori infections have been investigated due to their ability to be detected and replicated within the pancreas [124, 125], their association with pancreatitis [126, 127], and their ability to enhance inflammatory responses which may promote pancreatic carcinogenesis [128], respectively. A meta-analysis of five case-control and three cohort studies [129] observed a 20–60% higher pancreatic cancer risk with a previous hepatitis B infection, while a large Japanese cohort observed a null association [130]. For hepatitis C, a 26% higher risk was observed in the meta-analysis [129], while subsequent to the meta-analysis, a suggestive inverse association (OR = 0.69, 95% CI-0.28-1.69) was observed in the large Japanese cohort [130]. For H. pylori, a nested case-control study [128] and two meta-analyses [131, 132] observed no statistically significant association with H. pylori infection. In contrast, a case-control study examining CagA genes, found in some H. pylori strains, found a lower pancreatic cancer risk in CagA seropositive individuals (OR = 0.68; 95% CI 0.54–0.84) and a non-significant increased risk for CagA negative, H. pylori-positive individuals when compared with those who were seronegative for both H. pylori and CagA [133].
Periodontal Disease
The oral microbiome has recently been hypothesized to be involved in immune response and carcinogen metabolism [134]. Poor oral health has been associated with up to a twofold higher pancreatic cancer risk in multiple prospective studies [134, 135, 136•, 137]. Porphyromonas gingivalis, has specifically been implicated with reported significant odds ratios of 1.60 (presence vs. absence) [134] and 2.14 (presence vs. absence of antibodies) [136•].
Environmental (Other “Environmental” Exposures Are Discussed under the Lifestyle Section) and Occupational Exposures
Metals and Metalloids
Although the International Agency for Research on Cancer (IARC) concluded there are sufficient evidence to classify inorganic arsenic (As) and cadmium (Cd) as class I human carcinogens [138, 139•], these statements refer to other cancers. Few studies have examined these metals and metalloids with pancreatic cancer risk; the associations have been inconsistent with studies reporting null [140,141,142,143,144] and positive associations [145,146,147,148,149,150,151,152,153,154]. Furthermore, a recent study by Antwi et al. reported significant associations between exposure to asbestos, benzene, and chlorinated hydrocarbons and an increased pancreatic cancer risk with ORs ranging from 1.21 to 1.70 [155]. Given that most studies were small, had limited power, were retrospective or restricted to populations exposed to high occupational levels, future high-quality prospective studies with direct measurements of metal exposure are needed.
Summary of Risk Factors
As many of the suspected risk factors for pancreatic cancer may be modifiable, primary prevention by reducing harmful exposures and increasing preventative exposures over time may help to reduce incidence and mortality rates of this highly fatal cancer. Throughout the last 30 years, smoking rates have decreased in the USA [156] and worldwide [157], while obesity and diabetes rates have increased globally [158,159,160]. Changes in these key risk factors for pancreatic cancer, accounting for latency, may have a strong impact on future incidence and mortality of pancreatic cancer.
Screening
Primary Prevention of Pancreatic Cancer: Existing Pancreatic Cancer Risk Models Have Modest Discrimination
Given the high fatality rate and no current effective chemopreventive agents or screening tools for pancreatic cancer, prevention through identification of novel risk factors and behavioral modification of these factors offers the most promising approach to reducing incidence and mortality. As described above, these established or suspected risk factors [79, 161,162,163,164], the majority of which confirm risks < 1.5–2-fold [163], are insufficient, even jointly, for early detection or risk stratification. Currently, a few validated risk assessment models integrating established risk factors were developed for primary prevention [165•, 166•, 167, 168]. The PancPro model includes the number of family members affected, their relationship and age at diagnosis; the AUC was 0.61 (95% CI 0.51 to 0.71) for any family history, which increased to 0.75 (95% CI 0.68 to 0.81) when the relationship and age at onset were included [166•]. The Klein model includes smoking, diabetes, alcohol use, family history of pancreatic cancer, body mass index, ABO genotype, and three risk alleles; the AUC range from 0.57 for genetic factors, 0.58 for non-genetic factors to 0.61 for genetic and non-genetic factors [165•]. A third model included five SNPs, smoking, and family history of cancer (AUC = 0.63,95% CI 0.60–0.66) [167]. The last model included age, height, BMI, fasting glucose, urine glucose, smoking, and age at smoking initiation, and drinking habits showed similar c-statistics for men and women, 0.81 (95% CI:0.80–0.83) and 0.80 (95% CI:0.79–0.82), respectively [168]. The use of current risk assessment models has limited utility in the general population due to the low incidence of the disease [165•] and the modest discriminatory power for all models evaluated [169].
No Effective Screening Modality for Pancreatic Cancer Exists
Currently, the US Preventive Services Task Force does not recommend screening for pancreatic cancer in asymptomatic individuals [170]. Further, due to the low prevalence of the disease, no effective screening tool, and lack of effective treatments after diagnosis, population-level screening has the potential to cause significant harm that may outweigh the benefits [170]. However, screening recommendations for higher risk individuals have been proposed. The International Consortium for Pancreatic Cancer Screening (CAPs) recommends that individuals who are first-degree relatives (FDRs) of patients with pancreatic cancer from a familial pancreatic cancer kindred with at least two affected FDRs or patients with Peutz-Jeghers syndrome and p16, BRCA2, and hereditary non-polyposis colorectal cancer (HNPCC) mutation carriers with ≥ 1 affected FDR should undergo initial screening using endoscopic ultrasonography (EUS) and/or magnetic resonance cholangiopancreatography (MRI) [171•]. No consensus was reached for the age to initiate screening or stop surveillance, the optimal screening modalities, and intervals for follow-up imaging, and which screening abnormalities were of sufficient concern for surgery to be recommended. In contrast to CAPs, The American College of Gastroenterology (ACG) [172•] recommended endoscopic ultrasound (EUS) and/or magnetic resonance imaging (MRI) of the pancreas annually starting at age 50 years or 10 years younger than the earliest age of pancreatic cancer in the family. Further, they conditionally recommended, that patients with Peutz-Jeghers syndrome should start surveillance at age 35 years [172•]. Given the rareness of the disease, the lack of consensus regarding screening recommendations, a two-tiered approach in which risk assessment models are employed to identify high-risk individuals for screening using additional biomarkers in pathways known to affect pancreatic cancer risk may reduce false positives and mortality compared with just risk assessment or screening alone. Recent modeling has supported this approach for other diseases [173,174,175]; thus research into less invasive biomarkers may provide an opportunity to improve primary and secondary prevention approaches.
Early Detection Using Blood Markers
As most people are diagnosed at the late stage, surgical resection is only possible for approximately 15–20% of patients [176]. A major focus of pancreatic cancer research is to develop effective early detection methods through biomarkers (which includes genetic markers discussed in the familial and genetic risk section) with sufficient sensitivity and specificity to accurately detect asymptomatic pancreatic adenocarcinoma at the early stage when treatment might be more effective and thereby increase the 5-year survival. Several novel candidate biomarkers have been proposed for earlier diagnosis, though none have been adopted into routine clinical use. Prior studies, conducted for other cancers, suggest that the inclusion of biomarker and genetic data may improve the performance of existing risk models; the inclusion of biomarkers into existing risk models depends on easily being able to obtain these measures. As such, tissue does not lend itself to a screening or risk assessment as tissue sampling of the pancreas is not trivial. A promising alternative is measurement in blood, a less invasive and more easily collected biospecimen. Below, we summarize the latest research on blood biomarkers for early detection.
CA19-9
To date, CA19-9, a type of carbohydrate secreted by exocrine epithelial cells and, more specifically, an isolated form of Lewis antigen, is currently the best serological pancreatic cancer biomarker that is approved by the FDA for pancreatic cancer management (e.g., prognostic marker). Yet it lacks the sensitivity and specificity to be utilized as a screening tool. Prior retrospective, cross-sectional or nested case-control studies have suggested that CA19-9 has a sensitivity and specificity of 68–74% when examining pancreatic cancer cases with healthy or non-cancer controls [177, 178]. Further complicating the use of CA19-9 as a screening tool, CA19-9 may also be elevated in non-malignant conditions, such as pancreatitis and biliary obstruction or other malignancies (e.g., colorectal cancer), and it can only be expressed in individuals with Lewis a+/b− or Lewis a+/b+ genotypes (5–10% of population are Lewis a−/b− genotype and cannot express CA19-9) [179]. Therefore, many efforts have been taken to improve the performance of the CA19-9 test. Like most complex diseases, the etiology of pancreatic cancers involves a number and combination of risk factors. Thus, a panel of multiple biomarkers may be necessary for use as a screening tool [180,181,182,183, 184•]; the combined effect of a panel may increase sensitivity and reduce false positives. To this end, one large prospective study, the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO, examined 67 biomarkers including CA 19-9, carcinoembryonic antigen (CEA), neuron-specific enolase, beta human chorionic gonadotropin, carcinoembryonic antigen-related cell adhesion molecule 1, and prolactin (which are significantly altered in sera) in combination. CA19-9 plus CEA had the highest diagnostic power of 0.66 in all possible two biomarker panels; no biomarkers were identified that performed significantly better than CA19-9 alone (AUC = 0.66) [185]. Given the low diagnostic power, CA19-9 alone or in combination is not effective as a screening tool.
Proteins and Proteomics
Aberrant glycosylation of glycoproteins has been correlated to several diseases including cancer; a number of studies have examined select proteins or glycoproteins with pancreatic cancer risk. In one cross-sectional study, the combination of α-1-antichymotrypsin (AACT), thrombospondin-1 (THBS-1), and haptoglobin (HPT) (AUC = 0.95, AUC = 0.85) outperformed CA 19–9 (AUC = 0.89) in distinguishing 37 pancreatic cancer cases from 30 healthy control and 112 non-cancer controls, respectively [186]. Other studies have observed strong AUCs for MUC5AC, a member of the mucin family, a heterogeneous group of 21 abundant, high molecular weight O-glycoproteins that can be either secreted or membrane bound; the AUC for the combination of MUC5AC with CA19-9 to differentiate pancreatic cancer cases from benign and chronic pancreatitis controls was statistically significantly greater (0.91, 0.86–0.95) compared with the AUC for the CA19-9 model alone (0.61, CI 0.86–0.95). Inclusion of MUC5AC with CA19-9 improved its specificity (from 43 to 83%) and sensitivity (from 79 to 83%) for differentiating pancreatic cancer cases from controls (e.g., healthy, benign gastrointestinal conditions, chronic pancreatitis) [187]. Whereas, a large prospective study, United Kingdom Collaborative Trial of Ovarian Cancer Screening (UKCTOCS, which profiled 225 serum proteins, found the combination of THBS-1 and CA19–9 achieved a significantly higher AUC of 0.85 (P < 0.01) than both markers alone [188]. In addition, plasma thrombospondin-2 (THBS-2) concentrations discriminated among all stages of pancreatic adenocarcinoma with a receiver operating characteristic (ROC) c-statistic of 0.76–0.88 [189]; the c-statistic improved to 0.96–0.97 with CA19-9. Further, the sensitivity was 87% and specificity was 98% for the combination of THBS-2 and CA19-9. A recent study identified CA19-9 and melanoma inhibitory activity (MIA) or CA19-9 and macrophage inhibitory cytokine-1 (MIC-1) as best biomarkers to separate early stage pancreatic adenocarcinoma cases from chronic pancreatitis (AUC CA19-9 + MIA = 0.86 vs. AUC CA19-9 = 0.81) or IPMN (AUC CA19-9 + MIC-1 = 0.81 vs. AUC CA19-9 = 0.75) in 188 pancreatic adenocarcinoma cases and 220 non-cancer controls [190]. Future research should confirm these findings in larger prospective studies.
ctDNA
Nucleic acids are released due to apoptosis and necrosis of cells and circulate in the peripheral blood [191]. Circulating nucleic acids (DNA, mRNA, and microRNA (miRNA)) have been positively associated with tumor burden and malignant progression [191]. Thus, many attempts have been made to exploit ctDNA as a cancer biomarker for many tumor types including the pancreas. The major ctDNA biomarker of interest for pancreatic cancer is mutated KRAS, given it is the earliest genetic alteration, an important component in the pathogenesis of pancreatic cancer [192], and is mutated in > 90% of pancreas cancer patients [193]. Circulating mutated KRAS DNA was identified in 48% of individuals with localized pancreatic cancer and in 85% of patients with advanced disease in a cross-sectional study that included 155 pancreas cancer patients [194]. When KRAS mutations in ctDNA were combined with four protein markers (CA19-9, CEA, HGF, OPN), the sensitivity increased from 30% for detectable KRAS mutation alone to 64% with 99.5% specificity [195]. In a subsequent cross-sectional study, they tested CancerSEEK, a combined assay for genetic alterations and a panel of eight protein biomarkers, which detects 95% of pancreas cancer at 99% specificity [196•]. However, it should be noted that these studies were cross-sectional and not prospective, and mutations in KRAS are not specific to pancreatic cancer but arise in many other cancers.
Circulating Cancer Cells
The presence of circulating tumor cells (CTCs) that have disseminated into peripheral blood is the first step during the formation of metastasis [197]. Therefore, the detection of pancreatic tumor cells in the peripheral circulation may be a useful tool for screening. The greatest challenge in the detection of CTCs is their rarity in the blood (∼ 1 CTC per billion blood cells). In a cross-sectional study (N = 25 cases, 15 benign controls) [198], the positive expression rates of C-MET, h-TERT, CK20, and CEA in the pancreatic cancer group were 80% (20/25), 100% (25/25), 84% (21/25), and 80% (20/25), respectively, while in the benign disease control group the rates were 0% (0/15), 0% (0/15), 6.77% (1/15), and 0% (0/15), respectively. Several other studies also reported the presence of CTCs in peripheral blood from pancreatic cancer patients, but using different platforms make it challenging to reach a consensus for clinical application [199, 200]. Although promising, given the small clinical sample and cross-sectional nature, future prospective research is warranted.
Circulating Exosomal DNA
Exosomes are 40–150 nm extracellular vesicles that contain DNA, RNA, and proteins [201]. All living cells, including cancer cells, generate exosomes, and cancer cells generate higher levels of exosomes than normal cells [202]. Exosomes arise from viable cancer cells and may reflect different biology than circulating cell-free DNA (cfDNA) shed from dying tissues [203]. Emerging research has focused on exosomes and their molecular contents as a potential cancer biomarker [204]. Allenson et al. [203] compared exosome-derived DNA to cfDNA to validate KRAS detection rates in liquid biopsies of patients with pancreatic adenocarcinoma using a discovery cohort of 88 pancreatic adenocarcinoma patients, 54 age-matched healthy controls, and a validation cohort of 39 cancer patients and 82 healthy controls. KRAS mutations in exoDNA, were identified in 7.4%, 66.7%, 80%, and 85% of age-matched controls, localized, locally advanced, and metastatic pancreatic adenocarcinoma patients, respectively. Comparatively, mutant KRAS cfDNA was detected in 14.8%, 45.5%, 30.8%, and 57.9% of these individuals. Similarly, KRAS mutations (39.6%) was observed in 48 pancreatic adenocarcinoma patients but only 2.6% in healthy subject [205]. Other studies have also observed higher glypican-1–positive (GPC1) exosome levels [206•] in patients with pancreatic cancer than in controls; GPC1+ crExos (from pancreatic adenocarcinoma, chronic pancreatitis patients and healthy individuals) revealed a near perfect classifier with an AUC of 1.0 (95% CI 0.956–1.0). However, the sample size was small, and all studies were cross-sectional.
Antibody Arrays
Given antibodies are generated against certain tumor-associated antigens (e.g., mesothelin, TNP1) [207], antibody arrays may be useful as potential cancer biomarkers [208]. A three-protein (ERBB2, TNC, and ESR1) panel of plasma biomarkers was identified from 130 test set [209] and demonstrated an AUC of 0.68 and 0.86 when using prediagnostic and diagnostic specimens of pancreatic adenocarcinoma, respectively. When CA 19-9 was added to the panel, the AUC increased to 0.71 and 0.97 for prediagnostic and diagnostic specimens, respectively, suggesting the possibility for use as a diagnostic biomarker panel. Additional studies [210] suggest that IGFBP2 and IGFBP3 are statistically more effective (AUC = 0.94) than CA19-9 alone (AUC = 0.89) at discriminating pancreas cancer patients(n = 101) at an early stage from healthy controls(n = 38). Gerdtsson et al. [211] evaluated an antibody array on human recombinant antibody targeting cytokines and estimated AUC values in the test sets ranged from 0.77 to 0.87 to distinguish pancreatic adenocarcinoma vs. individuals not known to have pancreatic cancer as controls.
Metabolites
Interested in whether altered metabolism may indicate subclinical pancreatic cancer, Mayers et al. [212•] collected pre-diagnostic plasma from pancreatic cancer cases (N = 453) and matched controls (N = 900) in a pooled analysis of individual-level data from four prospective cohort studies (median time between blood collected and diagnosis was 8.7 years). They discovered three metabolites (out of 133 studied), the branched chain amino acids (BCAAs) isoleucine, leucine, and valine were significantly associated with a future diagnosis of pancreatic adenocarcinoma. The result also confirmed that plasma BCAAs were elevated in mice with early-stage pancreatic cancers driven by mutant Kras expression. Although not the focus of this review, select urinary metabolites have also been identified as potential early detection markers, including Acetone, O-Acetylcarnitine, Dimethylamine, and Choline. [213]
miRNA
MicroRNAs (miRNAs) are small RNAs (22–25 nt) that negatively regulate gene expression by binding to complementary mRNA resulting in gene silencing, translational repression, or target degradation. The deregulation of some miRNAs has been identified as a mechanism responsible for cell transformation including pancreatic cancer development [214]. Previous studies have reported miR-21, miR-375, miR-196, miR-210, and miR-200 as potential miRNA candidates [214,215,216,217]. One small cross-sectional study (n = 48 cases) conducted profiling of 45 miRNAs and suggested that MicroRNA-375 improves diagnosis of pancreatic adenocarcinoma in this study (70% accuracy) but did not outperform CA19-9 [218]. Lai et al. [219] found that exosomal glypican-1 (GPC1) is not diagnostic for pancreatic adenocarcinoma whereas the AUC for exosomal miR-10b, miR-21, miR-30c, miR-181a, and miR-let7a had 100% sensitivity and specificity with respect to their accuracy in distinguishing pancreatic adenocarcinoma from normal controls; only miR-106b and miR-483 failed to have an excellent AUC. However, their sample size is small, and the findings should be prospectively confirmed.
Conclusions
Given the late stage of diagnosis and the lack of effective treatment of pancreatic cancer, primary (reduction in exposure to risk factors) and secondary prevention efforts (effective screening modalities) are the best approaches to reduce the morbidity and mortality from this disease. Currently, pancreatic cancer has few known and suspected risk factors, and risk assessment tools have limited utility given their modest discriminatory power range of 0.57–0.81 [220]. Although emerging evidence suggests blood-based biomarkers may be useful as early detection markers, findings need to be confirmed in prospective studies. Due to the rarity of disease, future studies should consider a two-tiered approach in which risk assessment is used to identify high-risk individuals for screening, and then effective imaging and biomarkers in pathways known to affect pancreatic cancer risk are employed; these combination approaches may reduce false positives and mortality compared with just risk assessment or screening alone.
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Yu, A., Romero, T.A. & Genkinger, J.M. Primary and Secondary Prevention of Pancreatic Cancer. Curr Epidemiol Rep 6, 119–137 (2019). https://doi.org/10.1007/s40471-019-00189-2
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DOI: https://doi.org/10.1007/s40471-019-00189-2