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American Society for Gastrointestinal Endoscopy guideline on screening for pancreatic cancer in individuals with genetic susceptibility: methodology and review of evidence

Published:February 16, 2022DOI:https://doi.org/10.1016/j.gie.2021.12.002

      Abbreviations:

      ASGE (American Society for Gastrointestinal Endoscopy), ATM (ataxia-telangiectasia mutated), FAMMM (familial atypical multiple mole melanoma), FPC (familial pancreatic cancer), GRADE (Grading of Recommendations Assessment, Development and Evaluation), IPMN (intraductal papillary mucinous neoplasm), MRI (magnetic resonance imaging), OR (odds ratio), PanIN (pancreatic intraepithelial neoplasia), PICO (population, intervention, comparator, and outcomes), RR (relative risk), SEER (Surveillance, Epidemiology, and End Results Program), SIR (standardized incidence ratio)
      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 the 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.
      The American Society for Gastrointestinal Endoscopy (ASGE) Standards of Practice Committee has developed guidelines for pancreatic cancer screening in individuals at increased risk of pancreatic cancer because of genetic susceptibility. These guidelines follow the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology.
      • Qumseya B.
      • Sultan S.
      • Bain P.
      • et al.
      ASGE Standards of Practice Committee
      ASGE guideline on screening and surveillance of Barrett's esophagus.
      • Wani S.
      • Qumseya B.
      • Sultan S.
      • et al.
      ASGE Standards of Practice Committee
      Endoscopic eradication therapy for patients with Barrett's esophagus-associated dysplasia and intramucosal cancer.
      • Guyatt G.H.
      • Oxman A.D.
      • Vist G.E.
      • et al.
      GRADE: an emerging consensus on rating quality of evidence and strength of recommendations.
      In formulating these guidelines, we conducted extensive literature reviews, including 2 formal systematic reviews of the literature, and meta-analyses. To make all the information we collected and analyzed readily assessable, this guideline is presented in 2 documents. This document details guideline methodology including formulation of clinical questions, literature searches, data analyses, panel composition, evidence profiles, and other considerations like cost-effectiveness, patient preferences, and health equity. For each clinical question, this document includes outcomes of interest, pooled effect estimates, and evidence that was considered by the panel in making final recommendations. The “Summary and Recommendations” is published separately and provides a summary of our findings and final recommendations (this issue).

      Methods

      Formulation of clinical questions

      Our guideline addressed 3 questions using GRADE methodology (Table 1). For these questions we followed the PICO format: P, population in question; I, intervention; C, comparator; and O, outcomes of interest. For all clinical questions, potentially relevant patient-important outcomes were identified a priori and rated from “critical” to “important” through a consensus process. This guideline also addressed additional questions regarding frequency and timing of screening (Table 2).
      Table 1Summary of population, intervention, comparator, and outcomes questions
      QuestionPopulationInterventionComparatorOutcomesRating
      1Individuals at increased risk of pancreatic cancer because of genetic susceptibilityScreeningNo screeningAll-cause mortalityCritical
      2Individuals at increased risk of pancreatic cancer because of genetic susceptibility undergoing screeningMagnetic resonance imagingEUSPancreatic cancer mortalityCritical
      3aIndividuals with BRCA2 pathogenic variant
      For questions 3a and 3b, we also evaluated cumulative lifetime risk of pancreatic cancer.
      ScreeningNo screeningCumulative yield of screeningCritical
      3bIndividuals with BRCA1 pathogenic variant
      For questions 3a and 3b, we also evaluated cumulative lifetime risk of pancreatic cancer.
      ScreeningNo screeningDetection of resectable and borderline-resectable lesionsImportant
      Psychological benefitsImportant
      HarmsCritical
      For questions 3a and 3b, we also evaluated cumulative lifetime risk of pancreatic cancer.
      Table 2Summary of additional management questions addressed in the guideline using non–Grading of Recommendations Assessment, Development and Evaluation methodology
      QuestionPopulationManagement question
      4Individuals at increased risk of pancreatic cancer because of genetic susceptibilityHow often should screening for pancreatic cancer be performed?
      5Individuals at increased risk of pancreatic cancer because of genetic susceptibility undergoing screening
      • a)
        BRCA2 pathogenic variant
      • b)
        BRCA1 pathogenic variant
      • c)
        PALB2 pathogenic variant
      • d)
        Familial pancreatic cancer
      • e)
        Familial atypical multiple mole melanoma syndrome
      • f)
        Peutz-Jeghers syndrome
      • g)
        Ataxia-telangiectasia mutated heterozygotes with first- or second-degree relative with pancreatic cancer
      • h)
        Lynch syndrome with first- or second-degree relative with pancreatic cancer
      • i)
        hereditary pancreatitis
      At what age should screening for pancreatic cancer start?

      Literature search and study selection criteria

      To inform the guideline panel, 2 comprehensive literature searches were performed by a medical librarian using Ovid MEDLINE, EMBASE, and Wiley Cochrane. The searches were limited to English-language articles with animal studies excluded. The searches were divided into 2 broad categories:
      • 1.
        Screening for pancreatic cancer in populations at high risk because of genetic mutations. We identified an existing meta-analysis on this topic
        • Corral J.E.
        • Mareth K.F.
        • Riegert-Johnson D.L.
        • et al.
        Diagnostic yield from screening asymptomatic individuals at high risk for pancreatic cancer: a meta-analysis of cohort studies.
        and performed an updated literature search. We used Ovid MEDLINE and EMBASE from January 2017 through March 2020. We used major search terms and subheadings including “pancreas cancer,” pancreas neoplasm,” “screening,” “population surveillance,” “early detection,” “endoscopic ultrasound,” and “magnetic resonance imaging” (Appendix 1, available online at www.giejournal.org).
      • 2.
        Risk of pancreatic adenocarcinoma among individuals with BRCA1, BRCA2, and PALB2 pathogenic variants. We used Ovid MEDLINE from 1946 and EMBASE from 1988 to December 2019. We used major search terms and subheadings including “BRCA1,” “BRCA2,” “PALB2,” “hereditary breast and ovarian cancer syndrome,” “fanconi anemia,” “pancreas cancer,” pancreas neoplasm,” and “pancreas tumor” (Appendix 1).
      For each PICO question, a literature search for existing systematic reviews and meta-analyses was also performed. If none was identified, a full systematic review and meta-analysis (when possible) was conducted using the recommendations of the Preferred Reporting Items for Systematic Reviews and Meta-analyses criteria.
      • Moher D.
      • Liberati A.
      • Tetzlaff J.
      • et al.
      Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement.
      Citations were imported into EndNote (Thompson Reuters, Philadelphia, Pa, USA), and duplicates were removed. The EndNote library was then uploaded into Covidence (www.covidence.org). Studies were first screened by title and abstract and then by full text by 2 independent reviewers (D.S.F. and R.S.K.), and all conflicts were resolved by consensus. Exclusion criteria for reviewed studies included wrong disease, wrong study population, wrong outcome, or wrong study design. When applicable, available systematic reviews and meta-analyses were updated based on literature review as described above. A total of 36 studies were included as evidence for the guideline.

      Data extraction and statistical analysis

      Data were extracted by 2 independent reviewers (A.H.C. and M.S.S.) using Excel (Microsoft Corporation, Redmond, Wash, USA). The primary estimate of effect was based on a priori identified outcomes of interest. For PICO questions 1 and 2, we used a meta-analysis to generate summary estimates of diagnostic yield, pooled relative risk (RR), odds ratio (OR), or proportions. Heterogeneity was assessed using the I2 and Q statistic. Significant heterogeneity was defined at I2 > 50% and significant P < .05) on the Q statistic. Random-effects models were used for most analyses (if significant heterogeneity was detected); otherwise, fixed-effects models were used. Studies were weighted based on size. Publication bias was assessed using funnel plots. Statistical analyses were performed using Comprehensive Meta Analysis V3 (Biostat Inc, Englewood, NJ, USA).
      For PICO questions 3a and 3b, we used a meta-analysis to generate summary estimates of the RR, OR, or standardized incidence ratio (SIR) of pancreatic cancer overall, by BRCA1 versus BRCA2, male versus female, and by age at cancer diagnosis. We specified a random-effects model using the method of DerSimonian and Laird,
      • DerSimonian R.
      • Laird N.
      Meta-analysis in clinical trials.
      with the estimate of heterogeneity taken from the Mantel-Haenszel model. Our analysis pooled standardized mean differences by the method of Cohen.
      • Cohen J.
      Statistical powel analysis for the behavioral sciences.
      We pooled the RR and OR together, relying on the rare disease assumption that the RR and OR are measuring the same quantity for BRCA1/2-associated pancreatic cancer. We used the pooled estimates of RR and SIR to estimate the cumulative lifetime risk of pancreatic cancer to age 80.

      Panel composition and conflict of interest management

      We assembled an international panel of stakeholders to review evidence and make recommendations. The panel consisted of lead authors (A.H.C., M.S.S.), committee members with expertise in methodology, systematic reviews and meta-analyses (N.C.T. and S.W.), pancreatic cancer screening content experts (M.I.C., R.S.K., E.M.S.), cancer epidemiologist (T.R.), pancreatic cancer surgeon (C.M.V.), radiologist (D.V.S.), oncologists (T.G. and M.H.), cancer geneticist (D.L.R), pediatric gastroenterologist (D.S.F), and committee chair (B.J.Q.). Two patient representatives from the Facing Hereditary Cancer Empowered, an advocacy organization for families facing hereditary cancers, were also included.
      Two virtual meetings were convened on October 3 and October 24, 2020. All panel members were required to disclose potential financial and intellectual conflicts of interest, which were addressed according to ASGE policies set forth in the ASGE Conflict of Interest and Resolution Policy https://www.asge.org/docs/default-source/default-document-library/coi-full-policy-for-asge-and-publications_edd_2-10-20.pdf.

      Certainty in evidence, outcomes, and definitions

      The certainty in the body of evidence (also known as quality of the evidence or confidence in the estimated effects) was assessed using the GRADE framework as previously described (Table 3).
      • Qumseya B.
      • Sultan S.
      • Bain P.
      • et al.
      ASGE Standards of Practice Committee
      ASGE guideline on screening and surveillance of Barrett's esophagus.
      ,
      • Guyatt G.H.
      • Oxman A.D.
      • Vist G.E.
      • et al.
      GRADE: an emerging consensus on rating quality of evidence and strength of recommendations.
      ,
      • Jue T.L.
      • Storm A.C.
      • Naveed M.
      • et al.
      ASGE guideline on the role of endoscopy in the management of benign and malignant gastroduodenal obstruction.
      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. High-risk lesions were defined as pancreatic cancer, high-grade dysplasia, and grade III pancreatic intraepithelial neoplasia (PanIN).
      • Tanaka M.
      • Fernández-Del Castillo C.
      • Kamisawa T.
      • et al.
      Revisions of international consensus Fukuoka guidelines for the management of IPMN of the pancreas.
      • Andea A.
      • Sarkar F.
      • Adsay V.N.
      Clinicopathological correlates of pancreatic intraepithelial neoplasia: a comparative analysis of 82 cases with and 152 cases without pancreatic ductal adenocarcinoma.
      • McCarthy D.M.
      • Brat D.J.
      • Wilentz R.E.
      • et al.
      Pancreatic intraepithelial neoplasia and infiltrating adenocarcinoma: analysis of progression and recurrence by DPC4 immunohistochemical labeling.
      • Basturk O.
      • Hong S.M.
      • Wood L.D.
      • et al.
      A revised classification system and recommendations from the Baltimore consensus meeting for neoplastic precursor lesions in the pancreas.
      Resectable and borderline-resectable pancreatic cancers were defined any T1-3 and N0-2 pancreatic cancer, whereas cancers that were staged T4 or M1 were deemed unresectable. High-risk resectable lesions were defined as resectable and borderline-resectable pancreatic cancers, high-grade dysplasia, and grade III PanIN. Harms were defined as harms from the screening tests (EUS and/or magnetic resonance imaging [MRI]), rates of low-yield pancreatic surgery in the screened population, and rate of adverse events from pancreatic cancer surgery resulting from positive screening tests. Low-yield surgery was defined as surgery that did not yield cancer, high-grade dysplasia, or grade III PanIN. For individuals with BRCA1 and BRCA2 pathogenic variants, we also sought to determine the cumulative lifetime risk of pancreatic cancer and the impact of age, gender, and family history of pancreatic cancer on risk. For the purposes of this document, pancreatic cancer refers to pancreatic ductal adenocarcinoma.
      Table 3Interpretation of the definitions of the strength of recommendation using Grading of Recommendations Assessment, Development and Evaluation framework
      Implications forStrong recommendationConditional recommendation
      PatientsMost individuals in this situation would want the recommended course of action, and only a small proportion would not.Most individuals in this situation would want the suggested course of action, but many would not.
      CliniciansMost individuals should receive the test. Formal decision aids are not likely to be needed to help individual patients make decisions consistent with their values and preferences.Recognize that different choices will be appropriate for individual patients and that you must help each patient arrive at a management decision consistent with his or her values and preferences. Decision aids may be useful in helping individuals to make decisions consistent with their values and preferences.
      PolicymakersThe recommendation can be adopted as policy in most situations. Compliance with this recommendation according to the guideline could be used as a quality criterion or performance indicator.Policymaking will require substantial debate and involvement of various stakeholders.
      Adapted from Andrews et al, 2013.
      • Andrews J.
      • Guatt G.
      • Oxman A.D.
      • et al.
      GRADE guidelines: 14. Going from evidence to recommendations: the significance and presentation of recommendations.

      External review

      The guideline was reviewed by the GIE Editorial Board, Governing Board, and made available for public comment on the ASGE website.

      Results

      For each clinical question, we summarized the results for a priori identified outcomes of interested. Other considerations including cost-effectiveness, patient preferences and acceptability, and equity that are common to more than 1 questions have also been summarized.
      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).
      We performed a systematic review and meta-analysis (Fig. 1) that identified 25 studies for inclusion.
      • Al-Sukhni W.
      • Borgida A.
      • Rothenmund H.
      • et al.
      Screening for pancreatic cancer in a high-risk cohort: an eight-year experience.
      • Borgida A.
      • Holter S.
      • Thomas C.
      • et al.
      Screening individuals at increased risk for pancreatic cancer using biannual contrast MRI.
      • Canto 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.
      • Del Chiaro M.
      • Verbeke C.S.
      • Kartalis N.
      • et al.
      Short-term results of a magnetic resonance imaging-based swedish screening program for individuals at risk for pancreatic cancer.
      • Gangi A.
      • Malafa M.
      • Klapman J.
      Endoscopic ultrasound-based pancreatic cancer screening of high-risk individuals: a prospective observational trial.
      • Harinck 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.
      • Joergensen 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.
      • Kwon R.
      • Dust H.
      • McCarthy S.
      • et al.
      Outcomes of pancreatic cancer surveillance in high risk individuals.
      • Lachter J.
      • Rosenberg C.
      • Hananiya T.
      • et al.
      Screening to detect precursor lesions of pancreatic adenocarcinoma in high-risk individuals: a single-center experience.
      • Langer P.
      • Kann P.H.
      • Fendrich V.
      • et al.
      Five years of prospective screening of high-risk individuals from families with familial pancreatic cancer.
      • Lucas 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.
      • Mocci E.
      • Guillen-Ponce C.
      • Earl J.
      • et al.
      PanGen-Fam: Spanish registry of hereditary pancreatic cancer.
      • Montiel M.F.
      • Quesada P.R.
      • Dunseith M.
      • et al.
      Early outcomes of a high-risk cohort in pancreatic cancer surveillance.
      • Overbeek K.
      • Levink I.
      • Konings I.
      • et al.
      12 Years of prospective pancreatic cancer surveillance: results of the Dutch nationwide program in high-risk individuals.
      • Paiella 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.
      • Poley J.W.
      • Kluijt I.
      • Gouma D.J.
      • et al.
      The yield of first-time endoscopic ultrasonography in screening individuals at a high risk of developing pancreatic cancer.
      • Potjer T.P.
      • Schot I.
      • Langer P.
      • et al.
      Variation in precursor lesions of pancreatic cancer among high-risk groups.
      • Saldia A.
      • Olson S.H.
      • Nunes P.
      • et al.
      Outcome of pancreatic cancer surveillance among high-risk individuals tested for germline mutations in BRCA1 and BRCA2.
      • Sheel A.R.G.
      • Harrison S.
      • Sarantitis I.
      • et al.
      Identification of cystic lesions by secondary screening of familial pancreatic cancer (FPC) kindreds is not associated with the stratified risk of cancer.
      • Vasen H.
      • Ibrahim I.
      • Ponce C.G.
      • 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.
      • Verna E.C.
      • Hwang C.
      • Stevens P.D.
      • et al.
      Pancreatic cancer screening in a prospective cohort of high-risk patients: a comprehensive strategy of imaging and genetics.
      • Barnes C.A.
      • Krzywda E.
      • Lahiff S.
      • et al.
      Development of a high risk pancreatic screening clinic using 3.0 T MRI.
      • Ludwig E.
      • Olson S.H.
      • Bayuga S.
      • et al.
      Feasibility and yield of screening in relatives from familial pancreatic cancer families.
      • Sud A.
      • Wham D.
      • Catalano M.
      • et al.
      Promising outcomes of screening for pancreatic cancer by genetic testing and endoscopic ultrasound.
      • Zubarik R.
      • Gordon S.R.
      • Lidofsky S.D.
      • et al.
      Screening for pancreatic cancer in a high-risk population with serum CA 19-9 and targeted EUS: a feasibility study.
      All studies were conducted in Europe or North America, except 1 conducted in Asia. In aggregate, 3253 patients were enrolled, in whom 70 screen-detected pancreatic cancers were diagnosed. The most common indication for screening was familial pancreatic cancer (FPC), and the most common pathogenic variant noted was BRCA1/2. Considering all outcomes together, the overall quality of evidence was found to be low. A summary of outcomes and their assessment can be seen in Table 4.
      Figure thumbnail gr1
      Figure 1Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) diagram showing the studies included in the systematic review regarding screening for pancreatic cancer in individuals at increased risk of pancreatic cancer because of genetic susceptibility.
      Table 4Evidence profile for question 1: Should individuals at increased risk of pancreatic cancer because of genetic susceptibility undergo screening for pancreatic cancer?
      Certainty assessmentEffectCertaintyImportance
      No. of studiesStudy designRisk of biasInconsistencyIndirectnessImprecisionOther considerationsScreeningNo screeningRelative [95% confidence interval]Absolute [95% confidence interval]
      3-year survival
      1Observational studiesNot seriousNot seriousNot seriousSerious
      Very small number of patients.
      NoneSurvival 85% in screening group vs 25% in patients who stopped screening⊕◯◯◯

      Very low
      Critical
      5-year survival
      2Observational studiesNot seriousNot seriousNot seriousSerious
      Very small number of patients.
      None24% (Vasen et al
      • Vasen H.
      • Ibrahim I.
      • Ponce C.G.
      • 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.
      ) and 60% (Canto et al
      • Canto M.I.
      • Kerdsirichairat T.
      • Yeo C.J.
      • et al.
      Surgical outcomes after pancreatic resection of screening-detected lesions in individuals at high risk for developing pancreatic cancer.
      ) vs 8% from historical cohort (SEER)
      ⊕◯◯◯

      Very low
      Critical
      Cumulative yield of screening for high-risk lesions (pancreatic ductal adenocarcinoma, HGD, PanIN III)
      25Observational studiesNot seriousNot seriousNot seriousNot seriousNoneOverall 3.1% [2.5-4.3]; pancreatic ductal adenocarcinoma 2.7% [1.9-3.6]; HGD .89% [.58-1.4]; PanIN III .82% [.54-1.3]⊕◯◯

      Low
      Critical
      Cumulative yield of high risk lesions that are resectable/borderline-resectable
      25Observational studiesNot seriousNot seriousSeriousNot seriousNoneProportion of screen-detected cancers resectable or borderline-resectable = 68.2% [48.7%-82.9%] vs symptomatic cancers from SEER database resectable or borderline-resectable = 9%.⊕◯◯◯

      Very low
      Critical
      Psychological benefits
      6Observational studiesNot seriousNot seriousNot seriousNot seriousNoneOverall positive psychological impact. Cancer worry decreased significantly. Lower perceived risk of cancer even when lesions detected. Reduction in negative emotional consequences of psychological consequences questionnaire at 1 year⊕⊕◯◯

      Low
      Important
      Harms: Adverse outcomes from EUS or MRI
      22Observational studiesNot seriousNot seriousNot seriousNot seriousNoneNo adverse outcomes from screening EUS or MRI reported by 6/25 screening studies. External literature: diagnostic EUS <1%, EUS with FNA 2% adverse outcome rate

      MRI: claustrophobia 2%, very rare allergic reaction or nephrogenic systemic fibrosis
      ⊕⊕◯◯

      Low
      Important
      Harms: Surgery for low-yield lesions
      22Observational studiesNot seriousNot seriousNot seriousNot seriousNoneProportion of patient screened who underwent low-yield surgery = 2.8% [1.9-4.1]

      Proportion of all pancreatic surgeries that were low yield = 46.6% [34.1-59.4]
      ⊕⊕◯◯

      Low
      Important
      Harms: Adverse outcomes from surgery
      8Observational studiesNot seriousNot seriousNot seriousSerious
      Very small number of patients.
      NoneAdverse outcomes from surgery among all screened 1.5% [.6-3.6]

      Adverse outcomes from surgery among those undergoing surgery 19.9% [7.4-43.4]
      ⊕◯◯◯

      Very low
      Important
      SEER, Surveillance, Epidemiology, and End Results Program; HGD, high-grade dysplasia; MRI, magnetic resonance imaging; PanIN III, grade III pancreatic intraepithelial neoplasia.
      Very small number of patients.

      All-cause mortality

      For the outcome of all-cause mortality, we identified 2 studies from our systematic review that reported this outcome. In 1 study, 14 pancreatic cancers were found among a cohort of 354 high-risk individuals screened and followed for a median of 5.6 years.
      • Canto 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.
      Of the 10 screen-detected cancers, 9 were surgically resectable stage 1 or 2 cancers and 1 was metastatic cancer. Four patients were diagnosed with pancreatic cancer because of symptoms after stopping screening, of which 3 were metastatic. The 3-year survival was significantly higher in the screen-detected cancers when compared with symptomatic cancers (85% vs 25%).
      • Canto 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.
      Overall, for screen-detected pancreatic cancers, the 1- and 5-year survival rates were 90% and 60%, the latter of which is substantially better than reported for the general population within the Surveillance, Epidemiology, and End Results Program (SEER) database (8.9%).
      • Canto M.I.
      • Kerdsirichairat T.
      • Yeo C.J.
      • et al.
      Surgical outcomes after pancreatic resection of screening-detected lesions in individuals at high risk for developing pancreatic cancer.
      In a second study by Vasen et al,
      • Vasen H.
      • Ibrahim I.
      • Ponce C.G.
      • 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.
      among 411 high-risk individuals who underwent screening at 3 European centers, 75% of the screen-detected cancers were eligible for surgical resection and patients had a 5-year survival rate of 24%, outcomes that were substantially better than in historic control subjects.
      • Vasen H.
      • Ibrahim I.
      • Ponce C.G.
      • 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.
      While assessing the certainty of evidence, we rated down the evidence for imprecision because of small number of studies and patients and overall judged the quality of evidence to be very low. Our literature search resulted in no studies to inform the outcome of pancreatic cancer–related mortality in screen-detected pancreatic cancer.

      Yield of screening for high-risk lesions

      Our literature search identified 25 studies that assessed the yield of screening for patients with genetic susceptibility to pancreatic cancer. Screening results were stratified by yield of first-time screening and cumulative yield of screening, which included yield of all reported rounds of screening. In aggregate, studies included 3253 patients who underwent pancreatic cancer screening. Of these, 88 patients were found to have high-risk lesions on screening, including 10 with high-grade dysplasia, 11 with grade III PanIN, and 70 with pancreatic cancer. The cumulative yield of screening for high-risk lesions was 3.1% (95% confidence interval [CI], 2.2%-4.3%; P = .02 and I2 = 40.5) (Fig. 2). Detection of specific lesions was as follows: pancreatic cancer, 2.7% (95% CI, 2.0%-3.6%; P = .10 and I2 = 27.6%) (Fig. 3); high-grade dysplasia, .9% (95% CI, .6%-1.4%; P = .95 and I2 = .0); grade III PanIN lesions, .8% (95% CI, .5%-1.3%; P = .99 and I2 = .0). The yield of first-time screening for high-risk lesions was 1.9% (95% CI, 1.3%-2.6%; P = .10 and I2 = 28.7). The quality of evidence was judged to be low.
      Figure thumbnail gr2
      Figure 2Forest plot of the 25 studies showing the cumulative yield (ie, pancreatic cancer, high-grade dysplasia, grade III pancreatic intraepithelial neoplasia) of screening in individuals at increased risk of pancreatic cancer because of genetic susceptibility. CI, Confidence interval; MRI, magnetic resonance imaging.
      Figure thumbnail gr3
      Figure 3Forest plot of the 25 studies showing the cumulative yield of pancreatic cancer screening in individuals at increased risk of pancreatic cancer because of genetic susceptibility. PDAC, Pancreatic ductal adenocarcinoma; CI, confidence interval; MRI, magnetic resonance imaging.

      Yield of screening for resectable and borderline-resectable lesions

      The yield of screening for high-risk resectable lesions (defined as resectable or borderline-resectable pancreatic cancer, high-grade dysplasia, or grade III PanIN) was 2.1% (95% CI, 1.4%-3.1%; P = .007 and I2 = 45.6 (Fig. 4). The yield of screening for resectable or borderline-resectable pancreatic cancer was 1.9% (95% CI, 1.3%-2.7%; P = .11 and I2 = 26.7). The proportion of screen-detected cancers that were resectable or borderline-resectable was 60% (95% CI, 43.7%-74.4%; P = .51 and I2 = .0) (Fig. 5). Among cancers diagnosed within the SEER database, 9% were categorized as resectable, 10% borderline-resectable, and 80% unresectable at diagnosis.
      • Corral J.E.
      • Das A.
      • Bruno M.J.
      • et al.
      Cost-effectiveness of pancreatic cancer surveillance in high-risk individuals: an economic analysis.
      We rated the evidence down for indirectness, and therefore the quality of evidence was judged to be very low.
      Figure thumbnail gr4
      Figure 4Forest plot of the 24 studies showing the cumulative yield of resectable or borderline-resectable high-risk lesions (defined as resectable or borderline-resectable pancreatic cancer, high-grade dysplasia, or grade III pancreatic intraepithelial neoplasia) in screening in individuals at increased risk of pancreatic cancer because of genetic susceptibility. CI, Confidence interval; MRI, magnetic resonance imaging.
      Figure thumbnail gr5
      Figure 5Forest plot of the 12 studies showing the proportion of screen-detected pancreatic cancers that are resectable or borderline-resectable. PDAC, Pancreatic ductal adenocarcinoma; CI, confidence interval; MRI, magnetic resonance imaging.

      Psychological benefits of screening

      To assess the psychological impacts of pancreatic cancer screening, we used an existing systematic review by Cazacu et al
      • Cazacu 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.
      that included cross-sectional and prospective studies. Among high-risk individuals, screening was associated with positive psychological benefits. Screening participants had low-to-moderate levels of pancreatic cancer–related distress at the start that improved significantly over time. Participants rated their risk of developing pancreatic cancer significantly lower when they underwent annual screening than when they did not. One study showed a slight increase in cancer worry at a 1-year assessment that was associated with an elevated perceived risk of developing cancer and having a family member affected by pancreatic cancer before age 50 years.
      • Konings I.C.
      • Harinck F.
      • Kuenen M.A.
      • et al.
      Factors associated with cancer worries in individuals participating in annual pancreatic cancer surveillance.
      In 1 study measuring general quality of life, there was a significant reduction in the negative emotional scores at the 1-year postscreening.
      • Mckay S.
      • Gunasingam N.
      • Meiser B.
      • et al.
      Pancreatic cancer screening in high risk individuals does not have negative psychological impact in the short or long term.
      A study by O’Neill et al,
      • O'Neill R.S.
      • Meiser B.
      • Emmanuel S.
      • et al.
      Long-term positive psychological outcomes in an Australian pancreatic cancer screening program.
      published after the Cazacu et al systematic review, assessed participants of the national Australian pancreatic screening program and found positive psychological benefits at the 1-year postintervention, irrespective of screening result. No negative impact of screening was noted. The study reported improvements in the impact of events scale, psychological consequences questionnaire, and the cancer worry scale. While assessing the certainty of evidence of this outcome using the GRADE approach, we judged the quality of evidence to be low.

      Harms from screening

      We categorized harms from pancreatic cancer screening into adverse outcomes from screening tests (EUS and MRI), low-yield surgery as a result of positive screening results, and adverse events from pancreatic surgery performed for positive screening results.

      Adverse events from screening tests EUS and MRI

      For this outcome, we identified 6 studies from our systematic review that specifically reported on adverse events from EUS and MRI.
      • Joergensen 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.
      ,
      • Lachter J.
      • Rosenberg C.
      • Hananiya T.
      • et al.
      Screening to detect precursor lesions of pancreatic adenocarcinoma in high-risk individuals: a single-center experience.
      ,
      • Lucas 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.
      ,
      • Mocci E.
      • Guillen-Ponce C.
      • Earl J.
      • et al.
      PanGen-Fam: Spanish registry of hereditary pancreatic cancer.
      ,
      • Poley J.W.
      • Kluijt I.
      • Gouma D.J.
      • et al.
      The yield of first-time endoscopic ultrasonography in screening individuals at a high risk of developing pancreatic cancer.
      ,
      • Verna E.C.
      • Hwang C.
      • Stevens P.D.
      • et al.
      Pancreatic cancer screening in a prospective cohort of high-risk patients: a comprehensive strategy of imaging and genetics.
      No adverse events from EUS or MRI were noted among the 350 participants included in these 6 studies. Generally, harms from MRI are very uncommon and mostly limited to allergic reactions from intravenous contrast.
      • Dillman J.R.
      • Ellis J.H.
      • Cohan R.H.
      • et al.
      Frequency and severity of acute allergic-like reactions to gadolinium-containing i.v. contrast media in children and adults.
      Approximately 2% of patients experience claustrophobia in the scanner, necessitating intervention.
      • Dewey M.
      • Schink T.
      • Dewey C.F.
      Claustrophobia during magnetic resonance imaging: cohort study in over 55,000 patients.
      Implanted devices, metallic foreign bodies, pregnancy, and hemodynamic instability are all relative contraindications to MRI. Adverse events from diagnostic EUS are uncommon and occur in less than 1% of patients.
      • Jenssen C.
      • Alvarez-Sánchez M.V.
      • Napoléon B.
      • et al.
      Diagnostic endoscopic ultrasonography: assessment of safety and prevention of complications.
      In a study of 355 patients who underwent EUS with FNA for a solid pancreatic mass, adverse events were reported in 2.5% of patients, with 2% needing hospitalization.
      • Eloubeidi M.A.
      • Tamhane A.
      • Varadarajulu S.
      • et al.
      Frequency of major complications after EUS-guided FNA of solid pancreatic masses: a prospective evaluation.
      Adverse events included acute pancreatitis (n = 3), abdominal pain (n = 3), fever (n = 2), and sedation-related hypoxia (n = 1).

      Low-yield surgeries

      We defined low-yield surgeries as those where surgical pathology did not show pancreatic cancer, high-grade dysplasia, or grade III PanIN. In most such cases, pathology showed low-grade intraductal papillary mucinous neoplasms (IPMNs) or PanIN lesions. Low-grade pancreatic lesions can be safely managed with surveillance.
      • Tanaka M.
      • Fernández-Del Castillo C.
      • Kamisawa T.
      • et al.
      Revisions of international consensus Fukuoka guidelines for the management of IPMN of the pancreas.
      Therefore, we surmised that such surgeries constituted a potential harm. Patients in whom surgical pathology showed neuroendocrine tumors were excluded from this analysis because optimal management of these lesions remains controversial.
      • Falconi M.
      • Bartsch D.K.
      • Eriksson B.
      • et al.
      ENETS Consensus Guidelines for the management of patients with digestive neuroendocrine neoplasms of the digestive system: well-differentiated pancreatic non-functioning tumors.
      ,
      • Shah M.H.
      • Goldner W.S.
      • Benson A.B.
      • et al.
      Neuroendocrine and adrenal tumors, version 2.2021. NCCN Clinical Practice Guidelines in Oncology.
      For this outcome, we identified 22 studies from our meta-analysis that reported the rate of low-yield surgery. On meta-analysis using random-effects modeling, the pooled rate of low-yield surgery was 2.8% (95% CI, 1.9%-4.1%; P = .003 and I2 = 51.4) of the total screened population. Among all patients who had pancreatic surgery as a result of screening (n = 181), the pooled proportion of low-yield surgery was 46.6% (95% CI, 34.2%-59.4%; P = .15 and I2 = 26.2) (Fig. 6). Our findings are similar to those reported in a meta-analysis by Paiella et al
      • Paiella S.
      • Salvia R.
      • De Pastena M.
      • et al.
      Screening/surveillance programs for pancreatic cancer in familial high-risk individuals: a systematic review and proportion meta-analysis of screening results.
      where 6% of a pancreatic cancer screening population underwent surgery, of which 68.1% (95% CI, 59.5%-76.7%) were considered low yield.
      Figure thumbnail gr6
      Figure 6Forest plot of the 22 studies showing the proportion of patients screened who undergo low-yield surgery. CI, Confidence interval; MRI, magnetic resonance imaging.

      Adverse events from pancreatic surgery

      We identified 6 studies that reported adverse events from pancreatic surgery in patients undergoing screening. Three studies that included 13 pancreatic surgeries reported no adverse events.
      • Lachter J.
      • Rosenberg C.
      • Hananiya T.
      • et al.
      Screening to detect precursor lesions of pancreatic adenocarcinoma in high-risk individuals: a single-center experience.
      ,
      • Paiella 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.
      ,
      • Verna E.C.
      • Hwang C.
      • Stevens P.D.
      • et al.
      Pancreatic cancer screening in a prospective cohort of high-risk patients: a comprehensive strategy of imaging and genetics.
      Langer et al
      • Langer P.
      • Kann P.H.
      • Fendrich V.
      • et al.
      Five years of prospective screening of high-risk individuals from families with familial pancreatic cancer.
      reported on 7 pancreatic surgeries resulting in 4 adverse events (fistulae, postoperative diabetes, and hernia), Joergensen et al
      • Joergensen 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.
      reported on 2 pancreatic surgeries resulting in 2 adverse events (hepaticojejunostomy stricture with cholangitis and a “nonfatal complication”), and Canto et al
      • Canto 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.
      reported on surgeries in 48 patients with 17 patients developing adverse events (fistulae, surgical site infections, cholangitis, diabetes, delayed gastric emptying, and malabsorption). When a meta-analysis was performed, adverse events were noted in 19.9% of surgeries (95% CI, 7.4%-43.4%; P = .05 and I2 = 49.7). Among all patients undergoing screening, surgical adverse events were noted in 1.5% (95% CI, .6%-3.6%; P = .01 and I2 = 61.4) of the screening population. While assessing the certainty of evidence of these 3 outcomes using a GRADE approach, we judged the quality of evidence to be low.

      Other considerations

      Patient values

      We did not find any studies that compared patients undergoing screening with those who refused or were not offered participation in a screening program. Several studies found that diagnosing cancer at an early stage and contributing to scientific research were the most common motivations among patients to consider screening.
      • Lewis Z.K.
      • Frost C.J.
      • Venne V.L.
      Pancreatic cancer surveillance among high-risk populations: knowledge and intent.
      • Konings I.C.
      • Sidharta G.N.
      • Harinck F.
      • et al.
      Repeated participation in pancreatic cancer surveillance by high-risk individuals imposes low psychological burden.
      • Harinck F.
      • Nagtegaal T.
      • Kluijt I.
      • et al.
      Feasibility of a pancreatic cancer surveillance program from a psychological point of view.
      One study found that 88% of participants concluded that the advantages of screening outweighed disadvantages and 54% reported a lower personal risk of developing pancreatic cancer by participating in a screening program.
      • Harinck F.
      • Nagtegaal T.
      • Kluijt I.
      • et al.
      Feasibility of a pancreatic cancer surveillance program from a psychological point of view.
      Another study found that despite a desire for knowledge, most patients only had a limited understanding of pancreatic cancer screening.
      • Lewis Z.K.
      • Frost C.J.
      • Venne V.L.
      Pancreatic cancer surveillance among high-risk populations: knowledge and intent.
      This study also found that having a family history of cancer increased motivation to participate in screening. During panel discussions, patient representatives stated that providers rarely discussed pancreatic cancer risks with high-risk individuals, and most were unaware of any screening options.

      Cost-effectiveness of screening

      We performed a literature review to assess cost-effectiveness of pancreatic cancer screening. Corral et al
      • Corral J.E.
      • Das A.
      • Bruno M.J.
      • et al.
      Cost-effectiveness of pancreatic cancer surveillance in high-risk individuals: an economic analysis.
      used a Markov model to compare screening with no screening in high-risk individuals, defined as those with lifetime risk >5% or relative risk >5-fold for pancreatic cancer. Screening was found to be cost-effective for high-risk individuals between the ages of 40 and 76 years. Kowada
      • Kowada A.
      Cost-effectiveness of abdominal ultrasound versus magnetic resonance imaging for pancreatic cancer screening in familial high-risk individuals in Japan.
      reported on a cost-effectiveness study using a Markov model and found that no screening was the most expensive strategy with minimal benefits. Joergensen et al
      • Joergensen 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.
      used data from a Danish pancreatic cancer surveillance program on patients with FPC and hereditary pancreatitis and found yearly EUS to be a cost-effective strategy. In a cost-analysis, Bruenderman et al
      • Bruenderman E.
      • Martin 2nd, R.C.
      A cost analysis of a pancreatic cancer screening protocol in high-risk populations.
      found biannual screening using MRI for patients with Peutz-Jehgers syndrome, hereditary pancreatitis, FPC, p16-Leiden mutations, and new-onset diabetes over age 50 years to be “affordable.” Using a Markov model, Pandharipande et al
      • Pandharipande P.V.
      • Heberle C.
      • Dowling E.C.
      • et al.
      Targeted screening of individuals at high risk for pancreatic cancer: results of a simulation model.
      found that a 1-time MRI screening performed at age 50 years resulted in life expectancy gains for men with >2.4 times and women with >2.7 increased risk for pancreatic cancer. Of note, this model found that benefit was derived predominantly from the detection of cystic precursors and, to a lesser extent, early pancreatic ductal adenocarcinoma. In another disease simulation model, Pandharipande et al
      • Pandharipande P.V.
      • Jeon A.
      • Heberle C.R.
      • et al.
      Screening for pancreatic adenocarcinoma in BRCA2 mutation carriers: results of a disease simulation model.
      focused on BRCA2 patients and found that a 1-time screening resulted in only a small increase in life expectancy, whereas annual screening resulted in a decrease in life expectancy because of false-positive tests results. This model did not report on EUS or combined EUS and MRI screening strategy and assigned a lower RR for pancreatic cancer to BRCA2 patients than noted in our meta-analysis (3.5 vs 5.1). We did not review the analysis by Rulyak and Brentnall
      • Rulyak S.J.
      • Brentnall T.A.
      Inherited pancreatic cancer: surveillance and treatment strategies for affected families.
      or Rubenstein et al
      • Rubenstein J.H.
      • Scheiman J.M.
      • Anderson M.A.
      A clinical and economic evaluation of endoscopic ultrasound for patients at risk for familial pancreatic adenocarcinoma.
      because these were performed using data from >10 years ago. During discussion, our panel noted significant variability in cost of screening based on geographic location, practice setting, and type of insurance.

      Discussion

      The panel discussed the 25 studies from the systematic review and highlighted limitations regarding heterogeneity in patient population, screening protocols, outcomes ascertained, and result reporting. Panel members agreed that resectable or borderline-resectable pancreatic cancers were potentially curable and therefore appropriate targets for screening. Of note, previous guidelines had considered only stage 1 pancreatic cancer to be the primary target for screening.
      • Canto M.I.
      • Harinck F.
      • Hruban R.H.
      • et al.
      International Cancer of the Pancreas Screening (CAPS) Consortium summit on the management of patients with increased risk for familial pancreatic cancer.
      ,
      • Goggins 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.
      Our present definition of resectable or borderline-resectable pancreatic cancer (T1-3 and/or N0-2) may underestimate the positive impact of screening because some patients with even locally unresectable cancer like T4 cancers may be downstaged with chemoradiation therapy to allow for surgical resection. Surgical treatment may also be beneficial for selected patients with oligometastatic cancers.
      The panel questioned whether surgical resections for precursors lesions like low-grade IPMN should be categorized as a harm of screening. Some panelists stated that in selected young patients, given their long life expectancy, resection of even low-grade IPMNs may be appropriate to prevent malignant transformation in the future. The panel suggested an alternative approach to categorizing surgery based on surgical pathology findings: high-yield surgery: cancer, high-grade IPMN, or high-grade PanIN; intermediate-yield surgery: precancerous precursors like IPMN or PanIN lesions other than high-grade lesions; and low-yield surgery: non-neoplastic lesions like serous cystadenoma or pseudocysts. The panel also recommended that harms of screening should include failure of screening, recognizing that this was not reported in most studies.
      The panel noted that a significant number of low-yield surgeries were performed for pancreatic cysts and suggested that the low accuracy of preoperative tests in distinguishing between malignant and benign pancreatic cysts may explain several low-yield surgeries.
      • Sahora K.
      • Mino-Kenudson M.
      • Brugge W.
      • et al.
      Branch duct intraductal papillary mucinous neoplasms: Does cyst size change the tip of the scale? A critical analysis of the revised international consensus guidelines in a large single-institutional series.
      ,
      • Wu J.
      • Wang Y.
      • Li Z.
      • et al.
      Accuracy of Fukuoka and American Gastroenterological Association guidelines for predicting advanced neoplasia in pancreatic cyst neoplasm: a meta-analysis.
      Furthermore, in previous years even small branch-duct IPMNs were believed to have significant malignant potential in high-risk individuals, and surgery for such patients was recommended.
      • Canto M.I.
      • Harinck F.
      • Hruban R.H.
      • et al.
      International Cancer of the Pancreas Screening (CAPS) Consortium summit on the management of patients with increased risk for familial pancreatic cancer.
      Although the natural history of small IPMNs in high-risk individuals is still not fully understood, there is now growing consensus that individuals with genetic susceptibility to pancreatic cancer with IPMN should undergo pancreatic resection for broadly the same indications as average-risk individuals, and surgery for branch-duct IPMNs based on size alone is no longer recommended.
      • Goggins 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.
      Question 2: Should individuals at increased risk of pancreatic cancer because of genetic susceptibility undergo screening with EUS or with 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).
      We used the same systematic review from question 1 to inform this question. Of the 25 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. Considering all outcomes together, the overall quality of evidence was judged to be low. A summary of outcomes and their assessment can be seen in Table 5.
      Table 5Evidence profile for question 2: Should individuals at increased risk of pancreatic cancer because of genetic susceptibility undergo screening with EUS or MRI?
      Certainty assessmentEffectCertaintyImportance
      No. of studiesStudy designRisk of biasInconsistencyIndirectnessImprecisionOther considerationsCombined EUS-MRI vs. MRI vs. EUSRelative [95% confidence interval]Absolute [95% confidence interval]
      Cumulative yield for high-risk lesions (pancreatic ductal adenocarcinoma, high-grade dysplasia, grade III pancreatic intraepithelial neoplasia)
      25Observational studiesNot seriousNot seriousNot seriousNot seriousNoneCombined 3.1% [2.3-4.3] vs MRI 2.4% [1.0-5.4] vs EUS 4.0% [1.7-9.1]⊕⊕◯◯

      Low
      Critical
      Cumulative yield of pancreatic ductal adenocarcinoma
      25Observational studiesNot seriousNot seriousNot seriousNot seriousNoneCombined 2.6% [1.9-3.6] vs MRI 2.1% [.77-5.4] vs EUS 3.9% [1.7-8.5]⊕⊕◯◯

      Low
      Critical
      Cumulative yield of resectable/borderline-resectable high-risk lesions
      25Observational studiesNot seriousNot seriousNot seriousSerious
      Few people with high-risk lesions.
      NoneCombined 1.7% [1.0-2.9] vs MRI 1.8% [.77-4.0] vs EUS 3.9% [1.7-8.5]⊕◯◯◯

      Very low
      Critical
      MRI, Magnetic resonance imaging.
      Few people with high-risk lesions.

      Yield of screening for high-risk lesions

      The overall 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) in studies using only EUS, 2.4% (95% CI, 1.0%-5.4; P = .21 , I2 = 31.0) in studies using only MRI, and 3.1% (95% CI, 2.1%-4.6%; P = .022, I2 = 48.4) in studies that using a combination of EUS and MRI (Fig. 2). The yield of screening for pancreatic cancer was 3.9% (95% CI, 1.7%-8.5%; P = .18, I2 = 34.4) for studies using only EUS, 2.1% (95% CI, .8%-5.4%; P = .16, I2 = 39.7) for studies using only MRI, and 2.6% (95% CI, 1.9%-3.6%; P = .19, I2 = 24.3) for studies using a combination of EUS and MRI (Fig. 3). While assessing the certainty of evidence of this outcome using the GRADE approach, we judged the quality of evidence to be low.

      Yield of screening for high-risk resectable lesions

      Yield of screening for high-risk resectable lesions was 3.9% (95% CI, 1.7%-8.5%; P = .18, I2 = 34.4) for studies using only EUS, 1.8% (95% CI, .8%-4.0%; P = .38, I2 = 5.4) for studies using only MRI, and 1.7% (95% CI, 1.0%-3.0%; P = .006, I2 = 55.9) for studies using a combination of EUS and MRI (Fig. 4). While assessing the certainty of evidence, we rated down evidence for imprecision and overall judged the quality of evidence to be very low.

      Harms

      See Harms from screening under question 1, above.

      Other considerations

      Patient preferences

      We performed a literature review to assess the role of patient preferences in pancreatic cancer screening of high-risk populations. Harinck et al
      • Harinck F.
      • Nagtegaal T.
      • Kluijt I.
      • et al.
      Feasibility of a pancreatic cancer surveillance program from a psychological point of view.
      surveyed participants of the Dutch pancreatic cancer surveillance study of whom nearly 96% had undergone both EUS and MRI. Four percent did not undergone MRI because of claustrophobia or metallic foreign body. There was no significant difference between patient preference for EUS or MRI, with 10% reporting EUS to extremely uncomfortable, mostly because the sedation-related experience, and 11% reporting MRI to be extremely uncomfortable, predominantly because of claustrophobia. In a follow-up study, Konings et al
      • Konings I.C.
      • Sidharta G.N.
      • Harinck F.
      • et al.
      Repeated participation in pancreatic cancer surveillance by high-risk individuals imposes low psychological burden.
      reported that 10% of respondents continued to report MRI and 11% report EUS as uncomfortable. Only 3% of respondents “dreaded” their first MRI compared with 34% their first EUS. However, after having undergone the procedure, the percentage of respondents dreading their next EUS dropped significantly and to the same level as that of MRI (6%-9% vs 0%-8%, respectively). Another study found that patient motivation to undergo a particular screening test was related to whether the test was recommended by a physician, cost, degree of invasiveness, and comfort level.
      • Lewis Z.K.
      • Frost C.J.
      • Venne V.L.
      Pancreatic cancer surveillance among high-risk populations: knowledge and intent.
      Interestingly, those participants who had a family history of pancreatic cancer or a personal history of other cancers often preferred the more invasive screening techniques, believing that such tests were able to provide more accurate results. During the panel discussion, 1 patient representative noted that some patients may prefer MRI because it is noninvasive and does not require sedation, whereas others may prefer EUS because it is a “1 and done” procedure.

      Cost-effectiveness

      Corral et al
      • Corral J.E.
      • Das A.
      • Bruno M.J.
      • et al.
      Cost-effectiveness of pancreatic cancer surveillance in high-risk individuals: an economic analysis.
      used a Markov model to compare MRI with EUS for screening high-risk individuals (see Cost-effectiveness of screening under question 1, above). They found MRI was the dominant strategy for individuals who had a 5- to 20-fold increased risk of pancreatic cancer. EUS was the dominant strategy for those who had a >20-fold increased risk of pancreatic cancer or if the cost of MRI exceeded $1600. Of note, this study did not analyze combining MRI and EUS for screening. Kowada
      • Kowada A.
      Cost-effectiveness of abdominal ultrasound versus magnetic resonance imaging for pancreatic cancer screening in familial high-risk individuals in Japan.
      reported on a Markov model comparing cost-effectiveness of abdominal US, MRI, EUS, CT, and positron emission tomography for pancreatic cancer screening in familial high-risk individuals in Japan. Unexpectedly, this model found abdominal US to be the most cost-effective imaging modality for pancreatic cancer screening. Furthermore, unlike the Corral et al model, when the incidence of pancreatic cancer increased, MRI and not EUS became the dominant strategy. EUS was most cost-effective when the incidence of pancreatic cancer was between .008 and .016. The reason for divergent results noted in these 2 studies is not known.

      Discussion

      Previous studies and guidelines have found that abdominal US, CT, and ERCP are suboptimal for screening and have recommended that EUS and/or MRI should be used for pancreatic cancer screening.
      • Goggins 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.
      ,
      • Syngal S.
      • Brand R.E.
      • Church J.M.
      • et al.
      ACG clinical guideline: genetic testing and management of hereditary gastrointestinal cancer syndromes.
      • Săftoiu 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.
      • Daly 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.
      • Canto M.I.
      • Goggins M.
      • Hruban R.H.
      • et al.
      Screening for early pancreatic neoplasia in high-risk individuals: a prospective controlled study.
      • Burk K.S.
      • Lo G.C.
      • Gee M.S.
      • et al.
      Imaging and screening of pancreatic cancer.
      When EUS is used for screening, using a linear-array echoendoscope may be preferred over a radial echoendoscope. In a randomized controlled study of 278 high-risk individuals undergoing pancreatic cancer screening, EUS using a linear-array echoendoscope detected more pancreatic lesions than a radial echoendoscope (82% vs 67%, respectively; P < .001).
      • Shin 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.
      Interestingly, in this tandem study, expert endosonographers missed 17.5% of pancreatic lesions during the first examination of the pancreas. A structured approach to EUS examination of the pancreas, perhaps similar to examining the right-sided colon segment twice during screening colonoscopy, may improve lesion detection.
      • Cohen J.
      • Grunwald D.
      • Grossberg L.B.
      • et al.
      The effect of right colon retroflexion on adenoma detection: a systematic review and meta-analysis.
      When MRI is used for screening, a contrast-enhanced examination using intravenous agents such as gadolinium chelate is preferred. For MRI acquisition, a minimum 1.5-T magnet should be applied using phased-array coils to maximize the signal-to-noise ratio. A 3-T magnet may have an additional advantage in detection of small pancreatic lesions because of superior soft-tissue resolution. A typical protocol should include a (1) breath-hold 2-dimensional axial in- and out-of-phase T1-weighted gradient-recalled echo sequence, (2) axial and coronal single-shot fast spin-echo breath-hold T2-weighted acquisition, (3) T2-weighted 2-dimensional and/or 3-dimensional T2-weighted MRCP, and (4) breath-hold or respiratory navigated, dynamic 3-dimensional fat-suppressed T1-weighted spoiled gradient-recalled echo axial MR images through the pancreas before and after administration of intravenous gadolinium chelate contrast.
      • Barnes C.A.
      • Krzywda E.
      • Lahiff S.
      • et al.
      Development of a high risk pancreatic screening clinic using 3.0 T MRI.
      ,
      • Burk K.S.
      • Lo G.C.
      • Gee M.S.
      • et al.
      Imaging and screening of pancreatic cancer.
      The findings of early pancreatic cancer may be subtle, especially on noncontrast imaging, and may be seen best on enhanced 3-dimensional, T1-weighted, gradient-recalled echo sequences.
      • Barnes C.A.
      • Krzywda E.
      • Lahiff S.
      • et al.
      Development of a high risk pancreatic screening clinic using 3.0 T MRI.
      ,
      • Corrias G.
      • Raeside M.C.
      • Agostini A.
      • et al.
      Pilot study of rapid MR pancreas screening for patients with BRCA mutation.
      Question 3a: Should individuals with the BRCA2 pathogenic variant undergo screening for pancreatic cancer?
      Recommendation 3a. In individuals with the BRCA2 pathogenic variant, we suggest screening for pancreatic cancer compared with no screening (conditional recommendation, very low quality of evidence).
      In conjunction with an expert biostatistician and cancer epidemiologist (T.R.), we conducted a systematic review of risk of pancreatic cancer in individuals with the BRCA1 and BRCA2 pathogenic variant that resulted in 11 studies (n = 62,269) for our meta-analysis (Fig. 7).
      • Easton D.
      Cancer risks in BRCA2 mutation carriers: the breast cancer linkage consortium.
      • Thompson D.
      • Easton D.F.
      Cancer incidence in BRCA1 mutation carriers.
      • Brose M.S.
      • Rebbeck T.R.
      • Calzone K.A.
      • et al.
      Cancer risk estimates for BCRA1 mutation carriers identified in a risk evaluation program.
      • Van Asperen C.J.
      • Brohet R.M.
      • Meijers-Heijboer E.J.
      • et al.
      Cancer risks in BRCA2 families: estimates for sites other than breast and ovary.
      • Risch H.A.
      • McLaughlin J.R.
      • Cole D.E.C.
      • et al.
      Population BRCA1 and BRCA2 mutation frequencies and cancer penetrances: a kin-cohort study in Ontario, Canada.
      • Moran A.
      • O'Hara C.
      • Khan S.
      • et al.
      Risk of cancer other than breast or ovarian in individuals with BRCA1 and BRCA2 mutations.
      • Hu C.
      • Hart S.N.
      • Polley E.C.
      • et al.
      Association between inherited germline mutations in cancer predisposition genes and risk of pancreatic cancer.
      • Iqbal J.
      • Ragone A.
      • Lubinski J.
      • et al.
      The incidence of pancreatic cancer in BRCA1 and BRCA2 mutation carriers.
      • Mocci E.
      • Milne R.L.
      • Mendez-Villamil E.Y.
      • et al.
      Risk of pancreatic cancer in breast cancer families from the breast cancer family registry.
      • Mersch J.
      • Jackson M.A.
      • Park M.
      • et al.
      Cancers associated with BRCA1 and BRCA2 mutations other than breast and ovarian.
      • Hu C.
      • LaDuca H.
      • Shimelis H.
      • et al.
      Multigene hereditary cancer panels reveal high-risk pancreatic cancer susceptibility genes.
      No articles were excluded because of poor data quality or inadequate analyses. Estimates were generally made using small numbers of pancreatic cancer cases with BRCA1/2 pathogenic variants (often <10 per group), as reflected in the CIs of the estimates. A summary of outcomes and their assessment can be seen in Table 6.
      Figure thumbnail gr7
      Figure 7Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) diagram showing the studies included in the systematic review regarding risk of pancreatic cancer in individuals with BRCA2 and BRCA1 pathogenic variants.
      Table 6Evidence profile for question 3a: Should individuals with the BRCA2 pathogenic variant undergo screening for pancreatic cancer?
      Certainty assessmentEffectCertaintyImportance
      No. of studiesStudy designRisk of biasInconsistencyIndirectnessImprecisionOther considerationsScreeningNo screeningRelative [95% confidence interval]Absolute [95% confidence interval]
      BRCA2: Lifetime relative risk of PDAC
      5Observational studiesNot seriousNot seriousNot seriousNot seriousNoneRelative risk 5.1 [3.9-6.3]

      Absolute lifetime risk of PDAC 5.2%
      ⊕⊕◯◯

      Low
      Critical
      BRCA2: Lifetime SIR of PDAC
      3Observational studiesNot seriousNot seriousNot seriousSerious
      Few cancer outcomes.
      NoneSIR 7.2 [1.5-13.0]

      Absolute lifetime risk of PDAC 7.4%
      ⊕◯◯◯

      Very low
      Critical
      Cumulative yield of screening for high-risk lesions (BRCA1/2)
      8Observational studiesNot seriousNot seriousNot seriousSerious
      Few cancer outcomes.
      None8.6% [4.5-16.0]⊕◯◯◯

      Very low
      Critical
      PDAC, Pancreatic ductal adenocarcinoma; SIR, standardized incidence ratio.
      Few cancer outcomes.

      Lifetime risk of pancreatic cancer

      For the outcome of lifetime RR of pancreatic cancer in individuals with the BRCA2 pathogenic variant, we included 5 studies in our meta-analysis.
      • Easton D.
      Cancer risks in BRCA2 mutation carriers: the breast cancer linkage consortium.
      ,
      • Van Asperen C.J.
      • Brohet R.M.
      • Meijers-Heijboer E.J.
      • et al.
      Cancer risks in BRCA2 families: estimates for sites other than breast and ovary.
      • Risch H.A.
      • McLaughlin J.R.
      • Cole D.E.C.
      • et al.
      Population BRCA1 and BRCA2 mutation frequencies and cancer penetrances: a kin-cohort study in Ontario, Canada.
      • Moran A.
      • O'Hara C.
      • Khan S.
      • et al.
      Risk of cancer other than breast or ovarian in individuals with BRCA1 and BRCA2 mutations.
      • Hu C.
      • Hart S.N.
      • Polley E.C.
      • et al.
      Association between inherited germline mutations in cancer predisposition genes and risk of pancreatic cancer.
      The pooled estimate of RR was 5.1 (95% CI, 3.9-6.3; P = .28 and I2 = 21.0) (Table 7 and Fig. 8). When we used this estimate, the absolute lifetime risk of pancreatic cancer to age 80 was estimated to be 5.2%. While assessing the certainty of evidence, we judged the quality of evidence to be low.
      Table 7Summary of RR, SIR, and cumulative lifetime risk of pancreatic cancer to age 80 among BRCA1 and BRCA2 carriers
      BRCA1BRCA2
      RRSIRRRSIR
      Estimate1.93 (1.01-2.84)3.69 (2.54-4.84)5.14 (3.95-6.33)7.24 (1.51-12.97)
      Lifetime risk to age 80, %3.53.85.27.4
      Values in parentheses are 95% confidence intervals.
      RR, Relative risk; SIR, standardized incidence ratio.
      Figure thumbnail gr8
      Figure 8Forest plots of the 8 studies showing the (A) relative risk and (B) standardized incidence ratios for pancreatic cancer among individuals with BRCA2 pathogenic variants. CI, Confidence interval; ES, effect size.

      Lifetime SIR of pancreatic cancer

      For the outcome of lifetime SIR of pancreatic cancer in individuals with the BRCA2 pathogenic variant, we included 3 studies in our meta-analysis.
      • Iqbal J.
      • Ragone A.
      • Lubinski J.
      • et al.
      The incidence of pancreatic cancer in BRCA1 and BRCA2 mutation carriers.
      • Mocci E.
      • Milne R.L.
      • Mendez-Villamil E.Y.
      • et al.
      Risk of pancreatic cancer in breast cancer families from the breast cancer family registry.
      • Mersch J.
      • Jackson M.A.
      • Park M.
      • et al.
      Cancers associated with BRCA1 and BRCA2 mutations other than breast and ovarian.
      The pooled estimate of SIR was 7.2 (95% CI, 1.5-13.0; P = .45 and I2 = .0) (Table 7 and Fig. 8). When we used this estimate, the cumulative lifetime risk of pancreatic cancer to age 80 was estimated to be 7.4%. While assessing the certainty of evidence, we rated down for imprecision and therefore judged the quality of evidence to be very low.

      Mortality

      No studies reported on all-cause or pancreatic cancer–related mortality in screen-detected pancreatic cancer in individuals with the BRCA2 pathogenic variant compared with unscreened individuals.

      Yield of screening for high-risk lesions

      For the outcome of overall yield of screening, 8 studies from our pancreatic cancer screening studies meta-analysis (see questions 1 and 2, above) addressed screening for pancreatic cancer in those with BRCA1/2 and PALB2; however, these studies did not uniformly stratify results by mutation type. Across the 8 studies (n = 375), 219 patients were diagnosed with BRCA2, 50 with BRCA1, 11 with PALB2, and the remaining 95 were unspecified. The overall yield of high-risk lesions in this patient population undergoing screening with EUS, MRI, or a combined approach was 8.6% (95% CI, 4.5-16.0; P = .21 and I2 = 27.4) (Fig. 9). While assessing the certainty of evidence, we rated down the evidence for impreciseness and thus judged the quality of evidence to be very low.
      Figure thumbnail gr9
      Figure 9Forest plot of the 8 studies showing the cumulative yield (ie, pancreatic cancer, high-grade dysplasia, grade III pancreatic intraepithelial neoplasia) of screening among individuals with BRCA2 and BRCA1 pathogenic variants. HBOC, Hereditary breast ovarian cancer; CI, confidence interval; MRI, magnetic resonance imaging.

      Yield of screening of resectable and borderline-resectable lesions

      No studies reported on the detection of resectable and borderline-resectable lesions during screening in individuals with BRCA2 pathogenic variant.

      Psychological benefits of screening

      No studies reported on the psychological benefits of screening specific to individuals with the BRCA2 pathogenic variant. See the same section under question 1, above.

      Harms from screening

      No studies reported on the harms from screening specific to individuals with the BRCA2 pathogenic variant. See the same section under question 1, above.

      Other considerations

      Gender

      Our analysis did not show any significant difference in the risk of pancreatic cancer between males and female with the BRCA2 pathogenic variant. The pooled risk estimate was 5.05 (95% CI, 1.02-9.08) for BRCA2 males compared with 3.56 (95% CI, 1.50-5.61) for BRCA2 females, based on RR, and 5.81 (95% CI, 3.34-8.23) for BRCA2 males compared with 5.7 (95% CI, 3.11-8.43) for BRCA2 females, based on SIR.

      Family history of pancreatic cancer

      We were unable to determine whether family history of pancreatic cancer was a significant risk factor for pancreatic cancer in individuals with the BRCA2 pathogenic variant because most studies did not report on family history of pancreatic cancer in the enrolled population. In a study of over 5000 women with the BRCA1/2 pathogenic variant, Iqbal et al
      • Iqbal J.
      • Ragone A.
      • Lubinski J.
      • et al.
      The incidence of pancreatic cancer in BRCA1 and BRCA2 mutation carriers.
      found that the OR of developing pancreatic cancer for women with a affected first-degree relative with pancreatic cancer was 46.5 (95% CI, 9.5-230) compared with women without an affected first-degree relative. However, this estimate was based on just 1 patient with BRCA2 with a sister diagnosed with pancreatic cancer at age 79 years and 1 patient with BRCA1 whose mother was diagnosed with pancreatic cancer at age 77 years. Contrary results were reported in a study of 47 patients with the BRCA2 pathogenic variant and 36 patients with the BRCA1 pathogenic variant, where a family history of pancreatic cancer was not associated with pancreatic abnormalities on imaging studies.
      • Roch A.M.
      • Schneider J.
      • Carr R.A.
      • et al.
      Are BRCA1 and BRCA2 gene mutation patients underscreened for pancreatic adenocarcinoma?.
      In another study of BRCA1/2 patients, Chahla et al
      • Chahla E.
      • Cheesman A.
      • Mahon S.M.
      • et al.
      Frequency and significance of abnormal pancreatic imaging in patients with BRCA1 and BRCA2 genetic mutations.
      also found no association between family history of pancreatic cancer and pancreatic cancer risk and further noted that none of the patients with pancreatic cancer in their study had a family history of pancreatic cancer.
      In a provisional clinical opinion, the American Society of Clinical Oncology recommended universal genetic testing for all patients with pancreatic cancer regardless of family history because up to 50% of patients without a family history of pancreatic cancer have pancreatic cancer–predisposing mutations.
      • Stoffel E.M.
      • McKernin S.E.
      • Brand R.
      • et al.
      Evaluating susceptibility to pancreatic cancer: ASCO provisional clinical opinion.
      It is likely that a similar proportion of individuals with BRCA1/2 pathogenic variants with pancreatic cancer may not have a family history of pancreatic cancer. In a study of 71 patients with pancreatic cancer and BRCA1 (n = 21), BRCA2 (n = 49) or both (n = 1), a family history of pancreatic cancer (first- or second-degree relative) was noted in only 33% of pancreatic cancer patients, suggesting that almost 2 in 3 pancreatic cancers would have been missed had screening been limited to only those with a family history of pancreatic cancer.
      • Golan T.
      • Sella T.
      • O'Reilly E.M.
      • et al.
      Overall survival and clinical characteristics of BRCA mutation carriers with stage I/II pancreatic cancer.
      The panel therefore does not recommend that individuals with the BRCA1/2 pathogenic variant should be required to have a family history of pancreatic cancer to be considered for pancreatic cancer screening.

      Other risk factors

      Studies did not uniformly report on other risk factors, such as smoking, alcohol use, and history of pancreatitis or diabetes, and therefore we were unable to assess for their impact on risk of pancreatic cancer in individuals with the BRCA2 pathogenic variant.

      Discussion

      Our analysis had several limitations. Sampling was not at random and varied substantially across studies. Some studies selected patients enrolled based on cancer, some on familial cancer patterns in the family, and some on known BRCA1/2 pathogenic variant. Not all analyses used genetically tested individuals. Some studies inferred genetic mutation status (eg, in relatives) using statistical models. There could be overlap in the individuals reported in different studies because some centers may have contributed data to more than 1 study. Most, but not all, cancers were confirmed by review of medical records, resulting in the possibility of misclassification of cancer type. The extent of this misclassification appeared to be small but was difficult to estimate. Based on the above, we were confident of an increased risk of pancreatic cancer in individuals with the BRCA2 pathogenic variant. However, the exact magnitude of this increased risk could not be precisely estimated because of these limitations.
      The reliance on family history to identify patients at increased cancer risk was explored and included acknowledging that risk models that included family history may be flawed because of incomplete and inaccurate family history records, small families, and in situations where many family members died prematurely in wars or natural disasters.
      • Sijmons R.H.
      • Boonstra A.E.
      • Reefhuis J.
      • et al.
      Accuracy of family history of cancer: clinical genetic implications.
      • Murff H.J.
      • Byrne D.
      • Syngal S.
      Cancer risk assessment: quality and impact of the family history interview.
      • Church J.
      • McGannon E.
      Family history of colorectal cancer: How often and how accurately is it recorded?.
      One study reported that the accuracy of family history for cancers other than breast and colorectal was as low as 37%.
      • Sijmons R.H.
      • Boonstra A.E.
      • Reefhuis J.
      • et al.
      Accuracy of family history of cancer: clinical genetic implications.
      One panelist noted that some of their Ashkenazi Jewish patients with BRCA mutations were the only surviving members of their family from the Holocaust and would not qualify for pancreatic cancer screening if a family history threshold was applied. Some panelists noted that their institution already offered screening to all BRCA patients regardless of family history.
      A patient representative on the panel stated that for patients with the BRCA1/2 pathogenic variant, caregivers rarely discuss the risk of pancreatic cancer and that the discussion mostly centers around risks of breast and ovarian cancer. She believed most patients were unaware of their pancreatic cancer risk and screening options. She emphasized the need for patient and provider education on this topic.
      In balancing the desirable and undesirable effects of screening, the patient advocate also voiced the importance of the value patients place on cancer preventive surgery. The patient advocate and oncologists noted that the BRCA patient population was especially proactive and was accepting of preventive surgeries such as mastectomy, hysterectomy, and oophorectomy and therefore may also be accepting of pancreatic cancer screening and the option to decide about potential surgery.
      Question 3b: Should individuals with the BRCA1 pathogenic variant undergo screening for pancreatic cancer?
      Recommendation 3b. In individuals with the BRCA1 pathogenic variant, we suggest screening for pancreatic cancer compared with no screening (conditional recommendation, very low quality of evidence).
      We used the same systematic review as in question 3a to determine the risk of pancreatic cancer in individuals with the BRCA1 pathogenic variant (Fig. 7). A summary of outcomes and their assessment can be seen in Table 8.
      Table 8Evidence profiles for question 3b: Should individuals with the BRCA1 pathogenic variant undergo screening for pancreatic cancer?
      Certainty assessmentEffectCertaintyImportance
      No. of studiesStudy designRisk of biasInconsistencyIndirectnessImprecisionOther considerationsScreeningNo screeningRelative [95% confidence interval]Absolute [95% confidence interval]
      BRCA1: Lifetime relative risk PDAC
      4Observational studiesNot seriousNot seriousNot seriousNot seriousNoneRelative risk 1.9 [1.0-2.8]

      Absolute lifetime risk of PDAC 3.5%
      ⊕⊕◯◯

      Low
      Critical
      BRCA1: Lifetime SIR PDAC
      3Observational studiesNot seriousNot seriousNot seriousNot seriousNoneSIR 3.69 (2.54-4.84)

      Absolute lifetime risk of PDAC 3.8%
      ⊕⊕◯◯

      Low
      Critical
      Cumulative yield for screening for high risk lesions for BRCA1/2
      8Observational studiesNot seriousNot seriousNot seriousSerious
      Few cancer outcomes.
      None8.6% [4.5-16.0]⊕◯◯◯

      Very low
      Critical
      PDAC, Pancreatic ductal adenocarcinoma; SIR, standardized incidence ratio.
      Few cancer outcomes.

      Lifetime RR of pancreatic cancer

      For the outcome of lifetime RR of pancreatic cancer in individuals with the BRCA1 pathogenic variant, we included 4 studies in our meta-analysis.
      • Thompson D.
      • Easton D.F.
      Cancer incidence in BRCA1 mutation carriers.
      ,
      • Risch H.A.
      • McLaughlin J.R.
      • Cole D.E.C.
      • et al.
      Population BRCA1 and BRCA2 mutation frequencies and cancer penetrances: a kin-cohort study in Ontario, Canada.
      • Moran A.
      • O'Hara C.
      • Khan S.
      • et al.
      Risk of cancer other than breast or ovarian in individuals with BRCA1 and BRCA2 mutations.
      • Hu C.
      • Hart S.N.
      • Polley E.C.
      • et al.
      Association between inherited germline mutations in cancer predisposition genes and risk of pancreatic cancer.
      The pooled estimate of RR was 1.93 (95% CI, 1.01-2.84; P = .28 and I2 = 21.0) (Table 7 and Fig. 10). When we used this estimate, the cumulative lifetime risk of pancreatic cancer to age 80 was estimated to be 3.5%. While assessing the certainty of evidence of this outcome using the GRADE approach, we judged the quality of evidence to be low.
      Figure thumbnail gr10
      Figure 10Forest plots of the 7 studies showing the (A) relative risk and (B) standardized incidence ratios for pancreatic cancer among individuals with BRCA1 pathogenic variants. CI, Confidence interval; ES, effect size.

      Lifetime SIR of pancreatic cancer

      For the outcome of lifetime SIR of pancreatic cancer in individuals with the BRCA1 pathogenic variant, we included 3 studies in our meta-analysis.
      • Iqbal J.
      • Ragone A.
      • Lubinski J.
      • et al.
      The incidence of pancreatic cancer in BRCA1 and BRCA2 mutation carriers.
      • Mocci E.
      • Milne R.L.
      • Mendez-Villamil E.Y.
      • et al.
      Risk of pancreatic cancer in breast cancer families from the breast cancer family registry.
      • Mersch J.
      • Jackson M.A.
      • Park M.
      • et al.
      Cancers associated with BRCA1 and BRCA2 mutations other than breast and ovarian.
      The pooled estimate of SIR was 3.69 (95% CI, 2.54-4.84; P = .45 and I2 = .0) (Table 7 and Fig. 10). When we used this estimate, we estimated the absolute lifetime risk of pancreatic cancer to age 80 to be 3.8%. While assessing the certainty of evidence of this outcome using the GRADE approach, we judged the quality of evidence to be low.

      Mortality

      No studies reported on all-cause or pancreatic cancer–related mortality in screen-detected pancreatic cancer in individuals with the BRCA1 pathogenic variant compared with unscreened individuals.

      Yield of screening for high-risk lesions

      See the same section in question 3a, above.

      Yield of screening for resectable and borderline-resectable lesions

      No studies reported on the yield of resectable and borderline-resectable lesions during screening in individuals with the BRCA1 pathogenic variant.

      Psychological benefits of screening

      No studies reported on the psychological benefits of screening specific to individuals with the BRCA1 pathogenic variant. See the same section under question 1, above.

      Harms from screening

      No studies reported on the harms from screening specific to individuals with the BRCA1 pathogenic variant. See the same section under question 1, above.

      Other considerations

      Gender

      Our analysis did not show any significant difference in risk of pancreatic cancer between males and female with the BRCA1 pathogenic variant. The pooled risk estimate was 3.09 (95% CI, 1.86-5.15) for BRCA1 males compared with 5.52 (95% CI, 2.96-8.08) for BRCA1 females, based on SIR.

      Family history of pancreatic cancer and other risk factors

      See corresponding section under question 3a, above.

      Discussion

      We noted that the magnitude of association between pancreatic cancer and BRCA1 was less consistent when compared with BRCA2 because fewer individuals with BRCA1 pathogenic variants were included in studies and very few BRCA1-related pancreatic cancers were noted in these studies. The risk of selection bias mentioned in the BRCA2 panel discussion was also applicable to BRCA1 studies. We discussed the possibility that the lower risk of pancreatic cancer reported with BRCA1 compared with BRCA2 may be unrelated to biologic differences between the 2 pathogenic variants but related to selection and other biases in the literature. It was also noted that historically, before 2012, the association between pancreatic cancer and BRCA1 was largely ignored, thus further limiting long-term data on the subject. One oncologist noted that there were no differences in response to chemotherapy between BRCA1- and BRCA2-related pancreatic cancers.
      As with BRCA2, it was evident from the literature that patients with BRCA1 were at increased risk of pancreatic cancer; however, quantification of risk estimate was imprecise. The panel reviewed literature showing that tumors with homologous recombination repair gene abnormalities such as BRCA1/2 are responsive to platinum-based chemotherapeutic agents and poly(adenosine diphosphate-ribose) polymerase inhibitors.
      • Lord C.J.
      • Ashworth A.
      PARP inhibitors: synthetic lethality in the clinic.
      • Golan T.
      • Kanji Z.S.
      • Epelbaum R.
      • et al.
      Overall survival and clinical characteristics of pancreatic cancer in BRCA mutation carriers.
      • O'Reilly E.M.
      • Lee J.W.
      • Zalupski M.
      • et al.
      Randomized, multicenter, phase II trial of gemcitabine and cisplatin with or without veliparib in patients with pancreas adenocarcinoma and a germline BRCA/PALB2 mutation.
      • Golan T.
      • Hammel P.
      • Reni M.
      • et al.
      Maintenance olaparib for germline BRCA-mutated metastatic pancreatic cancer.
      A landmark randomized, placebo-controlled trial showed improved progression-free survival in patients with metastatic pancreatic cancer when treated with the poly(adenosine diphosphate-ribose) polymerase inhibitor olaparib.
      • Golan T.
      • Hammel P.
      • Reni M.
      • et al.
      Maintenance olaparib for germline BRCA-mutated metastatic pancreatic cancer.
      Patients with BRCA1/2 with borderline-resectable pancreatic cancers have also been shown to have higher rates of complete pathologic response to neoadjuvant platinum-based chemotherapy.
      • Golan 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.
      The panel recognized this as an opportunity to identify patients who may benefit for such treatments and therefore chose to accept a lower threshold to recommend pancreatic cancer screening than the widely accepted threshold of pancreatic cancer lifetime risk or a relative risk >5 (also see the discussion under question 6 in Summary and Recommendations article).
      • Sawhney M.S.
      • Calderwood A.H.
      • Thosani N.C.
      • et al.
      ASGE guideline on screening for pancreatic cancer in individuals with genetic susceptibility: summary and recommendations.
      Of note, even though the point estimate of RR and lifetime risk of pancreatic cancer in BRCA1 did not cross the RR ≥5 or lifetime risk ≥5% threshold, the 95% CIs were close to these thresholds.
      Question 4: How often should screening for pancreatic cancer be performed in individuals who are at increased risk of pancreatic cancer because of genetic susceptibility?
      Recommendation 4. In individuals at increased risk of pancreatic cancer because of genetic susceptibility, we suggest that annual screening should be performed (conditional recommendation, very low quality of evidence).
      We did not find any studies that reported patient outcomes based on screening intervals. We therefore used 2 methods to determine the frequency of pancreatic cancer screening. First, we reviewed screening intervals used within each of the 25 studies included in the systematic review to determine existing practices regarding screening frequency (Fig. 1). Sixteen studies did not report a screening interval or reported results of a 1-time screening. Of the remaining 9 studies, 7 used a 1-year screening interval.
      • Al-Sukhni W.
      • Borgida A.
      • Rothenmund H.
      • et al.
      Screening for pancreatic cancer in a high-risk cohort: an eight-year experience.
      ,
      • Canto 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.
      ,
      • Del Chiaro M.
      • Verbeke C.S.
      • Kartalis N.
      • et al.
      Short-term results of a magnetic resonance imaging-based swedish screening program for individuals at risk for pancreatic cancer.
      ,
      • Joergensen 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.
      ,
      • Potjer T.P.
      • Schot I.
      • Langer P.
      • et al.
      Variation in precursor lesions of pancreatic cancer among high-risk groups.
      ,
      • Saldia A.
      • Olson S.H.
      • Nunes P.
      • et al.
      Outcome of pancreatic cancer surveillance among high-risk individuals tested for germline mutations in BRCA1 and BRCA2.
      ,
      • Overbeek K.A.
      • Levink I.J.
      • Konings I.C.
      • et al.
      12 Years of prospective pancreatic cancer surveillance: results of the Dutch Nationwide Program in high-risk individuals.
      The screening interval of Mocci et al
      • Mocci E.
      • Guillen-Ponce C.
      • Earl J.
      • et al.
      PanGen-Fam: Spanish registry of hereditary pancreatic cancer.
      varied between 3 months and 1 year based on genetic condition and of Sheel et al
      • Sheel A.R.G.
      • Harrison S.
      • Sarantitis I.
      • et al.
      Identification of cystic lesions by secondary screening of familial pancreatic cancer (FPC) kindreds is not associated with the stratified risk of cancer.
      varied between 1 and 3 years based on results of duodenal aspirate analysis and previous tests. No study reported on mortality or yield of screening based on length of screening interval.
      Second, we reviewed models on the progression time of pancreatic cancers. A quantitative analysis of the timing of genetic evolution of pancreatic cancer predicted at least a decade and a half between the occurrence of the initiating mutation and acquisition of metastatic ability.
      • Yachida S.
      • Jones S.
      • Bozic I.
      • et al.
      Distant metastasis occurs late during the genetic evolution of pancreatic cancer.
      Although this model suggests ample opportunity for early intervention, it is likely that for much of its life cycle the tumor is too small to be clinically detected by current screening tests like EUS or MRI. To understand the timing of cancer progression, Yu et al
      • Yu J.
      • Blackford A.L.
      • Dal Molin M.
      • et al.
      Time to progression of pancreatic ductal adenocarcinoma from low-to-high tumour stages.
      compared the mean age of patients with pancreatic cancer at different stages. They found that patients with stage 1 cancer were only 1.3 years younger than those with stage IV cancer, whereas patients with T1 cancer were 1.06 years younger than those with T3 and 1.19 years younger than those with T4 cancers. In another study, Gangi et al
      • Gangi S.
      • Fletcher J.G.
      • Nathan M.A.
      • et al.
      Time interval between abnormalities seen on CT and the clinical diagnosis of pancreatic cancer: retrospective review of CT scans obtained before diagnosis.
      retrospectively reviewed CTs that were done in the months leading to a diagnosis of pancreatic cancer. Lesions that were definitive or suspicious for pancreatic cancer were noted in up to 50% of CTs done within 18 months before cancer diagnosis but were rarely noted on CTs done more than 18 months before. Taken together, these studies suggest once the tumor becomes clinically apparent, the progression from localized to advance stage may occur within a year, and we therefore concluded that screening should be done at yearly intervals for cancer to be detected at an early stage.
      Question 5: At what age should screening for pancreatic cancer start in individuals who are at increased risk of pancreatic cancer because of genetic susceptibility?
      Recommendation 5. In individuals at increased risk for pancreatic cancer because of genetic susceptibility, we suggest that the starting age for screening should vary based on the underlying genetic condition (conditional recommendation, very low quality of evidence).
      To determine which genetic conditions should undergo pancreatic cancer screening, we took into consideration the risk threshold at which pancreatic screening is usually recommended, available literature on pancreatic cancer risk for each genetic condition, patient population enrolled in studies included in our pancreatic cancer screening meta-analysis, and pancreatic cancer screening recommendations made by others (a table summarizing these recommendations can be found in Appendix 2, available online at www.giejournal.org).
      A lifetime risk of pancreatic cancer >5% or RR >5 has been proposed as the threshold to define individuals at high risk for pancreatic cancer.
      • Canto M.I.
      • Harinck F.
      • Hruban R.H.
      • et al.
      International Cancer of the Pancreas Screening (CAPS) Consortium summit on the management of patients with increased risk for familial pancreatic cancer.
      This threshold was initially proposed based on expert opinion and that screening for other cancers like colon cancer that had an equivalent lifetime prevalence was widely practiced.
      • Canto M.I.
      • Harinck F.
      • Hruban R.H.
      • et al.
      International Cancer of the Pancreas Screening (CAPS) Consortium summit on the management of patients with increased risk for familial pancreatic cancer.
      This threshold has now been widely accepted and acknowledged by guidelines and clinical practice updates to determine when pancreatic cancer screening is recommended.
      • Goggins 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.
      ,
      • Syngal S.
      • Brand R.E.
      • Church J.M.
      • et al.
      ACG clinical guideline: genetic testing and management of hereditary gastrointestinal cancer syndromes.
      ,
      • Săftoiu 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.
      ,
      • Aslanian H.R.
      • Lee J.H.
      • Canto M.I.
      AGA clinical practice update on pancreas cancer screening in high-risk individuals: expert review.
      Corral et al
      • Corral J.E.
      • Das A.
      • Bruno M.J.
      • et al.
      Cost-effectiveness of pancreatic cancer surveillance in high-risk individuals: an economic analysis.
      performed an economic analysis and found pancreatic cancer screening to be cost-effective at this threshold.
      We reviewed the patient population enrolled in each of the 25 studies in our systematic review and, when reported, categorized the population by individual genetic condition. When all studies were considered together, the enrolled patient population was as follows: FPC = 1780, familial atypical multiple mole melanoma (FAMMM) syndrome = 393, BRCA2 pathogenic variant = 219, BRCA1 pathogenic variant = 50, PALB2 pathogenic variant = 11, BRCA pathogenic variant not further specified = 88, hereditary pancreatitis = 42, Peutz-Jeghers syndrome = 41, Lynch syndrome = 20, and (ataxia-telangiectasia mutated) ATM pathogenic variant = 18. For several rare conditions (ie, FPC, FAMMM syndrome, Peutz-Jeghers syndrome, Lynch syndrome, hereditary pancreatitis, PALB2, and ATM pathogenic variant) only limited data were available to estimate pancreatic cancer risk, influence of family history of pancreatic cancer on pancreatic cancer risk, age at cancer onset, and outcomes of screening. These conditions were therefore not subjected to a systematic review of the literature, meta-analysis, or GRADE methodology. To make recommendations including age to initiate screening, the panel relied on existing literature, national and international guidelines, and the following principle: Conditions that moderately increased the risk of pancreatic cancer, defined as a lifetime risk of pancreatic cancer <10%, the panel generally recommended screening only in those who also had a family history of pancreatic cancer and to start screening at an age 1 standard deviation before the mean age of the pancreatic cancer diagnosis reported in that population. For conditions that significantly increased the risk of pancreatic cancer, defined as a lifetime risk of pancreatic cancer ≥10%, the panel generally recommended screening regardless of family history of pancreatic cancer and to start screening at an age 2 standard deviations before the mean age of pancreatic cancer diagnosis reported in that population. Below is a summary of evidence used to determine age at screening based on genetic susceptibility condition.

      BRCA2 pathogenic variant: age 50

      Four studies (97 patients) reported the age at diagnosis of pancreatic cancer in BRCA2 carriers with a mean age of 59.8 years (Iqbal et al
      • Iqbal J.
      • Ragone A.
      • Lubinski J.
      • et al.
      The incidence of pancreatic cancer in BRCA1 and BRCA2 mutation carriers.
      ), 62.9 ± 11.7 years (Kim
      • Kim D.H.
      • Crawford B.
      • Ziegler J.
      • et al.
      Prevalence and characteristics of pancreatic cancer in families with BRCA1 and BRCA2 mutations.
      ), 60 years (Van Asperen et al
      • Van Asperen C.J.
      • Brohet R.M.
      • Meijers-Heijboer E.J.
      • et al.
      Cancer risks in BRCA2 families: estimates for sites other than breast and ovary.
      ), and 63.1 ± 11.0 years (Mocci et al
      • Mocci E.
      • Milne R.L.
      • Mendez-Villamil E.Y.
      • et al.
      Risk of pancreatic cancer in breast cancer families from the breast cancer family registry.
      ), with a range from 33 to 87 years. The mean age at diagnoses is lower in BRCA2 than in the general U.S. population reflected in the SEER database of 70 years.

      BRCA1 pathogenic variant: age 50

      Three studies reported on the age at diagnosis of pancreatic cancer (103 patients) in BRCA1 carriers. The mean age at diagnoses is lower in BRCA1 than in the general U.S. population reflected in the SEER database of 70 years.

      PALB2 pathogenic variant: age 50

      At the time of our systematic review, no studies addressed the lifetime risk of pancreatic cancer in individuals with the PALB2 pathogenic variant in sufficient numbers or detail. Across the studies included in our systematic review of pancreatic cancer screening studies, only 11 carriers had the PALB2 pathogenic variant. A study published after the conduct of our systematic review that included 524 families of 976 individuals from 21 countries estimated the RR of pancreatic cancer to be 2.37 (95% CI, 1.24-4.50), which translated to an absolute risk to age 80 of 2.2% (95% CI, 1.2-4.2) for females and 2.8% (95% CI, 1.5-5.3) for males in their model.
      • Yang X.
      • Leslie G.
      • Doroszuk A.
      • et al.
      Cancer risks associated with germline PALB2 pathogenic variants: an international study of 524 families.

      FPC: age 50 years, or 10 years earlier than the youngest relative with pancreatic cancer, whichever comes first

      FPC kindreds are defined as those having at least 1 pair of first-degree relatives with pancreatic cancer without an association with a known hereditary cancer syndrome.
      • Klein A.P.
      • Brune K.A.
      • Petersen G.M.
      • et al.
      Prospective risk of pancreatic cancer in familial pancreatic cancer kindreds.
      • Tersmette 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.
      • Copur M.S.
      • Talmon G.A.
      • Wedel W.
      • et al.
      Hereditary vs familial pancreatic cancer: associated genetic syndromes and clinical perspective.
      • Petersen G.M.
      Familial pancreatic cancer.
      Familial pancreatic cancer. American Society of Clinical Oncology Cancer.Net.
      Although the putative gene for FPC has not been identified, modeling studies suggest autosomal-dominant inheritance of a rare allele as the likely etiology.
      • Klein A.P.
      • Beaty T.H.
      • Bailey-Wilson J.E.
      • et al.
      Evidence for a major gene influencing risk of pancreatic cancer.
      In a prospective registry-based study, SIR for pancreatic cancer was significantly elevated in FPC kindreds (9.0; 95% CI, 4.5-16.1).
      • Klein A.P.
      • Brune K.A.
      • Petersen G.M.
      • et al.
      Prospective risk of pancreatic cancer in familial pancreatic cancer kindreds.
      Pancreatic cancer risk in FPC kindreds was elevated in individuals with 3 (32.0; 95% CI, 10.2-74.7), 2 (6.4; 95% CI, 1.8-16.4), or 1 (4.6; 95% CI, .5-16.4) affected first-degree relative. FPC kindreds who smoked were at higher risk for pancreatic cancer (SIR, 19.2; 95% CI, 7.7-39.5). Another study using the same registry found that the lifetime risk of pancreatic cancer increased with decreasing age at pancreatic cancer onset in the kindred (hazard ratio, 1.55; 95% CI, 1.19-2.03 per year).
      • Brune K.A.
      • Lau B.
      • Palmisano E.
      • et al.
      Importance of age of onset in pancreatic cancer kindreds.
      In this registry the mean age at diagnosis for pancreatic cancer for men was 69.5 ± 8.5 years and for women was 68.4 ± 14.3 years. No incident pancreatic cancer was found in individuals <45 years of age.
      In our systematic review, 1780 patients with FPC syndrome underwent screening, of which 32 were diagnosed with pancreatic cancer. The mean age at cancer diagnosis was 63.6 ± 10.2 years (median, 62.5; range, 44-82). Only 3 cancers were diagnosed before age 50.
      Patients who have a family history of pancreatic cancer but do not meet the criteria for FPC are also at increased risk of developing pancreatic cancer. A meta-analysis of 7 case-control and 2 cohort studies involving 6568 pancreatic cancer patients found an overall RR for pancreatic cancer of 1.80 (95% CI, 1.48-2.12) for these patients.
      • Permuth-Wey J.
      • Egan K.M.
      Family history is a significant risk factor for pancreatic cancer: results from a systematic review and meta-analysis.
      No significant difference in cancer risk was noted between those with a first-degree or a second-degree relative with pancreatic cancer (RR, 3.3 [95% CI, 1.8-6.1] vs 2.9 [95% CI, 1.3-6.3]) or between those with early- or late-onset pancreatic cancer in the index case (RR, 2.69 [95% CI, .56-4.82] vs 3.41 [95% CI, .79-6.03]). Another report using data from the National Familial Pancreas Tumor Registry found the SIR for pancreatic cancer in those with a family history of pancreatic cancer who did not meet the criteria for FPC to be 2.41 (95% CI, 1.04-4.47).
      • Brune K.A.
      • Lau B.
      • Palmisano E.
      • et al.
      Importance of age of onset in pancreatic cancer kindreds.
      No difference in risk was noted between those with young and later-onset kindred with pancreatic cancer (2.74 [95% CI, .05-15.30] vs 2.36 [95% CI, .95-4.88]).
      Taken together, these data suggest that patients with a family history of pancreatic cancer who do not meet criteria for FPC are at an approximately 2-fold increased risk of developing pancreatic cancer. The degree of relatedness and age at onset of pancreatic cancer in the index patient does not appear to affect cancer risk. Pancreatic cancer screening is recommended for those in whom RR of pancreatic cancer exceeds 5 or the lifetime risk of pancreatic cancer exceeds 5%. Pancreatic cancer risk for patients with a family history of pancreatic cancer who do not meet criteria for FPC are likely to fall below this threshold and may not benefit from screening. Of note, a consensus guideline also recommended screening for individuals with 3 or more blood relatives with pancreatic cancer with at least 1 affected first-degree relative and for those with 2 affected blood relatives with pancreatic cancer with at least 1 first-degree relative.
      • Canto M.I.
      • Harinck F.
      • Hruban R.H.
      • et al.
      International Cancer of the Pancreas Screening (CAPS) Consortium summit on the management of patients with increased risk for familial pancreatic cancer.
      ,
      • Goggins 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.

      FAMMM syndrome: age 40, or 10 years earlier than the youngest relative with pancreatic cancer

      FAMMM syndrome is an autosomal-dominant condition characterized by the presence of multiple moles and a strong predisposition for the development of melanoma and pancreatic cancer.
      • Lynch H.T.
      • Shaw T.G.
      Familial atypical multiple mole melanoma (FAMMM) syndrome: history, genetics, and heterogeneity.
      ,
      • Soura E.
      • Eliades P.J.
      • Shannon K.
      • et al.
      Hereditary melanoma: update on syndromes and management: genetics of familial atypical multiple mole melanoma syndrome.
      FAMMM syndrome is associated with mutations in the CDKN2A gene and rarely CDK4 gene. In individuals with FAMMM syndrome, the SIR for pancreatic cancer is between 13.1 (95% CI, 1.5-47.4) and 21.8 (95% CI, 8.7-44.8).
      • Goldstein A.M.
      • Fraser M.C.
      • Struewing J.P.
      • et al.
      Increased risk of pancreatic cancer in melanoma-prone kindreds with p16INK4 mutations.
      The cumulative risk of developing pancreatic cancer by age 75 years is estimated to be 17%.
      • Vasen H.F.
      • Gruis N.A.
      • Frants R.R.
      • et al.
      Risk of developing pancreatic cancer in families with familial atypical multiple mole melanoma associated with a specific 19 deletion of p16 (p16-Leiden).
      In a study of 50 patients with pancreatic cancer with p16-Leiden founder mutation in the CDKN2A gene from the Netherlands, the median age at cancer diagnosis was 55 years, with a range of 21 to 76 years.
      • Potjer T.P.
      • van der Stoep N.
      • Houwing-Duistermaat J.J.
      • et al.
      Pancreatic cancer-associated gene polymorphisms in a nation-wide cohort of p16-Leiden germline mutation carriers; a case-control study.
      In a study of 22 patients with pancreatic cancer from 159 FAMMM syndrome families for whom the age at cancer diagnosis was known, the mean age at pancreatic cancer diagnosis was 59.2 ± 11.7 years (median, 58; range, 39-78).
      • Lynch H.T.
      • Brand R.E.
      • Hogg D.
      • et al.
      Phenotypic variation in eight extended CDKN2A germline mutation familial atypical multiple mole melanoma-pancreatic carcinoma-prone families: the familial atypical mole melanoma-pancreatic carcinoma syndrome.
      Our systematic review included 393 patients with FAMMM syndrome of whom 19 were diagnosed with pancreatic cancer. The mean age at diagnosis was 57.6 ± 10.2 years (median, 57; range, 39-77). Only 1 of 19 cancers was diagnosed in a patient before age 45.

      Peutz-Jeghers syndrome: age 35, or 10 years earlier than the youngest relative with pancreatic cancer

      Peutz-Jeghers syndrome is an autosomal-dominant syndrome characterized by hamartomatous GI polyps and mucocutaneous pigmentation.
      • Jeghers H.
      • Mc K.V.
      • Katz K.H.
      Generalized intestinal polyposis and melanin spots of the oral mucosa, lips and digits; a syndrome of diagnostic significance.
      Peutz-Jeghers syndrome is associated with germline mutations in the STK11 (LKB1) gene, and there in a marked increase in the risk of GI cancers including colorectal, small bowel, gastric, and pancreatic cancer and non-GI cancer such as breast cancer.
      • Hemminki A.
      • Markie D.
      • Tomlinson I.
      • et al.
      A serine/threonine kinase gene defective in Peutz-Jeghers syndrome.
      ,
      • van Lier M.G.
      • Wagner A.
      • Mathus-Vliegen E.M.
      • et al.
      High cancer risk in Peutz-Jeghers syndrome: a systematic review and surveillance recommendations.
      A systematic review found that Peutz-Jeghers syndrome individuals were 132 times more like to develop pancreatic cancer compared with the general population.
      • van Lier M.G.
      • Wagner A.
      • Mathus-Vliegen E.M.
      • et al.
      High cancer risk in Peutz-Jeghers syndrome: a systematic review and surveillance recommendations.
      In that report, the mean age at diagnosis was 52 years; however, the standard deviation and age range were not provided. The cumulative risk of developing pancreatic cancer to ages 65 to 70 years was estimated to be 11% to 36%.
      • Giardiello F.M.
      • Brensinger J.D.
      • Tersmette A.C.
      • et al.
      Very high risk of cancer in familial Peutz-Jeghers syndrome.
      ,
      • Hearle N.
      • Schumacher V.
      • Menko F.H.
      • et al.
      Frequency and spectrum of cancers in the Peutz-Jeghers syndrome.
      In a study of 240 individuals with Peutz-Jeghers syndrome with germline mutations in STK11, 6 patients were diagnosed with pancreatic cancer. All pancreatic carcinomas were diagnosed between ages 34 and 49 years.
      • Lim W.
      • Olschwang S.
      • Keller J.J.
      • et al.
      Relative frequency and morphology of cancers in STK11 mutation carriers.
      In another study of 144 Peutz-Jeghers syndrome patients, 7 pancreatic cancers were noted at a mean age of 50.9 ± 12.4 years (median, 54).
      • Korsse S.E.
      • Harinck F.
      • van Lier M.G.
      • et al.
      Pancreatic cancer risk in Peutz-Jeghers syndrome patients: a large cohort study and implications for surveillance.
      Based on 2 patients who developed cancer at the ages of 35 and 36 years, these authors suggested that screening in individuals with Peutz-Jeghers syndrome should start at age 30 years. In our meta-analysis, of 41 individuals with Peutz-Jeghers syndrome, 2 were diagnosed with pancreatic cancers at ages 47 and 66 years.

      ATM heterozygotes with a first- or second-degree relative with pancreatic cancer: age 50, or 10 years earlier than the youngest relative with pancreatic cancer

      Ataxia-telangiectasia is a rare autosomal-recessive disorder caused by mutations in the ataxia-telangiectasia mutated (ATM) gene.
      • Savitsky K.
      • Bar-Shira A.
      • Gilad S.
      • et al.
      A single ataxia telangiectasia gene with a product similar to PI-3 kinase.
      ,
      • Gatti R.A.
      • Berkel I.
      • Boder E.
      • et al.
      Localization of an ataxia-telangiectasia gene to chromosome 11q22-23.
      Homozygotes for the ATM pathogenic variant develop progressive neurologic abnormalities like cerebellar ataxia and oculocutaneous telangiectasias. Up to 2% of all whites in the United States may be heterozygotes for the ATM pathogenic variant.
      • Swift M.
      • Morrell D.
      • Cromartie E.
      • et al.
      The incidence and gene frequency of ataxia-telangiectasia in the United States.
      ,
      • Swift M.
      • Reitnauer P.J.
      • Morrell D.
      • et al.
      Breast and other cancers in families with ataxia-telangiectasia.
      Although heterozygotes do not develop neurologic disease, they may be at increased risk of breast and pancreatic cancer.
      • Renwick A.
      • Thompson D.
      • Seal S.
      • et al.
      ATM mutations that cause ataxia-telangiectasia are breast cancer susceptibility alleles.
      Hu et al found an ATM pathogenic variant in 41 of 1213 patients with pancreatic cancer (carrier frequency of 3.8% vs .38% in control subjects) and computed an OR for pancreatic cancer of 8.96 (95% CI, 6.1-13). The age at diagnosis was not provided. Of note, 38.1% of patients with pancreatic cancer had a first- or second-degree relative with pancreatic cancer. Our systematic review did not yield any pancreatic cancers in ATM carriers.

      Lynch syndrome with first- or second-degree relative with pancreatic cancer: age 50, or 10 years earlier than the youngest relative with pancreatic cancer

      Lynch syndrome is an autosomal-dominant disorder that is caused by pathogenic germline variants in any of the DNA mismatch repair genes (MLH1, MSH2, MSH6, PMS2, EPCAM). Individuals with Lynch syndrome are at increased risk of colorectal, endometrial, ovarian, stomach, small bowel, skin, and pancreatic cancer.
      In a prospective cohort of 446 unaffected individuals with a mismatch repair pathogenic variant who were followed for a median of 5 years, 2 pancreatic cancers were noted (SIR, 10.68; 95% CI, 2.7-47.7).
      • Win A.K.
      • Young J.P.
      • Lindor N.M.
      • et al.
      Colorectal and other cancer risks for carriers and noncarriers from families with a DNA mismatch repair gene mutation: a prospective cohort study.
      In another study using registries at the Dana Farber Cancer Institute and the University of Michigan with 6342 individuals with mismatch repair pathogenic variant,
      • Kastrinos F.
      • Mukherjee B.
      • Tayob N.
      • et al.
      Risk of pancreatic cancer in families with Lynch syndrome.
      the cumulative risk of pancreatic cancer was 1.3% (95% CI, .31-2.32) up to age 50 years and 3.7% (95% CI, 1.45-5.88) up to age 70 years. This pancreatic cancer risk was considered 8.6-fold (95% CI, 4.7-15.7) higher when compared with the general population. The median age at diagnosis and range for men was 51.5 years (19-85 years) and for women was 56.5 years (27-79 years). Fifty percent of cancers were diagnosed before age 50 years in men compared with 22% in women.
      Hu et al reported on 1652 patients with pancreatic cancer who were identified from a 140,000-patient cohort undergoing multigene panel testing of predisposition genes. The authors found the MSH2 pathogenic variant in 2 of 1190 patients with pancreatic cancer (carrier frequency of 0.17% vs .02% in control subjects) and computed an OR for pancreatic cancer of 7.1 (95% CI, 1.04-37.16). The authors found the MSH6 pathogenic variant in 12 of 1190 patients with pancreatic cancer (carrier frequency of 1.01% vs .13% in control subjects) and computed an OR for pancreatic cancer of 7.79 (95% CI, 8.1-26.2). Of note, the association between MSH2 and pancreatic cancer was based on a limited number of mutations detected among cancer cases. The age at diagnosis was not provided. Our systematic review did not yield any pancreatic cancers in Lynch syndrome patients.

      Hereditary pancreatitis: age 40

      Hereditary pancreatitis is defined as acute recurrent or chronic pancreatitis with a Mendelian pattern of inheritance, most often associated with mutations in the PRSSI gene.
      • Whitcomb D.C.
      • Gorry M.C.
      • Preston R.A.
      • et al.
      Hereditary pancreatitis is caused by a mutation in the cationic trypsinogen gene.
      Individuals with hereditary pancreatitis, especially those with the PRSSI pathogenic variant, are at increased risk for pancreatic cancer. Rebours et al
      • Rebours V.
      • Boutron-Ruault M.C.
      • Schnee M.
      • et al.
      The natural history of hereditary pancreatitis: a national series.
      analyzed a French hereditary pancreatitis registry and found the median age at pancreatic cancer was 55 years (range, 39-78) and the cumulative risk of pancreatic cancer at ages 50, 60, and 75 years was 10%, 18.7%, and 53.5%, respectively. Howes et al
      • Howes N.
      • Lerch M.M.
      • Greenhalf W.
      • et al.
      Clinical and genetic characteristics of hereditary pancreatitis in Europe.
      analyzed the European Registry of Hereditary Pancreatitis and Pancreatic Cancer and found the overall cumulative risk of pancreatic cancer was 0% at 30 years, .5% at 40 years, 3.4% at 50 years, 9.8% at 60 years, 18.8% at 70 years, and 33.3% at 80 years (95% CI, 19.0%-47.5%). The cumulative risk of pancreatic cancer from symptom onset was 1.5% at 20 years, 2.5% at 30 years, 8.5% at 40 years, 14.6% at 50 years, 25.3% at 60 years, and 44.0% at 70 years. Lowenfels et al
      • Lowenfels A.B.
      • Maisonneuve P.
      • DiMagno E.P.
      • et al.
      Hereditary pancreatitis and the risk of pancreatic cancer. International Hereditary Pancreatitis Study Group.
      invited members of the American Pancreatic Association and the International Association of Pancreatology to enroll their hereditary pancreatitis patients in a longitudinal study. Of the 246 hereditary pancreatitis patients enrolled, 8 pancreatic adenocarcinomas were noted with a mean age at cancer diagnosis of 56.9 ± 11.2 years during 8531 person-years of follow-up, yielding an SIR of 53. The estimated cumulative risk of pancreatic cancer to age 70 years was 40%. For patients with a paternal inheritance pattern, the cumulative risk of pancreatic cancer was approximately 75%. A study of 217 PRSSI pathogenic variant carriers from the United States found the SIR for pancreatic cancer to be 59 and the cumulative risk of pancreatic cancer by age 70 years to be 7.2%.
      • Shelton C.A.
      • Umapathy C.
      • Stello K.
      • et al.
      Hereditary pancreatitis in the United States: survival and rates of pancreatic cancer.
      The risk of pancreatic cancer in individuals with SPINK1 and other mutations associated with hereditary pancreatitis is less well studied.
      • Greenhalf W.
      • Lévy P.
      • Gress T.
      • et al.
      International consensus guidelines on surveillance for pancreatic cancer in chronic pancreatitis. Recommendations from the Working Group for the International Consensus Guidelines for Chronic Pancreatitis in collaboration with the International Association of Pancreatology, the American Pancreatic Association, the Japan Pancreas Society, and European Pancreatic Club.
      A study of 209 patients from France and England with the SPINK1 pathogenic variant found a 12-fold increase in pancreatic cancer risk.
      • Muller N.
      • Sarantitis I.
      • Rouanet M.
      • et al.
      Natural history of SPINK1 germline mutation related-pancreatitis.
      The cancer risk was .8% at 50 years, 11.9% at 60 years, 27.7% at 70 years, and 51.8% at 80 years.
      In addition to recommendations from the National Comprehensive Cancer Network, American College of Gastroenterology, and Cancer of the Pancreas Screening (Appendix 2), screening recommendations were also made by a multisociety pancreatology group.
      • Greenhalf W.
      • Lévy P.
      • Gress T.
      • et al.
      International consensus guidelines on surveillance for pancreatic cancer in chronic pancreatitis. Recommendations from the Working Group for the International Consensus Guidelines for Chronic Pancreatitis in collaboration with the International Association of Pancreatology, the American Pancreatic Association, the Japan Pancreas Society, and European Pancreatic Club.
      These guidelines recommend that screening should be considered for all affected individuals with an autosomal-dominant history of hereditary pancreatitis with and without known PRSS1 pathogenic variants. Screening was not recommended in those with chronic pancreatitis associated with SPINK1, CFTR, CTRC, CPA1, or CEL pathogenic variants. Screening should start at age 40 years and be performed with CT or MRI. These guidelines also recommended against using EUS for screening, noting that early tumors may be obscured by fibrosis and calcifications.

      Health disparities and health equity

      For each of the PICOs, the panel addressed feasibility and health equity, acknowledging that many patients have limited access to high-quality medical care and differences in use of cancer screening among diverse socioeconomic and racial groups contribute to health disparities. Out-of-pocket costs for patients for cancer screening tests can vary considerably depending on the type of health insurance plan and can act as a barrier to screening, which could further augment disparities in cancer outcomes.
      • Bruenderman E.
      • Martin 2nd, R.C.
      A cost analysis of a pancreatic cancer screening protocol in high-risk populations.
      Furthermore, the panel noted racial disparities in the diagnosis and treatment of pancreatic cancer, with African Americans experiencing higher incidences of pancreatic cancer and more frequently presenting with advanced-stage disease.
      • Noel M.
      • Fiscella K.
      Disparities in pancreatic cancer treatment and outcomes.
      African Americans are also less likely to receive some cancer screening tests (eg, colorectal and prostate cancer) when compared with white Americans, and this may have implications for pancreatic cancer screening.
      Although there is consensus that pancreatic screening and subsequent care should ideally be performed at high-volume centers with multidisciplinary expertise, many patients eligible for screening may not have access to such centers. A study using New York City area hospital discharge data found that even after adjusting for insurance type and comorbidities, nonwhite patients were more likely to be operated on by a low-volume surgeon at a low-volume hospital.
      • Epstein A.J.
      • Gray B.H.
      • Schlesinger M.
      Racial and ethnic differences in the use of high-volume hospitals and surgeons.
      Another study using the Nationwide Inpatient Sample found that patients operated on by high-volume pancreatic surgeons were more likely to be men, white, and residents of high-income zip codes.
      • Eppsteiner R.W.
      • Csikesz N.G.
      • McPhee J.T.
      • et al.
      Surgeon volume impacts hospital mortality for pancreatic resection.
      The panel cautioned that recommendations considered in this guideline had the potential to worsen health disparities depending on their implementation in clinical care. Therefore, every effort should be made to implement programs for pancreatic screening that are equitable and accessible for all who meet criteria for screening, with particular attention to specific groups at risk of experiencing disparities, such as African Americans or those with lower socioeconomic status.

      Disclosure

      The following authors disclosed financial relationships: M. S. Sawhney: Stockholder with Allurion Technology, Inc; research support and food and beverage compensation from Olympus Corporation of the Americas and Boston Scientific Corporation. N. C. Thosani: Consultant for and travel and food and beverage compensation from Boston Scientific Corporation; consultant for TaeWoong Medical; consultant for and research support, travel, and food and beverage compensation from Pentax of America, Inc; royalties from UpToDate; research support and food and beverage compensation from Endogastric Solutions; speaker for and food and beverage compensation from AbbVie, Inc; food and beverage compensation from Covidien LP; advisory board for ColubrisMX Inc. S. Wani: Consultant for and food and beverage compensation from Boston Scientific Corporation; consultant for Medtronic, Exact Sciences, and Interpace; research support from Cook Medical LLC; food and beverage compensation from Olympus America Inc; advisory board for Cernostics. M. I. Canto: Consultant for Exact Sciences; research support and food and beverage compensation from Endogastric Solutions and Pentax of America, Inc; has received food and beverage compensation from Boston Scientific Corporation, AbbVie, Inc, Daiichi Sankyo Inc, Merck Sharp & Dohme Corporation, and Shionogi Inc; royalties from UpToDate. D. S. Fishman: Food and beverage compensation from AbbVie, Inc and Boston Scientific Corporation. T. Golan: Consultant for AbbVie Inc, Teva Pharmaceutical Industries Ltd, and Bayer AG; consultant for and research support from AstraZeneca and Merck Sharp & Dohme Corp. M. Hidalgo: Stock and other ownership interests in Nelum Corp and Champions Oncology; stock and honoraria from Agenus and InxMed; research support from BiolineRx, Erytech Pharma, BioExcell, and TOP Alliance Biosciences; travel compensation from Bayer HealthCare Pharmaceuticals Inc; food and beverage compensation from Boehringer Ingelheim Pharmaceuticals, Inc, Pfizer Inc, and Sunovion Pharmaceuticals Inc. R. S. Kwon: Travel compensation from C2 Therapeutics, Inc; food and beverage compensation from Covidien LP. D. V. Sahani: Travel compensation and food and beverage compensation from GE Healthcare; food and beverage compensation from Abbott Laboratories. M. A. Al-Haddad: Research support and food and beverage compensation from Boston Scientific Corporation. S. K. Amateau: Consultant for and travel and food and beverage compensation from Boston Scientific Corporation and Olympus America Inc; consultant for and food and beverage compensation from Cook Medical LLC; consultant for Endo-Therapeutics, Hemostasis LLC, Merit Medical Systems Inc, and Steris Corporation. J. L. Buxbaum: Consultant for and research support, travel, and food and beverage compensation from Olympus America Inc; consultant for and travel and food and beverage compensation from Boston Scientific Corporation; consultant for Eagle Pharmaceuticals, Inc and Cook Incorporated; research support from Medtronic USA, Inc; food and beverage compensation from Covidien LP and AbbVie, Inc. C. J. DiMaio: Consultant for and travel and food and beverage compensation from Boston Scientific Corporation; consultant for Covidien LP and AbbVie, Inc; food and beverage compensation from Cook Medical LLC. L. L. Fujii-Lau: Research support from Cook Medical LLC; travel compensation from Ovesco; food and beverage compensation from Covidien LP and Boston Scientific Corporation. L. H. Jamil: Honoraria, travel compensation, and food and beverage compensation from Aries Pharmaceuticals, Inc; food and beverage compensation from AbbVie, Inc and Olympus America, Inc. T. L. Jue: Food and beverage compensation from Boston Scientific Corporation. J. Law has received food and beverage compensation from Cook Medical LLC. J. K. Lee: Research support from Pentax of America, Inc.. S. Pawa: Educational support from Alexion Pharmaceuticals, Inc; food and beverage compensation from Cook Medical LLC. A. C. Storm: Consultant for and travel and food and beverage compensation from Apollo Endo Surgery US Inc; consultant for Endo-TAGSS and Enterasense; data/safety monitoring from Erbe USA Inc and GI Dynamics; research support and food and beverage compensation from Boston Scientific Corporation. B. J. Qumseya: Food and beverage compensation from Boston Scientific Corporation and GlaxoSmithKline, LLC.

      Acknowledgments

      We thank Emily Groesbeck and Wenora Johnson, 2 patient representatives from the Facing Hereditary Cancer Empowered, an advocacy organization for families facing hereditary cancers, for participating in our panel. We also thank Dr Anne Marie Lennon, Dr Emad Qayed, Dr Ajay Pal Singh, and Dr Jenifer Lightdale for their review of this document. This guideline was funded exclusively by the American Society for Gastrointestinal Endoscopy; no outside funding was received to support the development of this guideline.

      GUIDELINE UPDATE

      ASGE guidelines are reviewed for updates approximately every 5 years, or in the event that new data may influence a recommendation. Updates follow the same ASGE guideline development process.

      Appendix 1

      Search strategies for the population, intervention, comparator, and outcomes (PICO) questions 1 and 2 (screening; EUS vs magnetic resonance imaging) and PICO questions 3 and 4 (risk of pancreatic cancer in BRCA1, BRCA2, and PALB2) for pancreatic cancer screening in individuals at increased risk because of genetic susceptibility Search strategies for pancreatic cancer screening in individuals at increased risk because of genetic susceptibility

      Search date: March 21, 2020
      Databases searched: Ovid MEDLINE: Epub Ahead of Print, In-Process & Other Non-Indexed Citations, Ovid MEDLINE® Daily and Ovid MEDLINE® 1946-Present, Embase Classic+Embase 1947 to 2020 March 20; Wiley Cochrane
      Limits: English language, human, 2017 to current
      Excluded: Case reports, letters, editorials, comments, notes
      Tabled 1
      No.SearchesResults
      1exp ∗pancreas cancer/ use emczd or exp ∗pancreas tumour/ use emczd91206
      2exp ∗Pancreatic Neoplasms/ use ppez61606
      3((Pancreatic or pancreas) adj2 (adenocarcinoma∗ or cancer∗ or neoplasm∗)).ti,ab,kw.133029
      4or/1-3196195
      5exp ∗mass screening/151526
      6exp ∗Population Surveillance/ use ppez24991
      7exp ∗health survey/ use emczd29583
      8exp ∗"Early Detection of Cancer"/ use ppez13729
      9exp ∗early cancer diagnosis/ use emczd or exp ∗early diagnosis/ use emczd13256
      10(screen∗ or surveil∗).ti,ab,kw.2162951
      11or/5-102242284
      124 and 1110522
      13exp Endosonography/ use ppez12454
      14exp endoscopic ultrasonography/ use emczd7966
      15(endoscop∗ adj2 (ultrasound∗ or ultrasonograph∗)).ti,ab,kw.33961
      16(eus or endosonograph∗).ti,ab,kw.34316
      17exp nuclear magnetic resonance imaging/ use emczd936957
      18exp Magnetic Resonance Imaging/ use ppez444251
      19((Magnetic Resonance or MR) adj2 (cholangiopancreatography or Imaging)).ti,ab,kw.610070
      20or/13-191550633
      2112 and 201680
      22limit 21 to english language1584
      23limit 22 to yr="2017 -Current"548
      24animals/ not (humans/ and animals/)6021236
      2523 not 24548
      26limit 25 to (case reports or comment or editorial or letter or note) [Limit not valid in Ovid MEDLINE(R),Ovid MEDLINE(R) Daily Update, Ovid MEDLINE(R) In-Process, Ovid MEDLINE(R) Publisher, Embase; records were retained]36
      27Case Report/4644397
      2825 not (26 or 27)442
      29remove duplicates from 28345
      Tabled 1
      IDSearchHits
      #1MeSH descriptor: [Pancreatic Neoplasms] explode all trees1673
      #2((Pancreatic or pancreas) NEAR/2 (adenocarcinoma∗ or cancer∗ or neoplasm∗)):ti,ab,kw4597
      #3#1 or #24627
      #4MeSH descriptor: [Mass Screening] explode all trees3626
      #5MeSH descriptor: [Population Surveillance] explode all trees499
      #6MeSH descriptor: [Early Detection of Cancer] explode all trees1043
      #7(screen∗ or surveil∗):ti,ab,kw73697
      #8#4 or #5 or #6 or #774138
      #9#3 and #8192
      #10MeSH descriptor: [Endosonography] explode all trees327
      #11(endoscop∗ NEAR/2 (ultrasound∗ or ultrasonograph∗)):ti,ab,kw1109
      #12(eus or endosonograph∗):ti,ab,kw1375
      #13MeSH descriptor: [Magnetic Resonance Imaging] explode all trees7394
      #14((Magnetic Resonance or MR) NEAR/2 (cholangiopancreatography or Imaging)):ti,ab,kw21872
      #15#10 or #11 or #12 or #13 or #1423889
      #16#9 and #15 with Cochrane Library publication date Between Jan 2017 and Jan 202014

      Search strategies for risk of pancreatic cancer in individuals with BRCA1, BRCA2, and PALB2 pathogenic variants

      Search date: December 13, 2019
      Databases searched: Ovid MEDLINE: Epub Ahead of Print, In-Process & Other Non-Indexed Citations, Ovid MEDLINE® Daily and Ovid MEDLINE® 1946-Present, Embase Classic+Embase 1947 to 2019 December 12; Wiley Cochrane
      Limits: Human, English, 1990 to current
      Excluded: Case reports, editorial, letters, notes, comments, and conference abstracts published before 2017
      Tabled 1
      No.SearchesResults
      1exp Genes, BRCA1/ use ppez5853
      2exp BRCA1 Protein/23005
      3exp Genes, BRCA2/ use ppez3792
      4exp BRCA2 Protein/16930
      5exp Fanconi Anemia Complementation Group N Protein/ use ppez283
      6(brca1 or brca2 or palb2 or fancn or Fanconi Anemia Complementation Group N).ti,ab,kf,kw.41352
      7('hereditary breast and ovarian cancer syndrome∗').ti,ab,kf,kw.832
      8or/1-750562
      9exp Pancreatic Neoplasms/ use ppez73615
      10exp pancreas tumor/ use emczd144623
      11exp pancreas cancer/ use emczd100198
      12(pancreas or pancreatic).ti,ab,kf,kw.593570
      13or/9-12641903
      148 and 132171
      15animals/ not (humans/ and animals/)5985793
      1614 not 152156
      17limit 16 to english language2098
      18limit 17 to yr="1990 -Current"2096
      19limit 18 to (case reports or comment or editorial or letter or note) [Limit not valid in Ovid MEDLINE(R),Ovid MEDLINE(R) Daily Update, Ovid MEDLINE(R) In-Process, Ovid MEDLINE(R) Publisher, Embase; records were retained]128
      20Case Report/ or case report.ti.4653589
      2118 not (19 or 20)1854
      22limit 21 to (congress or conference abstract) [Limit not valid in Ovid MEDLINE(R),Ovid MEDLINE(R) Daily Update, Ovid MEDLINE(R) In-Process, Ovid MEDLINE(R) Publisher, Embase; records were retained]516
      23limit 22 to yr="1860 - 2017"369
      2421 not 231485
      25remove duplicates from 241067
      Wiley Cochrane
      Tabled 1
      #1MeSH descriptor: [Genes, BRCA1] explode all trees80
      #2MeSH descriptor: [BRCA1 Protein] explode all trees61
      #3MeSH descriptor: [Genes, BRCA2] explode all trees65
      #4MeSH descriptor: [BRCA2 Protein] explode all trees47
      #5MeSH descriptor: [Fanconi Anemia Complementation Group N Protein] explode all trees0
      #6(brca1 or brca2 or palb2 or fancn or Fanconi Anemia Complementation Group N):ti,ab759
      #7('hereditary breast and ovarian cancer syndrome∗'):ti,ab24
      #8#1 or #2 or #3 or #4 or #5 or #6 or #7793
      #9MeSH descriptor: [Pancreatic Neoplasms] explode all trees1558
      #10(pancreas or pancreatic):ti,ab10918
      #11#9 or #1011106
      #12#8 and #1132
      Appendix 2Screening recommendations made by others for individuals with genetic susceptibility to pancreatic cancer
      National Comprehensive Cancer NetworkAmerican College of GastroenterologyInternational Cancer of the Pancreas Screening Consortium
      Familial pancreatic cancer≥2 FDRs with PC, or ≥3 relatives with PC on same side of family. Start at age 50 years, or 10 years earlier than youngest relative with PC.≥2 relatives with PC of whom at least 1 is an FDR, or ≥3 relatives with PC. Start at age 50 years, or 10 years earlier than youngest relative with PC.2 relatives with PC, with at least 1 an FDR. Start at age 50 or 55 years, or 10 years earlier than youngest relative with PC.
      Familial atypical multiple mole melanoma syndromeStart at age 40 years, or 10 years earlier than youngest relative with PC.Start at age 50 years, or 10 years earlier than youngest relative with PC.Start at age 40 years.
      Peutz-Jeghers syndrome30-35 years, or 10 years earlier than youngest relative with PC.Start at age 35 years.Start at age 40 years.
      Ataxia-telangiectasiaFirst- or second-degree relative with PC. Screening should start at age 50 years, or 10 years earlier than youngest relative with PC.First- or second-degree relative with PC. Screening should start at age 50 years, or 10 years earlier than youngest relative with PC.First-degree relative with PC. Screening should start at age 45-50 years, or 10 years earlier than youngest relative with PC.
      Lynch syndromeFirst- or second-degree relative with PC. Screening should start at age 50 years, or 10 years earlier than youngest relative with PC.First- or second-degree relative with PC. Screening should start at age 50 years, or 10 years earlier than youngest relative with PC.First-degree relative with PC. Screening should start at age 45-50 years, or 10 years earlier than youngest relative with PC.
      Hereditary pancreatitisPathogenic variants in PRSS1 or other hereditary pancreatitis genes and consistent clinical phenotype. Start 20 years after onset of pancreatitis or age 40 years.Age 50 years, or 10 years earlier than youngest relative with PC.Failed to reach consensus but stated that most experts recommended screening at age 40, or 20 years after the first pancreatitis attack.
      FDR, First-degree relative; PC, pancreatic cancer.

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