Early Detection of Pancreatic Cancer through the Evaluation

Early Detection of Pancreatic Cancer through the Evaluation

Early Detection of Pancreatic Cancer through the Evaluation of Pancreatic Cysts Aatur D. Singhi, MD PhD University of Pittsburgh Medical Center Department of Pathology [email protected] Disclosures I have no financial relationships to disclose. Randall Brand, MD Marina Nikiforova, MD N. Paul Ohori, MD Sara Monaco, MD Herbert Zeh, MD Amer Zureikat, MD Kevin McGrath, MD Jennifer Chennat, MD Kenneth Fasanella, MD Asif Khalid, MD Kenneth Lee, MD

Adam Slivka, MD PhD Melissa Hogg, MD Allan Tsung, MD J. Wallis Marsh, MD Ying Huang, PhD Walter Park, MD Michael Goggins, MD Charles Craik, PhD Koushik Das, MD Brian Habb, PhD Pancreatic Cancer rd Leading cause of cancer 3 deaths in the United States. st Mortality rate among all 1 major cancers. 74%

Die within the first year of diagnosis. 92% Die within 5 years of being diagnosed. 53,670 0 Estimated new cases of pancreatic cancer (equivalent number of deaths). Early detection methods and successful treatment options have been discovered. Adapted from http://www.pancan.org Pancreatic Cancer = Genetic Disease Invasive Cancer Normal Duct KRAS CDKN2A Telomere Shortening TP53 SMAD4 Precursors to Pancreatic Cancer Normal Duct 15% of Pancreatic Cancers IPMN MCN Invasive Cancer Mucinous Pancreatic Cysts IPMN = Intraductal Papillary Mucinous Neoplasm MCN = Mucinous Cystic Neoplasm

Precursors to Pancreatic Cancer Normal Duct Standard CT Invasive Cancer IPMN MCN IPMN = Intraductal Papillary Mucinous Neoplasm MCN = Mucinous Cystic Neoplasm 53,670 8,050 6,462,000 Estimated new cases of pancreatic cancer (equivalent number of deaths). Pancreatic cancers arising from a mucinous pancreatic cyst (IPMN/MCN). Number of Americans with a pancreatic cyst. Pseudocyst Foregut Cyst Retention Cyst Lymphoepithelial Cyst Acinar Cell Cystadenoma Squamoid Cyst Serous Cystadenoma (SCA) Cystic PanNET Solid-Pseudopapillary Neoplasm IPMN = Intraductal Papillary Mucinous Neoplasm MCN = Mucinous Cystic Neoplasm 53,670 8,050 6,462,000 Estimated new cases of pancreatic cancer (equivalent number of deaths). Pancreatic cancers arising from a

mucinous pancreatic cyst (IPMN/MCN). Number of Americans with a pancreatic cyst. Non-Mucinous Pancreatic Cyst Mucinous Pancreatic Cyst (IPMN/MCN) 53,670 8,050 Estimated new cases of pancreatic cancer (equivalent number of deaths). Pancreatic cancers arising from a mucinous pancreatic cyst (IPMN/MCN). 6,462,000 Number of Americans with a pancreatic cyst. 3,231,000 Number of Americans with a mucinous pancreatic cyst. Not all mucinous pancreatic cysts (IPMNs and MCNs) transform into Pancreatic Cancer. 53,670 8,050 Estimated new cases of pancreatic cancer (equivalent number of deaths). Pancreatic cancers arising from a mucinous pancreatic cyst (IPMN/MCN). 6,462,000 Number of Americans with a pancreatic cyst. 3,231,000 Number of Americans with a mucinous pancreatic cyst. Robotic Assisted Pancreatectomy

53,670 8,050 Estimated new cases of pancreatic cancer (equivalent number of deaths). Pancreatic cancers arising from a mucinous pancreatic cyst (IPMN/MCN). 6,462,000 Number of Americans with a pancreatic cyst. 3,231,000 Number of Americans with a mucinous pancreatic cyst. Pancreatic Cysts Diagnostic Modalities Endoscopic ultrasound (EUS) has variable sensitivity and specificity in pancreatic cyst classification. Ancillary studies using aspirated cyst fluid, such as CEA (marker of mucinous cysts) and cytology, have had limited success in cyst classification and the detection of malignancy. Endoscopic Ultrasound Fine Needle Aspiration Pancreatic Cyst Adapted from Brugge WR. Endosc Ultrasound 2012 Jul; 1(2):59-60. Pancreatic Cysts Endoscopic Ultrasound Fine Needle Aspiration

Pancreatic Cyst Adapted from Brugge WR. Endosc Ultrasound 2012 Jul; 1(2):59-60. Pancreatic Cyst (IPMN) Pancreatic Cysts Endoscopic Ultrasound Fine Needle Aspiration Exfoliated Cyst Epithelium Pancreatic Cyst Adapted from Brugge WR. Endosc Ultrasound 2012 Jul; 1(2):59-60. Pancreatic Cyst (IPMN) Pancreatic Cysts Lysed Cyst Epithelium (DNA) Endoscopic Ultrasound Fine Needle Aspiration Exfoliated Cyst Epithelium Pancreatic Cyst Adapted from Brugge WR. Endosc Ultrasound 2012 Jul; 1(2):59-60. Pancreatic Cyst (IPMN) Pancreatic Cysts Lysed Cyst Epithelium (DNA) Endoscopic Ultrasound Fine Needle Aspiration Exfoliated Cyst Epithelium Pancreatic Cyst Adapted from Brugge WR. Endosc Ultrasound 2012 Jul; 1(2):59-60. Pancreatic Cyst (IPMN) Molecular Analysis (Panc. Cyst Fluid) KRAS GNAS VHL CTNNB1 Intraductal papillary neoplasms (IPMN): IPMN IPMN +

+ - mucinous MCNKRAS+ and GNAS SCA + - (MCN): Mucinous cystic neoplasms MCN SPN KRAS+ Non Serous cystadenomas (SCA): SCA VHL Solid pseudopapillary neoplasms (SPN): SPN CTNNB1 Non-neoplastic Non cysts: Absent Molecular Analysis (Panc. Cyst Fluid) KRAS GNAS VHL CTNNB1 IPMN + + MCN + - Low-grade Dysplasia KRAS & GNAS High-grade Dysplasia AdenoCA Molecular Analysis (Panc. Cyst Fluid) KRAS GNAS VHL CTNNB1 TP53 PIK3CA PTEN IPMN + + HR HR

HR MCN ++ ---HR HR HR MCN SCA + SPN + Non Low-grade High-grade HR = High-risk of malignancy Dysplasia Dysplasia KRAS & GNAS TP53 PIK3CA TP53, & PTEN AdenoCA Molecular Analysis (Panc. Cyst Fluid) KRAS GNAS VHL CTNNB1 TP53 PIK3CA PTEN Next-generation sequencing panel (PancreaSeq) to assess preoperative EUS-FNA obtained pancreatic cyst fluid. Exons 1 through 3 of VHL were assessed by Sanger sequencing, limit of detection 10-20%. >1,000 hot spot mutations with over 1000x to 500x depth of coverage, corresponding to a limit of detection of 3% to 5%, respectively. Samples below 500x were not interpreted. Molecular Analysis (Panc. Cyst Fluid) KRAS GNAS VHL CTNNB1 TP53 PIK3CA PTEN For each mutation identified, an allele frequency (AF) was calculated based on the number of reads of the mutant allele versus the total (mutant + wild type) alleles and reported as a percentage. # of mutant allele reads AF = X 100% # of total allele reads (mt + wt)

Molecular Analysis (Panc. Cyst Fluid) KRAS GNAS VHL CTNNB1 TP53 PIK3CA PTEN # of mutant allele reads AF = X 100% # of total allele reads (mt + wt) 250 GNAS p.R201H reads GNAS AF = X 100% = 25%* 1000 GNAS (mt + wt) reads *KRAS and GNAS are heterozygous mutations, and an AF < 50% is expected. Molecular Analysis (Panc. Cyst Fluid) KRAS GNAS VHL CTNNB1 TP53 PIK3CA PTEN Over a 43-month period, 673 EUS-FNA pancreatic cyst fluid specimens from 642 patients were prospectively analyzed for genetic alterations. Among the 673 specimens, 626 (93%) PCs were satisfactory for molecular analysis (PancreaSeq). In comparison, 452 (72%) PCs were sufficient for CEA analysis. Additionally, 251 (40%) PCs were satisfactory for cytopathologic evaluation. Molecular Analysis KRAS/GNAS KRAS/GNAS Mutant (n = 308) KRAS/GNAS Wild type (n = 318) 49% 51% 6,462,000 Number of Americans with a pancreatic cyst. 3,231,000

Number of Americans with a mucinous pancreatic cyst. KRAS/GNAS Mutant (n = 308) KRAS/GNAS Wild type (n = 318) 49% 51% Molecular Analysis TP53/PIK3CA/PTEN TP53/PIK3CA/PTEN Mutant (n = 35) 6% 94% TP53/PIK3CA/PTEN Wild type (n = 591) 6,462,000 8,050 Number of Americans with a pancreatic cyst. Pancreatic cancers arising from a mucinous pancreatic cyst (IPMN/MCN). TP53/PIK3CA/PTEN Mutant (n = 35) 6% 94% TP53/PIK3CA/PTEN Wild type (n = 591) Molecular Analysis (Panc. Cyst Fluid) Surgical Resection Dx Total, n = 102 (18%) AdenoCA arising in an IPMN

13 IPMN with HGD 4 MCN with HGD 2 IPMN with LGD 39 MCN with LGD 8 Serous cystadenoma 3 Cystic PanNET 9 Acinar cell cystadenoma 1 Pseudocyst 17 Retention cyst 2 Lymphoepithelial cyst 2 Epidermoid cyst 1 Squamoid cyst

1 Molecular Analysis (Panc. Cyst Fluid) Surgical Resection Dx Total, n = 102 (18%) AdenoCA arising in an IPMN 13 IPMN with HGD 4 MCN with HGD 2 IPMN with LGD 39 MCN with LGD 8 Serous cystadenoma 3 Cystic PanNET 9 Acinar cell cystadenoma 1 Pseudocyst 17 Retention cyst 2 Lymphoepithelial cyst

2 Epidermoid cyst 1 Squamoid cyst 1 66 Mucinous Cysts: 56 IPMNs 10 MCNs Molecular Analysis (Panc. Cyst Fluid) Surgical Resection Dx Total, n = 102 (18%) AdenoCA arising in an IPMN 13 IPMN with HGD 4 MCN with HGD 2 IPMN with LGD 39 MCN with LGD 8 Serous cystadenoma 3 Cystic PanNET 9

Acinar cell cystadenoma 1 Pseudocyst 17 Retention cyst 2 Lymphoepithelial cyst 2 Epidermoid cyst 1 Squamoid cyst 1 66 Mucinous Cysts: 56 IPMNs 10 MCNs 36 Non-Mucinous Cysts Molecular Analysis (Panc. Cyst Fluid) Surgical Resection Dx Total, n = 102 (18%) AdenoCA arising in an IPMN 13 IPMN with HGD 4 MCN with HGD 2

IPMN with LGD 39 MCN with LGD 8 Serous cystadenoma 3 Cystic PanNET 9 Acinar cell cystadenoma 1 Pseudocyst 17 Retention cyst 2 Lymphoepithelial cyst 2 Epidermoid cyst 1 Squamoid cyst 1 IPMNs & MCNs KRAS &/or GNAS mutations Sensitivity: 89% Specificity: 100% Elevated CEA* Sensitivity: 57% Specificity: 80% Molecular Analysis (Panc. Cyst Fluid)

Surgical Resection Dx Total, n = 102 (18%) AdenoCA arising in an IPMN 13 IPMN with HGD 4 MCN with HGD 2 IPMN with LGD 39 MCN with LGD 8 Serous cystadenoma 3 Cystic PanNET 9 Acinar cell cystadenoma 1 Pseudocyst 17 Retention cyst 2 Lymphoepithelial cyst 2

Epidermoid cyst 1 Squamoid cyst 1 IPMNs & MCNs KRAS &/or GNAS mutations Sensitivity: 89% Specificity: 100% Elevated CEA* Sensitivity: 57% Specificity: 80% IPMNs KRAS &/or GNAS mutations Sensitivity: 100% MCNs KRAS mutations Sensitivity: 20% Molecular Analysis (Panc. Cyst Fluid) Surgical Resection Dx Total, n = 102 (18%) AdenoCA arising in an IPMN 13 IPMN with HGD 4 MCN with HGD 2 IPMN with LGD 39 MCN with LGD 8 Serous cystadenoma

3 Cystic PanNET 9 Acinar cell cystadenoma 1 Pseudocyst 17 Retention cyst 2 Lymphoepithelial cyst 2 Epidermoid cyst 1 Squamoid cyst 1 Molecular Analysis (Panc. Cyst Fluid) Surgical Resection Dx Total, n = 102 (18%) AdenoCA arising in an IPMN 13 IPMN with HGD 4 MCN with HGD 2

IPMN with LGD 39 MCN with LGD 8 Serous cystadenoma 3 Cystic PanNET 9 Acinar cell cystadenoma 1 Pseudocyst 17 Retention cyst 2 Lymphoepithelial cyst 2 Epidermoid cyst 1 Squamoid cyst 1 Adenocarcinoma or High-grade Dysplasia: 19 Cysts Molecular Analysis (Panc. Cyst Fluid) Surgical Resection Dx Total, n = 102 (18%)

AdenoCA arising in an IPMN 13 IPMN with HGD 4 MCN with HGD 2 IPMN with LGD 39 MCN with LGD 8 Serous cystadenoma 3 Cystic PanNET 9 Acinar cell cystadenoma 1 Pseudocyst 17 Retention cyst 2 Lymphoepithelial cyst 2 Epidermoid cyst 1

Squamoid cyst 1 Adenocarcinoma or High-grade Dysplasia: 19 Cysts Low-grade Dysplasia or No Dysplasia: 83 Cysts Molecular Analysis (Panc. Cyst Fluid) Surgical Resection Dx Total, n = 102 (18%) AdenoCA arising in an IPMN 13 IPMN with HGD 4 MCN with HGD 2 IPMN with LGD 39 MCN with LGD 8 Serous cystadenoma 3 Cystic PanNET 9 Acinar cell cystadenoma 1

Pseudocyst 17 Retention cyst 2 Lymphoepithelial cyst 2 Epidermoid cyst 1 Squamoid cyst 1 Advanced Neoplasia KRAS and/or GNAS and TP53, PIK3CA, and/or PTEN Sensitivity: 79% Specificity: 96% Cytology Sensitivity: 32% Specificity: 98% Molecular Analysis (Panc. Cyst Fluid) Surgical Resection Dx Total, n = 102 (18%) AdenoCA arising in an IPMN 13 IPMN with HGD 4 MCN with HGD 2 IPMN with LGD

39 MCN with LGD 8 Serous cystadenoma 3 Cystic PanNET 9 Acinar cell cystadenoma 1 Pseudocyst 17 Retention cyst 2 Lymphoepithelial cyst 2 Epidermoid cyst 1 Squamoid cyst 1 Advanced Neoplasia KRAS and/or GNAS and TP53, PIK3CA, and/or PTEN Sensitivity: 79% Specificity: 96% Cytology Sensitivity: 32% Specificity: 98% IPMNs w/ Advanced Neoplasia KRAS and/or GNAS and TP53,

PIK3CA, and/or PTEN Sensitivity: 88% Specificity: 97% Molecular Analysis (Panc. Cyst Fluid) Surgical Resection Dx Total, n = 102 (18%) TP53/PIK3CA/PTEN- TP53/PIK3CA/PTENmut, n = 18 (19%) wt, n = 84 (81%) AdenoCA arising in an IPMN 13 13 (100%) 0 (0%) IPMN with HGD 4 2 (50%) 2 (50%) MCN with HGD 2 0 (0%) 2 (100%) IPMN with LGD 39 3 (8%) 36 (92%) MCN with LGD 8

0 (0%) 8 (100%) Serous cystadenoma 3 0 (0%) 3 (100%) Cystic PanNET 9 0 (0%) 9 (100%) Acinar cell cystadenoma 1 0 (0%) 1 (100%) Pseudocyst 17 0 (0%) 17 (100%) Retention cyst 2 0 (0%) 2 (100%) Lymphoepithelial cyst 2 0 (0%)

2 (100%) Epidermoid cyst 1 0 (0%) 1 (100%) Squamoid cyst 1 0 (0%) 1 (100%) Molecular Analysis (Panc. Cyst Fluid) Surgical Resection Dx Total, n = 102 (18%) TP53/PIK3CA/PTEN- TP53/PIK3CA/PTENmut, n = 18 (19%) wt, n = 84 (81%) AdenoCA arising in an IPMN 13 13 (100%) 0 (0%) IPMN with HGD 4 2 (50%) 2 (50%) MCN with HGD 2 0 (0%)

2 (100%) IPMN with LGD 39 3 (8%) 36 (92%) MCN with LGD 8 0 (0%) 8 (100%) Serous cystadenoma 3 0 (0%) 3 (100%) 9TP53/PIK3CA/PTEN 0 (0%) 9 (100%) Alterations in Acinar cell cystadenoma 1 0 (0%) 1 (100%) Pseudocyst 17 0 (0%) (100%) were preoperatively found in 17all 13 Retention cyst 2 0 (0%) 2 (100%) (100%)

adenocarcinomas Lymphoepithelial cyst 2 0 (0%) 2 (100%) Cystic PanNET Epidermoid cyst 1 0 (0%) 1 (100%) Squamoid cyst 1 0 (0%) 1 (100%) Molecular Analysis (Panc. Cyst Fluid) Surgical Resection Dx Total, n = 102 (18%) TP53/PIK3CA/PTEN- TP53/PIK3CA/PTENmut, n = 18 (19%) wt, n = 84 (81%) AdenoCA arising in an IPMN 13 13 (100%) 0 (0%) IPMN with HGD 4 2 (50%) 2 (50%)

MCN with HGD 2 0 (0%) 2 (100%) IPMN with LGD 39 3 (8%) 36 (92%) MCN with LGD 8 0 (0%) 8 (100%) Serous cystadenoma 3 0 (0%) 3 (100%) 9TP53/PIK3CA/PTEN 0 (0%) 9 (100%) Alterations in Acinar cell cystadenoma 1 0 (0%) 1 (100%) Pseudocystdetected in 17 2 (50%) 0 (0%) IPMNs 17 (100%) were with Retention cyst 2

0 (0%) 2 (100%) HGD and 3 (8%) IPMNs Lymphoepithelial cyst 2 0 (0%) with LGD 2 (100%) Cystic PanNET Epidermoid cyst 1 0 (0%) 1 (100%) Squamoid cyst 1 0 (0%) 1 (100%) Molecular Analysis (Panc. Cyst Fluid) Surgical Resection Dx Total, n = 102 (18%) TP53/PIK3CA/PTEN- TP53/PIK3CA/PTENmut, n = 18 (19%) wt, n = 84 (81%) AdenoCA arising in an IPMN 13 13 (100%) 0 (0%) IPMN with HGD 4

2 (50%) 2 (50%) MCN with HGD 2 0 (0%) 2 (100%) IPMN with LGD 39 3 (8%) 36 (92%) MCN with LGD 8 0 (0%) 8 (100%) Serous cystadenoma 3 0 (0%) 3 (100%) 9TP53/PIK3CA/PTEN 0 (0%) 9 (100%) Alterations in Acinar cell cystadenoma 1 0 (0%) 1 (100%) Pseudocystdetected in 17 2 (50%) 0 (0%) IPMNs 17 (100%)

were with Retention cyst 2 0 (0%) 2 (100%) HGD and 3 (8%) IPMNs Lymphoepithelial cyst 2 0 (0%) with LGD 2 (100%) Cystic PanNET Epidermoid cyst 1 0 (0%) 1 (100%) Squamoid cyst 1 0 (0%) 1 (100%) Surgical Dx KRAS GNAS TP53 PIK3CA PTEN AdenoCA in IPMN IPMN with HGD 40%

29%, 7% 40% 19% 21% 15% 33% 11% 18% 41% 26% 7% - 48% 43% 15% 51% 30% H Deletion 38%, 18% H Deletion 16% 21% 16% 19% 23% 43% 29% 34% 28% 29% 50% 5% - H Deletion - IPMN with HGD - 39% 42% -

- IPMN with HGD 45% 92% - - - IPMN with HGD 41% 88% - - - AdenoCA in IPMN AdenoCA in IPMN AdenoCA in IPMN AdenoCA in IPMN AdenoCA in IPMN AdenoCA in IPMN AdenoCA in IPMN AdenoCA in IPMN AdenoCA in IPMN AdenoCA in IPMN AdenoCA in IPMN AdenoCA in IPMN KRAS/GNAS to TP53/PIK3CA/PTEN Surgical Dx KRAS GNAS

TP53 PIK3CA PTEN AdenoCA in IPMN IPMN with HGD 40% 29%, 7% 40% 19% 21% 15% 33% 11% 18% 41% 26% 7% - 48% 43% 15% 51% 30% H Deletion 38%, 18% H Deletion 16% 21% 16% 19% 23% 43% 29% 34% 28% 29% 50% 5% - H Deletion

- IPMN with HGD - 39% 42% - - IPMN with HGD 45% 92% - - - IPMN with HGD 41% 88% - - - AdenoCA in IPMN AdenoCA in IPMN AdenoCA in IPMN AdenoCA in IPMN AdenoCA in IPMN AdenoCA in IPMN AdenoCA in IPMN AdenoCA in IPMN AdenoCA in IPMN AdenoCA in IPMN AdenoCA in IPMN

AdenoCA in IPMN KRAS/GNAS to TP53/PIK3CA/PTEN Surgical Dx KRAS GNAS TP53 PIK3CA PTEN AdenoCA in IPMN IPMN with HGD 40% 29%, 7% 40% 19% 21% 15% 33% 11% 18% 41% 26% 7% - 48% 43% 15% 51% 30% H Deletion 38%, 18% H Deletion 16% 21% 16% 19% 23%

43% 29% 34% 28% 29% 50% 5% - H Deletion - IPMN with HGD - 39% 42% - - IPMN with HGD 45% 92% - - - IPMN with HGD 41% 88% - - -

AdenoCA in IPMN AdenoCA in IPMN AdenoCA in IPMN AdenoCA in IPMN AdenoCA in IPMN AdenoCA in IPMN AdenoCA in IPMN AdenoCA in IPMN AdenoCA in IPMN AdenoCA in IPMN AdenoCA in IPMN AdenoCA in IPMN KRAS/GNAS to TP53/PIK3CA/PTEN Surgical Dx KRAS GNAS TP53 PIK3CA PTEN AdenoCA in IPMN IPMN with HGD 40% 29%, 7% 40% 19% 21% 15% 33% 11% 18% 41% 26% 7% - 48% 43% 15%

51% 30% H Deletion 38%, 18% H Deletion 16% 21% 16% 19% 23% 43% 29% 34% 28% 29% 50% 5% - H Deletion - IPMN with HGD - 39% 42% - - IPMN with HGD 45% 92% - - - IPMN with HGD

41% 88% - - - AdenoCA in IPMN AdenoCA in IPMN AdenoCA in IPMN AdenoCA in IPMN AdenoCA in IPMN AdenoCA in IPMN AdenoCA in IPMN AdenoCA in IPMN AdenoCA in IPMN AdenoCA in IPMN AdenoCA in IPMN AdenoCA in IPMN KRAS/GNAS to TP53/PIK3CA/PTEN Equivalent AF Surgical Dx KRAS GNAS TP53 PIK3CA PTEN AdenoCA in IPMN IPMN with HGD 40% 29%, 7% 40% 19%

21% 15% 33% 11% 18% 41% 26% 7% - 48% 43% 15% 51% 30% H Deletion 38%, 18% H Deletion 16% 21% 16% 19% 23% 43% 29% 34% 28% 29% 50% 5% - H Deletion - IPMN with HGD - 39% 42% - -

IPMN with HGD 45% 92% - - - IPMN with HGD 41% 88% - - - AdenoCA in IPMN AdenoCA in IPMN AdenoCA in IPMN AdenoCA in IPMN AdenoCA in IPMN AdenoCA in IPMN AdenoCA in IPMN AdenoCA in IPMN AdenoCA in IPMN AdenoCA in IPMN AdenoCA in IPMN AdenoCA in IPMN KRAS/GNAS to TP53/PIK3CA/PTEN Equivalent AF Surgical Dx KRAS GNAS TP53

PIK3CA PTEN AdenoCA in IPMN IPMN with HGD 40% 29%, 7% 40% 19% 21% 15% 33% 11% 18% 41% 26% 7% - 48% 43% 15% 51% 30% H Deletion 38%, 18% H Deletion 16% 21% 16% 19% 23% 43% 29% 34% 28% 29% 50% 5% - H Deletion -

IPMN with HGD - 39% 42% - - IPMN with HGD 45% 92% - - - IPMN with HGD 41% 88% - - - AdenoCA in IPMN AdenoCA in IPMN AdenoCA in IPMN AdenoCA in IPMN AdenoCA in IPMN AdenoCA in IPMN AdenoCA in IPMN AdenoCA in IPMN AdenoCA in IPMN AdenoCA in IPMN AdenoCA in IPMN AdenoCA in IPMN

KRAS/GNAS to TP53/PIK3CA/PTEN Equivalent AF GNAS AF > 55% Surgical Dx KRAS GNAS TP53 PIK3CA PTEN AdenoCA in IPMN IPMN with HGD 40% 29%, 7% 40% 19% 21% 15% 33% 11% 18% 41% 26% 7% - 48% 43% 15% 51% 30% H Deletion 38%, 18% H Deletion 16% 21%

16% 19% 23% 43% 29% 34% 28% 29% 50% 5% - H Deletion - IPMN with HGD - 39% 42% - - IPMN with HGD 45% 92% - - - IPMN with HGD 41% 88% - -

- IPMN with LGD 47% 45% - 3% - IPMN with LGD 41% 42% - 3% - IPMN with LGD - 39% - 3% - AdenoCA in IPMN AdenoCA in IPMN AdenoCA in IPMN AdenoCA in IPMN AdenoCA in IPMN AdenoCA in IPMN AdenoCA in IPMN AdenoCA in IPMN AdenoCA in IPMN AdenoCA in IPMN

AdenoCA in IPMN AdenoCA in IPMN KRAS/GNAS to TP53/PIK3CA/PTEN Equivalent AF GNAS AF > 55% Surgical Dx KRAS GNAS TP53 PIK3CA PTEN AdenoCA in IPMN IPMN with HGD 40% 29%, 7% 40% 19% 21% 15% 33% 11% 18% 41% 26% 7% - 48% 43% 15% 51% 30% H Deletion 38%, 18% H Deletion

16% 21% 16% 19% 23% 43% 29% 34% 28% 29% 50% 5% - H Deletion - IPMN with HGD - 39% 42% - - IPMN with HGD 45% 92% - - - IPMN with HGD 41% 88% -

- - IPMN with LGD 47% 45% - 3% - IPMN with LGD 41% 42% - 3% - IPMN with LGD - 39% - 3% - AdenoCA in IPMN AdenoCA in IPMN AdenoCA in IPMN AdenoCA in IPMN AdenoCA in IPMN AdenoCA in IPMN AdenoCA in IPMN AdenoCA in IPMN

AdenoCA in IPMN AdenoCA in IPMN AdenoCA in IPMN AdenoCA in IPMN KRAS/GNAS to TP53/PIK3CA/PTEN Equivalent AF GNAS AF > 55% Surgical Dx KRAS GNAS TP53 PIK3CA PTEN AdenoCA in IPMN IPMN with HGD 40% 29%, 7% 40% 19% 21% 15% 33% 11% 18% 41% 26% 7% - 48% 43% 15% 51% 30% H Deletion

38%, 18% H Deletion 16% 21% 16% 19% 23% 43% 29% 34% 28% 29% 50% 5% - H Deletion - IPMN with HGD - 39% 42% - - IPMN with HGD 45% 92% - - - IPMN with HGD 41% 88%

- - - IPMN with LGD 47% 45% - 3% - IPMN with LGD 41% 42% - 3% - IPMN with LGD - 39% - 3% - AdenoCA in IPMN AdenoCA in IPMN AdenoCA in IPMN AdenoCA in IPMN AdenoCA in IPMN AdenoCA in IPMN

AdenoCA in IPMN AdenoCA in IPMN AdenoCA in IPMN AdenoCA in IPMN AdenoCA in IPMN AdenoCA in IPMN KRAS/GNAS to TP53/PIK3CA/PTEN Equivalent AF GNAS AF > 55% Surgical Dx KRAS GNAS TP53 PIK3CA PTEN AdenoCA in IPMN IPMN with HGD 40% 29%, 7% 40% 19% 21% 15% 33% 11% 18% 41% 26% 7% - 48% 43% 15% 51% 30%

H Deletion 38%, 18% H Deletion 16% 21% 16% 19% 23% 43% 29% 34% 28% 29% 50% 5% - H Deletion - IPMN with HGD - 39% 42% - - IPMN with HGD 45% 92% - - - IPMN with HGD 41%

88% - - - IPMN with LGD 47% 45% - 3% - IPMN with LGD 41% 42% - 3% - IPMN with LGD - 39% - 3% - AdenoCA in IPMN AdenoCA in IPMN AdenoCA in IPMN AdenoCA in IPMN

AdenoCA in IPMN AdenoCA in IPMN AdenoCA in IPMN AdenoCA in IPMN AdenoCA in IPMN AdenoCA in IPMN AdenoCA in IPMN AdenoCA in IPMN KRAS/GNAS to TP53/PIK3CA/PTEN Equivalent AF GNAS AF > 55% Not Equivalent Molecular Analysis (Panc. Cyst Fluid) Surgical Resection Dx Total, n = 102 (18%) AdenoCA arising in an IPMN 13 IPMN with HGD 4 MCN with HGD 2 IPMN with LGD 39 MCN with LGD 8 Serous cystadenoma 3 Cystic PanNET

9 Acinar cell cystadenoma 1 Pseudocyst 17 Retention cyst 2 Lymphoepithelial cyst 2 Epidermoid cyst 1 Squamoid cyst 1 IPMNs w/ Advanced Neoplasia GNAS AF >55% or KRAS and/ or GNAS AF = TP53, PIK3CA, and/or PTEN AF Sensitivity: 100% Specificity: 100% Molecular Analysis (Panc. Cyst Fluid) Surgical Resection Dx Total, n = 102 (18%) AdenoCA arising in an IPMN 13 IPMN with HGD 4 MCN with HGD

2 IPMN with LGD 39 MCN with LGD 8 Serous cystadenoma 3 Cystic PanNET 9 Acinar cell cystadenoma 1 Pseudocyst 17 Retention cyst 2 Lymphoepithelial cyst 2 Epidermoid cyst 1 Squamoid cyst 1 IPMNs w/ Advanced Neoplasia GNAS AF >55% or KRAS and/ or GNAS AF = TP53, PIK3CA, and/or PTEN AF Sensitivity: 100%

Specificity: 100% IPMNs & MCNs w/ Advanced Neoplasia GNAS AF >55% or KRAS and/ or GNAS AF = TP53, PIK3CA, and/or PTEN AF Sensitivity: 89% Specificity: 100% Summary Integrating molecular testing to pancreatic cyst fluid analysis using next generation sequencing is a useful adjunct in the evaluation of pancreatic cysts. Among IPMNs, preoperative mutations in KRAS and/or GNAS were identified in all resected IPMNs (n = 56). Mutations in TP53, PIK3CA and PTEN were detected in all pancreatic adenocarcinomas. Summary No genetic alterations were detected in TP53, PIK3CA and PTEN in 2 of 4 (50%) IPMNs with high-grade dysplasia. Three IPMNs with low-grade dysplasia harbored mutations in PIK3CA. Incorporation of allele frequency (AF) improved the detection of IPMNs with advanced neoplasia (100%): GNAS AF > 55% KRAS/GNAS AF = TP53/PIK3CA/PTEN AF Future Directions Surveillance protocol for molecularly profiled pancreatic cysts (risk vs. early detection). Future Directions Surveillance protocol for molecularly profiled pancreatic cysts (risk vs. early detection). 3,231,000 Number of Americans with a mucinous pancreatic cyst. Future Directions Surveillance protocol for molecularly profiled pancreatic cysts (risk vs. early detection).

387,720 Future Directions Surveillance protocol for molecularly profiled pancreatic cysts (risk vs. early detection). Expansion and optimization of the multigene panel (PancreaSeqV2). Integration of other testing modalities. Creation of the Pancreatic Cyst Biomarker Alliance (PCBA). Supported by the EDRN: Pancreatic Cyst Biomarker Validation Study. Pancreatic Cyst Biomarker Validation Study Pancreatic Cyst Biomarker Alliance Pancreatic Cyst Biomarker Validation Study Telomerase DNA Methylation Markers PancreaSeq Glucose Amphiregulin Glycoproteins Gastricsin Das-1 Cathepsin E Data Management Coordinating Center Pancreatic Cyst Biomarker Validation Study Telomerase PancreaSeq DNA Methylation Mucinous vs. Non-Mucinous Markers Cysts PancreaSeq

Glycoproteins Amphiregulin Gastricsin Glucose Das-1 Gastricsin Cathepsin E Cathepsin E Glucose Presence vs. Absence of Amphiregulin Advanced Neoplasia PancreaSeq DNA Methylation Markers Glycoproteins Das-1 Telomerase >350 Pancreatic Cysts (w/ Dx Path) Pancreatic Cyst Biomarker Validation Study Ying Huang, PhD Jackie Dahlgren, PhD Randall Brand, MD Pancreatic Cyst Biomarker Validation Study: Phase 2 Preclinical Exploratory Phase 1 (Exploratory studies to identify biomarkers) Clinical Assay and Validation Phase 2 (Determine capacity of discriminating biomarkers)) Retrospective Longitudinal Phase 3 (Testing of longitudinally collected cohorts)

Accrue additional biomarkers and sites. Future specimen types: pancreatic juice, serum, urine and stool. Randall Brand, MD Marina Nikiforova, MD N. Paul Ohori, MD Sara Monaco, MD Herbert Zeh, MD Amer Zureikat, MD Kevin McGrath, MD Jennifer Chennat, MD Kenneth Fasanella, MD Asif Khalid, MD Kenneth Lee, MD Adam Slivka, MD PhD Melissa

Hogg, MD Allan Tsung, MD J. Wallis Marsh, MD Ying Huang, PhD Walter Park, MD Michael Goggins, MD Charles Craik, PhD Koushik Das, MD Brian Habb, PhD Randall Brand, MD Marina Nikiforova, MD N. Paul Ohori, MD Sara Monaco, MD Herbert Zeh, MD Amer Zureikat, MD Kevin

McGrath, MD Jennifer Chennat, MD Kenneth Fasanella, MD Asif Khalid, MD Kenneth Lee, MD Adam Slivka, MD PhD Melissa Hogg, MD Allan Tsung, MD J. Wallis Marsh, MD Ying Huang, PhD Walter Park, MD Michael Goggins, MD Charles Craik, PhD Koushik Das, MD Brian Habb, PhD

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