Is Biannual Surveillance for Pancreatic Cancer Sufficient in Individuals With Genetic Syndromes or Familial Pancreatic Cancer?

View More View Less
  • 1 Department of Surgery, McGill University, Montreal, Quebec;
  • | 2 Research Institute of the McGill University Health Centre, Montreal, Quebec;
  • | 3 Rosalind and Morris Goodman Cancer Institute,
  • | 4 Division of Gastroenterology and Hepatology, and
  • | 5 Department of Diagnostic Radiology, McGill University, Montreal, Quebec;
  • | 6 Ontario Institute for Cancer Research, Toronto, Ontario;
  • | 7 Wallace McCain Centre for Pancreatic Cancer, Princess Margaret Cancer Centre, Toronto, Ontario;
  • | 8 Ontario Pancreas Cancer Study, Mount Sinai Hospital, Toronto, Ontario;
  • | 9 Molecular Diagnostics Laboratory, Sir Mortimer B. Davis-Jewish General Hospital, Montreal, Quebec;
  • | 10 Department of Pathology, University of Toronto, Ontario; and
  • | 11 Department of Pathology,
  • | 12 Department of Human Genetics, and
  • | 13 Lady Davis Institute for Medical Research, McGill University, Montreal, Quebec, Canada.

Background: Individuals with a family history of pancreatic adenocarcinoma (PC) or with a germline mutation in a PC susceptibility gene are at increased risk of developing PC. These high-risk individuals (HRIs) may benefit from PC surveillance. Methods: A PC surveillance program was developed to evaluate the detection of premalignant lesions and early-stage PCs using biannual imaging and to determine whether locally advanced or metastatic PCs develop despite biannual surveillance. From January 2013 to April 2020, asymptomatic HRIs were enrolled and followed with alternating MRI and endoscopic ultrasound every 6 months. Results: Of 75 HRIs, 43 (57.3%) had a germline mutation in a PC susceptibility gene and 32 (42.7%) had a familial pancreatic cancer (FPC) pedigree. Branch-duct intraductal papillary mucinous neoplasms (BD-IPMNs) were identified in 26 individuals (34.7%), but only 2 developed progressive lesions. 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 patient with PJS-associated PC from the same kindred revealed biallelic inactivation of STK11 in a KRAS-independent manner. A review of 3,853 patients from 2 PC registries identified an additional patient with PJS-associated PC. All 3 patients with PJS developed advanced PC consistent with the 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 that harbored polyclonal KRAS mutations. Conclusions: PC surveillance identifies a high prevalence of BD-IPMNs in HRIs. Patients with PJS with BD-IPMNs may be at risk for accelerated malignant transformation.

Submitted May 4, 2021; final revision received October 25, 2021; accepted for publication October 26, 2021.

Author contributions: Study concept: Wang, Foulkes, Waschke, Zogopoulos. Data curation: Wang, Cuggia, Parent, Stanek, Denroche, Domecq, Golesworthy, Shwaartz, Borgida, Holter, Chong, O’Kane, Waschke. Formal analysis: Wang, Denroche, Domecq, Golesworthy, Zogopoulos. Funding acquisition: Wilson, Knox, Gallinger, Zogopoulos. Investigation: Wang, Cuggia, Parent, Stanek, Zhang, Grant, Domecq, Golesworthy, Shwaartz, Holter, Chong, O’Kane, Fischer, Gao, Foulkes, Waschke, Zogopoulos. Methodology: Wang, Cuggia, Parent, Stanek, Denroche, Zhang, Grant, Domecq, Golesworthy, Borgida, Chong, Fischer, Gao, Foulkes, Waschke, Zogopoulos. Project administration: Wilson. Resources: Cuggia, Parent, Stanek, Borgida, Holter, Wilson, Chong, O’Kane, Knox, Fischer, Gallinger, Gao, Foulkes, Waschke, Zogopoulos. Software: Denroche, Zhang. Supervision: Gallinger, Foulkes, Zogopoulos. Visualization: Wang, Denroche, Zhang, Shwaartz. Writing—original draft: Wang, Zogopoulos. Writing—review and editing: All authors.

Disclosures: The 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: This work was supported through funding provided by the Terry Fox Research Institute (project 1078) and the Pancreatic Cancer Canada Foundation. This work was supported by the Quebec Cancer Consortium and the Ministère de l’Économie et de l’Innovation du Québec through the Fonds d’accélération des collaborations en santé. The Ontario Institute for Cancer Research (PanCuRx Translational Research Initiative) is supported through funding provided by the Government of Ontario, the Princess Margaret Cancer Foundation, and the Canadian Cancer Society Research Institute. Dr. Wang is supported by a Vanier Canada Graduate Scholarship, the Fonds de recherche du Québec—Santé/Ministère de la Santé et des Services sociaux training program, and the McGill University Surgical-Scientist Program. Dr. O’Kane is supported by the Lewitt Fellowship. Dr. Knox is the recipient of the Wilfred G. Lewitt Chair in Pancreatic Cancer Research. Dr. Gallinger is the recipient of an Investigator Award from the Ontario Institute for Cancer Research. Dr. Zogopoulos is a clinical research scholar of the Fonds de recherche du Québec—Santé and a recipient of the Michal and Renata Hornstein Career Award from McGill University.

Disclaimer: The funding agencies were not involved in the study design, collection, analysis, and interpretation of the data or in the writing of the manuscript.

Correspondence: George Zogopoulos, MD, PhD, Research Institute of the McGill University Health Centre, 1001 Decarie Boulevard, Room EM2.3210, Montreal, Quebec H4A 3J1, Canada. Email: george.zogopoulos@mcgill.ca

Supplementary Materials

    • Supplemental Materials (PDF 1.8 MB)
  • 1.

    Siegel RL, Miller KD, Jemal A. Cancer statistics, 2019. CA Cancer J Clin 2019;69:734.

  • 2.

    Von Hoff DD, Ervin T, Arena FP, et al. Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. N Engl J Med 2013;369:16911703.

  • 3.

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

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 4.

    Goggins M, Overbeek KA, 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;69:717.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 5.

    Petersen GM. Familial pancreatic cancer. Semin Oncol 2016;43:548553.

  • 6.

    Klein AP, Brune KA, Petersen GM, et al. Prospective risk of pancreatic cancer in familial pancreatic cancer kindreds. Cancer Res 2004;64:26342638.

  • 7.

    Syngal S, Brand RE, Church JM, et al. American College of Gastroenterology. ACG clinical guideline: genetic testing and management of hereditary gastrointestinal cancer syndromes. Am J Gastroenterol 2015;110:223262.

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

    Daly MB, Pal T, Berry MP, et al. NCCN Clinical Practice Guidelines in Oncology: Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic. Version 2.2021. Accessed May 4, 2021. To view the most recent version, visit NCCN.org

    • Search Google Scholar
    • Export Citation
  • 9.

    Corral JE, Mareth KF, Riegert-Johnson DL, et al. Diagnostic yield from screening asymptomatic individuals at high risk for pancreatic cancer: a meta-analysis of cohort studies. Clin Gastroenterol Hepatol 2019;17:4153.

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

    Signoretti M, Bruno MJ, Zerboni G, et al. Results of surveillance in individuals at high-risk of pancreatic cancer: a systematic review and meta-analysis. United European Gastroenterol J 2018;6:489499.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 11.

    Smith AL, Bascuñana C, Hall A, et al. Establishing a clinic-based pancreatic cancer and periampullary tumour research registry in Quebec. Curr Oncol 2015;22:113121.

  • 12.

    Canto MI, Harinck F, Hruban RH, 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;62:339347.

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

    Elta GH, Enestvedt BK, Sauer BG, et al. ACG clinical guideline: diagnosis and management of pancreatic cysts. Am J Gastroenterol 2018;113:464479.

  • 14.

    Schenkel LC, Kerkhof J, Stuart A, et al. Clinical next-generation sequencing pipeline outperforms a combined approach using Sanger sequencing and multiplex ligation-dependent probe amplification in targeted gene panel analysis. J Mol Diagn 2016;18:657667.

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

    Richards S, Aziz N, Bale S, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med 2015;17:405424.

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

    Wang W, Chen S, Brune KA, et al. PancPRO: risk assessment for individuals with a family history of pancreatic cancer. J Clin Oncol 2007;25:14171422.

  • 17.

    Aung KL, Fischer SE, Denroche RE, et al. Genomics-driven precision medicine for advanced pancreatic cancer: early results from the COMPASS Trial. Clin Cancer Res 2018;24:13441354.

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

    Denroche RE, Mullen L, Timms L, et al. A cancer cell-line titration series for evaluating somatic classification. BMC Res Notes 2015;8:823.

  • 19.

    Alexandrov LB, Nik-Zainal S, Wedge DC, et al. Signatures of mutational processes in human cancer. Nature 2013;500:415421.

  • 20.

    Borgida AE, Ashamalla S, Al-Sukhni W, et al. Management of pancreatic adenocarcinoma in Ontario, Canada: a population-based study using novel case ascertainment. Can J Surg 2011;54:5460.

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

    Catalano MF, Sahai A, Levy M, et al. EUS-based criteria for the diagnosis of chronic pancreatitis: the Rosemont classification. Gastrointest Endosc 2009;69:12511261.

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

    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.

  • 23.

    Cicenas J, Kvederaviciute K, Meskinyte I, et al. KRAS, TP53, CDKN2A, SMAD4, BRCA1, and BRCA2 mutations in pancreatic cancer. Cancers (Basel) 2017;9:42.

  • 24.

    Korsse SE, Biermann K, Offerhaus GJA, et al. Identification of molecular alterations in gastrointestinal carcinomas and dysplastic hamartomas in Peutz-Jeghers syndrome. Carcinogenesis 2013;34:16111619.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 25.

    Canto MI, Goggins M, Yeo CJ, et al. Screening for pancreatic neoplasia in high-risk individuals: an EUS-based approach. Clin Gastroenterol Hepatol 2004;2:606621.

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

    Canto MI, Goggins M, Hruban RH, et al. Screening for early pancreatic neoplasia in high-risk individuals: a prospective controlled study. Clin Gastroenterol Hepatol 2006;4:766781.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 27.

    Poley JW, Kluijt I, Gouma DJ, et al. The yield of first-time endoscopic ultrasonography in screening individuals at a high risk of developing pancreatic cancer. Am J Gastroenterol 2009;104:21752181.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 28.

    Al-Sukhni W, Borgida A, Rothenmund H, et al. Screening for pancreatic cancer in a high-risk cohort: an eight-year experience. J Gastrointest Surg 2012;16:771783.

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

    Canto, MI, Hruban RH, Fishman EK, et al. Frequent detection of pancreatic lesions in asymptomatic high-risk individuals. Gastroenterology 2012;142:796804.

  • 30.

    Sud A, Wham D, Catalano M, et al. Promising outcomes of screening for pancreatic cancer by genetic testing and endoscopic ultrasound. Pancreas 2014;43:458461.

  • 31.

    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.

    • Crossref
    • 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.

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

    Paiella S, Capurso G, Cavestro GM, et al. Results of first-round of surveillance in individuals at high-risk of pancreatic cancer from the AISP (Italian Association for the Study of the Pancreas) registry. Am J Gastroenterol 2019;114:665670.

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

    Barnes CA, Krzywda E, Lahiff S, et al. Development of a high risk pancreatic screening clinic using 3.0 T MRI. Fam Cancer 2018;17:101111.

  • 35.

    DaVee T, Coronel E, Papafragkakis C, et al. Pancreatic cancer screening in high-risk individuals with germline genetic mutations. Gastrointest Endosc 2018;87:14431450.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 36.

    Overbeek KA, Levink IJM, Koopmann BDM, et al. Long-term yield of pancreatic cancer surveillance in high-risk individuals [published online April 5, 2021]. Gut, doi:10.1136/gutjnl-2020-323611

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 37.

    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.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 38.

    Collet L, Ghurburrun E, Meyers N, et al. Kras and Lkb1 mutations synergistically induce intraductal papillary mucinous neoplasm derived from pancreatic duct cells. Gut 2020;69:704714.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 39.

    Balduzzi A, Marchegiani G, Pollini T, et al. Systematic review and meta-analysis of observational studies on BD-IPMNS progression to malignancy. Pancreatology 2021;21:11351145.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 40.

    Konings ICAW, Canto MI, Almario JA, et al. Surveillance for pancreatic cancer in high-risk individuals. BJS Open 2019;3:656665.

  • 41.

    Tanaka M, Chari S, Adsay V, et al. International consensus guidelines for management of intraductal papillary mucinous neoplasms and mucinous cystic neoplasms of the pancreas. Pancreatology 2006;6:1732.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 42.

    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.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 43.

    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.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 44.

    Hosoda W, Sasaki E, Murakami Y, et al. GNAS mutation is a frequent event in pancreatic intraductal papillary mucinous neoplasms and associated adenocarcinomas. Virchows Arch 2015;466:665674.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 45.

    Tan MC, Basturk O, Brannon AR, et al. GNAS and KRAS mutations define separate progression pathways in intraductal papillary mucinous neoplasm-associated carcinoma. J Am Coll Surg 2015;220:845854.e1.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 46.

    Omori Y, Ono Y, Tanino M, et al. Pathways of progression from intraductal papillary mucinous neoplasm to pancreatic ductal adenocarcinoma based on molecular features. Gastroenterology 2019;156:647661.e2.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 47.

    Thiruvengadam SS, Chuang J, Huang R, et al. Chronic pancreatitis changes in high-risk individuals for pancreatic ductal adenocarcinoma. Gastrointest Endosc 2019;89:842851.e1.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 48.

    Adsay NV, Pierson C, Sarkar F, et al. Colloid (mucinous noncystic) carcinoma of the pancreas. Am J Surg Pathol 2001;25:2642.

  • 49.

    Ross-Innes CS, Becq J, Warren A, et al. Whole-genome sequencing provides new insights into the clonal architecture of Barrett’s esophagus and esophageal adenocarcinoma. Nat Genet 2015;47:10381046.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 50.

    Secrier M, Li X, de Silva N, et al. Mutational signatures in esophageal adenocarcinoma define etiologically distinct subgroups with therapeutic relevance. Nat Genet 2016;48:11311141.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 51.

    Adsay NV, Merati K, Basturk O, et al. Pathologically and biologically distinct types of epithelium in intraductal papillary mucinous neoplasms: delineation of an “intestinal” pathway of carcinogenesis in the pancreas. Am J Surg Pathol 2004;28:839848.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 52.

    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.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
All Time Past Year Past 30 Days
Abstract Views 0 0 0
Full Text Views 587 587 587
PDF Downloads 392 392 392
EPUB Downloads 0 0 0