Evaluation of hereditary syndromes that include pancreatic cancer

UPR CCC 04/12/13

Jeffrey N. Weitzel, M.D. Chief, Division of Clinical Cancer Genetics

Cancer Screening & Prevention Program

City of Hope Comprehensive Cancer Center and Beckman Research Institute PANCREATIC CANCER

Worldwide estimates: • Incidence- 232,306 • Deaths- 227,000 A deadly disease

CA Cancer J Clin 2012 PANCREATIC CANCER

Non-Genetic Risk Factors Cigarette Smoking • Doubles Risk • Causes 26% of pancreatic cancer Obesity • Increases risk by ~70% Diabetes • Longterm (>10yrs) 2-Fold increase (Everhart 1995) • 1% of new-onset diabetics develop pancreatic cancer within 3 years (Chari 2005) DDx: Start with Pathology

Adenocarcinoma = >75% 5-year survival <5% Endocrine (AKA: islet cell) = ~ 1% Hormone-producing; control blood sugar levels Insulinoma, gastrinoma, VIPoma, glucagonoma, somatostatinoma, non-functional “oma’s” Slower-growing better prognosis 5-year survival 50-70% if surgically resectable DDx: Endocrine pancreatic tumor(s)

MEN1 VHL NF1 TSC sporadic MEN 1 and MEN 2

MEN 1 MEN 2 Anterior Pituitary Thyroid C-cells (MTC) Parathyroid Parathyroid Adrenal Adrenal medulla cortex (pheochromocytoma) Pancreatic islet cells

Germline mutations Germline mutations in MEN1, chr 11 in RET, chr 10 Genetics of MEN 1: The Menin Gene

Mutations in the MENIN (MEN1) gene on chromosome 11q13 Cloned in 1997 Tumor suppressor gene Involved in transcriptional regulation/cell growth and regulation > 400 distinct mutations identified throughout the gene; most are protein truncating MEN 1 mutation - Epidemiology

Two of the three main tumor types must be present (parathyroid, pancreatic, pituitary) Germline MEN1 mutations detected in 80-90% in families/cases with 2 or more major features >30% families with 1 major and 1 or more MEN1- associated tumors 10% de novo Penetrance: >50% by age 20 and 100% by age 60 MEN 1 – Hyperparathyroidism (HPT)

Generally the first manifestation Average age of diagnosis 14yrs, 80%-100% by age 40 Tumors usually multiglandular, hyperplastic Symptoms of HPT Fatigue, weakness Hypertension, nervousness Constipation, anorexia, nausia Polyuria, polydypsia, nocturia Kidney stones, bone disease MEN 1- Gastro-Entero-Pancreatic Tumors

Gastrinoma (50%) Major cause of morbidity and mortality Manifests as Zollinger-Ellison syndrome (peptic ulcer disease) Insulinoma (10%) Hypoglycemia VIPoma (2%) Watery diarrhea, hypokalemia, achlorhydria Glucagonoma (2%) Hyperglycemia, weight loss, anemia, skin rash Somatostatinoma, Pancreatic polypeptidoma, Enterochromaffin-like cell (ECL) Carcinoids MEN 1 – Screening Regimen

Age (y) to Biochemical tests Imaging tests, q 3 Tumor start annually years

Parathyroid adenoma 8 Calcium (esp Ca2+), None parathyroid hormone

Gastrinoma 20 Gastrin None Insulinoma 5 Glucose, insulin None Other enteropancreatic 20 Chromogranin-A Somatostatin tumors receptor scintigraphy, CT or MRI

Anterior pituitary tumors 5 Prolactin MRI

Thymus or bronchial 20 None CT carcinoid von Hippel-Lindau

Risk for benign cystic pancreatic lesions Also a risk for islet cell tumors (5-7%) Generally found in individuals with otherwise normal pancreas Malignant potential (<10%) Better prognosis than sporadic malignancies Main tumors: RCC, pheo, hemangioblastoma Annual abdominal ultrasound beginning at age 16, possible baseline MRI/CT, biochemical screening

Familial Pancreatic Adenocarcinoma

Associated with several hereditary syndromes/genes: Hereditary pancreatitis (PRSS1- cationic trypsinogen gene) Hereditary breast-ovarian cancer syndrome (BRCA2) FAMMM sydrome (p16/CDKN2A) Peutz-Jeghers syndrome (STK11/serine-threonine kinase) Lynch Syndrome (HNPCC) (MLH1, MSH2, MSH6 and PMS2) FAP (APC) PALB2 ATM

Pancreatitis Cystic Fibrosis

Risk to homozygotes maybe as high as 30% due to pancreatitis Risk to heterozygotes Sharer et al. 1998 studied 134 patients with chronic pancreatitis • 13.4% were CFTR mutation carriers (including T5 alleles) Pezzilli et al. 2003 studied 46 patients with chronic pancreatitis • 19.6% were CFTR mutation carriers (including T5 alleles) Hereditary Pancreatitis

PRSS1 gene Penetrance of 80% 40% risk for pancreatic cancer by age 70 Risk increased by paternal-line transmission, possibly as high as 70% Smoking increases risk Begin screening 10 years after pancreatitis diagnosis Hereditary Pancreatitis – not subtle

EUROPAC study: 112 families, 14 countries PRSS1 mutations in >80% of affected families Median onset of symptoms at 12 years over 70% symptomatic by age 20 years Median of 1.88 attacks per year 70/75 patients (93%) required hospital treatment pancreatitis BRCA1- and BRCA2-Associated Cancers: Lifetime Risk

Breast cancer 50%-85% (often early age at onset)

Second primary breast cancer 40%-60%

Ovarian cancer 15%-45%

Absolute risk likely to be higher than 10% - Prostate cancer Absolute risk 10% or lower - Male breast cancer - Fallopian tube cancer - Pancreatic cancer ASCO Population Relative Cancer Risks and 95% CI by Mutation status and Cancer Site

Risch et al. J Natl Cancer Inst 2006;98:1694-1706

First degree relatives of patients with BRCA1 (n=534); BRCA2 (n=446) Age specific cancer risks in Dutch BRCA2 mutation carriers*

For all presented cancer sites, p for difference is <0.001. *Among 1,811 at 50% carrier probability

Most striking risks are for earlier onset for pancreas, pharynx and prostate

van Asperen CJ et al: Cancer risks in BRCA2 families: estimates for sites other than breast and ovary. J Med Genet 42:711-9, 2005 Estimated cumulative risks for pancreas and prostate cancer in BRCA2 mutation carriers by sex and age

van Asperen CJ et al: Cancer risks in BRCA2 families: estimates for sites other than breast and ovary. J Med Genet 42:711-9, 2005 BRCA2 Mutations, Relative Risks (RR), and Lifetime Risk of Pancreatic Cancer in Jewish Patients and Controls

PAC (n = 145) Controls (n = 5,318)

Mutation No. (%) No. (%) RR (95% CI) LRP RR LRC BRCA2 6 (4.1) 59 1.1 3.85 (2.1 to 10.8) 1.3% 3.85 4.9% 6174delT

Abbreviations:

LRP, lifetime risk of pancreatic adenocarcinoma in the general population LRC, lifetime risk of pancreatic adenocarcinoma in the BRCA2 heterozygotes

Ferrone et al: BRCA Germline Mutations in Jewish Patients with Pancreatic Adenocarcinoma. JCO 27:433-438, 2009 BRCA and Prostate Cancer

• BRCA1 and BRCA2 mutations increase prostate cancer risk - BRCA1: relative risk 1-2 - BRCA2: relative risk 4-7 • BRCA2 may result in early onset prostate cancer • BRCA1 and BRCA2 are unlikely to account for a high percentage of familial prostate cancer

• BRCA2 may account for 2% of early onset PC and 5% of familial prostate cancer • HOXB13 and CHEK2 mutations may also play a role in prostate cancer susceptibility Familial Atypical Multiple Mole Melanoma (FAMMM) p16: cyclin dependent kinase (CDKN2A) at 9p21 Somatic mutations in 75-85% of pancreatic cancer Pancreatic cancer only present in some CDKN2A families Risk by age 75 is ~17% (10-40 fold increase) Phenotypically expressed FAMMM in 12% of families with familial pancreatic cancer Individuals with CDKN2A mutations should be considered for pancreatic cancer screening Melanoma and Pancreatic cancer

2 fold increase in risk in individuals diagnosed with melanoma <50 y Reports of pancreatic cancer in families lacking CDKN2A mutations, but uncommon Peutz-Jeghers Syndrome

Serine threonine kinase 11 (STK11) gene at 19p13 Literature review found the risk for pancreatic cancer to be 132 times the general population (Giardiello et al. 2000) Risk by age 65 of 11-36% EUS every 1-2 years beginning at age 30 HNPCC

MLH1 and MSH2 mutations reported in kindreds with pancreatic cancer Reported more frequently in Korean, Taiwanese, and Finnish families, less frequently in Dutch families Tumors are often MSI high Often of Medullary histology Not all kindreds meeting Amsterdam criteria for HNPCC have been found to have germ line mutation despite MSI high and absence of MLH1 expression Risk of pancreatic cancer up to 4%, but not well defined Familial Adenomatous Polyposis

APC gene at 5q21-22 RR 4.5 (1.2-11.4 CI) ~2% lifetime risk of pancreatic cancer Consider EUS after age 20

Giardiello (1993) Gut 34:1394 Pancreatoblastomas

Reported in individuals with APC mutations and Beckwith-Wiedemann Syndrome <1% of all pancreatic tumors Often occur in children Potentially similar mechanism to hepatoblastoma PALB2 (partner and localizer of BRCA2)

Cancer Risks (Casadei et al. 2011): Breast: 2.3-fold by 55 yo; 3.4-fold by 85 yo Male Breast CA: 4-fold Pancreas CA: 6-fold Prevalence in BrCa: 0-2% of unselected BrCa’s (ethnicity-based 3.4% (33/972) non-AJ FBC; 0/172 AJ FBC Prevalence in FPC: 3-4% (Jones 2009; Slater 2010) Hereditary Pancreatic cancer risk

Cancer Discovery 2: 41–6, 2011

WGS on 16 subjects in 6 families, followed by WES on 22 subjects from 10 families; 2.4% (4/166) of familial pancreatic cancer probands carried deleterious ATM mutations Progression Model Pancreatic Intraepithelial Neoplasia

Klapman J, Malafa MP: Early detection of pancreatic cancer: why, who, and how to screen. Cancer Control 15:280-7, 2008 Screening for pancreatic cancer

Three common precursor neoplastic lesions: Intraductal papillary mucinous neoplasms (IPMN) Mucinous cystic neoplasm (MCN) Pancreatic intraepithelial neoplasm (PanIN)

IPMN- papillary or rarely flat epith neoplasm arise from main duct or main branch ducts >1cm can be visualized by multidetector CT, MRI, US, or EUS Branch ducts are most common in high risk individuals Screening for pancreatic cancer

PanIN- papillary or flat noninvasive epith neoplasms arise in smaller pancreatic ducts usually <5mm low grade PanIN is not always distinguishable from IPMNs < 1cm Screening for pancreatic cancer

Imaging: Multidetector CT • High accuracy but may still miss EARLY stage disease • Concern for repeated exposure to radation if used for surveillance MRI/MRCP • No published data on accuracy • High costs; not tolerable by those with claustrophobia or metal implants Ultrasound (US) Endoscopic ultrasound (EUS)*

Gastrointest Endoscopy Clin N Am 2008 (18):535-553

Screening for pancreatic cancer

EUS Combines endoscopy and high frequency ultrasonography ± FNA Limited by potential adverse events, cost and operator dependence Pilot study in 36 patients- one time screening with EUS- diagnostic yield 5.3% • 2 pancreatic neoplasms; one CT neg ductal adenoca in woman from a kindred with 6 affected individuals, one benign IPMN adenoma in pt with PJS

Gastrointest Endoscopy Clin N Am 2008 (18):535-553 Endoscopic Ultrasound

Klapman J, Malafa MP: Early detection of pancreatic cancer: why, who, and how to screen. Cancer Control 15:280-7, 2008 Endoscopic ultrasound images of pancreatic lesions

Klapman J, Malafa MP: Early detection of pancreatic cancer: why, who, and how to screen. Cancer Control 15:280-7, 2008 Screening for pancreatic cancer

Goal of Screening: Detect and treat early pancreatic neoplasia in high risk individuals. • Should be offered only to those individuals who are willing and able to undergo treatment of pancreatic neoplasms detected by screening • No consensus • EUS or MRCP – two to four times a year for pts with pancreatic lesions – 1 to 3 year interval for high risk individuals who do not have pancreatic lesions.

Gastrointest Endoscopy Clin N Am 2008 (18):535-553 BRCA2 and Pancreatic Cancer - does “informative” testing make a difference? CASE-continued

Given Ashkenazi Jewish ancestry, tested patient for founder BRCA gene mutations: NEGATIVE How would we screen her? her children? and her brother’s children? Blood/DNA had been banked for deceased brother BRCA2 6174delT – POSITIVE Patient’s mother’s test was negative Abnormal Screen

Total pancreatectomy Partial pancreatectomy is not recommended due to mutifocal and widespread nature of dysplasia If opt not to have surgery, follow-up EUS and CT scan at 3-6 months to assess any changes Pancreatectomy

Risk of mortality is 3% Brittle diabetes Exocrine insufficiency requiring pancreatic enzyme replacement High rate of ulceration, lifelong acid- suppressive therapy Bleeding, infection, and poor wound healing Pancreatectomy

Cost effective when compared to cost of carcinoma Cost ~$37,000 Cost of diabetes care ~$11,000 Surgical approaches Partial pancreatectomy with frozen section analysis intraoperatively Laparoscopic distal pancreatectomy then complete pancreatectomy if dysplasia is found Pancreatic rests in the bowel are present in ~10% and should be removed

Recommendations: Genetic Testing

Need to know pathology/phenotype first May be pursued if family history is suggestive of syndrome Low yield for p16 absent melanoma (only pancreatic cancer family history) BRCA2/PALB2 testing may be considered in families with adenocarcinoma of the pancreas, especially with breast cancer Hx Multigene panels may help illuminate prevalence and phenotype of rare genes

Recommendations: Screening Careful evaluation of family history Some families may be at risks as high as 70% Evaluation of personal history Smoking is a large risk factor Assessment of psychosocial concerns and anxiety Screening is costly and is most advantageous under research protocols