The Pancreatic Cancer Early Detection (PRECEDE) Study is a Global Effort to Drive Early Detection: Baseline Imaging Findings in High-Risk Individuals

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George Zogopoulos McGill University Health Centre, Montreal, Quebec, Canada

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Ido Haimi New York University Langone Health, New York, NY

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Shenin A. Sanoba New York University Langone Health, New York, NY

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Jessica N. Everett New York University Langone Health, New York, NY

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Yifan Wang McGill University Health Centre, Montreal, Quebec, Canada

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Bryson W. Katona University of Pennsylvania Perelman School of Medicine, Philadelphia, PA

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James J. Farrell Yale School of Medicine, Yale University, New Haven, CT

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Aaron J. Grossberg Oregon Health & Science University, Portland, OR

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Salvatore Paiella General and Pancreatic Surgery Unit, Pancreas Institute, University of Verona, Verona, Italy

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Kelsey A. Klute University of Nebraska Medical Center, Omaha, NE

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Yan Bi Mayo Clinic, Jacksonville, FL

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Michael B. Wallace Mayo Clinic, Jacksonville, FL

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Richard S. Kwon Michigan Medicine, Ann Arbor, MI

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Elena M. Stoffel Michigan Medicine, Ann Arbor, MI

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Raymond C. Wadlow Inova Schar Cancer Institute, Fairfax, VA

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Daniel A. Sussman University of Miami Health System, Miami, FL

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Nipun B. Merchant University of Miami Health System, Miami, FL

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Jennifer B. Permuth Moffitt Cancer Center, Tampa, FL

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Talia Golan Sheba Medical Center and Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel

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Maria Raitses-Gurevich Sheba Medical Center and Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel

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Andrew M. Lowy UC San Diego Health, La Jolla, CA

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Joy Liau UC San Diego Health, La Jolla, CA

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Joanne M. Jeter Huntsman Cancer Institute, Salt Lake City, UT

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James M. Lindberg UMass Memorial Health, Worcester, MA

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Daniel C. Chung Massachusetts General Hospital and Harvard Medical School, Boston, MA

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Julie Earl Ramón y Cajal Health Research Institute, Madrid, Spain

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Teresa A. Brentnall University of Washington Medical Center, Seattle, WA

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Kasmintan A. Schrader BC Cancer, Vancouver, British Columbia, Canada

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Vivek Kaul University of Rochester Medical Center, Rochester, NY

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Chenchan Huang New York University Langone Health, New York, NY

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Hersh Chandarana New York University Langone Health, New York, NY

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Caroline Smerdon Arbor Research Collaborative for Health, Ann Arbor, MI

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John J. Graff Arbor Research Collaborative for Health, Ann Arbor, MI

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Fay Kastrinos Columbia University Irving Medical Center/Herbert Irving Comprehensive Cancer Center, New York, NY

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Sonia S. Kupfer University of Chicago, Chicago, IL

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Aimee L. Lucas Icahn School of Medicine at Mount Sinai, New York, NY

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Rosalie C. Sears Oregon Health & Science University, Portland, OR

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Randall E. Brand University of Pittsburgh, Pittsburgh, PA

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Giovanni Parmigiani Dana-Farber Cancer Institute and Harvard T.H. Chan School of Public Health, Boston, MA

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Diane M. Simeone New York University Langone Health, New York, NY

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on behalf of the PRECEDE Consortium
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Background: Pancreatic adenocarcinoma (PC) is a highly lethal malignancy with a survival rate of only 12%. Surveillance is recommended for high-risk individuals (HRIs), but it is not widely adopted. To address this unmet clinical need and drive early diagnosis research, we established the Pancreatic Cancer Early Detection (PRECEDE) Consortium. Methods: PRECEDE is a multi-institutional international collaboration that has undertaken an observational prospective cohort study. Individuals (aged 18–90 years) are enrolled into 1 of 7 cohorts based on family history and pathogenic germline variant (PGV) status. From April 1, 2020, to November 21, 2022, a total of 3,402 participants were enrolled in 1 of 7 study cohorts, with 1,759 (51.7%) meeting criteria for the highest-risk cohort (Cohort 1). Cohort 1 HRIs underwent germline testing and pancreas imaging by MRI/MR-cholangiopancreatography or endoscopic ultrasound. Results: A total of 1,400 participants in Cohort 1 (79.6%) had completed baseline imaging and were subclassified into 3 groups based on familial PC (FPC; n=670), a PGV and FPC (PGV+/FPC+; n=115), and a PGV with a pedigree that does not meet FPC criteria (PGV+/FPC–; n=615). One HRI was diagnosed with stage IIB PC on study entry, and 35.1% of HRIs harbored pancreatic cysts. Increasing age (odds ratio, 1.05; P<.001) and FPC group assignment (odds ratio, 1.57; P<.001; relative to PGV+/FPC–) were independent predictors of harboring a pancreatic cyst. Conclusions: PRECEDE provides infrastructure support to increase access to clinical surveillance for HRIs worldwide, while aiming to drive early PC detection advancements through longitudinal standardized clinical data, imaging, and biospecimen captures. Increased cyst prevalence in HRIs with FPC suggests that FPC may infer distinct biological processes. To enable the development of PC surveillance approaches better tailored to risk category, we recommend adoption of subclassification of HRIs into FPC, PGV+/FPC+, and PGV+/FPC– risk groups by surveillance protocols.

Background

The global incidence of pancreatic adenocarcinoma (PC) has doubled since the 1990s,1,2 whereas overall survival rates have only increased from 3% to 5% to just 12% as of 2023.3 The lethality of PC is attributed to advanced cancer stage at diagnosis and evasiveness to systemic therapies.4 Thus, because 80% of patients with PC are diagnosed with advanced-stage disease, early detection offers an opportunity to markedly impact survival. To this end, patients with stage IA disease who undergo surgical resection have a 5-year survival rate of >80%.5

Owing to the relatively low incidence of PC, surveillance for the general population is not recommended,6 and surveillance efforts have been steered toward individuals with an increased lifetime PC risk (>5%). However, high-risk individuals (HRIs) undergoing surveillance every 12 months may escape early detection using current imaging modalities, likely due to variability among HRI subpopulations in the rate of transformation of pancreatic epithelial cells to a premalignant state, then an invasive state, and then a metastatic state.711 Thus, there has been skepticism even toward surveilling HRIs. But more recent studies showing favorable clinical outcomes with surveillance of HRIs have renewed clinical interest in the field.1214 Expert groups now recommend surveilling HRIs, preferably in a research setting, considering the unanswered questions of which at-risk subpopulations will benefit from surveillance and how to optimally surveil these patients.1517

Despite these recommendations, surveillance of HRIs has not been widely adopted. Barriers to implementation include lack of awareness of indications for surveillance, availability of clinical expertise, heterogeneity in provider provisions for genetic testing and surveillance, and a lack of funding for research-embedded surveillance programs.18 To address these hurdles and drive early diagnosis, we established the Pancreatic Cancer Early Detection (PRECEDE) Consortium and the PRECEDE Longitudinal Cohort Study.19

PRECEDE is a global effort that recognizes the magnitude of the cohort sizes and the years of longitudinal data needed to develop effective, data-driven clinical practices.20 Here, we describe the PRECEDE Consortium and its longitudinal study design, with an interim enrollment analysis to demonstrate feasibility and potential for impact.

Methods

Study Design

The PRECEDE multi-institutional, observational, prospective cohort study (ClinicalTrials.gov identifier: NCT04970056) is being performed in the setting of a consortium. The governance of the consortium is shown in Figure S1 and described in the Supplemental Methods in the supplementary materials (available online with this article). The timeline of PRECEDE milestones is shown in Figure 1. Participants gave informed consent to participate in the study. Ethics approval, patient engagement, data availability, and management of clinical data and biospecimens statements are provided in the Supplemental Methods.

Figure 1.
Figure 1.

Timeline of PRECEDE Consortium milestones.

Abbreviations: DCC, data coordinating center; EUS, endoscopic ultrasound; IRB, Institutional Review Board; PRECEDE, Pancreatic Cancer Early Detection.

Citation: Journal of the National Comprehensive Cancer Network 22, 3; 10.6004/jnccn.2023.7097

Study Population

Individuals aged 18 to 90 years who present for PC risk assessment and surveillance are evaluated for eligibility and then assigned to 1 of 7 cohorts (Table 1) based on family history and carrier status of pathogenic germline variants (PGVs) in PC predisposition genes. A 3-generation family cancer pedigree is obtained at enrollment and updated during subsequent clinical visits. Standardized clinical germline testing is offered, with Cohort 1 participants required to undergo testing for PGVs in genes commonly associated with PC predisposition (ie, BRCA1, BRCA2, ATM, PALB2, CDKN2A, MLH1, MSH2, MSH6, PMS2, PRSS1, and STK11). Cohort 1 is the highest-risk cohort, for which PRECEDE requires annual surveillance by MRI/MR-cholangiopancreatography (MRCP) or endoscopic ultrasound (EUS) with standardized reporting (see supplementary materials).21,22

Table 1.

PRECEDE Cohorts

Table 1.

Cohort 1

From April 1, 2020, to November 21, 2022, a total of 1,759 patients from 25 sites were enrolled in Cohort 1. Demographics (sex, race, ethnicity, age), genetic testing results, family history of PC, pancreatitis and diabetes histories, and baseline MRI/MRCP and EUS data were obtained from the Data Coordinating Centre. Imaging variables were extracted from MRI/MRCP and EUS reports and consisted of (1) cysts with their sizes and the presence of mural nodules, (2) main pancreatic duct (MPD) caliber measurements and the presence of strictures, and (3) solid lesions.

We compared pancreatic abnormalities among 3 Cohort 1 subgroups: (1) individuals with familial PC (FPC) versus (2) individuals harboring a PGV and with a family history that meets FPC criteria (PGV+/FPC+) versus (3) individuals harboring a PGV but with a family history that does not meet FPC criteria (PGV+/FPC–). FPC was assigned to kindred if there were at least 2 individuals on the same side of the pedigree affected by PC with at least 2 of the affected individuals being first-degree relatives. FPC classification alone was assigned to FPC kindred that were not known to harbor a PGV in a PC susceptibility gene.

Categorical variables were compared using Pearson’s chi-square test. For post hoc pairwise comparisons of categorical variables, P values were adjusted for multiple comparisons using the Bonferroni correction. To identify factors associated with the presence of a pancreatic cyst, we first performed a univariable logistic regression using a set of predefined clinically relevant parameters. Variables with a P value <.10 in the univariable analysis were included in a multivariable logistic regression analysis to identify independent predictors of harboring a pancreatic cyst after adjusting for covariates. A P value <.05 was considered statistically significant. All statistical analyses were performed using R version 4.2.3 (R Foundation for Statistical Computing) and SPSS Statistics, version 27 (SPSS Inc.).

Results

Enrollment

From April 1, 2020, to November 21, 2022, the average monthly accrual, based on 25 enrolling sites (Supplementary Figure S2), was 122 participants across all cohorts and 51 participants into Cohort 1. As of April 1, 2023, 55 sites worldwide were activated or completing onboarding (Supplementary Figure S2). Figure 2A shows the overall enrollment across the different cohorts (N=3,402 participants) relative to Cohort 1 participants (n=1,759). Figure 2B shows enrollment progress for each cohort. Cohort 1 is the highest-risk cohort and represents 51.7% of the study enrollment across all cohorts.

Figure 2.
Figure 2.

Cumulative PRECEDE enrollment over study period. (A) Total and cohort 1 enrollment, and (B) enrollment of all PRECEDE cohorts.

Abbreviation: PRECEDE, Pancreatic Cancer Early Detection.

Citation: Journal of the National Comprehensive Cancer Network 22, 3; 10.6004/jnccn.2023.7097

Cohort 1 Characteristics

Cohort 1 was subclassified according to PGV and FPC status. Assignment of FPC requires testing for germline mutations in PC susceptibility genes. However, likely due to the limited availability of germline testing, large PC surveillance studies to date have assigned FPC status to HRIs based on FPC clustering alone.23 PRECEDE aims to assign FPC status more accurately with systematic germline testing of HRIs. Supplementary Table S1 shows the demographic characteristics of participants in Cohort 1 (n=1,759), according to their subclassification into FPC (n=839; 47.7%), PGV+/FPC+ (n=138; 7.8%), and PGV+/FPC– (n=782; 44.5%). Supplementary Table S2 lists the germline testing requirements for assignment into these 3 Cohort 1 groups. Importantly, 724 (86.3%) HRIs in the FPC group underwent germline testing (supplementary materials). Limited availability or unavailability of germline testing in their health care jurisdiction was the primary reason for HRIs (n=115; 13.7%) in the FPC group not to have met PRECEDE germline testing recommendations.

The distribution of PGVs in PC susceptibility genes in the PGV+/FPC+ and PGV+/FPC–groups is shown in Supplementary Table S3A, with 23 Cohort 1 patients harboring PGVs in >1 PC susceptibility gene (Supplementary Table S3B). BRCA2 was the most prevalent mutated gene among the HRIs (n=345), followed by ATM (n=149), BRCA1 (n=131), CDKN2A (n=90), and PALB2 (n=67). Notably, there are 27 HRIs with STK11 mutations and Peutz-Jeghers syndrome (PJS), which carries up to a 36% life-time risk of developing PC.24 This represents the largest reported PJS cohort under PC surveillance, which is of particular interest given that accelerated pancreatic malignant transformation in patients with PJS, including from branch-duct intraductal papillary mucinous neoplasms (BD-IPMNs), has been reported.8

Cohort 1 Pancreatic Findings

In all, 1,759 HRIs from Cohort 1 were evaluated for imaging features based on MRI/MRCP or EUS examinations at enrollment (Figure 3) according to subclassification of HRIs into FPC (n=839), PGV+/FPC+ (n=138), and PGV+/FPC– (n=782) subgroups. Overall, 79.6% of the Cohort 1 HRIs had baseline imaging. Table 2 shows a significant difference in the prevalence of pancreatic cysts among the 3 groups (FPC, 41.2%; PGV+/FPC+, 30.4%; PGV+/FPC–, 29.4%; P<.001). In pairwise comparisons, pancreatic cysts were significantly more prevalent in the FPC group compared with the PGV+/FPC– group (41.2 vs 29.4%, respectively; P<.001), whereas there was no significant difference in the prevalence of pancreatic cysts between the FPC and PGV+/FPC+ groups or between the PGV+/FPC– and PGV+/FPC+ subgroups. To further explore this finding, we evaluated the distribution of pancreatic cysts based on number and size within each group, but we did not observe a statistically significant difference. Mural nodules were not observed in any of the 3 groups. We also did not observe a difference in the rate of MPD abnormalities or solid pancreatic lesions among the 3 groups.

Figure 3.
Figure 3.

Baseline pancreatic imaging findings across cohort 1 participants. Imaging modality (MRI/MRCP, EUS) and absence or presence of pancreatic abnormalities are listed.

Abbreviations: EUS, endoscopic ultrasound; FPC, familial pancreatic cancer; MRCP, magnetic resonance cholangiopancreatography; PGV, pathogenic germline variant; PGV+/FPC+, a PGV and FPC; PGV+/FPC–, a PGV with a pedigree that does not meet FPC criteria; PRECEDE, Pancreatic Cancer Early Detection.

Citation: Journal of the National Comprehensive Cancer Network 22, 3; 10.6004/jnccn.2023.7097

Table 2.

Pancreatic Lesions Identified at Enrollment in Cohort 1

Table 2.

Pancreatic Cystic Lesions

A pancreatic cyst prevalence of 35.1% was observed for HRIs in Cohort 1 (Table 2). Cysts with a worrisome feature were observed in 2 patients (Supplementary Figure S3). Both individuals were from the FPC group and had cysts ≥3 cm, without high-risk stigmata for malignancy or additional worrisome clinical and radiologic features, including new-onset diabetes. Neither patient underwent surgical resection (see supplementary materials).

The higher prevalence of pancreatic cysts observed in the FPC group was an unexpected finding. Thus, we performed a univariable logistic regression analysis to identify clinical features that may be associated with the presence of a pancreatic cyst (Figure 4A). Clinical variables examined included age, sex, the presence of diabetes, history of pancreatitis, and subgroup classification (FPC vs PGV+/FPC+ vs PGV+/FPC–). On univariable analysis, increasing age (odds ratio [OR], 1.06; P<.001), presence of diabetes (OR, 1.60; P=.01), and FPC group assignment (OR, 1.70; P<.001; relative to PGV+/FPC–) were significantly associated with the presence of a pancreatic cyst. On multivariable logistic regression, increasing age (OR, 1.05; P<.001) and FPC group assignment (OR, 1.57; P<.001; relative to PGV+/FPC–) were independent predictors of harboring a pancreatic cyst, after adjusting for covariates (Figure 4B). Furthermore, we performed a subgroup analysis restricting the FPC group to only participants who had undergone germline testing (n=724). Increasing age (OR, 1.06; P<.001) and FPC group assignment (OR, 1.55; P<.001; relative to PGV+/FPC–) remained independently predictive of harboring a pancreatic cyst on multivariable logistic regression analysis (Supplementary Figure S4).

Figure 4.
Figure 4.

Forest plots identifying variables predictive of harboring a pancreatic cyst. (A) Univariable and (B) multivariable logistic regression analyses. Variables with a P value <.1 in the univariable analysis were included in the multivariable logistic regression analysis.

Abbreviations: FPC, familial pancreatic cancer; OR, odds ratio; PGV, pathogenic germline variant; PGV+/FPC+, a PGV and FPC; PGV+/FPC–, a PGV with a pedigree that does not meet FPC criteria.

Citation: Journal of the National Comprehensive Cancer Network 22, 3; 10.6004/jnccn.2023.7097

MPD Abnormalities

The distribution of maximal MPD diameter across evaluable Cohort 1 participants is shown in Table 3, according to FPC, PGV+/FPC+, and PGV+/FPC– classification. Either focal or diffuse MPD dilatation of ≥5 mm was reported for 19 HRIs. In each case, multidisciplinary clinical decisions were made to continue surveillance for these individuals, except for 1 HRI with an MPD dilatation of ≥10 mm who was offered but declined surgical resection and is continuing with imaging surveillance. Both patients with baseline MRI/MRCP imaging that suggested an MPD stricture were further evaluated by EUS examinations, which did not reveal worrisome findings, and both patients are continuing with surveillance at the time of writing.

Table 3.

Cohort 1 Distribution of Maximum Main Pancreatic Duct Diameters

Table 3.

Solid Lesions

A total of 23 patients in Cohort 1 were found to have solid lesions on baseline imaging. Supplementary Table S4 shows the solid lesions identified in Cohort 1 at enrollment imaging according to FPC, PGV+/FPC+, and PGV+/FPC– classification. An incidental PC was identified in an 84-year-old female with a CDKN2A PGV and a family history of PC that did not meet FPC criteria (PGV+/FPC– group; Supplementary Figure S5). This patient underwent a distal pancreatectomy and splenectomy, and histologic analysis of the resection specimen revealed a moderately differentiated nonmucinous ductal adenocarcinoma (pT2N1) with lymphovascular invasion, perineural invasion, and negative resection margins. The patient completed 6 months of adjuvant gemcitabine with capecitabine and is undergoing surveillance at the time of writing.

A pancreatic neuroendocrine tumor (pNET) was identified in 10 patients. An additional 9 patients had benign or nondiagnostic solid lesions. The clinical management of these 19 patients is detailed in the supplementary materials.

Adverse Events

There were no adverse events reported with surveillance examinations or invasive diagnostic procedures. Across Cohort 1, 14 EUS-guided fine-needle biopsies (n=11) or fine-needle aspirations (n=3) were performed to evaluate solid lesions, and 1 fine-needle aspiration was performed to assess a cystic lesion >3 cm. The 2 patients who underwent surgical resection did not have any significant postoperative complications.

Characteristics of the Other 6 Cohorts

The remaining 6 cohorts (Table 1) were established to support the growth of Cohort 1 or to serve as study controls. Cohort 2, 3, and 4 participants do not meet Cohort 1 criteria but may cross over to Cohort 1. Crossover may occur with new PC diagnoses in the kindred, when a participant reaches the age requirement for imaging surveillance, or if a PGV is identified in a participant after enrollment. Cohort 5 represents a control group of individuals who wish to participate but do not meet other cohort criteria, and includes unaffected nonmutation carriers from kindred harboring a PGV. Cohort 6 was established to support studies examining pancreatic carcinogenesis among HRIs. It encompasses patients with PC at enrollment and predisposition based on family history, PGV carrier status, or onset at a young age. The cyst cohort consists of patients with pancreatic cysts who are followed longitudinally and do not meet higher-risk cohort criteria. They will serve as controls for cyst outcome studies of patients in the higher-risk cohorts. Supplementary Tables S5 and S6 show the demographic and PGV characteristics among the 3,402 participants enrolled across the 7 cohorts.

Discussion

PRECEDE provides an opportunity for centers worldwide to offer HRIs surveillance in a setting to monitor the outcomes and inform revisions to early detection guidelines. We demonstrate feasibility through the rapid expansion of PRECEDE worldwide and a baseline enrollment imaging completeness rate of 79.6%, which is underestimated because patients at the time of data censoring had pending imaging examinations.

We confirm, in a multicenter international cohort, a high prevalence of pancreatic cysts among HRIs (35.1% in Cohort 1), which are inferred to be BD-IPMNs.8,25 The finding that HRIs with FPC, but without a PGV, have a higher likelihood of harboring pancreatic cysts suggests that FPC status may underlie risks for pancreatic abnormalities that do not fully overlap with risks inferred by known PC susceptibility genes. To decipher the biological differences driving pancreatic aberrations between FPC and PGV risk groups, assessment for PGVs in HRIs from FPC kindred should be routine practice for PC surveillance registries.

A subset of HRIs escape annual surveillance and have poor clinical outcomes after diagnoses of PC between surveillance imaging examinations.11 The Cancer of the Pancreas Screening-5 (CAPS5) study reported a median overall survival of 9.8 years for surveillance-detected PC, which was higher than 1.5 years for patients with PC diagnoses outside surveillance.13 Accelerated PC progression may underlie PCs that escape surveillance, whereby rapid evolutionary events, such as chromothripsis, drive rapid cancer development.26 Such rapid transformation substantially reduces the lag-time advantage for surveillance offered by the step-wise cancer progression model.27 Moreover, certain PGVs, such as STK11 mutations in patients with PJS, may predispose to accelerated pancreatic carcinogenesis that escapes even biannual imaging surveillance.8 To this end, loss of STK11 function promotes IPMN progression, and STK11-driven BD-IPMNs in patients with and without PJS have been proposed to be at high risk for malignant transformation through cataclysmic events.28,29 Molecular profiling of surveillance-detected PCs may identify specific PGVs and FPC characteristics with accelerated development of PC that warrant more individualized screening paradigms.

Improved biomarkers are needed to better risk-stratify precursor lesions in HRIs. The Fukuoka guidelines30 commonly used for surgical management of BD-IPMNs have moderate sensitivity and specificity in HRIs.25 Integration of cyst fluid mutational analysis into PC surveillance strategies may more accurately identify HRIs that benefit from earlier surgical intervention.31 Although there is clinical equipoise for cyst fluid analysis of dominant or evolving BD-IPMNs, particularly in STK11 PGV carriers, BD-IPMNs in HRIs are often multifocal, and centimetric or millimetric, without a differentiating cyst for invasive testing. This multifocality tendency suggests a pancreas field defect with predisposition for cyst development, and likely for other early precursor lesions. The clinical relevance of a higher cyst prevalence in HRIs with FPC may be the distinct biology underlying the gland in HRIs with FPC, rather than attribution of their pancreatic carcinogenesis risk primarily to BD-IPMN transformation, especially because PC among HRIs with FPC is not characteristically mucinous. Thus, surveillance of these HRIs must be conducted with clinical caution to not overtreat indolent pancreatic cysts. These clinical challenges highlight the need for the parallel development of more effective predictive liquid biopsy biomarkers and improved imaging modalities.

A limitation of our analysis is the lack of longitudinal surveillance outcomes and the need for even larger sample sizes in each HRI risk group. Addressing these limitations will allow for important questions to be answered, including those that will lead to a better understanding of the relationship of FPC, PGV carrier status, and sporadic setting with BD-IPMN malignant degeneration risk and rate. Moreover, larger sample sizes are needed to determine how the occurrence of FPC compares among kindred with higher- versus lower-risk PGVs (eg, STK11 vs BRCA2). PRECEDE is on track to enroll 10,000 participants with at least 5,000 individuals in Cohort 1 by 2025, attaining a sample size large enough to address the carcinogenesis heterogeneity among HRI risk groups. Our incident rates of high-risk lesions and PCs may be impacted by dropout from follow-up due to aging or mortality unrelated to PC.23 These dropout rates will be counterbalanced with crossover of participants from lower-risk cohorts. Patients with a PGV and/or FPC, who enroll after their PC diagnosis (Cohort 6), will provide additional resources to study pancreatic carcinogenesis driven by genetic or familial predisposition. Similarly, the pancreas sporadic cyst cohort will serve as a general population control resource for cyst analyses among HRIs. The secondary finding of a 0.7% pNET incidence among HRIs is intriguing and comparable to observations from other surveillance studies.10,32 Longitudinal observations are needed to determine whether there is an increased pNET risk among HRIs relative to the general population.

PRECEDE is committed to increasing participant diversity and equity in access to PC surveillance.33 Our interim analysis showed that participants are overwhelmingly non-Hispanic White (89%). To increase enrollment diversity, we are onboarding centers that historically serve marginalized populations. In addition, because social impacts, including racism-induced stressors, may promote cancer risk through chronic inflammation and other physiologic changes, we are capturing social determinants of health.34,35

Conclusions

PRECEDE is building a large-scale research resource with depth to advance the field of early PC detection, while improving access to PC surveillance for at-risk individuals worldwide. Our interim analysis suggests that classifying HRIs into FPC, PGV+/FPC+, and PGV+/FPC– risk groups may have biologic relevance with clinical significance for tailored surveillance of HRIs. We recommend that this subclassification of HRIs be adopted by surveillance protocols moving forward.

Acknowledgments

We thank our patients for their participation and commitment to the PRECEDE study. We also recognize the support of the Data Coordinating Center staff (Arbor Research), as well as the clinical coordinators, health care professionals, and research assistants at each of the PRECEDE clinical sites.

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  • 5.

    Blackford AL, Canto MI, Klein AP, et al. Recent trends in the incidence and survival of stage 1A pancreatic cancer: a Surveillance, Epidemiology, and End Results analysis. J Natl Cancer Inst 2020;112:11621169.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 6.

    Owens DK, Davidson KW, Krist AH, et al. Screening for pancreatic cancer: US Preventive Services Task Force reaffirmation recommendation statement. JAMA 2019;322:438444.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 7.

    Overbeek KA, Goggins MG, Dbouk M, et al. Timeline of development of pancreatic cancer and implications for successful early detection in high-risk individuals. Gastroenterology 2022;162:772785.e4.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 8.

    Wang Y, Cuggia A, Chen YI, et al. Is biannual surveillance for pancreatic cancer sufficient in individuals with genetic syndromes or familial pancreatic cancer? J Natl Compr Canc Netw 2022;20:663673.e12.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 9.

    Konings ICAW, Harinck F, Poley JW, et al. Prevalence and progression of pancreatic cystic precursor lesions differ between groups at high risk of developing pancreatic cancer. Pancreas 2017;46:2834.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 10.

    Overbeek KA, Levink IJM, Koopmann BDM, et al. Long-term yield of pancreatic cancer surveillance in high-risk individuals. Gut 2022;71:11521160.

  • 11.

    Chhoda A, Vodusek Z, Wattamwar K, et al. Late-stage pancreatic cancer detected during high-risk individual surveillance: a systematic review and meta-analysis. Gastroenterology 2022;162:786798.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 12.

    Klatte DCF, Boekestijn B, Wasser MN, et al. Pancreatic cancer surveillance in carriers of a germline CDKN2A pathogenic variant: yield and outcomes of a 20-year prospective follow-up. J Clin Oncol 2022;40:32673277.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 13.

    Dbouk M, Katona BW, Brand RE, et al. The multicenter cancer of pancreas screening study: impact on stage and survival. J Clin Oncol 2022;40:32573266.

  • 14.

    Klatte DCF, Boekestijn B, Onnekink AM, et al. Surveillance for pancreatic cancer in high-risk individuals leads to improved outcomes: a propensity score-matched analysis. Gastroenterology 2023;164:12231231.e4.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 15.

    Goggins M, Overbeek KA, Brand RE, et al. Management of patients with increased risk for familial pancreatic cancer: updated recommendations from the International Cancer of the Pancreas Screening (CAPS) Consortium. Gut 2020;69:717.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 16.

    Aslanian HR, Lee JH, Canto MI. AGA clinical practice update on pancreas cancer screening in high-risk individuals: expert review. Gastroenterology 2020;159:358362.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 17.

    Sawhney MS, Calderwood AH, Thosani NC, et al. ASGE guideline on screening for pancreatic cancer in individuals with genetic susceptibility: summary and recommendations. Gastrointest Endosc 2022;95:817826.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 18.

    Underhill ML, Pozzar R, Chung D, et al. Health care provider perceptions of caring for individuals with inherited pancreatic cancer risk. J Cancer Educ 2020;35:194203.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 19.

    Zogopoulos G, Bi Y, Brand RE, et al. The PRECEDE consortium: a longitudinal international cohort study of individuals with genetic risk or familial pancreatic cancer. J Clin Oncol 2022;40(Suppl):Abstract e16239.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 20.

    Gonda TA, Everett JN, Wallace M, et al. Recommendations for a more organized and effective approach to the early detection of pancreatic cancer from the PRECEDE (Pancreatic Cancer Early Detection) Consortium. Gastroenterology 2021;161:17511757.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 21.

    Gonda TA, Farrell J, Wallace M, et al. Standardization of EUS imaging and reporting in high-risk individuals of pancreatic adenocarcinoma: consensus statement of the Pancreatic Cancer Early Detection Consortium. Gastrointest Endosc 2022;95:723732.e7.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 22.

    Huang C, Simeone DM, Luk L, et al. Standardization of MRI screening and reporting in individuals with elevated risk of pancreatic ductal adenocarcinoma: consensus statement of the PRECEDE Consortium. AJR Am J Roentgenol 2022;219:903914.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 23.

    Abe T, Blackford AL, Tamura K, et al. Deleterious germline mutations are a risk factor for neoplastic progression among high-risk individuals undergoing pancreatic surveillance. J Clin Oncol 2019;37:10701080.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 24.

    Giardiello FM, Brensinger JD, Tersmette AC, et al. Very high risk of cancer in familial Peutz-Jeghers syndrome. Gastroenterology 2000;119:14471453.

  • 25.

    Dbouk M, Brewer Gutierrez OI, Lennon AM, et al. Guidelines on management of pancreatic cysts detected in high-risk individuals: an evaluation of the 2017 Fukuoka guidelines and the 2020 International Cancer of the Pancreas Screening (CAPS) Consortium statements. Pancreatology 2021;21:613621.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 26.

    Notta F, Chan-Seng-Yue M, Lemire M, et al. A renewed model of pancreatic cancer evolution based on genomic rearrangement patterns. Nature 2016;538:378382.

  • 27.

    Yachida S, Jones S, Bozic I, et al. Distant metastasis occurs late during the genetic evolution of pancreatic cancer. Nature 2010;467:11141117.

  • 28.

    Omori Y, Ono Y, Morikawa T, et al. Serine/threonine kinase 11 plays a canonical role in malignant progression of KRAS -mutant and GNAS -wild-type intraductal papillary mucinous neoplasms of the pancreas. Ann Surg 2023;277:e384395.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 29.

    Sato N, Rosty C, Jansen M, et al. STK11/LKB1 Peutz-Jeghers gene inactivation in intraductal papillary-mucinous neoplasms of the pancreas. Am J Pathol 2001;159:20172022.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 30.

    Tanaka M, Fernández-del Castillo C, Kamisawa T, et al. Revisions of international consensus Fukuoka guidelines for the management of IPMN of the pancreas. Pancreatology 2017;17:738753.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 31.

    Paniccia A, Polanco PM, Boone BA, et al. Prospective, multi-institutional, real-time next-generation sequencing of pancreatic cyst fluid reveals diverse genomic alterations that improve the clinical management of pancreatic cysts. Gastroenterology 2023;164:117133.e7.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 32.

    Canto MI, Almario JA, Schulick RD, et al. Risk of neoplastic progression in individuals at high risk for pancreatic cancer undergoing long-term surveillance. Gastroenterology 2018;155:740751.e2.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 33.

    Katona BW, Klute K, Brand RE, et al. Racial, ethnic, and sex-based disparities among high-risk individuals undergoing pancreatic cancer surveillance. Cancer Prev Res (Phila) 2023;16:343352.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 34.

    Simons RL, Lei MK, Beach SR, et al. Discrimination, segregation, and chronic inflammation: testing the weathering explanation for the poor health of Black Americans. Dev Psychol 2018;54:19932006.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 35.

    Williams DR, Lawrence JA, Davis BA, et al. Understanding how discrimination can affect health. Health Serv Res 2019;54(Suppl 2):13741388.

Submitted July 25, 2023; final revision received October 9, 2023; accepted for publication October 9, 2023.

A list of the PRECEDE Consortium collaborators is provided in Appendix 1 in the supplementary materials (available online with this article).

Author contributions: Study concept and design: Zogopoulos, Haimi, Simeone. Data acquisition: All authors. Data analysis and interpretation: Zogopoulos, Haimi, Sanoba, Everett, Wang, Parmigiani, Simeone. Funding acquisition: Zogopoulos, Kastrinos, Kupfer, Lucas, Sears, Brand, Parmigiani, Simeone. Administrative, technical, or material support: All authors. Supervision: Zogopoulos, Simeone. Writing—original draft: Zogopoulos, Haimi, Sanoba, Everett, Wang, Parmigiani, Simeone. Writing—review & editing: All authors.

Disclosures: Dr. Zogopoulos has disclosed receiving grant/research support from Immunovia. Dr. Farrell has disclosed serving as a member of the speaker’s bureau for Interpace Diagnostics. Dr. Paiella has disclosed serving as a consultant for Alpha Tau Medical. Dr. Golan has disclosed receiving grant/research support from AstraZeneca and Bristol Myers Squibb; serving as a consultant for AbbVie, AstraZeneca, Teva, and MSD Merck; and serving on a speaker’s bureau for AbbVie and Roche. Dr. Schrader has disclosed serving as a consultant for AstraZeneca Canada, Merck, and Precision Rx-Dx. Dr. Lucas has disclosed participating in research for Immunovia; serving as a scientific advisor for ClearNote Health and Immunovia; and serving as a consultant for Immunovia. Dr. Sears has disclosed serving as a scientific advisor for Rappta Therapeutics and Larkspur Biosciences; and receiving grant/research support from AstraZeneca and Cardiff Oncology. Dr. Brand has disclosed receiving grant/research support from Immunova and Freenome. Dr. Parmigiani has disclosed cofounding Phaeno Biotech; serving as a consultant for Delfi Diagnostics; and serving as a scientific advisor for REALM IDx. Dr. Simeone has disclosed serving as a scientific advisor for ClearNote Health, Interpace, Merck & Co., Bayer, and FibroGen; and receiving grant/research support from Micronoma, Immunovia, ClearNote Health, Biological Dynamics, and Tempus. The remaining authors have disclosed that they have not received any financial consideration from any person or organization to support the preparation, analysis, results, or discussion of this article.

Funding: Research reported in this publication was supported by an anonymous donor through NYU Langone (D.M. Simeone) and Ambry Genetics, TrovaNOW, Amazon Web Services, Project Purple, REALM IDx, and Invicro through the PRECEDE Consortium.

Disclaimer: The funders had no role in the design of the study; the collection, analysis, and interpretation of the data; the writing of the manuscript; or the decision to submit the manuscript for publication.

Supplementary material: Supplementary material associated with this article is available online at https://doi.org/10.6004/jnccn.2023.7097. The supplementary material has been supplied by the author(s) and appears in its originally submitted form. It has not been edited or vetted by JNCCN. All contents and opinions are solely those of the author. Any comments or questions related to the supplementary materials should be directed to the corresponding author.

Correspondence: George Zogopoulos, MD, PhD, Departments of Surgery and Oncology, McGill University, McGill University Health Centre, 1001 Decarie Boulevard, Room EM2.3210, Montreal, Quebec, H4A 3J1 Canada. Email: george.zogopoulos@mcgill.ca; and
Diane M. Simeone, MD, Department of Surgery and Department of Pathology, Perlmutter Cancer Center, New York University Langone Health, 240 East 38th Street, 20th Floor, New York, NY 10016. Email: diane.simeone@nyulangone.org

Supplementary Materials

  • Collapse
  • Expand
  • Figure 1.

    Timeline of PRECEDE Consortium milestones.

    Abbreviations: DCC, data coordinating center; EUS, endoscopic ultrasound; IRB, Institutional Review Board; PRECEDE, Pancreatic Cancer Early Detection.

  • Figure 2.

    Cumulative PRECEDE enrollment over study period. (A) Total and cohort 1 enrollment, and (B) enrollment of all PRECEDE cohorts.

    Abbreviation: PRECEDE, Pancreatic Cancer Early Detection.

  • Figure 3.

    Baseline pancreatic imaging findings across cohort 1 participants. Imaging modality (MRI/MRCP, EUS) and absence or presence of pancreatic abnormalities are listed.

    Abbreviations: EUS, endoscopic ultrasound; FPC, familial pancreatic cancer; MRCP, magnetic resonance cholangiopancreatography; PGV, pathogenic germline variant; PGV+/FPC+, a PGV and FPC; PGV+/FPC–, a PGV with a pedigree that does not meet FPC criteria; PRECEDE, Pancreatic Cancer Early Detection.

  • Figure 4.

    Forest plots identifying variables predictive of harboring a pancreatic cyst. (A) Univariable and (B) multivariable logistic regression analyses. Variables with a P value <.1 in the univariable analysis were included in the multivariable logistic regression analysis.

    Abbreviations: FPC, familial pancreatic cancer; OR, odds ratio; PGV, pathogenic germline variant; PGV+/FPC+, a PGV and FPC; PGV+/FPC–, a PGV with a pedigree that does not meet FPC criteria.

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    Ryan DP, Hong TS, Bardeesy N. Pancreatic adenocarcinoma. N Engl J Med 2014;371:10391049.

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    Blackford AL, Canto MI, Klein AP, et al. Recent trends in the incidence and survival of stage 1A pancreatic cancer: a Surveillance, Epidemiology, and End Results analysis. J Natl Cancer Inst 2020;112:11621169.

    • PubMed
    • Search Google Scholar
    • Export Citation
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    Owens DK, Davidson KW, Krist AH, et al. Screening for pancreatic cancer: US Preventive Services Task Force reaffirmation recommendation statement. JAMA 2019;322:438444.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 7.

    Overbeek KA, Goggins MG, Dbouk M, et al. Timeline of development of pancreatic cancer and implications for successful early detection in high-risk individuals. Gastroenterology 2022;162:772785.e4.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 8.

    Wang Y, Cuggia A, Chen YI, et al. Is biannual surveillance for pancreatic cancer sufficient in individuals with genetic syndromes or familial pancreatic cancer? J Natl Compr Canc Netw 2022;20:663673.e12.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 9.

    Konings ICAW, Harinck F, Poley JW, et al. Prevalence and progression of pancreatic cystic precursor lesions differ between groups at high risk of developing pancreatic cancer. Pancreas 2017;46:2834.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 10.

    Overbeek KA, Levink IJM, Koopmann BDM, et al. Long-term yield of pancreatic cancer surveillance in high-risk individuals. Gut 2022;71:11521160.

  • 11.

    Chhoda A, Vodusek Z, Wattamwar K, et al. Late-stage pancreatic cancer detected during high-risk individual surveillance: a systematic review and meta-analysis. Gastroenterology 2022;162:786798.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 12.

    Klatte DCF, Boekestijn B, Wasser MN, et al. Pancreatic cancer surveillance in carriers of a germline CDKN2A pathogenic variant: yield and outcomes of a 20-year prospective follow-up. J Clin Oncol 2022;40:32673277.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 13.

    Dbouk M, Katona BW, Brand RE, et al. The multicenter cancer of pancreas screening study: impact on stage and survival. J Clin Oncol 2022;40:32573266.

  • 14.

    Klatte DCF, Boekestijn B, Onnekink AM, et al. Surveillance for pancreatic cancer in high-risk individuals leads to improved outcomes: a propensity score-matched analysis. Gastroenterology 2023;164:12231231.e4.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 15.

    Goggins M, Overbeek KA, Brand RE, et al. Management of patients with increased risk for familial pancreatic cancer: updated recommendations from the International Cancer of the Pancreas Screening (CAPS) Consortium. Gut 2020;69:717.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 16.

    Aslanian HR, Lee JH, Canto MI. AGA clinical practice update on pancreas cancer screening in high-risk individuals: expert review. Gastroenterology 2020;159:358362.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 17.

    Sawhney MS, Calderwood AH, Thosani NC, et al. ASGE guideline on screening for pancreatic cancer in individuals with genetic susceptibility: summary and recommendations. Gastrointest Endosc 2022;95:817826.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 18.

    Underhill ML, Pozzar R, Chung D, et al. Health care provider perceptions of caring for individuals with inherited pancreatic cancer risk. J Cancer Educ 2020;35:194203.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 19.

    Zogopoulos G, Bi Y, Brand RE, et al. The PRECEDE consortium: a longitudinal international cohort study of individuals with genetic risk or familial pancreatic cancer. J Clin Oncol 2022;40(Suppl):Abstract e16239.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 20.

    Gonda TA, Everett JN, Wallace M, et al. Recommendations for a more organized and effective approach to the early detection of pancreatic cancer from the PRECEDE (Pancreatic Cancer Early Detection) Consortium. Gastroenterology 2021;161:17511757.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 21.

    Gonda TA, Farrell J, Wallace M, et al. Standardization of EUS imaging and reporting in high-risk individuals of pancreatic adenocarcinoma: consensus statement of the Pancreatic Cancer Early Detection Consortium. Gastrointest Endosc 2022;95:723732.e7.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 22.

    Huang C, Simeone DM, Luk L, et al. Standardization of MRI screening and reporting in individuals with elevated risk of pancreatic ductal adenocarcinoma: consensus statement of the PRECEDE Consortium. AJR Am J Roentgenol 2022;219:903914.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 23.

    Abe T, Blackford AL, Tamura K, et al. Deleterious germline mutations are a risk factor for neoplastic progression among high-risk individuals undergoing pancreatic surveillance. J Clin Oncol 2019;37:10701080.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 24.

    Giardiello FM, Brensinger JD, Tersmette AC, et al. Very high risk of cancer in familial Peutz-Jeghers syndrome. Gastroenterology 2000;119:14471453.

  • 25.

    Dbouk M, Brewer Gutierrez OI, Lennon AM, et al. Guidelines on management of pancreatic cysts detected in high-risk individuals: an evaluation of the 2017 Fukuoka guidelines and the 2020 International Cancer of the Pancreas Screening (CAPS) Consortium statements. Pancreatology 2021;21:613621.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 26.

    Notta F, Chan-Seng-Yue M, Lemire M, et al. A renewed model of pancreatic cancer evolution based on genomic rearrangement patterns. Nature 2016;538:378382.

  • 27.

    Yachida S, Jones S, Bozic I, et al. Distant metastasis occurs late during the genetic evolution of pancreatic cancer. Nature 2010;467:11141117.

  • 28.

    Omori Y, Ono Y, Morikawa T, et al. Serine/threonine kinase 11 plays a canonical role in malignant progression of KRAS -mutant and GNAS -wild-type intraductal papillary mucinous neoplasms of the pancreas. Ann Surg 2023;277:e384395.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 29.

    Sato N, Rosty C, Jansen M, et al. STK11/LKB1 Peutz-Jeghers gene inactivation in intraductal papillary-mucinous neoplasms of the pancreas. Am J Pathol 2001;159:20172022.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 30.

    Tanaka M, Fernández-del Castillo C, Kamisawa T, et al. Revisions of international consensus Fukuoka guidelines for the management of IPMN of the pancreas. Pancreatology 2017;17:738753.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 31.

    Paniccia A, Polanco PM, Boone BA, et al. Prospective, multi-institutional, real-time next-generation sequencing of pancreatic cyst fluid reveals diverse genomic alterations that improve the clinical management of pancreatic cysts. Gastroenterology 2023;164:117133.e7.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 32.

    Canto MI, Almario JA, Schulick RD, et al. Risk of neoplastic progression in individuals at high risk for pancreatic cancer undergoing long-term surveillance. Gastroenterology 2018;155:740751.e2.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 33.

    Katona BW, Klute K, Brand RE, et al. Racial, ethnic, and sex-based disparities among high-risk individuals undergoing pancreatic cancer surveillance. Cancer Prev Res (Phila) 2023;16:343352.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 34.

    Simons RL, Lei MK, Beach SR, et al. Discrimination, segregation, and chronic inflammation: testing the weathering explanation for the poor health of Black Americans. Dev Psychol 2018;54:19932006.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 35.

    Williams DR, Lawrence JA, Davis BA, et al. Understanding how discrimination can affect health. Health Serv Res 2019;54(Suppl 2):13741388.

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