ASGE guideline on screening for pancreatic cancer in individuals with genetic susceptibility: summary and recommendations

Abstract

This guideline document was prepared by the Standards of Practice Committee of the American Society for Gastrointestinal Endoscopy using the best available scientific evidence and considering a multitude of variables including, but not limited to, adverse events, patients’ values, and cost implications. The purpose of these guidelines is to provide best practice recommendations that may help standardize patient care, improve patient outcomes, and reduce variability in practice. We recognize that clinical decision-making is complex. Guidelines, therefore, are not a substitute for a clinician’s judgment. Such judgments may, at times, seem contradictory to our guidance because of many factors that are impossible to fully consider by guideline developers. Any clinical decisions should be based on the clinician’s experience, local expertise, resource availability, and patient values and preferences. This document is not a rule and should not be construed as establishing a legal standard of care or as encouraging, advocating for, mandating, or discouraging any particular treatment. Our guidelines should not be used in support of medical complaints, legal proceedings, and/or litigation because they were not designed for this purpose.Pancreatic cancer is a rare but lethal cancer with a lifetime incidence of approximately 1.6%1SEER cancer stat facts: pancreatic cancer. Available at https://seer.cancer.gov/statfacts/html/pancreas.html. Accessed July 15, 2021.Google Scholar,2American Cancer Society. Key statistics for pancreatic cancer. Available at https://www.cancer.org/cancer/pancreatic-cancer/about/key-statistics.html. Accessed July 15, 2021.Google Scholar and 5-year survival of 10%.3Siegel R.L. Miller K.D. Jemal A. Cancer statistics, 2020.CA Cancer J Clin. 2020; 70: 7-30Crossref PubMed Scopus (11640) Google Scholar Pancreatic cancer accounts for 3% of all newly diagnosed cancers and 8% of all cancer-related deaths in the United States in 2020,3Siegel R.L. Miller K.D. Jemal A. Cancer statistics, 2020.CA Cancer J Clin. 2020; 70: 7-30Crossref PubMed Scopus (11640) Google Scholar and the incidence is anticipated to rise over the next decade.4Rahib L. Smith B.D. Aizenberg R. et al.Projecting cancer incidence and deaths to 2030: the unexpected burden of thyroid, liver, and pancreas cancers in the United States.Cancer Res. 2014; 74: 2913-2921Crossref PubMed Scopus (4038) Google Scholar Biologically aggressive behavior, advanced stage at the time of diagnosis, and poor response to oncologic therapies have been proposed as reasons for dismal outcomes in pancreatic cancer.5Kamisawa T. Wood L.D. Itoi T. et al.Pancreatic cancer.Lancet. 2016; 388: 73-85Abstract Full Text Full Text PDF PubMed Scopus (1410) Google ScholarDiagnosis at earlier stages of disease is associated with improved survival, with 93% 10-year survival among stage 0 cancers and 34% to 39% 5-year survival among stage I cancers.6van Roessel S. Kasumova G.G. Verheij J. et al.International validation of the eighth edition of the American Joint Committee on Cancer (AJCC) TNM staging system in patients with resected pancreatic cancer.JAMA Surg. 2018; 153e183617Crossref PubMed Scopus (120) Google Scholar,7Kanno A. Masamune A. Hanada K. et al.Multicenter study of early pancreatic cancer in Japan.Pancreatology. 2018; 18: 61-67Crossref PubMed Scopus (92) Google Scholar However, by the time patients develop symptoms, almost 80% have advanced disease that is inoperable.8Henrikson N.B. Bowles E.J.A. Blasi P.R. et al.U.S. Preventive Services Task Force evidence syntheses, formerly systematic evidence reviews. Screening for pancreatic cancer: a systematic evidence review for the U.S. Preventive Services Task Force. Agency for Healthcare Research and Quality, Rockville, MD2019Google Scholar In 2019, the U.S. Preventive Services Task Force reaffirmed their earlier guidelines by continuing to recommend against screening for pancreatic cancer in average-risk adults.9Owens D.K. Davidson K.W. Krist A.H. et al.Screening for pancreatic cancer: US Preventive Services Task Force reaffirmation recommendation statement.JAMA. 2019; 322: 438-444Crossref PubMed Scopus (127) Google Scholar This decision was based in part on the low incidence of pancreatic cancer in the general population. Importantly, the U.S. Preventive Services Task Force specifically stated that those recommendations did not apply to high-risk populations because of inherited genetic susceptibility. Although other guidelines have provided recommendations for individuals with genetic susceptibility, those guidelines have relied primarily on consensus of expert opinion.10Goggins M. Overbeek K.A. Brand R. et al.Management of patients with increased risk for familial pancreatic cancer: updated recommendations from the International Cancer of the Pancreas Screening (CAPS) Consortium.Gut. 2020; 69: 7-17Crossref PubMed Scopus (206) Google Scholar, 11Aslanian H.R. Lee J.H. Canto M.I. AGA clinical practice update on pancreas cancer screening in high-risk individuals: expert review.Gastroenterology. 2020; 159: 358-362Abstract Full Text Full Text PDF PubMed Scopus (74) Google Scholar, 12Syngal S. Brand R.E. Church J.M. et al.ACG clinical guideline: genetic testing and management of hereditary gastrointestinal cancer syndromes.Am J Gastroenterol. 2015; 110 (quiz 263): 223-262Crossref PubMed Scopus (872) Google Scholar, 13Săftoiu A. Hassan C. Areia M. et al.Role of gastrointestinal endoscopy in the screening of digestive tract cancers in Europe: European Society of Gastrointestinal Endoscopy (ESGE) position statement.Endoscopy. 2020; 52: 293-304Crossref PubMed Scopus (48) Google Scholar, 14Daly M.B. Pal T. Berry M.P. et al.Genetic/familial high-risk assessment: breast, ovarian, and pancreatic, Version 2.2021, NCCN Clinical Practice Guidelines in Oncology.J Natl Compr Canc Netw. 2021; 19: 77-102Crossref PubMed Google ScholarThe aim of this American Society for Gastrointestinal Endoscopy (ASGE) guideline is to provide evidence-based recommendations on screening for pancreatic cancer in individuals with genetic susceptibility. Although pathogenic germline variants in several genes have been associated with increased risk for pancreatic cancer, these guidelines focus on BRCA1 and BRCA2 because of their higher prevalence in the population.15Dudley B. Karloski E. Monzon F.A. et al.Germline mutation prevalence in individuals with pancreatic cancer and a history of previous malignancy.Cancer. 2018; 124: 1691-1700Crossref PubMed Scopus (17) Google Scholar, 16Golan T. Barenboim A. Lahat G. et al.Increased rate of complete pathologic response after neoadjuvant FOLFIRINOX for BRCA mutation carriers with borderline resectable pancreatic cancer.Ann Surg Oncol. 2020; 27: 3963-3970Crossref PubMed Scopus (32) Google Scholar, 17Golan T. Hammel P. Reni M. et al.Maintenance olaparib for germline BRCA-mutated metastatic pancreatic cancer.N Engl J Med. 2019; 381: 317-327Crossref PubMed Scopus (947) Google Scholar, 18Grant R.C. Selander I. Connor A.A. et al.Prevalence of germline mutations in cancer predisposition genes in patients with pancreatic cancer.Gastroenterology. 2015; 148: 556-564Abstract Full Text Full Text PDF PubMed Scopus (207) Google Scholar, 19Hu C, LaDuca H, Shimelis H, et al. Multigene hereditary cancer panels reveal high-risk pancreatic cancer susceptibility genes. JCO Precis Oncol. Epub 2018 Jul 25.Google Scholar, 20Lucas A.L. Frado L.E. Hwang C. et al.BRCA1 and BRCA2 germline mutations are frequently demonstrated in both high-risk pancreatic cancer screening and pancreatic cancer cohorts.Cancer. 2014; 120: 1960-1967Crossref PubMed Scopus (43) Google Scholar, 21Salo-Mullen E.E. O'Reilly E.M. Kelsen D.P. et al.Identification of germline genetic mutations in patients with pancreatic cancer.Cancer. 2015; 121: 4382-4388Crossref PubMed Scopus (135) Google Scholar, 22Yurgelun M.B. Chittenden A.B. Morales-Oyarvide V. et al.Germline cancer susceptibility gene variants, somatic second hits, and survival outcomes in patients with resected pancreatic cancer.Genet Med. 2019; 21: 213-223Abstract Full Text Full Text PDF PubMed Scopus (102) Google Scholar, 23Golan T. Kindler H.L. Park J.O. et al.Geographic and ethnic heterogeneity of germline BRCA1 or BRCA2 mutation prevalence among patients with metastatic pancreatic cancer screened for entry into the POLO trial.J Clin Oncol. 2020; 38: 1442-1454Crossref PubMed Scopus (30) Google Scholar Familial pancreatic cancer (FPC) kindreds were defined as kindreds containing at least a pair of first-degree relatives with pancreatic cancer without an association with a known hereditary cancer syndrome.24Klein A.P. Brune K.A. Petersen G.M. et al.Prospective risk of pancreatic cancer in familial pancreatic cancer kindreds.Cancer Res. 2004; 64: 2634-2638Crossref PubMed Scopus (498) Google Scholar, 25Tersmette A.C. Petersen G.M. Offerhaus G.J. et al.Increased risk of incident pancreatic cancer among first-degree relatives of patients with familial pancreatic cancer.Clin Cancer Res. 2001; 7: 738-744PubMed Google Scholar, 26Copur M.S. Talmon G.A. Wedel W. et al.Hereditary vs familial pancreatic cancer: associated genetic syndromes and clinical perspective.Oncology. 2020; 34: 196-201PubMed Google Scholar, 27Petersen G.M. Familial pancreatic cancer.Semin Oncol. 2016; 43: 548-553Crossref PubMed Scopus (76) Google Scholar Modeling studies strongly suggest autosomal-dominant inheritance of a rare allele as the likely etiology.28Klein A.P. Beaty T.H. Bailey-Wilson J.E. et al.Evidence for a major gene influencing risk of pancreatic cancer.Genet Epidemiol. 2002; 23: 133-149Crossref PubMed Scopus (115) Google Scholar Furthermore, most pancreatic cancer screening studies included those with FPC syndrome, and therefore we made screening recommendations for these individuals. Recommendations made in these guidelines should be used in the context of the individual patient and clinical setting, such that the ultimate decision regarding pancreatic cancer screening should be made with consideration of patient values, preferences, and availability of local expertise.MethodsThis document was prepared by the Standards of Practice Committee of the ASGE and was conceptualized and conducted according to the Grading of Recommendations Assessment, Development and Evaluation (GRADE).29Qumseya B. Sultan S. et al.ASGE Standards of Practice CommitteeASGE guideline on screening and surveillance of Barrett's esophagus.Gastrointest Endosc. 2019; 90: 335-359Abstract Full Text Full Text PDF PubMed Scopus (134) Google Scholar, 30Wani S. Qumseya B. et al.Standards of Practice CommitteeEndoscopic eradication therapy for patients with Barrett's esophagus-associated dysplasia and intramucosal cancer.Gastrointest Endosc. 2018; 87: 907-931Abstract Full Text Full Text PDF PubMed Scopus (87) Google Scholar, 31Guyatt G.H. Oxman A.D. Vist G.E. et al.GRADE: an emerging consensus on rating quality of evidence and strength of recommendations.BMJ. 2008; 336: 924-926Crossref PubMed Google Scholar Evidence was presented to a panel of experts representing various stakeholders including oncology, radiology, genetics, epidemiology, and gastroenterology. Two patient advocates were also included. All panel members were required to disclose potential financial and intellectual conflicts of interest, which were addressed according to ASGE policies. In developing these recommendations, we took into consideration the certainty in the evidence, benefits and harms of different management options, feasibility, patient values and preferences, resources utilization, cost-effectiveness, and health equity. The final wording of the recommendations including direction and strength were approved by all members of the panel and the ASGE governing board. Stronger recommendations are typically stated as “we recommend…,” whereas weaker recommendations are indicated by phrases such as “we suggest….”These guidelines addressed the following clinical questions using the GRADE format:1.Should individuals at increased risk of pancreatic cancer because of genetic susceptibility undergo screening for pancreatic cancer?2.Should individuals at increased risk of pancreatic cancer because of genetic susceptibility undergo screening with endoscopic ultrasound EUS or magnetic resonance imaging (MRI)?3.(a) Should individuals with the BRCA2 pathogenic variant undergo screening for pancreatic cancer?(b)Should individuals with the BRCA1 pathogenic variant undergo screening for pancreatic cancer?Relevant clinical outcomes included all-cause mortality, pancreatic cancer mortality, overall yield of screening, detection of surgically resectable and borderline-resectable pancreatic cancer, psychological benefits, and harms. Yield of screening was defined as detection of any high-risk lesions, pancreatic cancer, high-grade dysplasia, and grade III pancreatic intraepithelial neoplasia. Surgically resectable and borderline-resectable pancreatic lesions were defined as any T1-3 and N0-2 pancreatic cancer, high-grade dysplasia, or grade III pancreatic intraepithelial neoplasia. Harms were defined as harms from screening tests, rates of low-yield pancreatic surgery in the screened population, and rates of adverse events from pancreatic cancer surgery resulting from positive screening tests. For the purposes of this document, pancreatic cancer refers to pancreatic ductal adenocarcinoma.This guideline also addressed the frequency of and starting age at screening using a non-GRADE format for individuals with the following genetic susceptibility conditions: FPC, familial atypical multiple mole melanoma (FAMMM) syndrome, Peutz-Jeghers syndrome, ataxia telangiectasia due to mutation in the ataxia telangiectasia mutated (ATM) gene, Lynch syndrome, and hereditary pancreatitis. In making these recommendations, the panel considered available literature and existing guidelines.Summary of RecommendationsDetails of our literature searches, data analyses, pooled effect estimates, evidence profiles, forest plots, and panel deliberation for each outcome can be found in the methodology and technical review document (this issue). A summary of our final recommendations for screening patients at high risk of pancreatic cancer are listed in Table 1.Table 1Summary of recommendationsQuestionRecommendation and quality of evidence1In individuals at increased risk of pancreatic cancer because of genetic susceptibility, we suggest screening for pancreatic cancer compared with no screening (conditional, low quality)2In individuals at increased risk of pancreatic cancer because of genetic susceptibility, we suggest screening with EUS, EUS alternating with MRI, or MRI based on patient preference and available expertise (conditional, very low quality)•EUS may be preferred: as the initial screening test; for patients at very high risk for pancreatic cancer like Peutz-Jeghers syndrome and FAMMM; when EUS can be combined with screening upper endoscopy or colonoscopy (eg, Lynch and Peutz-Jeghers syndrome); when there is a contraindication to MRI (eg, claustrophobia, contrast allergy, implanted metal, and renal failure)•MRI may be preferred: for patients at increased risk of adverse events from anesthesia or invasive procedures; for patients who place a high value on avoiding invasive testing; when MRI may be combined with other imaging (eg, enterography for Peutz-Jeghers syndrome).3aIn individuals with BRCA2 pathogenic variant, we suggest screening for pancreatic cancer compared with no screening (conditional, very low quality)3bIn individuals with BRCA1 pathogenic variant, we suggest screening for pancreatic cancer compared with no screening (conditional, very low quality)4In individuals at increased risk of pancreatic cancer because of genetic susceptibility, we suggest that annual screening be performed (conditional, very low quality)5In individuals at increased risk for pancreatic cancer, we suggest the age at which to begin screening should vary by individual genetic condition (conditional, very low quality)6For each of the following conditions, we recommend the following starting ages:(a)BRCA2 pathogenic variant: age 50 or 10 years earlier than the youngest relative with pancreatic cancer.(b)BRCA1 pathogenic variant: age 50 or 10 years earlier than the youngest relative with pancreatic cancer.(c)PALB2 pathogenic variant: age 50 or 10 years earlier than the youngest relative with pancreatic cancer.(d)FPC syndrome: age 50 or 10 years earlier than the youngest relative with pancreatic cancer (screening is recommended for all first-degree relatives of affected family members).(e)FAMMM syndrome: age 40 or 10 years earlier than the youngest relative with pancreatic cancer.(f)Peutz-Jeghers syndrome: age 35 or 10 years earlier than the youngest relative with pancreatic cancer.(g)Heterozygotes for ATM pathogenic variant with first- or second-degree relative with pancreatic cancer: age 50 or 10 years earlier than the youngest relative with pancreatic cancer.(h)Lynch syndrome with first- or second-degree relative with pancreatic cancer: age 50 or 10 years earlier than the youngest relative with pancreatic cancer.(i)Autosomal-dominant hereditary pancreatitis: age 40.ATM, Ataxia-telangiectasia mutated; EUS, endoscopic ultrasound; FAMMM, familial atypical multiple mole melanoma; FPC, familial pancreatic cancer; MRI, magnetic resonance imaging. Open table in a new tab Question 1: Should individuals at increased risk of pancreatic cancer because of genetic susceptibility undergo screening for pancreatic cancer?Recommendation 1. In individuals at increased risk of pancreatic cancer because of genetic susceptibility, we suggest screening for pancreatic cancer compared with no screening (conditional recommendation, low quality of evidence).Summary of evidenceFor this question, we performed a systematic review and meta-analysis. Our search identified 25 studies for inclusion. These studies included individuals with FPC, Peutz-Jeghers syndrome, FAMMM, and Lynch syndrome as well as those with BRCA1, BRCA2, ATM, and PALB2 pathogenic variants. Outcomes of interest were all-cause mortality, yield of screening for high-risk lesions, yield of screening for resectable and borderline-resectable lesions, and harms from screening.We did not find any clinical trials that compared outcomes of screen-detected pancreatic cancers with a control group of patients who did not undergo screening. Two studies compared outcomes of screen-detected pancreatic cancers with historic control subjects and found improved survival in screen-detected pancreatic cancer.32Canto M.I. Almario J.A. Schulick R.D. et al.Risk of neoplastic progression in individuals at high risk for pancreatic cancer undergoing long-term surveillance.Gastroenterology. 2018; 155: 740-751Abstract Full Text Full Text PDF PubMed Scopus (186) Google Scholar,33Vasen H. Ibrahim I. Robbers K. et al.Benefit of surveillance for pancreatic cancer in high-risk individuals: outcome of long-term prospective follow-up studies from three European expert centers.J Clin Oncol. 2016; 34: 2010-2019Crossref PubMed Scopus (213) Google Scholar One study found that 3-year survival was significantly higher in screen-detected cancers when compared with individuals with symptomatic cancers who were noncompliant with screening (85% vs 25%).32Canto M.I. Almario J.A. Schulick R.D. et al.Risk of neoplastic progression in individuals at high risk for pancreatic cancer undergoing long-term surveillance.Gastroenterology. 2018; 155: 740-751Abstract Full Text Full Text PDF PubMed Scopus (186) Google ScholarFor the outcome of cumulative yield of screening for high-risk lesions, our analysis showed a pooled yield of 3.1% (95% confidence interval [CI], 2.2%-4.3%; P = .02, I2 = 40.5). For resectable and borderline-resectable lesions, the pooled yield was 2.1% (95% CI, 1.4%-3.1%; P = .007 and I2 = 45.6). The proportion of screen-detected cancers that were resectable or borderline-resectable was 60.0% (95% CI, 43.7%-74.4%; P = .51 and I2 = .0). Population-based data show that only 20% of symptomatic cancers were diagnosed when they were resectable or borderline-resectable, whereas 30% were locally advanced and 50% were metastatic.8Henrikson N.B. Bowles E.J.A. Blasi P.R. et al.U.S. Preventive Services Task Force evidence syntheses, formerly systematic evidence reviews. Screening for pancreatic cancer: a systematic evidence review for the U.S. Preventive Services Task Force. Agency for Healthcare Research and Quality, Rockville, MD2019Google Scholar This suggests that screening was associated with a substantial stage shift because almost 2 of 3 screen-detected pancreatic cancers were resectable or borderline-resectable.Among included studies, no adverse events were reported because of screening EUS or MRI. Although EUS and MRI were safe, these tests can be costly and may result in overdiagnosis.Considering all patients who underwent screening for pancreatic cancer, in 22 studies, the pooled rate of low-yield pancreatic surgery was low at 2.8% (95% CI, 1.9%-4.1%; P = .003 and I2 = 51.4). Low-yield surgery was defined as surgery that did not yield cancer, high-grade dysplasia, or grade III pancreatic intraepithelial neoplasia. However, among 181 patients who had pancreatic surgery as a result of screening, the pooled proportion of low-yield surgery was high at 46.6% (95% CI, 34.2-59.4%; P = .15 and I2 = 26.2), and the pooled rate of adverse events was also high at 19.9% (95% CI, 7.4%-43.4%; P = .05 and I2 = 49.7). Therefore, the potential harms from screening must be carefully considered when enrolling individuals into a screening program.On the other hand, pancreatic cancer screening was associated with several psychological benefits based on a systematic review of 7 studies.34Cazacu I.M. Luzuriaga Chavez A.A. Saftoiu A. et al.Psychological impact of pancreatic cancer screening by EUS or magnetic resonance imaging in high-risk individuals: a systematic review.Endosc Ultrasound. 2019; 8: 17-24Crossref PubMed Scopus (15) Google Scholar Screening participants had low-to-moderate levels of pancreatic cancer-related distress at the start, which improved significantly over time. Lastly, several studies reported screening to be cost-effective in high-risk populations.35Corral J.E. Das A. Bruno M.J. et al.Cost-effectiveness of pancreatic cancer surveillance in high-risk individuals: an economic analysis.Pancreas. 2019; 48: 526-536Crossref PubMed Scopus (23) Google Scholar, 36Joergensen M.T. Gerdes A.M. Sorensen J. et al.Is screening for pancreatic cancer in high-risk groups cost-effective? Experience from a Danish national screening program.Pancreatology. 2016; 16: 584-592Crossref PubMed Scopus (33) Google Scholar, 37Bruenderman E. Martin 2nd, R.C. A cost analysis of a pancreatic cancer screening protocol in high-risk populations.Am J Surg. 2015; 210: 409-416Abstract Full Text Full Text PDF PubMed Scopus (26) Google ScholarBased on our analysis and panel discussions, we concluded that the benefits of screening for pancreatic cancer in those with genetic susceptibility to pancreatic cancer outweigh the potential risks and made a conditional recommendation for screening. The overall quality of evidence was low. Patients should be counseled about the risks and benefits of screening before screening is initiated.Question 2: Should individuals at increased risk of pancreatic cancer because of genetic susceptibility undergo screening with EUS or MRI?Recommendation 2. In patients at increased risk of pancreatic cancer because of genetic susceptibility, we suggest screening with EUS, EUS alternating with MRI, or MRI based on patient preference and available expertise (conditional recommendation, very low quality of evidence).•EUS:oMay be preferred: as the initial screening test; for patients at very high risk for pancreatic cancer like Peutz-Jeghers syndrome and FAMMM; when EUS can be combined with screening upper endoscopy or colonoscopy (eg, Lynch and Peutz-Jeghers syndrome); when there is a contraindication to MRI (eg, claustrophobia, contrast allergy, implanted metal, and renal failure).oA linear array echoendoscope may be preferable over a radial echoendoscope.•MRI:oMay be preferred: for patients at increased risk of adverse events from anesthesia or endoscopic procedures; for patients who place a high value on avoiding invasive testing; when MRI may be combined with other imaging (eg, enterography for Peutz-Jeghers syndrome).oA contrast-enhanced exam using intravenous agents is preferred, a minimum of 1.5-T magnet should be applied using phased-array coils, and a 3-T magnet may have an additional advantage in detection of small pancreatic lesions because of superior soft tissue resolution.Summary of evidenceWe conducted a meta-analysis based on the systematic review performed for Question 1. Of the 25 included studies, 6 studies (n = 338) used only EUS, 5 studies (n = 455) used only MRI, and 14 studies (n = 2460) used a combination of EUS and MRI. Outcomes of interest for this question were yield of screening for high-risk lesions, high-risk resectable lesions, and harms from screening EUS and MRI. The pooled cumulative yield of screening for high-risk lesions did not differ between EUS and MRI (4.0% [95% CI, 1.7%-9.1%], P = .18, I2 = 34.4 for EUS; 2.4% [95% CI, 1.0%-5.4%], P = .21, I2 = 31.0 for MRI; and 3.1% [95% CI, 2.1%-4.6%], P = .022, I2 = 48.4 for a combination of EUS and MRI). The pooled yield of screening for high-risk resectable lesions also did not differ among the 2 modalities (3.9% [95% CI, 1.7%-8.5%], P = .18, I2 = 34.4 for EUS; 1.8% [95% CI, .8%-4.0%], P = .38, I2 = 5.4 for MRI; and 1.7% [95% CI, 1.0%-3.0%], P = .006, I2 = 55.9 for a combination of EUS and MRI). Although there was a trend toward EUS demonstrating a higher diagnostic yield when compared with MRI, this did not reach statistical significance. There may be 2 possible explanations for this trend. First, referral bias may be present because patients at higher risk for pancreatic cancer may be more likely to undergo EUS. Second, EUS may be more sensitive than MRI at detecting small solid pancreatic lesions as demonstrated in 2 studies where almost all solid pancreatic cancers were only found by EUS.38Harinck F. Konings I.C. Kluijt I. et al.A multicentre comparative prospective blinded analysis of EUS and MRI for screening of pancreatic cancer in high-risk individuals.Gut. 2016; 65: 1505-1513Crossref PubMed Scopus (118) Google Scholar,39Paiella S. Capurso G. Cavestro G.M. et al.Results of first-round of surveillance in individuals at high-risk of pancreatic cancer from the AISP (Italian Association for the Study of the Pancreas) Registry.Am J Gastroenterol. 2019; 114: 665-670Crossref PubMed Scopus (26) Google ScholarSix studies (n = 350) reporting on adverse outcomes from screening EUS or MRI found none.20Lucas A.L. Frado L.E. Hwang C. et al.BRCA1 and BRCA2 germline mutations are frequently demonstrated in both high-risk pancreatic cancer screening and pancreatic cancer cohorts.Cancer. 2014; 120: 1960-1967Crossref PubMed Scopus (43) Google Scholar,36Joergensen M.T. Gerdes A.M. Sorensen J. et al.Is screening for pancreatic cancer in high-risk groups cost-effective? Experience from a Danish national screening program.Pancreatology. 2016; 16: 584-592Crossref PubMed Scopus (33) Google Scholar,40Verna E.C. Hwang C. 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Thus, the overall quality of evidence was very low.When EUS is performed for screening, a linear-array echoendoscope may be preferable because a randomized controlled study showed that it detected more pancreas lesions than a radial echoendoscope (82% vs 67%, P < .001).44Shin E.J. Topazian M. Goggins M.G. et al.Linear-array EUS improves detection of pancreatic lesions in high-risk individuals: a randomized tandem study.Gastrointest Endosc. 2015; 82: 812-818Abstract Full Text Full Text PDF PubMed Scopus (34) Google Scholar The choice of echoendoscope should also take into consideration the endoscopist’s training and experience. When MRI is performed for screening, we suggest the study should be performed with and without intravenous contrast, using at minimum a 1.5-T magnet.45Burk K.S. Lo G.C. Gee M.S. et al.Imaging and screening of pancreatic cancer.Radiol Clin North Am. 2017; 55: 1223-1234Abstract Full Text Full Text PDF PubMed Scopus (11) Google Scholar,46Corrias G. Raeside M.C. Agostini A. et al.Pilot study of rapid MR pancreas screening for patients with BRCA mutation.Eur Radiol. 2019; 29: 3976-3985Crossref PubMed Scopus (10) Google Scholar A 3-T magnet may provide additional advantage in detection of small pancreatic lesions because of superior soft tissue resolution.47Barnes C.A. Krzywda E. Lahiff S. et al.Development of a high risk pancreatic screening clinic using 3.0 T MRI.Fam Cancer. 2018; 17: 101-111Crossref PubMed Scopus (16) Google ScholarQuestion 3a: Should individuals with BRCA2 pathogenic varian