New Developments in Pancreatic Cancer

Julia B. Greer & Randall E. Brand

Published online: 22 January 2011# Springer Science+Business Media, LLC 2011

Abstract Pancreatic adenocarcinoma presents in anadvanced stage and has a dismal prognosis. Extensiverecent research efforts have provided us with greaterinsight into the etiology of pancreatic cancer and havealso improved our means of prognostication. Molecularanalysis demonstrated that specific pathways involved inpancreatic carcinogenesis are perhaps more valuable tostudy than single genetic aberrations. Previous riskfactors, including family history, body mass index, andcurrent cigarette smoking, were validated and novel risks,such as ABO blood group alleles, were identified.Similar to other illnesses, combinations of healthfulhabits, such as not smoking, adhering to a Mediterraneandietary pattern, and engaging in physical activity, maydecrease pancreatic cancer risk. Finally, CA 19-9 levels,the presence of diabetes mellitus, and a six-genesignature provided critical information regarding survivalthat could help guide treatment of individuals diagnosedwith pancreatic adenocarcinoma.

Keywords Pancreatic adenocarcinoma . Gene . Signalingpathways . Genome-wide association study (GWAS) . Geneexpression . Family history . Diabetes mellitus . Obesity .

Body mass index (BMI) . ABO blood group . Cigarettesmoking . PALB2 . CA 19-9 . Alcohol . Vitamin D . Folate

Introduction

Almost every article written about pancreatic adenocarci-noma quotes the same grim statisticsa 5-year survivalrate of less than 5%, an annual incidence that practicallymatches mortality, and the highest case-fatality rate of anyof the major cancers [1]. Too rare to advocate population-based screening and hampered by the inability to reliablydetect advanced precursor lesions, pancreatic adenocarci-noma typically presents in an advanced stage [2]. Over thepast year, little advancement occurred in diagnosis orsurvival of pancreatic cancer patients. Progress is beingmade in validating risk factors for pancreatic adenocarci-noma, defining the prognosis of certain patients, andassessing the effectiveness of new treatments for advanceddisease.

Preclinical Studies

A multi-institutional US collaboration recently performed acomprehensive genetic analysis of 24 pancreatic cancersusing state-of-the-art DNA sequencing of 20,735 genes, aswell as gene expression and gene copy number analysis, ina sophisticated bioinformatic approach [3]. On average,63 altered genes per tumor were identified. Although therewas marked variability from tumor to tumor in the specific

J. B. GreerDepartment of Medicine, Division of Gastroenterology,Hepatology, and Nutrition,University of Pittsburgh School of Medicine,Medical Arts Building, 3708 Fifth Avenue, Fourth Floor,Pittsburgh, PA 15213, USAe-mail: greerjb@upmc.edu

R. E. Brand (*)Department of Medicine, Division of Gastroenterology,Hepatology, and Nutrition, Hillman Cancer Center,University of Pittsburgh School of Medicine,Suite 2.32, 5117 Centre Avenue,Pittsburgh, PA 15213, USAe-mail: reb53@pitt.edu

Curr Gastroenterol Rep (2011) 13:131139DOI 10.1007/s11894-011-0175-y

genes that were mutated, the investigators demonstrated 12cellular signaling pathways and processes that had at leastone altered gene in at least 70% of tumors. The six specificpathways that had alterations of at least one gene in all 24pancreatic cancers were KRAS signaling, apoptosis, Wnt/Notch signaling, transforming growth factor- signaling,Hedgehog signaling, and regulation of G1/S phase transi-tion (Fig. 1). Several of these core pathways would not havebeen shown to be critical to tumor development if one lookedsolely at an individual gene from a pathway, rather thanincluding all genes in a given pathway. To demonstrate tumorheterogeneity, the authors cite an example of two differenttumors which, although they had alterations in almost everyone of these 12 core processes, a distinct mutated gene fromwithin that signaling pathway or process was identified as thecause. This landmark study illustrates the need to fundamen-tally change our approach to cancer treatment, suggesting thattargeting an individual gene for cancer therapy may be

ineffective. Newer approaches to drug development shouldfocus on agents that target the physiologic effects of themutated cellular signaling pathways.

To further comprehend genetic changes that drivepancreatic carcinogenesis, a recent genome-wide associa-tion study (GWAS) was conducted by Petersen et al. [4]using sizeable data from 12 prospective cohort studies (thePancreatic Cancer Cohort Consortium) and one hospital-based case-control study (the Mayo Clinic MolecularEpidemiology of Pancreatic Cancer Study) to identify locibesides the previously identified ABO gene on chromosome9q34.2 from their earlier study [5]. Combined analysis of3851 individuals with pancreatic cancer and 3934 controlsyielded three new genomic regions associated with pancre-atic cancer, all at a modest odds ratio (OR) per allele of lessthan 1.26; two of these harbor candidate genes and thethird, on chromosome 13q22.1, maps to a large genomicregion that appears to be specific for pancreatic cancer.

Fig. 1 The pathways and processes involved in pancreatic carcino-genesis. Entities involved in these signal-transduction pathways havediverse roles in the promotion of tumor growth, resistance toapoptosis, invasion, metastasis, and angiogenesis. Reactivation ofphysiologic, embryonic development pathways is also frequentlyobserved in pancreatic cancer. Matrix metalloproteinases (MMP) areimportant for tumor invasion and neovascularization. Telomerase isinvolved in the maintenance of telomeres and is activated in the

majority of pancreatic cancers. The micro-RNAs (miRNA) regulategene expression post-transcriptionally and can be either oncogenic ortumor suppressive. Cancer stem cells have been implicated in tumorprogression, resistance to chemotherapy and radiotherapy, and diseaserelapse. (Reprinted by permission from Macmillan Publishers Ltd:[49] Wong HH, Lemoine NR, Wong HH, et al.: Pancreatic cancer:molecular pathogenesis and new therapeutic targets. Nature ReviewsGastroenterology & Hepatology 2009, 6:412422)

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These study results emphasize that it is highly unlikely thata single common allele confers risk for developing themajority of sporadic pancreatic cancers; rather, the majorityof susceptibility alleles remaining to be discovered willlikely only have minor effects (OR likely

and functions as the molecular scaffold in the formation ofthe BRCA1-PALB2-BRCA2 complex [16]. Jones et al. [17]identified a mutation in PALB2 in a patient with FPC whohad undergone exomic sequencing of their germline DNA.Thereafter, they performed genomic sequencing of PALB2and identified truncation mutations in 3 (3.1%) of 96additional American FPC patients; each mutation caused adifferent stop codon to be produced. A 2010 study by Slateret al. [18] evaluated these same truncating mutations in theEuropean Registry of Hereditary Pancreatitis and FamilialPancreatic Cancer (EUROPAC) and the German NationalCase Collection for Familial Pancreatic Cancer (FaPaCa).They directly sequenced the 13 exons of the PALB2 gene inaffected index patients from 81 FPC familiesnone ofwhom carried a BRCA2 mutationand identified three(3.7%) truncating PALB2 mutations, each of which pro-duced a unique stop codon. One of the mutations thatcaused a deletion in exon 4 was also identified by Jones etal. [17]. A history of breast cancer was noted for all threefamilies carrying a PALB2 mutation. Thus, FPC kindredsshould also be considered for PALB2 mutation testing,especially if there is also a family history of breast cancer.

ABO Blood Group and ABO Alleles

Blood group may influence ones risk of developingpancreatic cancer. In 2009, Wolpin et al. [19] published aprospective study of pancreatic cancer from the combinedcohort of the Nurses Health Study and the HealthProfessionals Follow-Up Study (n = 107,503), noting thatblood groups A, B, and AB were associated with higherrates of pancreatic adenocarcinoma, whereas blood group Oappeared to be protective. In this study, 17% of thepancreatic cancer cases could be attributed to inheriting anon-O blood group (blood group A, B, or AB). Theetiologic connection between blood group and pancreaticcancer was confirmed through the previously mentionedrecent GWAS involving the multinational Pancreatic Can-cer Cohort Consortium (PanScan) [5]. Similarly, Wolpin etal. [20] recently published a study that assessed ABOblood group alleles and how each allele relates to pancreaticcancer risk. They classified ABO genotypes (OO, AO, AA,AB, BO, and BB) in 1534 cases and 1583 controls from 12prospective cohorts in PanScan and used logistic regressionto determine adjusted ORs of pancreatic cancer. Incomparison to the OO genotype, study participants withAO and AA genotype had ORs of 1.33 (95% CI, 1.131.58) and 1.61 (95% CI, 1.222.18), whereas participantswith BO and BB genotypes had ORs of 1.45 (95% CI,1.141.85) and 2.42 (1.284.57). The population-attributable fraction for non-O blood group was 19.5%.Current smokers with non-O blood group were noted tohave an adjusted OR of 2.68 (95% CI, 2.033.54)

compared with nonsmokers of blood group O. Interactionsof blood group and H. pylori infection are also relevant topancreatic cancer. In a recent study of 373 case patients and690 gender- and age-matched control subjects, seropositiv-ity for H. pylori and its virulence protein CagA wasdetermined by enzyme-linked immunosorbent assay andevaluated in relation to ABO blood group [13]. Anassociation between pancreatic cancer risk and CagA-negative H. pylori seropositivity was observed amongindividuals with non-O blood group, but not among thosewith O blood group (OR 2.78, 95% CI, 1.495.20,P = .0014; OR 1.28, 95% CI, 0.622.64, P = .51,respectively).

Body Mass Index and Adiposity

Increased body mass index (BMI) indicative of overweight(2529.9 kg/m2) or obesity (30 kg/m2) is associated withnumerous types of cancer [21]. Because of the highprevalence of overweight and obesity among US adults,and their rising incidence among children and adolescents,BMI should be included in cancer risk assessment profiles[22]. A 2010 pooled analysis from PanScan demonstratedthat anthropometric factors impact the likelihood ofdeveloping pancreatic adenocarcinoma [23]. Using anested case-control design of 2170 cases and 2209 controls,researchers observed a positive association between pre-diagnosis BMI and risk of pancreatic cancer (adjusted ORfor highest vs lowest BMI quartile, 1.33; 95% CI, 1.121.58, Ptrend < 0.001). Elevated BMI and increasing trendsfor pancreatic cancer were noted among both men andwomen. Higher waist-to-hip ratio was also significantlyassociated with pancreatic cancer risk among women(adjusted OR for highest vs lowest quartile in women,1.87; 95%CI, 1.312.69, Ptrend = .003) but not among men.Hypotheses have been offered regarding the relationshipbetween higher BMI and pancreatic cancer, includingincreases in insulin-like growth factors due to hyperglyce-mia, imbalances in adipokines, and the low-grade systemicinflammation that is fostered by states of obesity [24].Obesity itself predisposes to type 2 diabetes mellitus, arecognized risk factor for pancreatic cancer [25]. Continu-ing prospective studies may provide additional proof for theassociation.

Folate and Vitamin D

Dietary folate is essential for DNAmethylation, synthesis, andrepair, and inadequate intake may drive carcinogenesis [26].Two recent studies determined that higher folate intake maybe related to decreased risk of pancreatic cancer. Oaks et al.[27] examined dietary folate and pancreatic cancer riskamong the 51,988 male and 57,187 female participants in the

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Prostate, Lung, Colon, Ovary (PLCO) trial. Using Coxproportional hazards ratio, they found that the highestcompared with the lowest quartile of food folate intake wasassociated with a significantly decreased pancreatic cancerrisk among women (253.3 compared with 179.1 g/d; HR0.47; 95% CI, 0.230.94; Ptrend 0.09) but not among men(229.6 compared with 158.0 g/d; HR 1.20; 95% CI,0.702.04; Ptrend 0.67; P for interaction by gender: 0.03).Gong et al. [28] recently published a large case-control studyinvolving residents of the San Francisco Bay area. Using asemiquantitative food questionnaire, they determined thatdietary folate was significantly inversely associated withpancreatic cancer (fifth vs first quintile of intake: OR 0.67;95% CI, 0.480.93, Ptrend 0.0001).

Vitamin D has been touted as a wonder nutrient,capable of fighting osteoporosis, heart disease, kidneydisease, memory loss, and diabetes [29]. Laboratory studiesdemonstrate that vitamin D may function in an antineo-plastic manner by inducing cellular differentiation, initiat-ing apoptosis, and inhibiting proliferation and angiogenesis[30]. Additional epidemiologic studies show that vitamin Dis associated with decreased risks of colon, breast, ovarian,and prostate cancers, although the evidence of a protectiveeffect on pancreatic carcinogenesis has been inconsistent[31]. In a 2010 study published in the British Journal ofCancer, Bao et al. [32] evaluated the predicted 25(OH)Dlevels in 118,597 participants in the combined NursesHealth Study and Health Professionals Follow-up Studyfrom 1986 to 2006. Their predicted value was based onboth dietary intake and sunlight exposure and was derivedby using linear regression with the dependent variable asthe serum sample 25(OH)D level of 1095 men who werefree of cancer at the time of the blood draw, and theindependent variables of race, geographic region, vitamin Dintake, BMI, and physical activity. During 20 years offollow-up, 575 incident pancreatic cancers occurred; com-pared with the lowest quintile, participants in the highestquintile of 25(OH)D had an adjusted risk ratio of 0.65 (95%CI, 0.500.86; Ptrend = 0.001).

Cigarette Smoking and Alcohol Consumption

Current or recent cigarette smoking is the most commonlyimplicated behavioral risk factor for pancreatic cancer,whereas alcohol consumption has provided conflictingevidence regarding risk. Recent epidemiologic researchsuggests that we should start looking more closely at heavyalcohol consumption. In our 2009 study, we found thatpancreatic cancer patients who currently smoked cigarettesand drank alcohol were diagnosed at ages as much as10.2 years younger than patients who abstained fromalcohol and cigarettes [33]. A recent study from Italyre-examined the risks associated with these lifestyle habits

in a sizeable case-control study, and reinforced theobservation that current, but not former, cigarette smokingis associated with pancreatic cancer risk [34]. Overall riskwas higher for current smokers (OR 1.68; 95% CI, 1.132.48) and was greater for those who smoked 20 or morecigarettes per day (OR 2.04; 95% CI, 1.143.66). Heavyand very heavy drinkers (defined as consuming 21 to 34and 35 drinks per week, respectively) had adjusted ORsfor pancreatic cancer of 2.03 and 3.42. Combined smokingand drinking had an additive effect, with current heavysmokers who were heavy drinkers demonstrating 4.3-foldhigher pancreatic cancer risk than never smokers whoconsumed fewer than seven alcoholic beverages a week.

Combinations of Behaviors

An amalgamation of behavioral factors may help definedisease risk. Researchers in the United States and Englanddeveloped a lifestyle score that could predict the relativerisk of pancreatic cancer based on five healthy lifestylefactors: not smoking, limiting alcohol consumption, adher-ing to a Mediterranean dietary pattern, having normal BMI(18 and

predictive or prognostic variable. CA 19-9 levels, totalbilirubin, pathologic findings, and survival were evaluatedamong 143 patients who underwent pancreatoduodenec-tomy between July 2001 and April 2006 at the MayoClinic, and CA 19-9 levels were associated with increasedoverall and recurrence-free survival [39]. Researchers usedCox proportional hazards model to determine a cutoff valuefor CA 19-9 of 120 U/mL, and observed overall survival at1, 3, and 5 months for patients with subthreshold CA 19-9to be 76%, 41%, and 31%, respectively, while it was 64%,17%, and 10%, respectively, for patients with a preopera-tive serum CA 19-9 level greater than 120 U/mL (P = .002).Higher CA 19-9 levels were not associated with a greaterchance of an R1 or R2 resection, tumor involving themargin of the superior mesenteric artery or at the portalvein groove, or lymph node metastases.

For the subset of patients diagnosed with pancreaticcancer who are fortunate enough to have resectable disease,survival has been shown to be improved with the use ofadjuvant therapy. Nonetheless, a large percentage ofpatients still do not receive any postsurgical treatment. Apopulation-based 2010 study of US practices examined the

SEER Medicare-linked database for the years between 1991and 2002 [40]. A total of 1910 pancreatic cancer patientsavailable in the database underwent pancreatic resectionduring this period, and 47.9% (n = 915) were treated withsome form of adjuvant therapy, with 34.4% (n = 658)receiving adjuvant combination chemoradiotherapy. Over-all, the use of chemoradiation increased significantly duringthis timeframe, from 29.2% to 37.5% (P < 0.0001). Nochanges were observed in rates of in-hospital mortality or inKaplan-Meier survival, stratified by year group of diagno-sis. Comparing patients treated with adjuvant chemoradia-tion to those not treated, univariate analyses demonstratedthat patients who did not receive postsurgical treatmentwere generally older, were more likely to have experiencedpostoperative complications, and were more commonlyreadmitted to the hospital within 1 month of their surgery(all P values

diabetes compared to nondiabetic patients (HR 1.75; 95%CI, 1.102.78).

A multi-institutional US group recently analyzed thegene expression profiles of primary pancreatic tumors frompatients with localized compared to metastatic disease, andidentified a six-gene signature associated with metastaticdisease [43]. Using a training set of 34 patients and a testset of 67 patients, both with localized and resectedpancreatic adenocarcinoma, they observed that their six-gene signature was independently predictive of survival andwas superior to established clinical prognostic factors,including tumor grade, tumor size, and nodal status (HR4.1; 95% CI, 1.710.0). As evidence, patients who wereclassified as being high-risk by the six-gene signature had a1-year survival rate of 55% compared to 91% 1-yearsurvival in the low-risk group.

Treatment Directions

In the United States, treatment for early-stage pancreaticcancer hinges on radical surgery and adjuvant chemo-radiation. Both 5-fluorouracil and gemcitabine are acceptedadjuvant chemotherapeutic agents for patients who haveundergone pancreatic resection [44]. A provocative studyby the European Study Group for Cancer (ESPAC)-3compared treatments with fluorouracil plus folinic acid(folinic acid, 20 mg/m2, intravenous bolus injection,followed by fluorouracil, 425 mg/m2, intravenous bolusinjection given 15 days every 28 days) (n = 551) orgemcitabine (1000 mg/m2, intravenous infusion once aweek for 3 of every 4 weeks) (n = 537) for 6 months in1088 pancreatic cancer patients who had undergoneresection at 159 participating centers in Europe, Australia,Japan, and Canada [45]. They found no survival advan-tage to gemcitabine over fluorouracil plus folinic acid,although more serious adverse events were documented inpatients treated with fluorouracil. The gold standard forlocally advanced and metastatic pancreatic adenocarcinomaremains gemcitabine [46]. Myriad novel therapies foradvanced pancreatic cancer have been or are being evaluatedin phase 2 and phase 3 clinical trials. To date, the majority ofstudies have not demonstrated a significant treatment orsurvival advantage to these therapeutic agents, and manyinvestigators have observed potent toxicities that may affectquality of life. Recent reviews more fully describe andsummarize the most relevant studies of novel agents beingused in conjunction with gemcitabine [44, 4750]. Currentconsensus is that gemcitabine should be used alone or incombinations with a platinum agent (oxaliplatin), erlotinib,or a fluoropyrimidine (5-FU or capecitabine), especially inselected patients with high performance status [44, 45, 4750]. Continued work should be devoted to assessing the

efficacy of newer agents, particularly natural compounds (eg,curcurmin) and inhibitors of tyrosine kinase, cyclooxyge-nase, and topoisomerase I.

Conclusions

Pancreatic cancer is an insidious, lethal disease that isunequivocally challenging to treat. Although survivalremains unchanged, recent research has assisted in morethoroughly understanding the risk factors and pathologicprogression of pancreatic neoplasia. Sustained efforts ininvestigating etiologic genetic pathways of progression andsignatures for survival, coupled with treatment responsethat is predicted via personalized medicine, may lead toeffective surveillance and preventive strategies as well asbetter treatment of this devastating disease.

Disclosure Conflicts of interest; J.B. Greernone; R.E. Brandspeakers honoraria, Myriad Genetic Laboratories.

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New Developments in Pancreatic CancerAbstractIntroductionPreclinical StudiesRisk Factors for Pancreatic CancerMedical HistoryFamily HistoryPALB2 MutationsABO Blood Group and ABO AllelesBody Mass Index and AdiposityFolate and Vitamin DCigarette Smoking and Alcohol ConsumptionCombinations of Behaviors

Trends in Pancreatic Cancer Prognosis and SurvivalTreatment DirectionsConclusionsReferencesPapers of particular interest, published recently, have been highlighted as: Of importance Of major importance

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