Ongoing Study of Early Detection for Pancreatic Cancer

Pancreatic Cancer: Pancreatic CancerInvestigators in a large-scale global initiative to improve pancreatic cancer survival will soon begin testing two blood-based biomarkers for their ability to distinguish between normal cells and early-stage disease in high-risk individuals. Validating these molecular markers is expected to take 3-5 years. Their identification arises from the collaborative research efforts of the Pancreatic Cancer Early Detection (PRECEDE) Consortium, now underway at 51 medical centers around the world. The consortium's goal is to improve patients' 5-year relative survival from a dismal 11 percent for all stages of disease today to 50 percent in the coming decade. Some 5,226 participants have been enrolled in the study so far with a goal of 10,000 participants, enabling researchers to address questions about risk factors, the level of that risk, and early-detection strategies to prevent or delay cancer development. Although PRECEDE is a 10-year observational study, “We're already starting to get some results,” said Diane Simeone, MD, the study's principal investigator and Director of the Pancreatic Cancer Center at NYU Langone Health. The newly identified biomarkers will be assessed for how well they perform in the largest of the study's six cohorts—individuals whose family histories, germ-line DNA mutations, or cystic tumors put them at increased risk for these complex cancers. One of the blood-based biomarkers measures specific proteins found on the surface of exosomes—sac-like structures inside cells—which house a grab bag of genetic debris, including DNA, RNA, and metabolites. Another product measures methylated DNA, which regulates gene expression. While PRECEDE is not the only research group actively assessing candidate biomarkers for early pancreatic cancers, the consortium's broad scope and collaborative data-sharing—a prerequisite for joining—could help move the needle closer to early detection sooner, according to Simeone. In addition to the 51 medical centers now in the consortium, at least 25 others from the U.K., India, Japan, and Hungary recently expressed an interest in joining. The American Cancer Society estimates that 64,050 men and women in the U.S. will be diagnosed with pancreatic cancer in 2023, while 50,500 are expected to die of the disease. Less than 10-15 percent of these cancers are detected early when they are resectable and amenable to surgery, but even then, experts say most exceed the size that carries the best hope for long-term survival. Moreover, “in half of patients, we still can't pinpoint why they got this cancer,” Simeone said. Hurdles to early detection lie, in part, to the pancreas' location deep within the abdomen and also to vague symptoms similar to other illnesses. Also, no effective screening test yet exists, nor is one recommended for the general population as yet because of high costs and the likelihood of overdiagnosis. However, ironically perhaps, early Stage I disease, which carries estimated long-term survival rates of 70-80 percent, usually are found through imaging scans for other health conditions. In the U.S., pancreatic cancers currently rank as the third deadliest cancer behind colorectal and lung cancers. But by 2030, these cancers are expected to move into second place as a cause of cancer mortality, given an aging population, increases in obesity and diabetes and even smoking, despite a downward trend in the U.S. Also, experts believe that contributing to this trend is an unrecognized genetic vulnerability complicated by environmental factors. “Pancreatic cancer carries an underappreciated heritable risk,” maybe as high as 20 percent, nearly double that seen in other cancers, Simeone suggested. Among the 15 known pathogenic mutations identified to date, the most common, BRCA2—one of the breast cancer genes—is thought to raise lifetime risk for pancreatic cancers by 6-7 percent, she said, while inheriting mutations in the other—BRCA1—raises that risk by 3 percent. Familial melanoma, though rare, also has been linked to a higher lifetime risk for one of these cancers, as high as 18 percent. “Part of the equation we're missing” is layering together these genetic vulnerabilities with suspected medical risks and subtle epigenetic changes that have not yet been widely studied, Simone noted. Because of dramatic advances in technologies, from next-generation DNA sequencing to radiomics and artificial intelligence, “we're in a unique unparalleled time to reimagine how we detect these cancers,” she said. In addition to the highest-risk group, PRECEDE's cohorts include individuals diagnosed with early-onset pancreatic cancer before age 45 and individuals without any prior history of the disease. More recently, the consortium added a small cohort of patients already diagnosed with pancreatic cancer who will undergo germline testing to determine the best available drug options to meet their needs. Susan Jenks is a contributing writer.