Pancreatic cancer is the fourth leading cause of death from cancer in the United States. (1) Close to 44,000 new diagnoses of and 37,000 deaths from pancreatic cancer have been estimated for 2012. (1) The large majority of patients are diagnosed with locally advanced or metastatic disease. To improve overall survival, a better understanding of the impact of family history and inherited risk is needed.
Roughly 10 percent of all patients with pancreatic adenocarcinoma have a hereditary predisposition for the disease. (2) Two broad categories of hereditary predisposition for pancreatic adenocarcinoma can be defined. The first category, familial pancreatic cancer, occurs in families in which there are multiple first- and second-degree relatives with pancreatic adenocarcinoma in the absence of a known genetic syndrome. The second and smaller category, pancreatic adenocarcinoma due to currently known and well-defined genetic syndromes, occurs where an identifiable germline mutation may lead to the development of pancreatic adenocarcinoma. A confounding factor in this research of hereditary predisposition is that pancreatic adenocarcinoma is a relatively common cancer: Several family members may be affected solely by chance alone.
In 2002, investigators at Memorial Sloan Kettering Cancer Center established the Familial Pancreatic Tumor Registry to facilitate study of family history and inherited risk in pancreatic cancer, primarily pancreatic adenocarcinomas. The four key objectives of this registry are to enroll pancreatic cancer patients and family members in cases where pancreatic cancer appears to be familial; to obtain pilot data on the feasibility of surveillance of unaffected members of pancreatic cancer families; to collect preliminary data on environmental and lifestyle risk factors and genetic predisposition for pancreatic cancer in patients with familial pancreatic cancer; and, through DNA banking, to identify known genetic mutations associated with the development of pancreatic cancer and to identify additional genetic mutations and variants associated with pancreatic cancer. All registrants are interviewed and asked to complete both an epidemiology and a family history questionnaire. They also provide DNA samples from blood or a mouthwash rinse.
As of June 2012, the registry profile comprises more than 200 patients who have pancreatic adenocarcinoma and a strong family history; more than 400 healthy individuals with a strong family history of pancreatic adenocarcinoma; more than 700 patients with pancreatic adenocarcinoma and no family history (for comparison group data in future studies); and more than 500 individuals without pancreatic adenocarcinoma and with no family history of the disease (for control group data). More recently, patients with benign intraductal papillary mucinous neoplasm who are being followed by MSKCC physicians for long-term outcomes have been referred to the registry.
In 2011, gastroenterologist Emmy Ludwig and colleagues (3) from our group published initial results from our registry-based pancreatic tumor surveillance program in the American Journal of Gastroenterology. The purpose of this study was to determine the safety and diagnostic yield of a screening protocol for premalignant pancreatic lesions and early-stage pancreatic adenocarcinoma in “at-risk” relatives. The protocol involved magnetic resonance cholangiopancreaticogram (MRCP) — a specialized MRI of the abdomen and the pancreas — followed by endoscopic ultrasound (EUS) if pancreatic abnormalities were found on initial screening, and fine-needle aspiration (FNA) of any suspicious lesion. For any findings that appeared suspicious for a premalignant or malignant pancreatic lesion, surgical consultation was obtained. “At risk” was defined as having one or more first-degree relatives (FDR) with pancreatic adenocarcinoma before age 50, having two or more relatives with pancreatic adenocarcinoma (one of whom is an FDR), having three or more second-degree relatives with pancreatic adenocarcinoma, or being a known BRCA mutation carrier and having one or more relatives with pancreatic adenocarcinoma. Eligibility criteria also included being asymptomatic and at least 35 years of age.
Eighteen (16.5 percent) of the 109 registry-enrolled study participants who completed at least one cycle of screening had a prevalent abnormal finding on the initial cross-sectional imaging. Of these 18, 15 (83.3 percent) underwent EUS; of these 15, nine had significant findings. The yield from screening was 8.3 percent (9/109), comparable to that reported in similar published screening/surveillance programs of familial pancreatic cancer relatives. In this study, yield was greatest in relatives over age 65 (35 percent, 6/17), when compared with relatives between 55 and 65 years (3 percent, 1/31) and relatives less than 55 years (3 percent, 2/61).
Dr. Ludwig’s study supports the use of MRCP followed by EUS as an effective and safe surveillance method in individuals from high-risk families. Last year, we expanded enrollment eligibility for the Familial Pancreatic Tumor Registry to include individuals with other known genetic cancer-susceptibility gene mutations, such as those mutations that occur in the heritable breast and ovarian cancer syndrome or Lynch syndrome, provided these individuals also have a family history of pancreatic cancer. Individuals who carry these genetic abnormalities are also offered surveillance with MRCP and EUS.
Additional studies using data and genetic specimens collected from participants in our Familial Pancreatic Tumor Registry have been reported in the peer-review literature. These reports include studies of allergy and pancreatic adenocarcinoma risk; smoking and pancreatic adenocarcinoma risk; and body-mass index and pancreatic adenocarcinoma risk and survival. In 2012, our group published a review article on the epidemiology of pancreatic adenocarcinoma and the role of family history. (4) Genome-wide association studies looking for areas of the human genome that may be associated with pancreatic adenocarcinoma susceptibility are being performed both at MSKCC, (5) and by national and international consortiums.
Further information about the MSKCC Familial Pancreatic Tumor Registry.