A newly identified biomarker panel could pave the way to earlier detection and better treatment for pancreatic cancer, according to research from the Perelman School of Medicine at University of Pennsylvania. Currently over 53,000 people in the US are diagnosed with pancreatic cancer – the fourth leading cause of cancer death – every year. The blood biomarkers correctly detected pancreatic cancer in blood samples from patients at different stages of their disease.
The majority of pancreatic cancer patients are not diagnosed until an advanced stage, beyond the point at which their tumours can be surgically removed. A team led by Dr Ken Zaret, director of the Penn Institute for Regenerative Medicine and the Joseph Leidy professor of cell and developmental biology, and Dr Gloria Petersen, from the Mayo Clinic, identified a pair of biomarkers that physicians could soon use to discover the disease earlier.
“Starting with our cell model that mimics human pancreatic cancer progression, we identified released proteins, then tested and validated a subset of these proteins as potential plasma biomarkers of this cancer,” Zaret said.
The authors anticipate that health care providers will use the early-detection biomarkers to test for their presence and levels in blood from pancreatic cancer patients and blood drawn from individuals with a high risk of developing pancreatic cancer, including those who have a first-degree relative with pancreatic cancer, are genetically predisposed to the disease, or who had a sudden onset of diabetes after the age of 50.
“Early detection of cancer has had a critical influence on lessening the impact of many types of cancer, including breast, colon, and cervical cancer. A long-standing concern has been that patients with pancreatic cancer are often not diagnosed until it is too late for the best chance at effective treatment,” said Dr Robert Vonderheide, director of the Abramson Cancer Centre (ACC) at the University of Pennsylvania. “Having a biomarker test for this disease could dramatically alter the outlook for these patients.”
The biomarker panel, enabled by discovery work of first author Dr Jungsun Kim, a post-doctoral fellow in Zaret’s lab, builds on a first-of-its-kind human-cell model of pancreatic cancer progression the lab described in 2013. They used stem-cell technology to create a cell line from a patient with advanced pancreatic ductal adenocarcinoma. Genetically reprogramming late-stage human cancer cells to a stem-cell state enabled them to force the reprogrammed cells to progress to an early cancerous state, revealing secreted blood biomarkers of early-stage disease along the way.
The best candidate biomarker, plasma thrombospondin-2 (THBS2), was screened against 746 cancer and control plasma samples using an inexpensive, commercially available protein-detection assay. The team found that blood levels of THBS2, combined with levels of a known later-stage biomarker called CA19-9, was reliable at detecting the presence of pancreatic cancer in patients.
The team refined the assay with independent investigations of plasma samples from patients with different stages of cancer, from individuals with benign pancreatic disease, and from healthy controls, all obtained from Petersen, who directs the bio-specimen resource programme for pancreas research at the Mayo Clinic.
“Positive results for THBS2 or CA19-9 concentrations in the blood consistently and correctly identified all stages of the cancer,” Zaret said. “Notably, THBS2 concentrations combined with CA19-9 identified early stages better than any other known method.” The combination panel also improved the ability to distinguish cases of cancer from pancreatitis. The panel will next be validated in a set of samples from pancreatic cancer patients who provided a research blood sample prior to their diagnosis.
Markers are needed to facilitate early detection of pancreatic ductal adenocarcinoma (PDAC), which is often diagnosed too late for effective therapy. Starting with a PDAC cell reprogramming model that recapitulated the progression of human PDAC, we identified secreted proteins and tested a subset as potential markers of PDAC. We optimized an enzyme-linked immunosorbent assay (ELISA) using plasma samples from patients with various stages of PDAC, from individuals with benign pancreatic disease, and from healthy controls. A phase 1 discovery study (n = 20), a phase 2a validation study (n = 189), and a second phase 2b validation study (n = 537) revealed that concentrations of plasma thrombospondin-2 (THBS2) discriminated among all stages of PDAC consistently. The receiver operating characteristic (ROC) c-statistic was 0.76 in the phase 1 study, 0.84 in the phase 2a study, and 0.87 in the phase 2b study. The plasma concentration of THBS2 was able to discriminate resectable stage I cancer as readily as stage III/IV PDAC tumors. THBS2 plasma concentrations combined with those for CA19-9, a previously identified PDAC marker, yielded a c-statistic of 0.96 in the phase 2a study and 0.97 in the phase 2b study. THBS2 data improved the ability of CA19-9 to distinguish PDAC from pancreatitis. With a specificity of 98%, the combination of THBS2 and CA19-9 yielded a sensitivity of 87% for PDAC in the phase 2b study. A THBS2 and CA19-9 blood marker panel measured with a conventional ELISA may improve the detection of patients at high risk for PDAC.
Jungsun Kim, William R Bamlet, Ann L Oberg, Kari G Chaffee, Greg Donahue, Xing-Jun Cao, Suresh Chari, Benjamin A Garcia, Gloria M Petersen, Kenneth S Zaret