TheEarlyDetectionofPancreaticCancer:WhatWillItTaketo...

Review

TheEarlyDetection of PancreaticCancer:WhatWill It Take toDiagnose and Treat Curable Pancreatic Neoplasia?

Anne Marie Lennon1,2, Christopher L. Wolfgang2,3,4, Marcia Irene Canto1, Alison P. Klein3,4,7,JosephM. Herman4,5, Michael Goggins1,3,4, Elliot K. Fishman6, Ihab Kamel6, Matthew J. Weiss2, Luis A. Diaz4,Nickolas Papadopoulos4, Kenneth W. Kinzler4, Bert Vogelstein3,4, and Ralph H. Hruban3,4

AbstractPancreatic cancer is the deadliest of all solid malignancies. Early detection offers the best hope for a cure, but

characteristics of this disease, such as the lack of early clinical symptoms, make the early detection difficult.Recent genetic mapping of the molecular evolution of pancreatic cancer suggests that a large window ofopportunity exists for the early detection of pancreatic neoplasia, and developments in cancer genetics offer new,potentially highly specific approaches for screening of curable pancreatic neoplasia. We review the challenges ofscreening for early pancreatic neoplasia, as well as opportunities presented by incorporating molecular geneticsinto these efforts. Cancer Res; 74(13); 3381–9. �2014 AACR.

IntroductionThere are as many as a billion neoplastic cells in a cubic

centimeter of a cancer (1). Invasive pancreatic cancers, whoseaverage diameter is 4 cm at the time of diagnosis, contain asmany as 25 billion cancer cells. This is clearly a large number ofcells, though not much larger than the number of neoplasticcells in other tumor types. The problem with pancreaticcancers is that they have usually metastasized by the timethey are diagnosed, and once this occurs, it is virtually impos-sible to cure most patients (2).As has been nicely demonstrated for colon cancer, the best

hope for reducing the cancer-specific mortality of pancreaticcancer lies in early diagnosis and treatment, ideally at a pre-cancerous stage (3). Six issues, however, need to be addressedfor the early detection and cure of pancreatic neoplasia to cometo fruition. First, the curable lesions that give rise to advanced,noncurable pancreatic cancers have to be characterized. Sec-ond, there has to be a reasonable window of opportunity todetect these potentially curable lesions. That is, the progressionfrom localized curable lesions to advanced cancers has to beslow enough that there is a reasonable chance that the localizedlesions can be detected clinically. In this paper, we define"localized" as tumors that have not yet metastasized or

advanced to the point that they cannot be removed surgicallybecause of their involvement of other tissues, particularlymajorarteries. Third, a test has to be developed to detect the com-pendium of curable localized lesions. This is not a trivialproblem for lesions arising in an organ that lies deep in theabdomen.Fourth, because treating lesions in thepancreas isnottrivial, there has to be a method to distinguish localized lesionswith a reasonable chance of progressing to an advanced cancerfrom lesions with little or no risk of progressing. Fifth, theprevalence of the disease has to be reasonably high in thepopulation to be screened, such that screening tests withachievable sensitivities and specificitieswill have a high positivepredictive value. Sixth, an evidence base has to be developedthat demonstrates that screening actually saves lives.

Using the framework of the six issues described above, thisarticle will review recent developments that bring the earlydetection of pancreatic cancer closer to clinical practice. Equalemphasis will be placed on the opportunities and on thechallenges that lie ahead.

Characterize the curable lesions that give rise tometastatic pancreatic cancer

Pancreatic intraepithelial neoplasia. Pathologists haverecognized precursor lesions in the pancreas for more than acentury (4). S.P.L. Hulst (Boerhaave Laboratory at Leiden), in1905, described small microscopic lesions in the pancreasthat he felt were in between normal and invasive cancer,which he called "zwischenformen." These lesions, which wenow call "pancreatic intraepithelial neoplasia (PanIN)," weresubsequently shown to be more common in pancreata withan invasive carcinoma than in pancreata without a cancer,to increase with age, and to harbor many of the same geneticalterations as do invasive adenocarcinomas of the pancreas(5). PanINs have been reported in 16% to 45% of pancreatathat do not harbor an invasive cancer (6–8).

PanIN lesions are noninvasive epithelial proliferations with-in the smaller pancreatic ducts (5). They can beflat or papillary,

Authors' Affiliations: Departments of 1Medicine; 2Surgery; 3Pathology;4Oncology; 5Radiation Oncology; and 6Radiology, The Sol Goldman Pan-creatic Cancer Research Center, The Johns Hopkins University School ofMedicine; and 7Department of Epidemiology, the Bloomberg School ofPublic Health, Baltimore, Maryland

A.M. Lennon and C.L. Wolfgang contributed equally to this work.

Corresponding Author: Ralph H. Hruban, Department of Pathology andOncology, The Sol Goldman Pancreatic Cancer Research Center, TheJohns Hopkins University School of Medicine, Weinberg 2242, 401 NorthBroadway, Baltimore, MD 21231. Phone: 410-955-9132; Fax: 410-955-0115; E-mail: [email protected]

doi: 10.1158/0008-5472.CAN-14-0734

�2014 American Association for Cancer Research.

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and are graded histologically as PanIN-1 (low-grade), PanIN-2(intermediate-grade), or PanIN-3 (high-grade) based on thedegree of architectural and cellular atypia present in the lesion(Fig. 1; ref. 5). Paralleling this histologic progression is a geneticprogression. The lower grade lesions (PanIN-1 and PanIN-2)often harbor genetic alterations in the KRAS and p16/CDKN2Agenes, whereas the higher grade PanIN-3 lesions and invasiveadenocarcinomas, in addition to genetic alterations in KRASand p16/CDKN2A, also often harbor mutations in TP53 andSMAD4 (9–11). Autopsy studies indicate that low-grade PanINsare found in the pancreata of most adults once they reachmiddle age (6, 8). High-grade PanINs, however, are rarely found,unless there is an associated invasive pancreatic cancer or thepatient has a strong family history of pancreatic cancer (6, 8, 12,13). In total, these observations support the hypothesis thatPanIN lesions are precursors to invasive adenocarcinoma andthat there is a progression from normal ductal epithelium, tolow-grade PanIN, to high-grade PanIN, to localized adenocar-cinoma, and to metastatic adenocarcinoma (5).

Intraductal papillary mucinous neoplasms. The secondmajor precursor lesion to be identified in the pancreaswas theintraductal papillary mucinous neoplasm (IPMN; refs. 5, 14).Pancreatic cysts are very common, being identified in almost3% of asymptomatic individuals who undergo a computedtomography scan (15), with IPMN accounting for almost 50%of resected pancreatic cysts (16). IPMNs arise in the largerpancreatic ducts and, as the name suggests, they are typicallypapillary and often produce copious amounts of mucin.IPMNs are, by definition, larger than PanINs. PanINs areusually <0.5 cm, while most IPMNs are �1.0 cm (5). IPMNsaremore prevalent in the elderly than in the young, and up to athird of IPMNs harbor an associated invasive adenocarcino-ma (9). As is observed with PanINs, low-grade IPMNs oftenharbor KRAS and p16/CDKN2A gene mutations, and high-grade IPMNs harbor further mutations in TP53 and SMAD4

(5). In addition, the GNAS and RNF43 genes are mutated in amajor fraction of IPMNs (17, 18). When an adenocarcinomaarises in associationwith an IPMN, the IPMN and the invasivecarcinoma almost always harbor the same genetic alterations,supporting the hypothesis that IPMNs are a precursor toinvasive adenocarcinomas (10).

Mucinous cystic neoplasms. Mucinous cystic neoplasms(MCN) are large mucin-producing precancerous lesions of thepancreas that almost always arise in the body or tail of thegland and commonly arise in women (14). They are far lesscommon than IPMNs, accounting for only 16% of resectedpancreatic cysts in large surgical series (16). In contrast withIPMNs, MCNs do not significantly involve the pancreatic ductsystem, and, in contrast with IPMNs, MCNs have a distinctive"ovarian-type" stroma (14). Like IPMNs, however, MCNs canprogress to adenocarcinoma. The KRAS, p16/CDKN2A, RNF43,TP53, and SMAD4 genes have all been reported to bemutated inMCNs (thoughGNAS is not, thereby distinguishing IPMNs fromMCNs; refs. 14, 18, 19).

Small invasive cancers. Although they are rarely encoun-tered outside of screening trials, there have been severalreports of long-term survival ("cures") of patients with surgi-cally resected small, lymph node negative, pancreatic cancers(20–22). For example, Egawa and colleagues reported thatpatients with surgically resected stage I pancreatic cancerhave a median survival of 78 months and a 5-year survivalrate of 58% (21). Similarly, Ishikawa and colleagues reported a5-year survival rate close to 70% for patientswith small (�1 cm)pancreatic cancers who were not jaundiced and who did nothave a mass-forming lesion on imaging (22).

In summary, three distinct lesions, PanINs, IPMNs, andMCNs, have each been identified as distinct precursors toductal adenocarcinomas of the pancreas. These precursorlesions, together with some small invasive cancers, arecurable.

Figure 1. A normal pancreaticduct (A) and multiple (PanIN)lesions from the pancreas of asingle patient with a family historyof pancreatic cancer (B–F). Theseinclude PanIN-1 (B), PanIN withassociated lobulocentric atrophy(B andC), PanIN-2 (E), andPanIN-3(F; all hematoxylin and eosin).KRAS mutations and telomereshortening occur early in PanIN-1lesions, p16/CDKN2A loss occursslightly later in PanIN-2, andSMAD4 and TP53 inactivation arelate events (PanIN-3 and invasivecarcinoma).

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Demonstrate a sufficient window of opportunity todetect the curable lesions that give rise to metastaticpancreatic cancerIf early screening is to be effective, curable lesions have to be

present for a relatively long period of time before they progressto metastatic carcinoma. If these lesions were fleeting, rapidlyprogressing to metastatic carcinomas, then screening wouldhave to be performed so frequently as to be impractical.There is strong direct evidence that IPMNs and MCNs are

present for years before they progress to invasive cancer. Somepatients with IPMNs report that they had symptoms caused bytheir IPMNs for years, and some even had symptoms fordecades, before their tumors were diagnosed, suggesting thattheir lesions had been present for years (14). In addition, theaverage age of patients with noninvasive IPMNs is 3 to 5 yearsyounger than the average age of patients with an IPMNwith anassociated adenocarcinoma, again suggesting that IPMNs arepresent for years before they progress to invasive cancer (14).Finally, hundreds of patients with an IPMN have been followedclinically with serial imaging and the vast majority IPMNs arerelatively stable over months to years, or at most, grow slowly(23–25). Although the numbers are smaller, similar evidenceexists for MCNs (14).Because of their small size, it is much more difficult to

directly observe PanIN lesions. The best estimates of thetimeline for the progression of PanIN lesions to invasivecarcinoma come from the genetic sequencing studies (26).Iacobuzio-Donahue and colleagues sequenced a series of pri-mary invasive pancreatic cancers and multiple matchedmetastases from the same patients (26). They applied model-ing, similar to modeling used by evolutionary biologists, to thepatterns of genetic alterations present in multiple lesions fromthe same patient, and estimated that it takes at least a decadefor a cell with an initiating mutation in the pancreas toprogress to what they designated as the parental, nonmeta-static founder cell (a cell likely present in an advanced PanINlesion, before the onset of the invasion required to define thelesion as an adenocarcinoma; ref. 26). This study furtherestimated that it takes at least another 5 years for the neo-plastic clone to develop the ability to metastasize (26).Although the timeline for progression calculated is based onseveral assumptions, it does correspond nicely to the timelineobserved for other epithelial neoplasms (27). For example,Jones and colleagues sequenced a series of well-characterizedadenomas and invasive carcinomas of the colon and calculatedthat, for those lesions that progress to invasive cancer, it takesalmost 17 years for a microadenoma to progress into anadvanced cancer (28).Clearly, as in other tumor sites, there is a large window of

opportunity to detect potentially curable, neoplastic lesions inthe pancreas.

Establish a method to detect curable neoplastic lesionsTwo broad approaches have been taken to detect curable

neoplastic lesions in the pancreas. The first is imaging, par-ticularly with endoscopic ultrasound (EUS). The secondinvolvesmolecularmethods, such as those to detect circulatingmutant DNA shed by the neoplastic lesions.

CT, MRI, and EUS have all been used to detect curablelesions in the pancreas. All three imagingmodalities have beencompared in a prospective study of 225 asymptomatic high-risk individuals by Canto and colleagues (29). EUS detected apancreatic abnormality in 43% of patients, in contrast withMRI and CT, which identified lesions in 33% and 11%, respec-tively. Five of the lesions identified on EUS were resected, ofwhich three were IPMNs with high-grade dysplasia. It is clearthat cystic precursor lesions can be detected by existingimaging, and that EUS seems to be themost sensitivemodality,and that some of these will be curable, high-grade precursorlesions.

Smaller precursor lesions, such as PanINs, are not directlydetectable by EUS, but their presence can be inferred indirectly.PanINs produce small areas of fibrosis called "lobulocentricatrophy," and when multiple PanIN lesions are present, theycreate multiple areas of fibrosis that can be detected aschanges of chronic pancreatitis by EUS (13, 30). Brune andcolleagues demonstrated a linear correlation between thenumber of PanIN lesions present in a pancreas and the EUSscore of the severity of chronic pancreatitis (13). The contri-bution of imaging to the detection of precursor lesionswill onlyincrease as the resolution of imaging improves in the comingyears.

Two recent advances highlight the enormous potential ofmolecular-based approaches as tools for the detection ofcurable lesions in the pancreas. First, whole exome sequencingof well-characterized cyst-forming precursor lesions hasdefined the genes targeted (mutated) in each of the differentprecursor lesions in the pancreas (Table 1). Second, newtechnologies have been developed that can detect rare mutantalleles, even when these mutant alleles are admixed with a1000-fold more wild-type alleles (17, 18, 31).

Pancreatic secretion (juice) is a natural place to look formutant genes shed from precursor lesions in the pancreas andcan easily be obtained by stimulating pancreatic juice secretinwith secretin, and then collecting the juice with an endoscope(Fig. 2). As noted earlier, both IPMNs and PanINs involve thepancreatic duct system, and mutant DNA from both of theselesions is therefore likely to be shed into the pancreatic juice(32, 33). Indeed, Goggins and colleagues have shown thatGNASmutations can be detected in endoscopically obtained pan-creatic juice samples in two-thirds of patients with an IPMN(34). Of note,GNASmutations were also detected in pancreaticjuice samples from patients with a clinically normal pancreaswho only later developed an IPMN, portending the power ofmolecular-based tests (34).

Sequencing pancreatic juice requires endoscopy, whichreduces the applicability of juice-based approaches. Kinde andcolleagues therefore applied a technology that can be used todetect rare mutant alleles, called SafeSeqS, and showed that itis possible to detect KRAS genemutations in the plasma of 85%of patients with advanced pancreatic cancer (31, 35). Despitethis highly sensitive technique,KRAS genemutations were onlydetected in 45% of patients with surgically resectable pancre-atic cancer highlighting the difficulties of early tumor detectionusing blood. Small noninvasive precursor lesions are unlikelyto shed large quantities of DNA into the blood. We, therefore,

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believe it is unlikely that it will be possible to detect mutantDNA in the plasma of patients with noninvasive precursorlesions such as IPMNs, MCNs, or PanINs (36).

Although beyond the scope of this review, it should be notedthat a number of other approaches are being developed todetect early pancreatic neoplasia. These include detectingcirculating tumor cells, as well as proteins, mucins, and miR-NAs shed by the tumors (37, 38).

In sum, curable lesions of the pancreas, both large and small,are detectable with technologies already in clinical practice,including EUS, MRI, and CT. Molecular-based technologieshave enormous potential, particularly if they can be applied tobiosamples, such as blood or stool, which are obtainablenoninvasively. The resolution of imaging and the sensitivityand specificity of molecular-based screening tools are certain

to improve in the coming years, and the two technologies mayeven be combined with molecular-based imaging (37).

Distinguishing between precursor lesions and benignmimics

Oneof the problems in screening for precursor lesions is thatharmless benign lesions can mimic these lesions and lead toovertreatment with just over 20% of pancreatic cysts found tobe benign following resection (16, 39–41). Although this is not asignificant problem for superficial organs such as the skin(freezing or surgically removing a small harmless skin lesionthatmimics an in situ squamous carcinoma is not a substantialproblem), these mimickers can be a real problem when moredeeply seated organs are studied. For example, H.G. Welch andH.J. Passow (The Dartmouth Institute for Health Policy and

Figure 2. Genetic changes shed byprecursor lesions involving thepancreatic duct system can bedetected in pancreatic secretionscollected at the time of endoscopy.Illustration by Christian Rose,copyright Johns HopkinsUniversity.

Table 1. Genes targeted (mutated) in the most common precursor and cystic lesions in the pancreas

Gene IPMN-LG IPMN-HG MCN-LG MCN-HG PanIN-1 and -2 PanIN-3 SCA SPN

KRAS X X X X X XP16/CDKN2A X X X X X XTP53 X X XSMAD4 X X XRNF43 X X X XGNAS X XCTNNB1 XVHL X

Abbreviations: HG, high grade; LG, low grade.

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Clinical Practice, The Geisel School of Medicine at Dartmouth,Hanover, NH) analyzed the literature on screening for breastcancer, and concluded that if 1,000 50-year-old Americanwomen are screened annually for a decade, 490 to 670 womenwill have at least one false alarm (recallmammogram), and that70 to 100 of the women will have a false positive biopsyrecommendation (42, 43).As troublesome as false positive biopsy recommendations

are for breast lesions, such recommendations would be amuchgreater problem for pancreatic lesions (39–41). The pancreaslies deep in the back of the abdomen and lesions in thepancreas are not easily accessed (2). Furthermore, surgicalresection is sometimes the only way to diagnose a lesiondefinitively, and the surgical resection of pancreatic lesions isassociated with significant morbidity and a nontrivial risk ofmortality. Tools to distinguish harmless lesions in the pancre-as, such as serous cystadenomas (SCA), from true precursorlesions, such as IPMNs and MCNs, are needed, as are tools todistinguish low-grade PanINs, MCNs, and IPMNs from high-grade PanINs, MCNs, and IPMNs.Geneticmarkers have the potential to distinguish among the

various cystic lesions of the pancreas and therefore could helpdistinguish harmless lesions and precursor lesions. Wu andcolleagues sequenced the exomes of the four most commoncystic neoplasms of the pancreas [SCA, IPMN, MCN, and solidpseudopapillary neoplasms (SPN)] and found that each ofthese four tumors was associated with a specific pattern ofgenetic alterations (Table 1; refs. 17, 18). SCAs are character-ized by VHL gene alterations, SPNs by CTNN1 (b-catenin) gene

mutations, IPMNs by KRAS, GNAS, RNF43, TP53, p16/CDKN2Aand SMAD4 gene mutations, and MCNs by KRAS, RNF43, TP53,p16/CDKN2A, and SMAD4 gene mutations (17, 18). The muta-tions present in the neoplastic cells in these cystic neoplasmsare shed into the cystfluid and therefore can be detected in cystfluid (Fig. 3). For example, in a study that included analyses ofboth neoplasms and cystfluid, 96% of 132 IPMNswere found toharbor amutation inGNAS and/orKRAS, whereasmutations inthese genes were not observed in 44 SCAs (18). With theseadvances, we can easily envision that harmless cysts of thepancreas will be readily distinguishable from true precursorlesions in the near future.

Distinguishing PanINs lesions that are likely to progress fromPanIN lesions that are unlikely to progress to invasive cancer issignificantly more complex. PanINs, particularly low-gradePanIN lesions, are fairly common in the population, and yetmost do not progress to invasive cancer (6, 7, 8, 44). For example,Andea and colleagues reported that 54% of 152 pancreataresected from patients without a pancreatic malignancy har-bored at least one PanIN lesion, yet clearly 54% of the populationdoes not develop pancreatic cancer (45). Indeed, Terhune andcolleagues, in a "back of the envelope" calculation estimated thatless than 1% of PanIN lesions progress to invasive carcinoma(44). Although it is assumed that the higher grade PanIN lesions(PanIN-3) are more likely to progress than lower grade lesions(PanIN-1 and PanIN-2), there is currently no way, other thanresection and histologic examination, to determine the grade ofa PanIN lesion. The challenge posed by PanIN lesions will onlygrow as imaging andmolecular detection technologies improve.

Figure 3. Fluid from pancreaticcysts can be aspirated at the timeof EUS, and the mutations presentin the cyst fluid can suggest cysttype. Illustration by Christian Rose,copyright Johns HopkinsUniversity.






Although genetic markers can be used to distinguish harm-less cystic lesions (such as SCA) from those that are precursorlesions (IPMNs andMCNs), geneticmarkers cannot yet be usedto determine the grade of a precursor lesion (17, 18).

Identify populations at risk for pancreatic cancer whowill benefit from screening

The positive predictive value of any test can be greatlyimproved by increasing the prevalence of the disease beingtested for in the population being tested. The prevalence ofpancreatic cancer in the general United States population (allages) is approximately nine per 100,000, and it rises to approx-imately 68 of 100,000 in individuals above the age of 55 years (2).This low prevalence is problematic for screening. For example,if 100,000 people over the age of 55 years were screened forpancreatic cancer using a test with a specificity of 98% and asensitivity of 100%, it would generate 1,999 false-positive testresults but only 68 true-positive results. A specificity of higherthan 99% would be required for a more acceptable positivepredictive value. Alternatively, populations whose risk is ele-vated above the general population could derive benefit fromscreening methods that were inadequately specific for thegeneral population.

A variety of factors increase the risk of pancreatic can-cer, but after age, a family history of pancreatic cancerseems to increase the risk the most (46). For example,Klein and colleagues followed 5,179 individuals from 838kindreds enrolled in the National Familial Pancreas TumorRegistry (NFPTR, http://pathology.jhu.edu/pc/nfptr/index.php) and found that individuals in families with at least apair of first-degree relatives diagnosed with pancreaticcancer (designated "familial pancreatic cancer kindreds")are 9-fold more likely to develop pancreatic cancer than isthe general population (47). In the study by Klein andcolleagues, the risk of pancreatic cancer rose with thenumber of family members diagnosed with pancreaticcancer, such that individuals with three first-degree rela-tives with pancreatic cancer had a 32-fold increased risk(47). Thus, individuals with a strong family history ofpancreatic cancer represent a well-defined population witha significantly increased risk.

Risk-prediction models aimed at identifying families thatcarry a high-penetrance pancreatic cancer gene, such as Panc-PRO, have been developed that can be used to calculate the riskof pancreatic cancer basedondisease patternswithin a specificpedigree (48). For example, the risk of pancreatic cancer ishigher for individuals with two first-degree relatives withpancreatic cancer (e.g., a mother and a brother), than it isfor individuals with a first-degree and a second-degree relative(e.g., a sister and an aunt; ref. 48). These models can helpidentify individuals that may have a greatly elevated risk ofdeveloping pancreatic cancer. In contrast, risk models thatpredict the risk of pancreatic cancer using low-penetranceSNPs as well as known pancreatic cancer risk factors (age,diabetes mellitus, heavy alcohol use, body-mass index, andpresence or absence of a family history) have not been shown toidentify individuals with a substantively elevated risk of pan-creatic cancer (49).

Risk can be further refined when the causative genes areknown and individuals can now undergo genetic testing to seewhether they carry a familial pancreatic cancer susceptibilitygene. A number of genes have been identified that, whenmutated in the germline, increase the risk of pancreatic cancer(Table 2; refs. 50, 51). These include BRCA2, ATM, PALB2, p16/CDKN2A, STK11/LKB1,BRCA1,PRSS1, and the genes associatedwith the hereditary nonpolyposis colorectal cancer syndrome.Importantly, as shown in Table 2, pancreatic cancer risk canoften be quantified when the gene is known (51).

Individuals with an inherited genetic abnormality thatincreases their risk of developing pancreatic cancer, as wellas individuals without a known predisposing gene mutationbut who are predicted to be at increased risk based on theirfamily history, would therefore be a natural first group tobenefit from screening.

Another way to increase the prevalence of a disease in apopulation is to select members of the population that areknown to have a preexisting condition that predisposes to thedisease. As noted earlier, two of the precursor lesions in thepancreas form cysts, and cysts can be detected by CT and MRI(15, 52). Approximately 70 million CT scans are performed inthe United States every year, and 2.6% of the CT scans thatinclude the pancreas will reveal a cystic lesion in the pancreas

Table 2. Genes associated with familial pancreatic cancer

Individual/gene % of Families Relative risk Risk by age of 70 y

No history 1 0.5%ATM <2 ? ?BRCA1 <1 ? ?BRCA2 6–12 3.5–10 3.5%HNPCC-associated genes ? 8 3.7%p16/CDKN2A 1–3 20–34 10%–17%PALB2 3 ? ?PRSS1 <1 50–80 25%–40%STK11 <1 132 30%–60%

Abbreviation: HNPCC, hereditary non-polyposis colorectal cancer.

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(15). This fraction is even higher for patients who have MRIexams (52). The prevalence of cysts detectable by either CT orbyMRI increaseswith age, such that cysts can be found in 7% to12% of individuals over the age of 70 years (15, 52). Some ofthese cysts will be the precursor lesions IPMNs and MCNs.When applied to individuals with a pancreatic cyst, tests formarkers such as circulating tumor DNA will have a signifi-cantly higher positive predictive value than when these sametests are applied to the general population (35).The screening of patients with multiple risk factors, such as

elderly individuals with family history and a pancreatic cyst,would lead to even higher positive predictive values for anyearly screening test.

Develop an evidence base establishing that screening at-risk individuals is beneficialDemonstrating that screening actually saves lives is

extremely difficult (53, 54). Screening for colonic neoplasiaand cervical cancers are examples of screening that has beenshown to save lives, but this was only shown through very largepopulation studies carried out years after such screening hadbecome routine. For example, among 88,902 participantsfollowed over a period of 22 years in the Nurses' Health Studyand the Health Professionals Follow-up Study, colon cancermortality was reduced after screening sigmoidoscopy (HR ¼0.59) and screening colonoscopy (HR ¼ 0.32). In contrast,evidence in support of pancreatic cancer screening is similarto the evidence that was available to justify colorectal cancer

screening 20 years ago, that is, studies suggest that screeningcan detect asymptomatic precursor lesions, but it is only anexpectation that removing these precursor lesionswill improveoutcomes for patients (55). Ongoing collaborative researchenabled by a worldwide Cancer of the Pancreas Screeningconsortium will provide a larger study population base todetermine the yield and clinical outcomes of screening high-risk individuals (55–58). Even so, it will take an extremely largestudy population followed for many years to show that screen-ing for pancreatic neoplasia actually saves lives (29, 55–59).

Summary and ConclusionsIt has been established that curable precursor lesions do

exist in the pancreas, that these lesions are long-lived beforethey progress to adenocarcinomas, that curable precursorlesions can be detected, and that groups at high-risk ofdeveloping the disease can be identified (Fig. 4). Small invasivecancers are also detectable and small pancreatic adenocarci-nomas are much more likely to be surgically curable than arelarger ones (20–22). Furthermore, as new medical therapiesfor pancreatic adenocarcinoma are developed, they are likelyto be considerably more efficacious against less advancedcancers than against more advanced ones. Thus, screeningtests that detect smaller adenocarcinomas may still be useful,as they could increase the chances of success with subsequenttherapy.

As technologies advance and the opportunities for the earlydetection of pancreatic neoplasia grow, it is likely that patients,

• Germline sequencing• Pancreatic cysts• Other risk factors

Prioritize

Earlyinvasivecancer

Surgery forsuspicious

lesions

Surveillancefor otherlesions

Surgery

PanIN

IPMN

MCN

SPN

SCNGeneral population Population at risk

Surveillancewhen possible

High-grade

dysplasia

Low-grade

dysplasia

KRAS CDKN2A TP53SMAD4

KRASGNAS

CDKN2ARNF43

TP53SMAD4

KRAS

VHL

CTNNB1

CDKN2ARNF43

TP53SMAD4

Distinguish Intervene

• Pancreatic imaging• Cyst aspiration• Pancreatic juice

Detect

Figure 4. This figure highlights the series of steps required to allow for the early detection of curable pancreatic neoplasia. Adapted from an original illustrationby Corinne Sandone, Johns Hopkins University.






guided by their physicians, will have to decidewhether or not tobe screened on the basis of an imperfect understanding of therisks and benefits of screening. This situation is not unprec-edented, as it has previously been applied to all other effectivescreening methods at their inception, such as those for colo-rectal, cervical, and breast tumors. Hopefully, the principlesoutlined in this review, as well as additional data and commonsense, will guide the development and implementation of thesetests, as these tests are sorely needed.

Disclosure of Potential Conflicts of InterestA.M. Lennon is a consultant/advisory board member for Boston Scientific.

M. Canto and A.P. Klein have provided expert testimony for Myriad Genetics.L.A. Diaz has ownership interest (including patents) in Personal GenomeDiagnostics and is a consultant/advisory board member for Amgen and Anae-

ropharma. N. Papadopoulos has ownership interest (including patents) in PGDxand PapGene and is a consultant/advisory board member for Sysmex-Inostics.K.W. Kinzler has ownership interest (including patents) in PGDx and PapGeneInc., is a consultant/advisory boardmember for Symex-Inostics, and has licensedinventions through Johns Hopkins University. B. Vogelstein has ownershipinterest (including patents) in PGDx and PapGene Inc., is a consultant/advisoryboard member for Symex-Inostics, and has licensed inventions through JohnsHopkins University. R.H. Hruban has ownership interest (including patents) inMyriad Genetics. No potential conflicts of interest were disclosed by the otherauthors.

Grant SupportThis work was supported by NIH grant P50 CA62924, the Lustgarten Foun-

dation for Pancreatic Cancer Research, Susan Wojcicki and Dennis Troper, andthe Michael Rolfe Foundation.

Received March 10, 2014; revised May 15, 2014; accepted May 15, 2014;published OnlineFirst June 12, 2014.

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2014;74:3381-3389. Published OnlineFirst June 12, 2014.Cancer Res Anne Marie Lennon, Christopher L. Wolfgang, Marcia Irene Canto, et al. Diagnose and Treat Curable Pancreatic Neoplasia?The Early Detection of Pancreatic Cancer: What Will It Take to

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