Risk Factors and Early Detection Efforts for Pancreatic Cancer

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1 HEADER SLIDE Risk Factors and Early Detection Efforts for Pancreatic Cancer by Jennifer B. Permuth, PhD, MS Assistant Member Departments of Cancer Epidemiology and Gastrointestinal Oncology Moffitt Cancer Center Tampa, Florida

2 Outline Introduction to pancreatic cancer Known risk factors Environmental/Lifestyle Genetic Risk assessment Research on PC screening and early detection biomarkers Resources

3 INTRODUCTION

4 Leading Causes of Cancer Deaths in the US * American Cancer Society, 2016 *Pancreatic ductal adenocarcinoma (PDAC)

5 Pancreatic Cancer is Projected to Become the 2 nd Leading Cancer Killer by 2020 Rahib, Can Res 2014

6 PC poses numerous clinical challenges Usually very aggressive. Early, operable tumors are difficult to detect. Need strategies to identify those at increased risk. Most patients do not respond to standard treatment options. Quality of life (QOL) is sub-optimal.

7 RISK FACTORS AND ASSESSMENT

8 Modifiable and non-modifiable risk factors Average age: 71 Males African American Ashkenazi Jewish Age, gender, race, and ethnicity Lifestyle/ Environment Obesity Pancreatitis Diabetes chronic & new Infections Medical conditions Family history/ genetics Familial Inherited cancer syndrome

9 Ranking of individual risk factors Maisonneuve and Lowenfels, IJE 2015

10 Sporadic vs. Familial vs. Inherited PC Risk increases with # of affected first degree relatives (FDR): 2-4.6x (1 FDR), 3-6.4x (2 FDR), 32-57x (3 FDR) 7% 3% Sporadic Familial 90% (Average lifetime risk = 1 in 67 (1.5%)) Inherited Cancer Syndrome Chari et al (2015) Pancreas

11 Inherited Predisposition to PC Inherited Syndrome Gene(s) Risk by age Hereditary Breast and Ovarian Cancer BRCA2 BRCA1, PALB % 3.6% Peutz-Jeghers STK11/LKB1 36% Familial atypical multiple-mole melanoma (FAMMM) Hereditary non-polyposis colorectal cancer p16/cdkn2a 13-17% MSH2, MLH1, MSH6, PMS1, PMS2 3.7% Familial adenomatous polyposis APC 1.7% Ataxia telangiectasia ATM <5% Li Fraumeni TP53 <5 Syndromes with chronic inflammation of the pancreas Hereditary pancreatitis PRSS1, SPINK % Cystic Fibrosis CFTR <5%

12 Tidbits about BRCA2 carriers and PC 3-6x increased PC risk (vs. non-carriers) ~10% of BRCA2+ families have >1 relative with PC BRCA2 mutations are identified in 4-17% of families with familial PC, and are the most common alteration in this condition Prevalence of BRCA2 mutations in patients with sporadic PC is 4-7% vs. 0.2% in general population BRCA2 mutations (6174delT) are associated with 10-20% of unselected, sporadic PC in Ashkenazi Jews Patients with BRCA2+ PC are younger than counterparts with sporadic PC (63 vs 70 years old) The survival rate in patients with familial PC tends to be better than those with sporadic PC

13 Rare and common genetic variants contribute to PC susceptibility From Stolzenberg-Solomon and Amundadottir Hematol Oncol Clin North Am (2015)

14 What is my risk to develop PC?

15 Risk assessment is provided during genetic counseling ( PancPro Provides probability of: carrying a concerning mutation in a PC susceptibility gene developing PC Takes into account: cancer history for counselee and family members, age(s) at diagnosis, and current age/age at last follow-up Absolute risk model Provides probability of: developing PC Takes into account: Established risk factors (age, sex, ethnicity, smoking history, diabetes, alcohol use, family history, body mass index, common genetic variants) Wang, JCO, 2007 Klein, PLoS One, 2013

16 What can I do about my risk? Is it possible to prevent PC cancer or detect it really early?

17 PRIME OPPORTUNITY FOR EARLY DETECTION AND PREVENTION EFFORTS Precursors to pancreatic cancer

18 Three pancreatic cancer precursors exist Pre-cancerous pancreatic cysts IPMN=intraductal papillary mucinous neoplasms noninvasive MCN=mucinous cystic neoplasms Distler et al (2014), Biomed Research International

19 IPMNs Account for up to 40% of the ~150,000 pancreatic cysts detected incidentally each year in the general US population. Detected in high-risk cohorts. Found more often in familial than sporadic cases. Challenging to manage due to the inability to predict: which lesions can be safely monitored, which are likely to progress to invasion, and which may have an associated invasive component.

20 Need better strategies to identify concerning IPMNs Only accurate way to determine severity surgery & pathologic evaluation Consensus guidelines exist to predict IPMN severity based on standard clinical and radiologic features. inaccurate for at least 30-70% of cases!

21 Screening for Pancreatic Cancer Endoscopic ultrasound (EUS) MRI-MRCP Computed Tomography (CT) +/-Fine needle aspiration (FNA) Can detect lesions <1 cm; FNA allows cytological sampling, but is invasive; operator dependent Best visualization of cyst communication with main pancreatic duct Can visualize large lesions; accurate in depicting vascular invasion and metastases; radiation exposure MRI-MRCP= Magnetic Resonance Imaging (MRI)-Magnetic resonance cholangiopancreatography (MRCP)

22 Comparison of selected screening strategy recommendations

23 Current Yield of High-risk Screening Programs Canto (2013) Gut Nearly all studies reported precursor lesions (mostly IPMNs). Tests are complementary rather than interchangeable. Prevalence of lesions increased with age. CT, MRI, and EUS detected abnormalities in 11%, 33.3%, and 42.6% of individuals, respectively (Canto, 2012) Prevalence of pancreatic cysts in the general population approximates 20-23%.

24 Canto (2013) Gut Candidates for screening: FDR of patient with PC from a familial PC kindred with >2 affected FDRs; patients with PJS; p16, BRCA2, and HNPCC mutation carriers with >1 affected FDR No consensus on age to initiate screening or stop surveillance Initial screening should include EUS and/or MRI/MRCP accessible, low morbidity, good concordance for lesion size, number, & location; EUS better for detecting small solid lesions; MRI sensitive for small cysts Need long-term multicenter studies

25 EARLY DETECTION BIOMARKERS FOR PC Research in Progress at Moffitt Cancer Center

26 Painting a Radiogenomic Portrait of Early Pancreatic Cancer Develop a clinical decision-making tool that has added diagnostic value in predicting IPMN pathology beyond that provided by standard radiologic and clinical characteristics. -non-invasive -cost-effective -reliable -objective -can easily be integrated clinically Clinical data/radiologic features mirna expression Low-risk IPMN (low- or moderate grade) Surveillance High-risk IPMN (high-grade or invasive) Surgery Funding Decision Pending: NCI (PI: J. Permuth)

27 MicroRNAs (mirnas) as attractive candidate biomarkers of early pancreatic malignancy regulate cancer-related pathways. Each mirna regulates 100 s-1000 s of genes. remarkably stable in tissue and biofluids. dysregulated in PC vs. normal pancreas tissue. differentiate between IPMN grade and/or normal pancreas tissue 1,2,3,4,5. 1 Habbe 2009; 2 Park 2011; 3 Matthaei 2012; 4 Lubezky 2013; 5 Permuth-Wey 2015 Ruan et al (2009) Cancer Letters

28 Total Cancer Care

29 Radiomics High-throughput extraction of quantitative features (from standard-of-care images) into mineable data. Image Segment Area= mm 2 Perimeter=152.4 mm Volume=2615 mm 3 Surf. area= mm 2 Surf. Area/volume=0.42 mm -1 Density, Necrosis Mean = HU SD = HU Min = -249 HU Max = 118 HU Spiculations Slope at margin =133.5±31.3 HU/mm Low density inclusions Rel. vol.= 0.21 mm 3 Number=110 Volume=4.89±8.35 mm 3 Feature extraction Analyze Image acquisition and reconstruction - Contrast Issues - Slice thickness - Semi- Automatic - Texture Features (smooth, coarse, regularity) - Non-texture (shape/size/ volume) - Prediction of clinical parameters - Scanner setting Slide courtesy of Yoganand Balagurunathan, PhD

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31 Linc-ing Circulating Long Non-coding RNAs (lncrnas) to Pancreatic Cancer Precursors: An Exploratory Study Long non-coding RNAs (IncRNA): class of noncoding RNAs >200 nucleotides in length without open reading frames. Predominant type of transcribed RNAs. Regulate gene expression and promote carcinogenesis via various mechanisms. Emerging data support the role of lncrnas in PC initiation, progression, and outcomes. Evidence supports lncrna detection in circulation. Our goal: To be the first to explore the abundance of candidate lncrnas in archived plasma from patients with IPMNs. Funding: Departmental Innovation Award (PI: J. Permuth)

32 Using blood-derived mirna expression levels and tumor DNA mutations to personalize care for individuals with pancreatic cancer precursors Goal: Identify a combination of plasma-derived mirnas and novel somatic mutations that reliably predict IPMN risk status pre-operatively. Funded by the DeBartolo Personalized Medicine Institute (PI: J. Permuth)

33 The Florida Pancreas Collaborative (FPC): A Partnership Dedicated to the Early Detection and Prevention of Pancreatic Cancer Co-PIs: Jennifer B. Permuth, PhD, MS Mokenge Malafa, MD Nipun Merchant, MD Jose Trevino, MD Funded by the Florida Academic Cancer Center Alliance (FACCA)

34 Eligibility Kimberly Quinn Amber Bouton Dr. Suzanne Lechner (MOF) (UF) (SCCC/UM) Males and females 18+ who present to the GI Clinic, surgery, or endoscopy at MCC, UF, or SCCC/UM with a clinical suspicion for (or diagnosis of) a pancreatic lesion, mass, or cyst or pancreatitis based on symptoms, imaging, or blood-work (and no prior treatment) Approach to recruit and obtain written informed consent Healthy individuals 18+ without a self-reported personal history of pancreatic disease or related symptoms (companions and high-risk cohort).

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37 Who can participate in the Florida Pancreas Collaborative (and how) Asymptomatic first or second degree relatives of a family member affected by pancreatic cancer Asymptomatic carriers of known PC predisposition mutations Individuals with a suspected or diagnosed condition affecting the pancreas. Feel free to send in the response form. Any q s, Dr. Jenny Permuth or Kim Quinn jenny.permuth@moffitt.org; kimberly.quinn@moffitt.org

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39 Thanks to an interdisciplinary team Epidemiology &Genetics Endoscopy & Permuth Wang Malafa Surgery Hodul Merchant Endoscopy Immunology Klapman Harris Abate-Daga Gillies Trevino Soares Biostatistics Chen Carvajal G-Calderon Pathology Balagurunathan Kim IT/ Bioinformatics Rivera Radiology Choi Oncology Coppola Magliocco Centeno Jiang

40 ..and PC survivors and advocates

41 Know it. Fight it. End it. Wage Hope.