In an absolutely remarkable, fascinating and possible game-changing study, Joo Mi Yi and Nita Ahuja and colleagues (primarily) from Johns Hopkins University have identified a “panel” of biomarkers based on DNA methylation of two relatively obscure genes (that can be identified in serum) for use, at least at an experimental level at this stage, for the earlier detection of early pancreatic cancer (ductal adenocarcinoma of the pancreas).
In this area of earlier detection research, there has been large attention given to discovering genetic DNA mutations that are common to pancreatic cancer tumors. For example, about a year ago in the journal Nature (November 15, 2012) an international group of researchers aiming for a comprehensive listing of such mutations identified 16 significantly mutated genes with 2,016 mutations and many other genetic variations. We commented on this study here on Pancreatica in a 12/09/12 blog entry.
Another area of recent active such research, for example, has been in the arena of MicroRNAs. And notably at Johns Hopkins (along with other institutions) there has been a consistent but less heralded look at DNA methylation changes that occur in pancreatic cancer. Methylation is the natural process (as related to DNA in mammals) whereby a methyl group is found at cytosine-phosphate-guanine (CpG) sites on DNA, effectively tending to silence the activity of the underlying referent gene. About 60% to 90% of CpG sites are methylated in mammals. So, one key point in looking for such changes is to seek sites which ARE methylated in tumor conditions, but which are NOT methylated with normal tissue.
Yi, Ahuja and colleagues electronically published the results of their elaborate research on November 1, 2013 in Clinical Cancer Research, the official journal of the American Association for Cancer Research. Using cell lines as well as human samples, they narrowed methylated gene candidates down from 1,427 genes to eight that showed methylation in pancreatic cancer. Of these eight, they identified two that were the two most methylated genes: BNC1 (91% frequency) and ADAMTS1 (67% frequency). These genes have heretofore not been particularly associated with pancreatic cancer. And it is not entirely clear what their full functions are – although BNC1 appears to have a tumor suppressor role, and ADAMTS1 may be involved in angiogenesis. Both of these genes showed “dense” methylation in cell lines and in pancreatic cancer, and showed almost no methylation in normal pancreatic samples. Also, these genes did not tend to demonstrate increased methylation in pancreatitis.
Additionally (importantly), the authors used a fairly newly developed very sensitive “nano-enabled” assay to test the serum of patients diagnosed in various stages of pancreatic cancer (including the possible precursor to pancreatic adenocarcinoma: pancreatic intraepithelial neoplasia), and as compared to CA 19-9 levels. The rates of methylation increased at every stage of disease, and demonstrated higher rates than those of CA 19-9 (until stages III and IV where methylation and CA 19-9 levels were both 100%).
The overall sensitivity of this two-gene methylation “panel” was a respectable 81%; the specificity was 85%. Thus, this panel appears to represent a highly promising approach aimed at the earlier diagnosis of early pancreatic cancer. Further research is required to verify and expand the findings, but these results are indeed encouraging.
Dale O’Brien, MD
Gress and colleagues from the University of Marburg in Germany published the results of a Phase II trial in the October 2013 issue of the Annals of Oncology, the official journal of the European Society for Medical Oncology. They did a prospective multi-center study of 76 pancreatic cancer (ductal adenocarcinoma of the pancreas) patients over a two-year period which offered the adjuvant regimen of gemcitabine in combination with cetuximab (Tarceva) to patients for a 24 week period post-pancreatic cancer surgery.
The authors compared the results of these pancreatic cancer study subjects to previously reported survival statistics at 18 months of a 35% disease-free survival rate for gemcitabine alone. Their conclusion was that adding Tarceva to the gemcitabine did NOT improve either disease-free survival or overall survival of those with pancreatic cancer receiving this combination above receiving gemcitabine alone.
Dale O’Brien, MD
“Half the lies they tell about me aren’t true.” -Yogi Berra
There are legitimate controversies in pancreatic cancer. Often over time, the pendulum can swing to one side or the other of a scientific conflict – as new evidence supports a contention or not. Sometimes, with a greater understanding of the complexity of an issue, both sides can even turn out to be right – or wrong.
For example, one legitimate controversy that has been raging for over a decade now, is whether adding radiation to chemotherapy will help increase patient survival after receiving surgery for pancreatic cancer (ductal adenocarcinoma of the pancreas). There are some interesting recent studies on this topic but the issue is not yet fully resolved.
Below are discussions of recent studies on THREE such issues that have been matters of some inquiry and even controversy in pancreatic cancer. These results are not presented as definitive (as the pendulum never fully settles in real science) but they are fairly compelling – for now.
We should probably herewith highly complement the authors of these studies – as often studies that don’t show a “positive” outcome tend NOT to get published. This phenomenon results in what is called publication bias, and represents a skewing of reality through an inadvertent withholding of what is deemed worthy of being published – and therefore distorts the meaning of the medical literature. Increasingly, we at Pancreatica have noticed that authors have more recently been bucking this trend, and commendably have started often publishing studies that do not have what are seen as positive results.
Coffee intake is not a causative element for pancreatic cancer European and Malaysian researchers published work in the November 2013 issue of Clinical Gastroenterology and Hepatology, the journal of the American Gastroenterological Association. The researchers examined data from the European Prospective Investigation into Nutrition and Cancer, and found NO association between coffee, decaffeinated coffee or tea intake and the risk of pancreatic cancer.
Helicobacter pylori (bacteria) is not a cause of pancreatic cancer Researchers from the Division of Cancer Epidemiology and Genetics of the U.S. National Cancer Institute E-published an article on October 2, 2013 for the journal Cancer Epidemiology, Biomarkers & Prevention, a publication (in part) of the American Association for Cancer Research. These authors in a nested case-control study looked at a group of Finnish males in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study, and found no association between H. pylori antigen status (bacteria associated with peptic ulcer disease) in the subjects’ serum and the risk of pancreatic cancer.
Metformin exposure does not increase survival in pancreatic cancer Yang and colleagues from the University of Pennsylvania published the results of a retrospective cohort study in the October issue of the journal Pancreas using data from The Health Improvement Network. The authors found that there was no difference of overall survival in those with pancreatic cancer who were exposed or not exposed to the diabetes drug: metformin.
More here (coffee)
More here (H. pylori)
More here (metformin)
Dale O’Brien, MD