Surveillance Of High-risk Individuals Research Articles

Aspects and outcomes of surveillance for individuals at high-risk of pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) is a leading cause of cancer-related deaths and is associated with a poor prognosis. The majority of these cancers are detected at a late stage, contributing to the bad prognosis. This underscores the need for novel, enhanced early detection strategies to improve the outcomes. While population-based screening is not recommended due to the relatively low incidence of PDAC, surveillance is recommended for individuals at high risk for PDAC due to their increased incidence of the disease. However, the outcomes of pancreatic cancer surveillance in high-risk individuals are not sorted out yet. In this review, we will address the identification of individuals at high risk for PDAC, discuss the objectives and targets of surveillance, outline how surveillance programs are organized, summarize the outcomes of high-risk individuals undergoing pancreatic cancer surveillance, and conclude with a future perspective on pancreatic cancer surveillance and novel developments.

The role of endoscopic ultrasound in the detection of pancreatic lesions in high-risk individuals.

Individuals at high risk of developing pancreatic ductal adenocarcinoma are eligible for surveillance within research programs. These programs employ periodic imaging in the form of magnetic resonance imaging/magnetic resonance cholangiopancreatography or endoscopic ultrasound for the detection of early cancer or high-grade precursor lesions. This narrative review discusses the role of endoscopic ultrasound within these surveillance programs. It details its overall strengths and limitations, yield, burden on patients, and how it compares to magnetic resonance imaging. Finally, recommendations are given when and how to incorporate endoscopic ultrasound in the surveillance of high-risk individuals.

The Italian registry of families at risk for pancreatic cancer (IRFARPC): implementation and evolution of a national program for pancreatic cancer surveillance in high-risk individuals.

Screening programs for early detection and treatment of pancreatic cancer (PC) and its precursor lesions are increasingly implemented worldwide to reduce disease-specific lethality. Given the relatively low prevalence of the disease, the ideal target of such approaches is an enriched cohort of individuals harboring a lifetime risk of developing PC significantly higher compared to the general population, given either a substantial aggregation of PC cases in their family (i.e. familial pancreatic cancer) or a genomic landscape enriched with pathogenic variants associated with pancreatic carcinogenesis (i.e. mutation carriers). In Italy, a national registry for the census and surveillance of high-risk individuals for PC was launched in 2015, enrolling some 1200 subjects as of today. In this perspective, the scientific background, multi-level structure, and evolution of IRFARPC are outlined, as well as its long-term results, future developments, and areas for improvement.

Assessment of the Psychosocial Impact of Pancreatic Cancer Surveillance in High-Risk Individuals.

Pancreatic cancer (PC) surveillance of high-risk individuals (HRIs) downstages PC and improves survival. However, it remains less clear whether PC surveillance has a positive psychosocial impact on HRIs. Herein, we aimed to define the attitudes and beliefs of HRIs undergoing PC surveillance, and the immediate and sustained psychosocial impact of PC surveillance in HRIs. 100 HRIs undergoing PC surveillance by endoscopic ultrasound (EUS) completed three surveys addressing different components of the psychosocial impact of PC surveillance. Logistic regression analyses were performed to identify predictive factors relating to these components. Most HRIs reported increased perceived benefits of PC surveillance, self-efficacy, and perceived severity of PC. HRIs reported few negative emotions prior to surveillance and frequent positive emotions after surveillance. Compared to prior to surveillance, there was a 53.5% decrease in the level of distress reported by HRIs after surveillance, which was sustained for 4-6 weeks post-surveillance. Family history of PC and lower self-reported mental health were identified as predictors for increased perceived susceptibility to PC (p < 0.01) and greater change in distress pre- to post-surveillance (p < 0.01), respectively. Our findings suggest that PC surveillance can lead to sustained psychosocial benefits in HRIs.

Outcomes of a 3-Year Prospective Surveillance in Individuals at High Risk of Pancreatic Cancer.

Pancreatic cancer (PC) surveillance of high-risk individuals (HRI) is becoming more common worldwide, aiming at anticipating PC diagnosis at a preclinical stage. In 2015, the Italian Registry of Families at Risk of Pancreatic Cancer was created. We aimed to assess the prevalence and incidence of pancreatic findings, oncological outcomes, and harms 7 years after the Italian Registry of Families at Risk of Pancreatic Cancer inception, focusing on individuals with at least a 3-year follow-up or developing events before. HRI (subjects with a family history or mutation carriers with/without a family history were enrolled in 18 centers). They underwent annual magnetic resonance with cholangiopancreatography or endoscopic ultrasound (NCT04095195). During the study period (June 2015-September 2022), 679 individuals were enrolled. Of these, 524 (77.2%) underwent at least baseline imaging, and 156 (29.8%) with at least a 3-year follow-up or pancreatic malignancy/premalignancy-related events, and represented the study population. The median age was 51 (interquartile range 16) years. Familial PC cases accounted for 81.4% of HRI and individuals with pathogenic variant for 18.6%. Malignant (n = 8) and premalignant (1 PanIN3) lesions were found in 9 individuals. Five of these 8 cases occurred in pathogenic variant carriers, 4 in familial PC cases (2 tested negative at germline testing and 2 others were not tested). Three of the 8 PC were stage I. Five of the 8 PC were resectable, 3 Stage I, all advanced cases being prevalent. The 1-, 2-, and 3-year cumulative hazard of PC was 1.7%, 2.5%, and 3%, respectively. Median overall and disease-free survival of patients with resected PC were 18 and 12 months (95% CI not computable). Considering HRI who underwent baseline imaging, 6 pancreatic neuroendocrine neoplasms (1 resected) and 1 low-yield surgery (low-grade mixed-intraductal papillary mucinous neoplasm) were also reported. PC surveillance in a fully public health care system is feasible and safe, and leads to early PC or premalignant lesions diagnoses, mostly at baseline but also over time.

Global and regional quality of care index (QCI) by gender and age in oesophageal cancer: A systematic analysis of the Global Burden of Disease Study 1990-2019.

The aim of this study was to examine the quality of care by age and gender in oesophageal cancer using Global Burden of Disease (GBD) database. Patients aged 20 and over with oesophageal cancer were included in this longitudinal study using GBD 1990-2019 data. We used the Socio-Demographic Index (SDI) to classify the regions. We used Principal Component Analysis (PCA) method to calculate the Quality of Care Index (QCI). The QCI was rescaled into a 0-100 single index, demonstrating that the higher the score, the better the QC. The age-standardized QCI for oesophageal cancer dramatically increased from 23.5 in 1990 to 41.1 in 2019 for both sexes, globally. The high SDI regions showed higher QCI than the rest of the regions (45.1 in 1990 and 65.7 in 2019) whereas the low SDI regions had the lowest QCI, which showed a 4.5% decrease through the years (from 13.3 in 1990 to 12.7 in 2019). Globally, in 2019, the QCI showed the highest scores for patients aged 80-84, reported 48.2, and the lowest score for patients aged 25-29 reported 31.5, for both sexes. Globally, in 2019, age-standardized Gender Disparity Ratio (GDR) was 1.2, showing higher QCI in females than males. There were fundamental differences in the QCI both globally and regionally between different age groups as well as between males and females. To achieve the goal of providing high-quality services equally to people in need in all over the world, health systems need to invest in effective diagnostic services, treatments, facilities, and equipment and to plan for screening and surveillance of high-risk individuals.

Abstract 12575: Subgroup Comparison of Deep-Learning Electrocardiogram Model Performance for Predicting New-Onset 1-Year Atrial Fibrillation Incidence

Background: Surveillance of high-risk individuals as determined by an atrial fibrillation (AF) prediction model would be a good strategy to prevent stroke and other complications from AF. Recently, several deep learning (DL) models to predict new onset AF using 12-lead electrocardiography (ECG) have been introduced. However, their performance has not been compared among different patient groups. Methods : Data of 99,281 patients who underwent 12-lead ECG at Korea University Anam Hospital from January 2017 to December 2019, excluding patients already diagnosed with AF, were studied. The data was split into a 60% training set, 20% validation set and 20% test set. Using age, sex, and raw ECG waveforms as inputs, DL models of ResNet and a multi-layered perceptron module were developed to predict 1-year new onset AF incidence. Results: The DL model using both ECG waves and simple demographic information (age and sex) as input (ECG-AS model) showed better performance compared to the DL model using only ECG waves (ECG model) for AF prediction in the test dataset (area under the receiver operating characteristics curves [AUROCs] 0.79 for ECG model and 0.89 for ECG-AS model, respectively). In subgroup analysis divided by clinical features such as CHA2DS2-VASC score, there was little difference in the performance of the DL model. Interestingly, The DL model performed worse in patients with normal sinus rhythm (NSR) compared to patients with non-NSR (AUROC 0.70 vs 0.81 for ECG model, 0.82 vs 0.90 for ECG-AS model, Table 1). Conclusions: ECG of NSR may not have sufficient information to predict AF. In applying the AF prediction DL model using 12-lead ECG to real-world clinical practice, it may be helpful to add clinical information to the input along with appropriate patient selection.

Initial outcomes and insights from a novel high-risk prostate cancer screening clinic.

Guidelines for germline testing in patients with prostate cancer (PCa) are identifying family members who require additional surveillance given pathogenic variants (PVs) that confer increased PCa risk. We established an interdisciplinary clinic for cancer surveillance in high-risk individuals aimed to implement screening recommendations. This study aimed to characterize the clinical features of this cohort. The Prostate Cancer Risk Clinic (PCRC) was established for unaffected individuals with germline PVs or a strong PCa family history. PCa screening, urine labs, and questionnaires were included in the visit. Individuals with BRCA1/2 PVs underwent clinical breast exam as well. Data from the initial visit were abstracted from the medical record and questionnaires for analysis. Thirty-five individuals with increased PCa risk were followed by the PCRC with a median age of 47 years of age. Twenty individuals (57%) had a family history of PCa, and 34 (97%) had a germline PV associated with an increased risk for developing PCa. Four individuals underwent biopsy due to care in the PCRC, with one PCa identified in an individual with TP53 PV. Median patient response scores indicated mild symptoms of an enlarged prostate (AUASS), normal erectile function (SHIM), and relatively low anxiety about developing PCa (MAX-PC). However, there were notable "outlier" scores on each questionnaire. Individuals with prostates and BRCA1/2 PVs, among other germline PVs, can benefit from a comprehensive interdisciplinary approach to high-risk management. PCa was identified in an individual with a non-BRCA PV, emphasizing the importance and need for high-risk screening guidelines across all genes with increased risk for PCa. "Outlier" patient response scores demonstrate that some participants experienced worse symptoms or anxiety than was indicated by median scores alone.

Current Screening Strategies for Pancreatic Cancer.

Pancreatic ductal adenocarcinoma (PDAC) is a dreaded malignancy with a dismal 5-year survival rate despite maximal efforts on optimizing treatment strategies. Radical surgery is the only potential curative procedure. Unfortunately, the majority of patients are diagnosed with locally advanced or metastatic disease, which renders them ineligible for curative resection. Early detection of PDAC is thus considered to be the most effective way to improve survival. In this regard, pancreatic screening has been proposed to improve results by detecting asymptomatic stages of PDAC and its precursors. There is now evidence of benefits of systematic surveillance in high-risk individuals, and the current guidelines emphasize the potential of screening to affect overall survival in individuals with genetic susceptibility syndromes or familial occurrence of PDAC. Here we aim to summarize the current knowledge about screening strategies for PDAC, including the latest epidemiological data, risk factors, associated hereditary syndromes, available screening modalities, benefits, limitations, as well as management implications.

Pancreatic Cancer Surveillance in Carriers of a Germline CDKN2A Pathogenic Variant: Yield and Outcomes of a 20-Year Prospective Follow-Up.

Pancreatic cancer surveillance in high-risk individuals may lead to detection of pancreatic ductal adenocarcinoma (PDAC) at an earlier stage and with improved survival. This study evaluated the yield and outcomes of 20 years of prospective surveillance in a large cohort of individuals with germline pathogenic variants (PVs) in CDKN2A. Prospectively collected data were analyzed from individuals participating in pancreatic cancer surveillance. Surveillance consisted of annual magnetic resonance imaging with magnetic resonance cholangiopancreatography and optional endoscopic ultrasound. Three hundred forty-seven germline PV carriers participated in surveillance and were followed for a median of 5.6 (interquartile range 2.3-9.9) years. A total of 36 cases of PDAC were diagnosed in 31 (8.9%) patients at a median age of 60.4 (interquartile range 51.3-64.1) years. The cumulative incidence of primary PDAC was 20.7% by age 70 years. Five carriers (5 of 31; 16.1%) were diagnosed with a second primary PDAC. Thirty (83.3%) of 36 PDACs were considered resectable at the time of imaging. Twelve cases (12 of 36; 33.3%) presented with stage I disease. The median survival after diagnosis of primary PDAC was 26.8 months, and the 5-year survival rate was 32.4% (95% CI, 19.1 to 54.8). Individuals with primary PDAC who underwent resection (22 of 31; 71.0%) had an overall 5-year survival rate of 44.1% (95% CI, 27.2 to 71.3). Nine (2.6%; 9 of 347) individuals underwent surgery for a suspected malignant lesion, which proved to not be PDAC, and this included five lesions with low-grade dysplasia. This long-term surveillance study demonstrates a high incidence of PDAC in carriers of a PV in CDKN2A. This provides evidence that surveillance in such a high-risk population leads to detection of early-stage PDAC with improved resectability and survival.

Identifying the pre-malignant stomach: from guidelines to practice.

Gastric adenocarcinoma develops after stepwise progression from normal mucosa through to adenocarcinoma most commonly after being triggered by Helicobacter pylori (H. pylori) infection. As disease is often diagnosed late, the prognosis for gastric adenocarcinoma is poor. Identifying pre-malignant mucosal lesions such as atrophic gastritis, intestinal metaplasia and dysplasia is one strategy adopted by clinicians to reduce cancer related mortality. Surveillance of high-risk individuals and endoscopic resection of dysplastic lesions is recommended by international and UK guidelines. The early detection and endoscopic management reduce the need for invasive surgery. The advancement of image enhanced endoscopy technology, endoscopic training, risk stratification and histological assessment has proven pivotal to the management of pre-malignant lesions. In this review we outline the development of a high-risk stomach, endoscopic assessment and review practical guidelines on identifying pre-malignant gastric mucosa.

Late-Stage Pancreatic Cancer Detected During High-Risk Individual Surveillance: A Systematic Review and Meta-Analysis

Identification and resection of successful targets, that is, T1 N0M0 pancreatic ductal adenocarcinoma (PDAC) and high-grade precursors during surveillance of high-risk individuals (HRIs) confers improved survival. Late-stage PDACs refer to T2-4 N0M0 and nodal or distant metastatic PDAC stages diagnosed during the follow-up phase of HRI surveillance. This study aimed to quantify late-stage PDACs during HRI surveillance and identify associated clinicoradiologic factors. A systematic search (PROSPERO:CRD42018117189) from Cochrane Library, Embase, Google Scholar, Medline, PubMed, Scopus, and Web of Science was last performed on April 18, 2021. Only original HRI surveillance manuscripts that specified follow-up strategies were included, and studies with only baseline information were excluded. Cumulative incidences of advanced neoplasia: high-grade precursors and all PDACs, and surveillance-detected/interval late-stage PDACs were calculated through random-effects model. Incidence of late-stage PDACs underwent metaregression to identify association with HRI clinicoradiologic features. Publication bias was assessed through the funnel plot and Egger's regression line. Thirteen original surveillance studies included 2169 HRIs followed over 7302.72 patient-years. Cumulative incidence of advanced neoplasia and late-stage PDACs was 3.3 (95% confidence interval [CI]: 0.6-7.4) and 1.7 (95% CI: 0.2-4.0) per 1000 patient-years, respectively. Late-stage PDACs lacked significant association with surveillance imaging, baseline pancreatic morphology, study location, genetic background, gender, or age. Limited information on diagnostic error, symptoms, timing of presentation, lesion site, and surveillance adherence precluded formal meta-analysis. A sizeable proportion of late-stage PDACs were detected during follow-up. Their incidence lacked association with baseline clinicoradiologic features. Further causal investigation of stage-based outcomes is warranted for overall improvement in HRI surveillance.

Recommendations for a More Organized and Effective Approach to the Early Detection of Pancreatic Cancer From the PRECEDE (Pancreatic Cancer Early Detection) Consortium

Pancreatic cancer is an aggressive, difficult-to-treat disease that is on track to become the second most deadly malignancy in adults by 2030.1Rahib L. Smith B.D. Aizenberg R. et al.Projecting cancer incidence and deaths to 2030: the unexpected burden of thyroid, liver, and pancreas cancers in the United States.Cancer Res. 2014; 74: 2913-2921Crossref PubMed Scopus (3761) Google Scholar Although significant advances in treatment are being made, screening and early detection hold the greatest promise in affecting mortality. Effective screening for pancreatic cancer, per National Cancer Institute recommendations, should: (1) demonstrate ability to detect early cancer; (2) show that screening reduces cancer mortality, and (3) prove that benefits of screening outweigh harms.2Screening tests. National Cancer Institute.https://www.cancer.gov/about-cancer/screening/screening-testsGoogle Scholar Pancreatic cancer presents several challenges in meeting these screening criteria, including its relatively low incidence in the general population, the small independent effect sizes of known environmental and nutritional risk factors, limited ability to detect the highest-risk premalignant lesions (ie, pancreatic intraepithelial neoplasia), early metastasis, and resistance to standard treatments that can be curative in other cancer types. Here we discuss the current state of pancreatic cancer screening and recommend strategic steps needed to overcome these challenges and allow proper studies to be performed to ultimately demonstrate efficacy, decreased mortality, and favorable balance of benefit over harm. Implementation of an effective screening test requires identification of a target population. Because of its relatively low incidence, sensitivity and specificity levels of existing techniques are inadequate for pancreatic cancer screening in the general population.3Owens D.K. Davidson K.W. et al.US Preventive Services Task ForceScreening for pancreatic cancer: US Preventive Services Task Force reaffirmation recommendation statement.JAMA. 2019; 322: 438-444Crossref PubMed Scopus (101) Google Scholar Individuals meeting specific criteria based on family history of pancreatic cancer and/or presence of pathogenic germline variants (PGV) in relevant cancer risk genes, referred to as high-risk individuals (HRIs), are currently the only cohort with published guidelines recommending pancreatic cancer screening at regular intervals.4Goggins M. Overbeek K.A. Brand R. et al.Management of patients with increased risk for familial pancreatic cancer: updated recommendations from the International Cancer of the Pancreas Screening (CAPS) Consortium.Gut. 2020; 69: 7-17Crossref PubMed Scopus (164) Google Scholar, 5Syngal S. Brand R.E. Church J.M. et al.ACG clinical guideline: genetic testing and management of hereditary gastrointestinal cancer syndromes.Am J Gastroenterol. 2015; 110 (quiz 263): 223-262Crossref PubMed Scopus (815) Google Scholar, 6National Comprehensive Cancer Network. Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic. Version 1.2021. National Comprehensive Cancer Network, 2020.Google Scholar In Table 1, we summarized the current genetic and family history inclusion criteria for pancreatic cancer screening. These recommendations have been made based on expert consensus opinion, and the collection of supporting evidence is ongoing.Table 1Definitions of High-Risk Individuals, Estimated Risk, and Initiation of Screening RecommendationsInclusion criteriaPublished risk estimatesInitiation of screening recommendationsPeutz-Jeghers syndromeSTK11 PGV or meeting clinical diagnostic criteriaCumulative risk by age 70 y, 32%–36%Age 30 y or olderFamilial atypical multiple mole and melanomaCDKN2A PGVCumulative risk by 75 y, 17%SIR, 21.8Age 35 y or olderFPCOverall SIR in FPC kindreds: 9.0Age 50 y or older or 10 y younger than youngest diagnosis of PDA in family 2 or more relatives with PDA1 FDR SIR, 4.5 First- or second-degree relative with PDA2 FDR SIR, 6.43 FDR SIR, 32Hereditary pancreatitisPRSS1 PGV or confirmed family history of pancreatitisSymptomatic pancreatitisSIR, 53Cumulative risk to 70 y, 33%–44%Age 40 y or olderConfirmed PGV in below listed genesFirst- or second-degree relative with PDAAge 50 y or older or 10 y younger than youngest diagnosis of PDA in family ATMOR, 4.2–5.7— BRCA1RR, 2.6— BRCA2RR, 3.5–5.9— MLH1, MSH2, MSH6, PMS2, EPCAMCumulative risk to 70 y, 3.68%6.8% MLH10.5% MSH21.4% MSH6— PALB2Not known—FDR, first-degree relative; FPC, familial pancreatic cancer; OR, odds ratio; PDA, pancreatic ductal adenocarcinoma; RR, risk ratio; SIR, standardized incidence ratio. Open table in a new tab FDR, first-degree relative; FPC, familial pancreatic cancer; OR, odds ratio; PDA, pancreatic ductal adenocarcinoma; RR, risk ratio; SIR, standardized incidence ratio. Published screening studies in HRIs have shown promise in the ability to detect early cancer (T1N0M0) and precursor lesions with high-grade dysplasia, another important criteria for effective screening programs. However, these studies have been limited by relatively small sample sizes, short follow-up, heterogeneity of inclusion criteria, and variability in screening techniques.7Overbeek KA, Levink IJM, Koopmann BDM, et al. Long-term yield of pancreatic cancer surveillance in high-risk individuals [published online ahead of print April 5, 2021]. Gut https://doi.org/10.1136/gutjnl-2020-323611Google Scholar A meta-analysis of 16 studies published between 2004 and 2016, which included 1550 participants, found nearly 2% of HRIs had pancreatic cancer or a high-grade precursor lesion identified.8Paiella 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.Pancreatology. 2018; 18: 420-428Crossref PubMed Scopus (21) Google Scholar A 2018 study of 350 HRIs found that 9 of 10 incident pancreatic cancers discovered during a median follow-up time of 5.6 years were surgically resectable,9Canto M.I. Almario J.A. Schulick R.D. et al.Risk of neoplastic progression in individuals at high risk for pancreatic cancer undergoing long-term surveillance.Gastroenterology. 2018; 155: 740-751.e2Abstract Full Text Full Text PDF PubMed Scopus (157) Google Scholar with a resulting 5-year survival rate of 60% in the surgically treated group.10Canto 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.J Gastrointest Surg. 2020; 24: 1101-1110Crossref PubMed Scopus (21) Google Scholar The study cohort included 97% of patients meeting criteria based on family history of pancreatic cancer alone, and gene status was unknown for the majority. This is relevant in light of a 2021 study that found a cumulative incidence of pancreatic cancer of 3.1% at 5 years and 4.7% at 10 years, with all cases occurring in PGV carriers.7Overbeek KA, Levink IJM, Koopmann BDM, et al. Long-term yield of pancreatic cancer surveillance in high-risk individuals [published online ahead of print April 5, 2021]. Gut https://doi.org/10.1136/gutjnl-2020-323611Google Scholar This study also found that 4 of 8 incident pancreatic cancers were resectable. This shift toward detection of earlier stage, resectable disease is encouraging, but larger studies with longer follow-up will be needed to exclude the possibility of lead-time bias. Two large-scale studies of ovarian cancer and prostate cancer both found that increased detection of early-stage disease did not result in a corresponding decrease in cancer mortality after long-term follow-up of 16 years and 10 years, respectively.11Menon U. Gentry-Maharaj A. Burnell M. et al.Ovarian cancer population screening and mortality after long-term follow-up in the UK Collaborative Trial of Ovarian Cancer Screening (UKCTOCS): a randomised controlled trial.Lancet. 2021; 397: 2182-2193Abstract Full Text Full Text PDF PubMed Scopus (57) Google Scholar,12Martin R.M. Donovan J.L. Turner E.L. et al.Effect of a low-intensity PSA-based screening intervention on prostate cancer mortality: the CAP randomized clinical trial.JAMA. 2018; 319: 883-895Crossref PubMed Scopus (204) Google Scholar In addition, it is important to note that several of the published pancreatic cancer screening series have reported cancers diagnosed between screening examinations and advanced cancers apparently missed with current screening techniques.13Corral 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.Clin Gastroenterol Hepatol. 2019; 17: 41-53Abstract Full Text Full Text PDF PubMed Scopus (42) Google Scholar Understanding the possible explanations for these interval or missed cancers and the strategies to reduce them will require consistency in intervals and methods for screening across centers and more clearly defined study populations. National Cancer Institute and World Health Organization14World Health Organization Screening ProgrammesA Short Guide. Increase Effectiveness, Maximize Benefits and Minimize Harm. World Health Organization, 2020Google Scholar recommendations for effective screening also involve the weighing of benefits vs harms, both at the individual and societal level. Pancreatic cancer screening techniques have relatively low procedural risks, but published studies have reported a substantial number of noncancerous findings, including branch duct intrapapillary mucinous neoplasms, chronic pancreatitis, and extrapancreatic findings. This raises the possibility of overdiagnosis or overtreatment, issues that have complicated screening efforts for lung and prostate cancers.15Callister M.E.J. Sasieni P. Robbins H.A. Overdiagnosis in lung cancer screening.Lancet Respir Med. 2021; 9: 7-9Abstract Full Text Full Text PDF PubMed Scopus (3) Google Scholar,16Loeb S. Bjurlin M.A. Nicholson J. et al.Overdiagnosis and overtreatment of prostate cancer.Eur Urol. 2014; 65: 1046-1055Abstract Full Text Full Text PDF PubMed Scopus (539) Google Scholar A 2019 meta-analysis found that pancreatic cancer screening in 1660 patients led to 473 abnormal imaging examinations and 257 surgical procedures, with 43 pancreatic cancers and 25 findings of high-grade dysplasia in intrapapillary mucinous neoplasms or pancreatic intraepithelial neoplasia 3 lesions.13Corral 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.Clin Gastroenterol Hepatol. 2019; 17: 41-53Abstract Full Text Full Text PDF PubMed Scopus (42) Google Scholar Although perioperative mortality is <2% in high-volume centers, consideration of risk for postoperative complications, including diabetes after surgery, for what might ultimately prove to be a benign lesion is a necessary part of individual risk–benefit analysis in current screening programs. Other unintended individual-level harms can include anxiety associated with screening procedures or abnormal findings that require additional follow-up. Small studies in HRIs have suggested no significant psychological impact with screening, but additional studies in this area are needed. Currently available imaging modalities have a reasonable ability to detect lesions >1 cm, but not precursor lesions. These modalities are also expensive and, in the case of endoscopic ultrasound (EUS), invasive. Even with consensus recommendations for HRIs, insurance coverage is variable and can impact access to care. The cost and highly specialized nature of these modalities also creates disparities in access both economically and geographically. Cost–benefit analyses will be an important part of the necessary steps toward meeting National Institutes of Health and World Health Organization standards for screening, and will be critical to developing guidelines for medical necessity and consistent insurance coverage. Significant evolution in the recognition and treatment of precursor lesions will be required before the aims of screening can ultimately shift from proving reduction in mortality due to detection of early-stage pancreatic cancers to reduction of cancer incidence. Implementing strategies to address screening challenges in pancreatic cancer is a critical and timely issue. Expanded use of germline genetic testing in patients with pancreatic cancer has led to increased recognition of genes linked to pancreatic cancer risk. Germline testing identifies a clinically relevant PGV in approximately 10% of patients with pancreatic cancer,17Brand R. Borazanci E. Speare V. et al.Prospective study of germline genetic testing in incident cases of pancreatic adenocarcinoma.Cancer. 2018; 124: 3520-3527Crossref PubMed Scopus (37) Google Scholar, 18Yurgelun M.B. Chittenden A.B. Morales-Oyarvide V. et al.Germline cancer susceptibility gene variants, somatic second hits, and survival outcomes in patients with resected pancreatic cancer.Genet Med. 2019; 21: 213-223Abstract Full Text Full Text PDF PubMed Scopus (85) Google Scholar, 19Shindo K. Yu J. Suenaga M. et al.Deleterious germline mutations in patients with apparently sporadic pancreatic adenocarcinoma.J Clin Oncol. 2017; 35: 3382-3390Crossref PubMed Scopus (203) Google Scholar, 20Grant R.C. Selander I. Connor A.A. et al.Prevalence of germline mutations in cancer predisposition genes in patients with pancreatic cancer.Gastroenterology. 2015; 148: 556-564Abstract Full Text Full Text PDF PubMed Scopus (195) Google Scholar, 21Hu C. Hart S.N. Bamlet W.R. et al.Prevalence of pathogenic mutations in cancer predisposition genes among pancreatic cancer patients.Cancer Epidemiol Biomarkers Prev. 2016; 25: 207-211Crossref PubMed Scopus (88) Google Scholar and at least another 2%–5% of pancreatic cancers occur in individuals with a family history of pancreatic cancer but without an identifiable PGV. For all individuals with a newly diagnosed pancreatic cancer, germline genetic testing is now part of routine care recommended by National Comprehensive Cancer Network6National Comprehensive Cancer Network. Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic. Version 1.2021. National Comprehensive Cancer Network, 2020.Google Scholar and American Society of Clinical Oncology22Stoffel E.M. McKernin S.E. Brand R. et al.Evaluating susceptibility to pancreatic cancer: ASCO Provisional Clinical Opinion.J Clin Oncol. 2019; 37: 153-164Crossref PubMed Scopus (71) Google Scholar guidelines, regardless of family history. The National Comprehensive Cancer Network guidelines also now recommend germline genetic testing for individuals who have a first-degree relative with pancreatic cancer.6National Comprehensive Cancer Network. Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic. Version 1.2021. National Comprehensive Cancer Network, 2020.Google Scholar These expanded criteria for genetic testing will identify new HRIs eligible for pancreatic surveillance based on the consensus guidelines. With more than 60,000 new cases of pancreatic cancer per year in the United States, and known rates of PGV identification and positive family history of pancreatic cancer, in combination with increased awareness of pancreatic cancer detection, at least 120,000 individuals will be eligible for surveillance annually in the United States alone. At this volume, it is likely that both genetic testing and imaging or procedures will be performed by an increasing number of centers and providers. Our main goal was to address an important step in the World Health Organization screening program pathway: to conduct and report testing using agreed on and standardized methods. This step is critical to move toward eventual reporting of outcomes on a scale large enough to demonstrate screening efficacy. There is a need to optimize screening algorithms and collection of longitudinal demographic, genetic, imaging, and biomarker data over an extended period of time. Although consortia and multicenter collaborations are ideal for data collection, it is likely that a significant proportion of screening will be performed outside of these efforts, further emphasizing the need for standardization. Here, we outline important elements that can be incorporated into current practice to improve and standardize data collection for HRIs and pave the road for future research to establish the efficacy of screening and to recognize novel risk factors, markers, or imaging characteristics of early-stage cancer or precursor lesions. The type of data we collect today, and how we collect those data, will determine our ability to ultimately reduce the mortality of pancreatic cancer with a favorable ratio of benefit to harm at an acceptable societal cost. The collection and documentation of cancer family history is a key component of risk stratification and clinical management for families at risk for pancreatic cancer. In a general clinic setting, pertinent positive family history, including primary site of cancer and age at diagnosis in first- and second-degree relatives, is sufficient for determining surveillance eligibility.5Syngal S. Brand R.E. Church J.M. et al.ACG clinical guideline: genetic testing and management of hereditary gastrointestinal cancer syndromes.Am J Gastroenterol. 2015; 110 (quiz 263): 223-262Crossref PubMed Scopus (815) Google Scholar The gold standard for cancer genetic counseling and the best practice approach for the high-risk clinic setting is a 3-generation pedigree, including information about primary cancer sites and ages at diagnosis for all relatives with cancer history. Confirmation of pancreatic cancer diagnoses via medical records is preferred when possible, particularly for second- or third-degree relatives, as accuracy of reporting decreases beyond first-degree relationships.23Ziogas A. Anton-Culver H. Validation of family history data in cancer family registries.Am J Prev Med. 2003; 24: 190-198Abstract Full Text Full Text PDF PubMed Scopus (197) Google Scholar Pedigree documentation should also include results of genetic testing and the specific genes analyzed for any family member completing it. Discovery of new genes or new associations with known genes over time might mean that updated testing is indicated for HRIs or their tested family members.24Riley B.D. Culver J.O. Skrzynia C. et al.Essential elements of genetic cancer risk assessment, counseling, and testing: updated recommendations of the National Society of Genetic Counselors.J Genet Couns. 2012; 21: 151-161Crossref PubMed Scopus (228) Google Scholar With the evolving use of multigene panel testing, there has been considerable variation in the content of genetic testing offered to HRIs. Current testing in this setting should include a minimum list of the following genes from published surveillance guidelines4Goggins M. Overbeek K.A. Brand R. et al.Management of patients with increased risk for familial pancreatic cancer: updated recommendations from the International Cancer of the Pancreas Screening (CAPS) Consortium.Gut. 2020; 69: 7-17Crossref PubMed Scopus (164) Google Scholar,5Syngal S. Brand R.E. Church J.M. et al.ACG clinical guideline: genetic testing and management of hereditary gastrointestinal cancer syndromes.Am J Gastroenterol. 2015; 110 (quiz 263): 223-262Crossref PubMed Scopus (815) Google Scholar: APC, ATM, BRCA1, BRCA2, CDKN2A, MLH1, MSH2, MSH6, PALB2, PMS2, STK11, and TP53. Among families who present meeting criteria for familial pancreatic cancer, about 15%–20% have an identifiable pathogenic germline variant, leaving 80%–85% of the heritable component of familial pancreatic cancer unknown. Standard collection of full pedigrees in this setting will power studies to identify new genetic associations. Documentation of full pedigree information in high-risk families will also allow improvements in penetrance estimation and risk modeling to provide accurate risk information to patients and families that will refine surveillance guidelines over time. We therefore include standardized reporting of pedigrees in HRIs (Table 2).Table 2Proposed Areas of Standardization of Template Use in High-Risk IndividualsAreas of standardizationProposed template elementsExamplesFamily historyPedigree templates (ie, commercially available templates [Prodigy])3- to 4-generation pedigree with PGV informationConfirmation of reported pancreatic cancers with recordsGenetic testingMinimum gene list and plan for updatingPanels including all known genes linked to pancreatic cancer riskUpdated testing for families with outdated resultsIndication for screeningPathogenic germline variants in specific genes or family historyFamilial pancreatic cancerPathogenic germline variantsFamily history of pancreatic cancerAcquisition of specific EUS viewsConfirmation of capture of 8 key views of the pancreas and peripancreatic structures from the duodenal and gastric positionDuodenal views:Distal CBD/proximal PD/ampulla viewPorta hepatisHOP with PDPancreas parenchyma, portal confluenceGastric views:Celiac axis, SMA, aortaTail of pancreas view with splenorenal angleBody of pancreas view at level of SA and SVRight lateral pancreas margin (PD toward HOP)EUS procedural detailsTemplated acquisition of procedural data pointsType of EUS performed (radial vs linear); length of procedure; sedation usedEUS parenchymal descriptorsUse of templated drop-down menu for specific predefined parenchymal changesHyperechoic foci or strands; lobularity; microcysts; atrophy; calcifications; heterogeneous pancreas; fatty pancreasEUS pancreatic duct descriptorsUse of drop-down menu for specific measurements and characteristics of MPDRecord diameter in head, body, and tail of pancreasStricture, wall irregularities, filling defects and ampullary examinationSolid and cystic lesion descriptorsUse of drop-down menu for characteristics and biopsy/aspiration techniques and detailsSize in 2 dimensions; location; echogenicity; communication with MPD; cystic component; vascular invasion; upstream dilation or atrophy; EUS impressionTissue acquisitionUse of template for procedural details and tissue or fluid obtainedTechnical details (needle size, approach, number of passes); biopsy details (amount of fluid or number of cores obtained)Testing performed (cytology, tumor sequencing, fluid analysis, other cyst fluid–based biomarkers)Assessment of EUS adequacy and overall impressionTemplate for assessment of procedural adequacy, recommendations for future imagingProvide scale of adequacy (adequate, partially adequate or limited/inadequate) and ability to make recommendations based on examination (recommend continued use of EUS vs other modalities for screening)Assessment of overall impressionTemplate for overall impression and changes (if applicable) to prior EUS examinationProvide description of overall impression (normal/abnormal of uncertain significance/worrisome or significant abnormalities and provide comparison to prior examinationCBD, common bile duct; HOP, head of pancreas; MPD, main pancreatic duct; PC, pancreatic cancer; PD, pancreatic duct; SA, splenic artery; SMA, superior mesenteric artery; SV, splenic vein. Open table in a new tab CBD, common bile duct; HOP, head of pancreas; MPD, main pancreatic duct; PC, pancreatic cancer; PD, pancreatic duct; SA, splenic artery; SMA, superior mesenteric artery; SV, splenic vein. Improving identification of individuals at risk for pancreatic cancer will also require a deeper understanding of all significant contributing risk factors. Both modifiable and nonmodifiable risk factors beyond the known high-/moderate-penetrance genes contribute to pancreatic cancer risk, but understanding the impact of, and interactions among, individual risk factors in HRIs remains elusive. Standard documentation of known pancreatic cancer risk factors should be part of high-risk care, and will help to drive discovery, risk stratification, and risk modeling in this population. Key risk factor variables to document include history of diabetes, along with current fasting blood glucose or hemoglobin A1C and time of onset and course of pre-existing diabetes; current weight and BMI; blood type; current and past smoking; and current and past alcohol use, including binge drinking. Few studies have comprehensively investigated the effects of modifiable factors including dietary habits, nutrition, or physical activity on pancreatic cancer risk, and future efforts to document these variables in HRIs may be warranted. Most studies have found imaging by magnetic resonance imaging (MRI), magnetic resonance cholangiopancreatography, and EUS to be superior to other modalities, similar to each other in accuracy and complementary for early lesion detection.13Corral 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.Clin Gastroenterol Hepatol. 2019; 17: 41-53Abstract Full Text Full Text PDF PubMed Scopus (42) Google Scholar At present, there is no other surveillance test, including serum-based or endoscopically obtained biomarkers, that compares in accuracy or yield. Both EUS and MRI have excellent accuracy for the detection of pancreatic masses or cystic lesions >1 cm and changes in pancreatic duct caliber. EUS, however, currently has a higher sensitivity in the identification of small lesions (<1 cm) and in the identification of parenchymal abnormalities. Although MRI images are stored and accessible, EUS images are rarely, if ever, recorded in a high-resolution manner. This significantly limits both the clinical ability to compare studies between multiple time points and the potential for image analysis-based research. Although radiology reporting is increasingly standardized, there are no specific templates developed for patients undergoing screening procedures. EUS reporting is less frequently templated and most current reporting templates have been developed for different contexts, which leads to further gaps in both clinical care and research. With an expected increase in demand for these studies, it is imperative that we enhance our ability to acquire and report EUS abnormalities in a standardized manner. The goal of EUS imaging in HRIs is to provide complete and reproducible examination of the pancreas and generate a uniform format report that can allow for both image and description comparison between time points and across different providers. A first step in standardization is to create a definition of a complete examination defined by imaging landmarks to assess imaging adequacy. Reporting of landmarks should be analogous to now-established colonoscopy standards,25Lieberman D. Nadel M. Smith R.A. et al.Standardized colonoscopy reporting and data system: report of the Quality Assurance Task Group of the National Colorectal Cancer Roundtable.Gastrointest Endosc. 2007; 65: 757-766Abstract Full Text Full Text PDF PubMed Scopus (244) Google Scholar and recording of these landmarks should be mandatory. A list of proposed EUS landmarks is provided in Table 2. Adequacy of a pancreatic EUS examination can be analogous to colonoscopy quality assessment,26Rex D.K. Schoenfeld P.S. Cohen J. et al.Quality indicators for colonoscopy.Gastrointest Endosc. 2015; 81: 31-53Abstract Full Text Full Text PDF PubMed Scopus (571) Google Scholar and will depend on procedural-, anatomic-, and sedation-related factors. However, this assessment will likely be impactful, as it will guide further recommendations and use of EUS in surveillance. Standardized reporting exists for pancreatic mass27Al-Hawary M.M. Francis I.R. Chari S.T. et al.Pancreatic ductal adenocarcinoma radiology reporting template: consensus statement of the Society of Abdominal Radiology and the american Pancreatic Association.Gastroenterology. 2014; 146: 291-304.e1Abstract Full Text Full Text PDF PubMed Scopus (158) Google Scholar or cystic neoplasia assessment, and these can generally be adopted for screening of HRIs. However, in only a minority of patients are these findings identified, and our current understanding of evolution of pancreatic precursors suggests that more subtle findings, such as parenchymal changes, can be important to recognize precursors.28Konings I. Cahen D.L. Harinck F. et al.Evolution of features of chronic pancreatitis during endoscopic ultrasound-based surveillance of individuals at high risk for pancreatic cancer.Endosc Int Open. 2018; 6: E541-E548Crossref PubMed Google Scholar,29Catalano M.F. Sahai A. Levy M. et al.EUS-based criteria for the diagnosis of chronic pancreatitis: the Rosemont classification.Gastrointest Endosc. 2009; 69: 1251-1261Abstract Full Text Full Text PDF PubMed Scopus (359) Google Scholar Most of these parenchymal changes were initially described in relation to chronic pancreatitis-associated changes, but have since been associated with changes observed in neoplastic progression.28Konings I. Cahen D.L. Harinck F. et al.Evolution of features of chronic pancreatitis during endoscopic ultrasound-based surveillance of individuals at high risk for pancreatic cancer.Endosc Int Open. 2018; 6: E541-E548Crossref PubMed Google Scholar,30LeBlanc J.K. Chen J.H. Al-Haddad M. et al.Can endoscopic ultrasound predict pancreatic intraepithelial neoplasia lesions in chronic pancreatitis?: a retrospective study of pathologic correlation.Pancreas. 2014; 43: 849-854Crossref PubMed Scopus (17) Google Scholar Improved resolution of B-mode EUS imaging and enhanced imaging modalities (ie, elastography and contrast enhancement) will likely further improve our ability to characterize parenchymal changes associated with early neoplastic development. An obvious parallel to draw on is the unequivocal benefit of high-resolution white light and virtual chromoendoscopy in detection of gastric and colonic neoplasia in luminal imaging. Substantial efforts have been made to define and characterize mucosal changes and patterns, and only through these efforts was the significance of these findings validated.31Shaukat A. Kaltenbach T. Dominitz J.A. et al.Endoscopic recognition and management strategies for malignant colorectal polyps: recommendations of the US Multi-Society Task Force on Colorectal Cancer.Gastroenterology. 2020; 159: 1916-1934.e2Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar A similar effort might be required to understand the parenchymal changes seen in pancreatic EUS, to understand the temporal evolution of these changes in HRIs, and perhaps to identify the phenotype of pancreatic parenchymal changes associated with specific germline mutational status. This can only be accomplished if we define specific terminology and use predetermined image-capture areas to document these changes. An achievable immediate goal for the EUS field will be to standardize image capture and template reporting. This will result in higher-quality care in surveillance of HRIs and allow comparison of data between time points and providers. We would even propose the creation of a training module to aid in uniform image capture and terminology use by providers who care for HRIs. These objectives can likely be fulfilled with currently available technologies and resources. However, the evolving role of enhanced image analysis and artificial intelligence–based evaluation will require higher quality and resolution image capture and the ability to store these images or video segments for future analysis. This is a much more resource-intensive proposition, which will likely require greater integration of EUS images in standard image repositories, such as picture archiving and communication systems. This is an area where multicenter collaborative consortiums will play a critical role. We are at an inflection point in the history of pancreatic cancer screening. There is an increasing opportunity to decrease mortality of pancreatic cancer through early detection, and the growing number of patients who will be eligible for screening highlights the importance of well-organized, large-scale, long-term, longitudinal follow-up studies of a population with sufficiently high risk for cancer that screening impact can be assessed adequately. Undoubtedly, progress toward more effective early-detection biomarkers and less invasive (and less expensive) screening approaches will become available in the future. However, for patients with familial pancreatic cancer and those with pathogenic germline variants that increase risk for pancreatic cancer, cross-sectional and endoscopic imaging will likely remain the cornerstone of surveillance for a period of time. Consortiums like PRECEDE (Pancreatic Cancer Early Detection),32The Pancreatic Cancer Early Detection Research Consortium (PRECEDE).www.precedestudy.orgGoogle Scholar CAPS (Cancer of the Pancreas Screening),33Canto 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.Gut. 2013; 62: 339-347Crossref PubMed Scopus (496) Google Scholar the Dutch Familial Pancreatic Cancer Surveillance study,7Overbeek KA, Levink IJM, Koopmann BDM, et al. Long-term yield of pancreatic cancer surveillance in high-risk individuals [published online ahead of print April 5, 2021]. Gut https://doi.org/10.1136/gutjnl-2020-323611Google Scholar and EUROPAC (European Registry of Hereditary Pancreatitis and Familial Pancreatic Cancer)34The European Registry of Hereditary Pancreatitis and Familial Pancreatic Cancer (EUROPAC). Volume 2021.Google Scholar are well positioned to collect these data and, given the relatively low event rate in surveillance cohorts, these large, multi-institutional studies will be critical in defining the natural history and predictors of progression. However, given the expected volume of screening procedures, it is essential that standardization is broadly practiced even outside of these registries and that we define and develop resources to achieve a common standard irrespective of the practice setting.

COVID-19 related pancreatic cancer surveillance disruptions amongst high-risk individuals

BackgroundCOVID-19 pandemic-related disruptions to EUS-based pancreatic cancer surveillance in high-risk individuals remain uncertain. MethodsAnalysis of enrolled participants in the CAPS5 Study, a prospective multicenter study of pancreatic cancer surveillance in high-risk individuals. ResultsAmongst 693 enrolled high-risk individuals under active surveillance, 108 (16%) had an EUS scheduled during the COVID-19 pandemic-related shutdown (median length of 78 days) in the spring of 2020, with 97% of these procedures being canceled. Of these canceled surveillance EUSs, 83% were rescheduled in a median of 4.1 months, however 17% were not rescheduled after 6 months follow-up. Prior history of cancer was associated with increased likelihood of rescheduling. To date no pancreatic cancer has been diagnosed among those whose surveillance was delayed. ConclusionsCOVID-19 delayed pancreatic cancer surveillance with no adverse outcomes in efficiently rescheduled individuals. However, 1 in 6 high-risk individuals had not rescheduled surveillance, indicating the need for vigilance to ensure timely surveillance rescheduling.

Long-term yield of pancreatic cancer surveillance in high-risk individuals

ObjectiveWe aimed to determine the long-term yield of pancreatic cancer surveillance in hereditary predisposed high-risk individuals.DesignFrom 2006 to 2019, we prospectively enrolled asymptomatic individuals with an estimated 10% or greater...

A biannual pancreatic cancer surveillance program identifies a high prevalence of intraductal papillary mucinous neoplasms: accelerated malignant transformation in Peutz-Jeghers syndrome

Presenter: Yifan Wang MD | McGill University Background: Individuals with a family history of pancreatic adenocarcinoma (PC) or with a germline mutation in a PC susceptibility gene are at higher risk of developing PC. Surveillance of high-risk individuals (HRIs) may allow earlier detection of PC and its precursor lesions. Since advanced-stage PCs have been reported despite annual surveillance, shorter interval surveillance may be justified. Methods: From 2013 to 2020, asymptomatic HRIs were enrolled in a PC surveillance program alternating between magnetic resonance imaging and endoscopic ultrasound every 6 months. Results: Of 75 HRIs enrolled, 43 (57.3%) had a germline mutation in a PC susceptibility gene (GS), and 32 (42.7%) had a familial pancreatic cancer (FPC) pedigree. Branch-duct intraductal papillary mucinous neoplasms (BD-IPMNs) were identified in 26 (34.7%) individuals, but only 2 developed progressive lesions. Despite biannual surveillance, one patient with Peutz-Jeghers syndrome (PJS) developed locally advanced PC arising from a BD-IPMN. Whole genome sequencing of this patient’s PC and of a second PJS-associated PC from the kindred revealed that both tumours were driven by biallelic inactivation of STK11 in a KRAS-independent manner. From a review of 3,853 patients across two PC registries, we identified one additional PJS patient with PC. Importantly, all 3 PJS patients developed advanced PC consistent with malignant transformation of an underlying BD-IPMN in < 6 months. The other surveillance patient with a progressive lesion had FPC and underwent resection of a mixed-type IPMN which harboured polyclonal KRAS mutations. Furthermore, we found that colloid-type PCs, which develop from IPMNs, display COSMIC signature 17. Conclusion: Biannual PC surveillance identifies a high rate of BD-IPMNs in HRIs, but only a minority of these progress to PC. Our findings suggest that BD-IPMNs in patients with PJS are at risk of rapid malignant transformation. In PJS individuals, a lower threshold for resection of BD-IPMNs may be more effective than shortening surveillance intervals.

The Role of Imaging in Current Treatment Strategies for Pancreatic Adenocarcinoma.

In pancreatic cancer, imaging plays an essential role in surveillance, diagnosis, resectability evaluation, and treatment response evaluation. Pancreatic cancer surveillance in high-risk individuals has been attempted using endoscopic ultrasound (EUS) or magnetic resonance imaging (MRI). Imaging diagnosis and resectability evaluation are the most important factors influencing treatment decisions, where computed tomography (CT) is the preferred modality. EUS, MRI, and positron emission tomography play a complementary role to CT. Treatment response evaluation is of increasing clinical importance, especially in patients undergoing neoadjuvant therapy. This review aimed to comprehensively review the role of imaging in relation to the current treatment strategy for pancreatic cancer, including surveillance, diagnosis, evaluation of resectability and treatment response, and prediction of prognosis.

Genetic counselling and personalised risk assessment in the Australian pancreatic cancer screening program

BackgroundPancreatic cancer (PC) is an aggressive disease with a dismal 5-year survival rate. Surveillance of high-risk individuals is hoped to improve survival outcomes by detection of precursor lesions or early-stage malignancy.MethodsSince 2011, a national high-risk cohort recruited through St Vincent’s Hospital, Sydney, has undergone prospective PC screening incorporating annual endoscopic ultrasound, formal genetic counselling and mutation analysis as appropriate. PancPRO, a Bayesian PC risk assessment model, was used to estimate 5-year and lifetime PC risks for familial pancreatic cancer (FPC) participants and this was compared to their perceived chance of pancreatic and other cancers. Genetic counselling guidelines were developed to improve consistency. Follow-up questionnaires were used to assess the role of genetic counselling and testing.ResultsWe describe the Australian PC screening program design and recruitment strategy and the results of the first 102 individuals who have completed at least one-year of follow-up. Seventy-nine participants met the FPC criteria (≥ two first-degree relatives affected), 22 individuals had both a BRCA2 pathogenic variant and a close relative with PC and one had a clinical diagnosis of Peutz-Jeghers syndrome. Participants reported a high perceived chance of developing PC regardless of their genetic testing status. PancPRO reported FPC participants’ mean 5-year and lifetime PC risks as 1.81% (range 0.2–3.2%) and 10.17% (range 2.4–14.4%), respectively. Participants’ perceived PC chance did not correlate with their PancPRO 5-year (r = − 0.17, p = 0.128) and lifetime PC risks (r = 0.19, p = 0.091). Two-thirds felt that current genetic testing would help them, and 91% of tested participants were glad to have undergone genetic testing. Overall, 79% of participants found genetic counselling to be helpful, and 88% reported they would recommend counselling to their relatives.ConclusionsParticipants reported multiple benefits of genetic counselling and testing but continue to seek greater clarification about their individual PC risk. Extension of PancPRO is required to enable personalised PC risk assessment for all high-risk sub-groups. More detailed discussion of PC risk for BRCA2 pathogenic variant carriers, providing a written summary in all cases and a plan for genetics review were identified as areas for improvement.

32 Outcomes of Pancreatic Cancer Surveillance in High Risk Individuals

INTRODUCTION: Consensus guidelines recommend surveillance for pancreatic cancer (PC) for individuals who meet specific high-risk criteria, however outcome data are lacking. We report findings of pancreatic surveillance in individuals at high risk for PC. METHODS: Subjects at high risk for PC were identified through the Cancer Genetics Registry at the University of Michigan. High risk individuals (HRI) included the following: 1) familial pancreatic cancer (FPC) defined as ≥3 relatives, or 2 first degree relatives with PC, 2) pathogenic germline variant in BRCA1/BRCA2, PALB2, ATM or Lynch Syndrome (LS) DNA Mismatch repair genes (LS) with ≥1 relative affected with PC or 3) pathogenic germline variant in CDKN2A, STK11, or PRSS1. Results of pancreatic imaging tests were ascertained through chart review. RESULTS: 121 patients (65 FPC, 20 CDKN2A, 13 LS, 10 ATM, 6 STK11, 4 BRCA, 2 PALB2,1 PRSS1) underwent ≥1 pancreatic imaging tests. Mean age at first screening was 56 ± 10 y with mean of 4 exams per subject (range 1–16). 53 (44%) subjects had abnormalities noted on exam, including parenchymal abnormalities in 28 (53%), cystic lesions in 20 (38%) and ductal abnormalities in 3 (6%). 29 (24%) patients had worrisome findings associated with increased risk for PC (multiple cysts (21), possible solid mass (5), dilated main pancreatic duct (3), cyst &gt;3cm (2)). Of these, there were 13 patients (23%) with a germline mutation (5 CDKN2A, 3 ATM, 2 LS, 2 STK11, 1 PRSS1) versus 16 FPC pts (24%) (P = NS). Seven (24%) patients underwent surgical resection after median 1.9 y (range 0.6–8.6 y) surveillance (indication = mass (2), main duct involvement (3), cyst &gt;3 cm (2)) (Table 1). Pathology revealed PC (1), main duct IPMN with high grade dysplasia (1), neuroendocrine tumors (2, both with IPMN), IPMN with low grade dysplasia (2), and chronic pancreatitis (1). In our cohort, there was one other patient (LS) with PC (a 2cm mass found on initial imaging (MRI); pt now undergoing treatment). The remaining 21 pts are cancer-free with mean 4.3 ± 3.8y follow up. CONCLUSION: One in 4 high risk individuals have worrisome pancreatic lesions. The presence of a mass, main duct dilation, and cyst size appear to be the most important findings. Further studies are necessary to better stratify patients and imaging findings at highest risk for progression to PC.

Cost-effectiveness of Pancreatic Cancer Surveillance in High-Risk Individuals: An Economic Analysis.

The aim of the study was to perform an economic analysis to identify the clinical and cost determinants of pancreatic cancer (PC) surveillance in high-risk individuals (HRIs). A Markov model was created to compare the following 3 strategies: no screening, endoscopic ultrasound (EUS), and magnetic resonance imaging (MRI) screening. Patients were considered HRIs according to the Cancer of the Pancreas Screening consortium recommendations. Risk for developing PC, survival, and costs data were obtained from the Surveillance, Epidemiology, and End Results and Medicare databases. Surveillance effectiveness was obtained from a recent meta-analysis. Analysis of a cohort with fivefold relative risk of PC higher than the US population showed that MRI is the most cost-effective strategy. For those with the highest risk (>×20 relative risk), EUS became the dominant strategy. Our model was impacted by cost and imaging performance, but still cost-effective within the range reported in literature. Threshold analysis showed that if MRI increases greater than US $1600, EUS becomes more cost-effective. Once patients reached the age of 76 years, "no screening" was favored. Both surveillance strategies were cost-effective over a wide range of willingness to pay. Abdominal imaging followed by pancreatectomy is cost-effective to prevent PC in HRIs, favoring MRI in moderate risk cases but EUS in those with highest risk.