Pancreatic Cancer: Collaborative Efforts to Promote Early Detection

How do you improve survival rates for pancreatic cancer? Better early detection methods? More accurate risk assessments and profiles? A better understanding of the genetic variants, both inherited and acquired? The answer is yes to all three. However, there’s a unifying force working behind all of these paths. That force is collaboration — locally, nationally, and internationally. Without it, we likely won’t be successful, or won’t be nearly as successful or timely as we could be to improve survivability.

Randall Brand, MD, is a professor of medicine with an extensive background in pancreatic diseases and an interest in familial pancreatic cancer. His work as a physician-scientist is focused on the early diagnosis of pancreatic cancer and cystic lesions of the pancreas. Dr. Brand’s research interests involve familial pancreatic cancer and other hereditary GI disorders. He was recruited to the University of Pittsburgh more than 10 years ago to pursue ground-breaking pancreatic cancer research and, since his arrival, has been the leader of the University of Pittsburgh Pancreatic Adenocarcinoma Gene-Environment Registry (PAGER) study. The pancreatic cancer biospecimen repository developed through the PAGER study is a nationally recognized resource for multiple NIH/NCI-funded projects, along with national and international collaborations. At present, the biorepository contains data and samples from more than 7,000 individuals. It has become an immensely powerful, shared tool for advancing the research of pancreatic cancer in the United States.

Dr. Brand is a key contributor to the National Cancer Institute’s Early Detection Research Network (EDRN), especially for research related to pancreatic cancer and cystic neoplasms. He is currently funded as an EDRN principal investigator leading both a multicenter Pancreatic Cancer Clinical Validation Center and a Biomarker Developmental Laboratory.

Dr. Brand’s clinical practice focuses on the management of pancreatic cancer, cystic lesions of the pancreas, and patients with other gastrointestinal (GI) cancers. As director of the Hereditary GI Tumor Program, Dr. Brand specializes in the management of individuals at high risk for the development of colon cancer, pancreatic cancer, and other GI malignancies.

“I am privileged to be part of this dedicated field and to work with so many exemplary and accomplished collaborators within our Division, through the EDRN, and in our collaborative, multicenter NIH studies. The difficulties associated with pancreatic cancer — its relative rarity and its generally late presentation at an advanced stage — make it such a deadly disease. These challenges will only be overcome through shared investigations, as we use combined resources to fight for the support of more studies across the United States and internationally,” says Dr. Brand.

Pancreatic cancer is the third-leading cause of cancer death in the United States.1 The vast majority of pancreatic cancer cases present at a late stage with metastasis to distant sites, making successful treatment extremely difficult. Five-year survival rates remain dismally low. If treatments for late-stage disease are unable to improve outcomes, the only alternative may be to find the disease early when it is amenable to surgery or other treatment modalities. The same can be said for many types of cancer.

“It continues to be true that treatments for late-stage disease remain suboptimal. In most cases, we are unable to effectively treat late-stage pancreatic cancer. However, advances in late-stage disease management are being made. We see much better survival with cases of early-stage disease when the tumor is localized to just the pancreas (resectable) and the burden is much less.

If you look at the advances that have been made with colon cancer in recent years, five-year survival rates now approach 80 to 85 percent because of the surgical and adjuvant treatments available, along with our ability to detect the disease early. Similarly, finding pancreatic tumors when they are resectable, and aggressively treating systemic disease, may be our best approach. We must do a better job of finding pancreatic cancer at an early stage. Much of my work, and that of my collaborators here at UPMC and the University of Pittsburgh and beyond, is dedicated to making early detection a real possibility,” says Dr. Brand.

Pancreatic Cancer Research: Early Detection Through Cyst Fluid, Biomarkers, and Germline Research

Early detection of pancreatic cancer on a molecular level may be the ultimate method of early detection. A number of avenues of research are under active investigation by Dr. Brand and his colleagues at the University of Pittsburgh and the EDRN member sites.

Pancreatic Cysts and Fluid Research

Pancreatic cyst fluid may be the most viable way to identify potential cancer at an early stage. Work along these lines is progressing with Aatur Singhi, MD, PhD, from the UPMC Department of Pathology. Dr. Singhi’s efforts were preceded by the research of Asif Khalid, MD, associate professor of medicine and chief of GI services at the VA Pittsburgh Healthcare System, along with Kevin McGrath, MD, and other members of the Division. Dr. Khalid led the PANDA study on pancreatic cyst fluid analysis that was published in 2006.

Funding from the Pancreatic Cyst Biomarker Alliance (PCBA), a collaborative funded by the EDRN, and six member sites, including the University of Pittsburgh, Johns Hopkins University, Stanford University, University of California San Fran cisco, Washington University in St. Louis, and the Van Andel Research Institute in Grand Rapids, Mich., has enabled research teams to attempt the validation of promising biomarkers from cystic fluid.

“Our goal with this line of research is to better understand which pancreatic cysts need to be watched, which ones need to be resected, and which ones are benign with little risk of a cancerous future. This unique project, which to the best of our knowledge has never been done with cyst fluid, allows for the testing of multiple potential biomarkers on a common set of samples. The tests determine how these markers can be combined to develop a panel of markers to improve the management of patients with pancreatic cysts through identification of those cysts that have a high and low risk for progressing to a malignant state,” says Dr. Brand.

Blood-Based Biomarkers for Early Detection

One of Dr. Brand’s current studies is now  in its third year of funding and is quite promising. He is leading an EDRN-funded clinical validation center (CVC) along with Surinder Batra, MD, at the University of Nebraska to evaluate the ability of the biomarkers MUC5AC and MUC4 to distinguish pancreatic adenocarcinoma among healthy individuals and diseased control patients, including patients with a benign biliary obstruction or chronic pancreatitis.

“Certain mucins have been shown to be overexpressed in pancreatic cancer in EDRN studies thereby, presenting as a hallmark of the disease. MUC5AC and MUC4 are two forms of mucin that have been shown to be promising biomarkers of disease. This study evaluates these two markers using samples from our PAGER biorepository to see if we can validate them with respect to their ability to distinguish between cancers and healthy and diseased controls. In a separate study aim, promising mucin markers are being developed to determine if they can be used to predict those 
cysts that are at high risk for progressing to pancreatic cancer. There is much excitement in our collective groups about the promise of these studies, and in a few years, we will likely have some answers,” says Dr. Brand.

Along and with EDRN partners, a number of open investigations are aimed at finding biomarkers that can point to the presence of pancreatic cancer at its most early stage.

Brian Haab, PhD, from his laboratory at Van Andel, and Dr. Brand at the University of Pittsburgh have been involved in glyco - biology research concerning pancreatic cancer as part of their EDRN-funded Biomarker Developmental Laboratory. Dr. Brand and his colleagues also have been working with industry as part of a large, multicenter trial to test various biomarkers and a novel panel for early detection of pancreatic cancer in high-risk individuals with a genetic predisposition.

“We are fortunate to learn from, work with, and, when possible, assist our colleagues in their efforts as part of our shared objectives of making pancreatic cancer a more treatable illness,” says Dr. Brand.

Collaboration Is the Key

“For certain, our success will be proportion ate with the diverse shared samples and comple - mentary acumen found in our collaborative efforts. I am both grateful and honored that our national and international pancreatic cancer research groups are so robust.

So much of what we do is shared within the field, but we also benefit greatly from internal UPMC partnerships, as well as collaborations with like-minded institutions and industry colleagues,” says Dr. Brand.

Specifically, at the University of Pittsburgh and UPMC, Dr. Brand notes numerous pancreatic research collaborators. In addition to Dr. Singhi, Dr. McGrath, and Dr. Khalid, who were discussed earlier in this article, Kenneth Fasanella, MD, and Jennifer Chennat, MD, are working on related and independent lines of investigation in pancreatic cancer.

“Dr. Fasanella has a sharp focus on surveill ance of cystic pancreatic lesions, and Dr. McGrath is working along similar lines. Dr. Khalid’s work with pancreatic tumors and cysts continues to advance the field. Together with Dr. Singhi, and our surgical collaborators, most notably Amer Zureikat, MD, chief of Gastrointestinal Surgical Oncology and co-director of the UPMC Pancreatic Cancer Center, and Nathan Bahary, MD, PhD, medical director of the UPMC Pancreatic Cancer Program, we continue to build a world-class pancreatic cancer research program,” says Dr. Brand.

In the long term, finding biomarkers to identify traces of the earliest stages of disease at the molecular level is the proverbial “Holy Grail” of pancreatology. Of course, we will also need to understand how to intervene at the molecular level to suppress or eliminate the growing malignancy.

References

1 https://www.pancan.org

Further Reading

Brand R, Borazanci E, Speare V, et al. Prospective Study of Germline Genetic Testing in Incident Cases of Pancreatic Adenocarcinoma. Cancer. 2018; 124(17): 3520-3527.

Zhan W, Shelton CA, Greer PJ, Brand RE, Whitcomb DC. Germline Variants and Risk for Pancreatic Cancer: A Systematic Review and Emerging Concepts. Pancreas. 2018 Sep; 47(8): 924-936.

Validation of Biomarkers for Early Diagnosis and Risk Prediction of Pancreatic Neoplasms. NIH Project Number: 5UO1CA200466-03.

Detection and Prognosis of Early-Stage Pancreatic Cancer by Interdependent Plasma Markers. NIH Project Number: 5UO1CA15265308.