The most frequently used screening modality was EUS. Computed tomography (CT) scan was only performed as part of baseline investigation, unless clinically indicated due to positive findings in other modalities. Magnetic resonance imaging (MRI) was only routinely introduced into the screening protocol from 2014.
Of the 35 screened individuals with a known causative mutation, only 2 had a significant finding on screening; 1 out of 22 with a BRCA2 mutation had a 10 mm BD-IPMN that regressed during clinical follow-up, and 1 out of 5 individuals with a CDKN2a mutation had an 11 mm BD-IPMN which has remained stable after 36 months of follow-up.
Only 48 participants consented for endoscopic retrograde cholangiopancreatography with molecular analysis of pancreatic juice and only 4 patients had positive molecular test results in at least two analyses. This is too small a group to make any significant conclusions. Two of these patients had cystic lesions that were too small for further characterisation. Both of the remaining participants with two positive tests had EUS findings consistent with minimal change chronic pancreatitis (although neither had symptoms or diagnosis of pancreatitis and the imaging abnormalities resolved). The single PDAC case and one of the pNETs did not undergo pancreatic juice molecular analysis. The other pNET had undergone two separate pancreatic juice collections. The first gave wild-type KRAS and normal levels of CDKN2a promoter methylation (0.01%), and Tp53 analysis failed. The second test gave wild-type KRAS and Tp53, with CDKN2a analysis failing. The MD-IPMN case did not undergo pancreatic juice analysis in the screening cycle where the lesion was identified, and in a previous analysis they had wild-type KRAS and Tp53 with normal CDKN2a promoter methylation (0.018%).
In Fig. 2 each screening event is shown with the outcome colour coded, red for the cancer, pink for the pNETs, amber for the mainduct IPMN, green for no significant finding, etc. The participants are ranked according to the risk score of the individual at the time of screening estimated as above. Four individuals were included for screening because of family history, but were found not to have the disease mutation (a CDKN2a mutation) identified subsequently in this family, and they therefore were classified as having a zero elevated risk. The PDAC case was identified in an individual who at the time of screening had 5 cases of PDAC in the family and 17 individuals in the family tree over the age of 40 years, giving an FI of 1.179. There was a 50% chance of the individual being a carrier and so the risk score was 58.95. This put the individual’s familial risk in the top 10% of risk scores in the screened population.
Splitting the screening participants evenly into three groups (low, medium and high) as shown in Fig. 2 indicated no correlation between risk and incidence for branch-duct IPMN ( χ2 = 0.937; P = 0.632).
The screening described here was carried out under the assumption of autosomal dominant predisposition for PDAC. Multigenic cancer predisposition will give heterogeneous risk with only particular combinations of alleles passing a threshold that would allow predictable development of malignancy, even if all family members have some small elevated risk (39). The combination of alleles responsible for specific cancer cases will be unlikely to be seen again in the same family, so prospective risk would be too low to justify cancer screening. Effective screening requires a single mutant gene that confers the bulk of risk, although this may well be context specific (some genetic backgrounds giving high penetrance and some low penetrance); in such a situation family members who are noncarriers must be assumed not to be at any elevated risk.
The probability of a cluster of PDAC without such predisposition will increase with the number of at-risk individuals in a kindred and will reduce with the number of pancreatic cancer cases. Risk for an individual will depend on their age, exposure to environmental risk factors and lifestyle, but none of these factors, alone or in combination, would merit inclusion of an individual in a screening programme, nor would they influence the prospective risk of other family members.
A screening finding must therefore be judged according to the genetic risk of an individual. The one case of PDAC occurred within the top 10% of familial risk and the one case of MD-IPMN was identified in a medium risk family. Twenty-two branch-duct IPMNs were identified with equal probability in individuals of all familial risk categories.
The 5-year follow-up of 367 individuals from the populationbased Study of Health in Pomerania (SHIP) identified 48 participants who developed cystic lesions (12.9%). Although the SHIP study is not directly comparable with the prospective screening described here, it is notable that we identified a total of 41 cystic lesions in our population of 321 participants (12.8%), and hence our data are entirely consistent with the expected discovery of cystic lesions in the general population (40). Age is a risk factor both for the development of pancreatic cancer and IPMN (as shown in the SHIP analysis), and we deliberately did not include age in our risk model, as the question was whether genetic predisposition increased the risk of cystic lesions. Our hypothesis was that the cystic lesions were intermediates in a genetic predisposition for pancreatic cancer and could therefore be taken as a positive result in a cancer screen. The cystic lesions within the EUROPAC screening cohort were more common in older participants, but this was true even for the low-risk group, although very few prospective cancers occur in this group of patients (see Table 3) and presumably many of the individuals in this group were at no greater risk of pancreatic cancer than any other individual of a similar age. The BD-IPMNs were also no larger or more likely to progress in the high-risk group than in the low-risk group.
There is little doubt that BD-IPMNs are associated with cancer risk. However, although an individual with a BD-IPMN may be at greater risk of cancer, our data suggest individuals with a higher inherited risk of PDAC are not at a higher risk of developing BD-IPMN. Previously, Capurso et al. (41) showed that IPMNs were more frequent in individuals with a familly history of pancreatic cancer, and this was based on 21 IPMN cases (5.4 %) with a first-degree family history of PDAC compared to 6 controls (1.6 %), but only 1 of these would have fitted the criteria for FPC and this patient still only had 1 first-degree relative with PDAC (plus 2 second-degree relatives). Our findings indicate that FPC is not associated with greater predisposition for IPMN; genetic predisposition for IPMN may well be associated with higher risk of PDAC. Similarly, patients who smoke or who have diabetes may well be more likely to develop IPMN and be more likely to develop cancer.
The link between genetic predispostion to cancer and to precursor lesions is complex, and syndromes such as familial adenomatous polyposis predispose to cancer because they predispose to precursor lesions. These precursor lesions, albeit more commonly found, are not greatly more prone to progression than similar lesions found in individuals without genetic predisposition for cancer (42). In contrast, Lynch Syndrome (or hereditary nonpolyposis colorectal cancer (HNPCC)) increases the risk of precursor lesions progressing (43), and hence lesions are less likely to be found but are much more worrisome if identified. Naturally, if lesions are not related to the genetic predisposition for cancer then they will neither be more frequent nor more aggressive. There is emerging support for an alternative to the traditional progression model. A catastrophic process of cancer development associated with Acinar Ductal Metaplasia and lobular atrophy, independent of PanIN (44,45), fits with observations in familial pancreatic cancer (46). Atypical flat lesions may be positive screening results on the basis that they are the pre-cancerous lesion typical for FPC (47), but unfortunately, these cannot be identified without first resecting the pancreas.
Thus, the EUROPAC study does not support the inclusion of non-malignant pancreatic cystic lesions, including branch-duct IPMNs, as positive findings on screening individuals from FPC families.
The screening results presented here are consistent with the outcomes described by other groups, with discovery of cystic lesions far outweighing identification of PDAC (14–34). The poor return of screening programmes can be explained by inclusion of too many low-risk individuals in the screening cohorts. Any individual’s chance of being at high risk will be the same as the chance of carrying a predisposing mutation (e.g., 50% for a first-degree relative). The actual risk will be lower because superimposed is the chance that the family may just represent a random cluster of cases. This means that most individuals undergoing screening for PDAC on the sole basis of family history of the disease have no elevated risk. No elevated risk of PDAC means no elevated risk of precursor lesions.
In 2007, Wang et al. (39) developed the PancPro Mendelian model to identify high-risk individuals within FPC kindreds. In our report we used a much simpler (pragmatic) risk score based on the number of cases of pancreatic cancer in the family, which is the most widely recognised measure of familial risk (35), with the added advantage of stratifying risk within groups of families with equal numbers of pancreatic cancer cases (see Table 3). Although Table 3 shows that the prospective cancer cases have a higher FI than equivalent individuals in our screened cohort, who have not so far developed cancer, this cannot be considered as validation of FI as a concept as in order to do this we would have to show greater risk of cancer in a prospective cohort of individuals with standardisation for all other risk factors (smoking, age, diabetes etc.). We are carrying out such a prospective analysis with the families shown in Table 1, but these data will not be available for some years. This arbitrary risk score, although inferior to PancPro in accuracy for quantifying PDAC risk, has the advantage for our purpose that it avoids factors that would apply to sporadic pancreatic cancer and cystic lesions, such as age and smoking. Independence of such risk factors was essential in showing that the familial predisposition for cancer was largely (or entirely) independent of risk of developing BD-IPMN. The prospective reporting of new cases of PDAC in individuals at higher familial risk than those being screened indicates the need for a strategy to encourage more high-risk individuals to participate in screening. By restricting screening using PancPro (or equivalent) it should be possible to focus resources on encouraging higher risk individuals to participate.
If we had identified an increased frequency of IPMN in higher-risk individuals, we could have reasonably concluded that FPC predisposes to the development of IPMN which in turn predisposes to PDAC, but this was not the case. If we had found that IPMNs encountered during screening progressed to PDAC, we could have reasonably concluded that FPC increases the probability of an IPMN progressing, but again this was not the case. We cannot conclude from this work that IPMNs are an intermediate stage in the development of PDAC within FPC kindreds. IPMNs identified during screening should on this basis be treated in the same way as IPMNs discovered incidentally in the general population (according to the appropriate guidelines). A desirable feature of risk stratification is that it is unlikely to increase the yield of branch-duct IPMNs.
We are grateful to all the screening centres, EUROPAC participants and their referring clinicians. Specifically, the authors would like to express their gratitude to John Neoptolemos who was responsible for establishing EUROPAC and to the following individuals. UK: Mr. C Johnson, Mr. D Berry, Mr. M Cooper, Prof. C Imrie, Miss S Norton, Mrs. M Finch-jones, Mr. T Brown, Prof. G Evans, Dr. B Kerr, Dr. JA Cook, Dr. R Eeles, Dr. D Eccles, Dr. A Lucassen, Dr. S Tomkins, Mr. R Charnley, Dr. F Lalloo, Dr. J Adlard, Dr. L Walker, Dr. P Brennan, Mr. P Burgess, Dr. J Mackay, Mrs. L Snadden, Mrs. L O’Dair, Mrs. C Cummings, Mr. M Deakin, Mr. K Wedgwood, Prof. J Raeburn, Mrs. S Hamer, Prof. AM Gerdes, Dr. S Price. Belgium: Prof. M Delhaye, Prof. J Deviere, Prof. Van Steenbergen, Dr. S Tejpar. Czech Republic: Dr. J Martinek. Denmark: Prof. Schaffilitzky de Muckadell, Dr. MT Jorgensen, Dr. L Sunde. Finland: Prof. I Nordback. France: Prof. R Laugier. Germany: Prof. D. Bartsch Greece: Prof. C Dervenis, Dr. N Alexakis. Hungary: Prof. A Oláh, Dr. V Ruszinko. Ireland: Prof. NC Nevin. Italy: Prof. G Uomo, Dr. D Campra, Prof. S Pedrazzoli, Prof. V Lucidi, Prof. G Cavallini, Dr. L Frulloni, Dr. G Mandrile. Latvia: Dr. A Staka. The Netherlands: Prof. J Drenth, Prof. J Jansen. Poland: Dr. B Korczowski. Spain: Dr. FX Real, Dr. N Malats, Prof. JE Dominguez-Munoz, Dr. L Robles. Sweden: Prof. Å Andrén-Sandberg, Dr. E Bjorck, Dr. E Holmberg, Prof. I Ihse, Dr. M Soller, Prof. J Permert. Switzerland: Prof. R Ammann. Turkey: Dr. F Guraken. USA: Prof. D Whitcomb, Prof. A Lowenfels.
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CONFLICTS OF INTEREST
Guarantor of the article: W. Greenhalf.
Specific author contributions: EUROPAC was established in 1996, the lead clinician is CH. The lead scientist for EUROPAC is WG supported by EC. SH supported the description of family trees including ascertaining diagnosis. The initial concept and study design included WG, EC and MML. ARGS, IS, JAN, CH, CG, MR, MC, AS, RC, CM, ZH, GPA, PH, MML and SPP supported patient recruitment and surveillance. JR provided expertise in endoscopic procedures and AF provided expertise in radiological procedures. RJ provided statistical support. The initial draft was written by ARGS, WG and IS. All authors contributed to the final version of the paper.
Financial support: Pancreatic Cancer UK (PCUK) currently supports EUROPAC. Previous funding was received from Mylan (Solvay then Abbott), Cancer Research UK, the National Institute of Health Research including the NIHR University College London Hospitals Biomedical Research Centre, the European Union and the Royal Liverpool and Broadgreen University Hospitals NHS Trust. The Royal College of Surgeons of England supported ARGS.
Potential competing interests: None.
WHAT IS CURRENT KNOWLEDGE
- ✓ There are families with multiple cases of pancreatic cancer suggesting autosomal dominant predisposition (true FPC).
- ✓ Clusters of pancreatic cancer cases will occur by chance giving little prospective increased cancer risk.
- ✓ Screening of pancreatic cancer families frequently yields pancreatic cystic lesions but not many cancers.
- ✓ Some sporadic pancreatic cystic lesions lead to cancer but most remain indolent.
- ✓ It is unknown whether FPC influences either the incidence or progression of cystic lesions.
WHAT IS NEW HERE
© The American College of Gastroenterology 2019. All Rights Reserved.
- ✓ Stratification by family history makes no difference to yield of cystic lesions within FPC kindreds.
- ✓ BD-IPMNs may be incidental and so cannot be taken as a positive screening outcome.
- ✓ BD-IPMNs found during screening should be managed in the same way as those found incidentally.