Principal Investigator

Shounak
Majumder
Awardee Organization

Mayo Clinic Rochester
United States

Fiscal Year
2023
Activity Code
U01
Early Stage Investigator Grants (ESI)
Not Applicable
Project End Date

Mayo Clinic Prospective Resource for Biomarker Validation and Early Detection of Pancreatic Cancer

Pancreatic ductal adenocarcinoma (PDAC) is typically detected at late stage due to absence of a cancer screening strategy, with concomitant poor survival rates. Detection of PDAC at an early stage positively impacts survival, and currently screening in eligible high-risk individuals (HRIs) defined by family history and germline mutation status is considered best practice. The overall goal of this proposal is to use knowledge gained during the last grant period to considerably enhance our ability to develop and validate the diagnostic performance of new blood protein and methylated DNA (MDM) biomarkers for early detection of PDAC, using prospective specimen collection and retrospective blinded evaluation (PRoBE) compliant methods. We hypothesize that a combination of proteins, MDMs, and CA19-9 will accurately identify early stage PDAC in HRIs. We will assess the performance characteristics of our approaches in early stage and pre-diagnostic phase of PDAC and identify approaches that are optimized for clinical translation as an early detection tool using HRIs. For over two decades, Mayo Clinic’s prospective biospecimen resources have accrued, using standardized high-quality procedures, well-annotated biospecimens from thousands of PDAC patients including those with germline mutations in pancreas cancer susceptibility genes, high risk members in familial pancreatic cancer kindreds, patients with high-risk pancreatic conditions, and healthy controls. We have also launched the PCDC Signature Protocols at our center. Among those at risk with biospecimens who we have followed longitudinally over two decades, incident PDAC cases have developed, enabling us to utilize novel approaches to address the challenges and better design PRoBE phase 3 studies. Based on our findings in the last grant period, we now focus on tailoring samples for PRoBE phase 2 studies and characterizing performance to improve phase 3 studies. Our approach will allow us to assess, for example, variability in biomarker expression for intended use HRI settings, and temporality of biomarker expression to improve the ability to detect early onset PDAC. Our Specific Aims are to: 1) Accrue formal biospecimen sets from blood sample products and pancreatic cyst fluid suitable for PCDC biomarker studies; 2) Leverage our past knowledge and experience to develop new biomarker panels using tailored phase 2 designs and incorporating covariates to refine detection (age, sex, race, smoking, personal history of diabetes mellitus, symptoms at diagnosis) to optimize detection; and 3) Evaluate needed performance parameters that will inform the design of a successful phase 3 study for PDAC in a surveillance setting of HRIs. Our multidisciplinary team is committed to continue its leadership and contribution to the PCDC organization to advance the early detection of pancreatic cancer. Our project leverages existing infrastructures and biospecimen banks of pancreatic cancer and other pancreatic diseases at Mayo Clinic and University of Pennsylvania, and it will extend new prospective collections of blood and pancreatic cyst fluid from patients, contributing to PCDC Signature Protocol cohorts and a PCDC central biorepository.

Publications

  • Kim J, Bamlet WR, Oberg AL, Chaffee KG, Donahue G, Cao XJ, Chari S, Garcia BA, Petersen GM, Zaret KS. Detection of early pancreatic ductal adenocarcinoma with thrombospondin-2 and CA19-9 blood markers. Science translational medicine. 2017 Jul 12;9. (398). PMID: 28701476
  • Majumder S, Taylor WR, Foote PH, Berger CK, Wu CW, Mahoney DW, Bamlet WR, Burger KN, Postier N, de la Fuente J, Doering KA, Lidgard GP, Allawi HT, Petersen GM, Chari ST, Ahlquist DA, Kisiel JB. High Detection Rates of Pancreatic Cancer Across Stages by Plasma Assay of Novel Methylated DNA Markers and CA19-9. Clinical cancer research : an official journal of the American Association for Cancer Research. 2021 May 1;27(9):2523-2532. Epub 2021 Feb 16. PMID: 33593879
  • Chen X, Meyer MA, Kemppainen JL, Horibe M, Chandra S, Majumder S, Petersen GM, Rabe KG. Risk of Syndrome-Associated Cancers Among First-Degree Relatives of Patients With Pancreatic Ductal Adenocarcinoma With Pathogenic or Likely Pathogenic Germline Variants. JAMA oncology. 2023 Jul 1;9(7):955-961. PMID: 37200008
  • Gimotty PA, Till JE, Udgata S, Takenaka N, Yee SS, LaRiviere MJ, O'Hara MH, Reiss KA, O'Dwyer P, Katona BW, Herman D, Carpenter EL, Zaret KS. THSB2 as a prognostic biomarker for patients diagnosed with metastatic pancreatic ductal adenocarcinoma. Oncotarget. 2021 Oct 26;12(22):2266-2272. doi: 10.18632/oncotarget.28099. eCollection 2021 Oct 26. PMID: 34733417
  • de la Fuente J, Chatterjee A, Lui J, Nehra AK, Bell MG, Lennon RJ, Kassmeyer BA, Graham RP, Nagayama H, Schulte PJ, Doering KA, Delgado AM, Vege SS, Chari ST, Takahashi N, Majumder S. Long-Term Outcomes and Risk of Pancreatic Cancer in Intraductal Papillary Mucinous Neoplasms. JAMA network open. 2023 Oct 2;6(10):e2337799. PMID: 37847503
  • Udgata S, Takenaka N, Bamlet WR, Oberg AL, Yee SS, Carpenter EL, Herman D, Kim J, Petersen GM, Zaret KS. THBS2/CA19-9 Detecting Pancreatic Ductal Adenocarcinoma at Diagnosis Underperforms in Prediagnostic Detection: Implications for Biomarker Advancement. Cancer prevention research (Philadelphia, Pa.). 2021 Feb;14(2):223-232. Epub 2020 Oct 16. PMID: 33067248
  • Stevens MA, Rabe KG, Boursi B, Kolluri A, Singh DP, Bamlet WR, Petersen GM. Accuracy of Smoking Status Reporting: Proxy Information in a Rapidly Fatal Cancer Setting. Mayo Clinic proceedings. Innovations, quality & outcomes. 2020 Dec 10;4(6):801-809. doi: 10.1016/j.mayocpiqo.2020.07.010. eCollection 2020 Dec. PMID: 33367216
  • Rabe KG, Stevens MA, Hernández AT, Chandra S, Hubbard JM, Kemppainen JL, Majumder S, Petersen GM. Pancreatic cancer risk to siblings of probands in bilineal cancer settings. Genetics in medicine : official journal of the American College of Medical Genetics. 2022 May;24(5):1008-1016. Epub 2022 Feb 25. PMID: 35227607
  • Antwi SO, Rabe KG, Bamlet WR, Meyer M, Chandra S, Fagan SE, Hu C, Couch FJ, McWilliams RR, Oberg AL, Petersen GM. Influence of Cancer Susceptibility Gene Mutations and ABO Blood Group of Pancreatic Cancer Probands on Concomitant Risk to First-Degree Relatives. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology. 2022 Feb;31(2):372-381. Epub 2021 Nov 15. PMID: 34782396

Clinical Trials

Study Name Clinical Trial ID
Molecular Detection of Advanced Neoplasia in Pancreatic Cysts NCT03855800
Cohort Study of Pancreatic Cancer Risk NCT04247503
Pancreatic Cancer Detection Consortium (PCDC) Prospective Cohorts NCT06271291