A majority of cases of pancreatic cancer (ductal adenocarcinoma of the pancreas) are diagnosed in advanced stage. The main reason is that early stage disease tends to have no symptoms, or vague symptoms. And there is no good screening test for early pancreatic cancer, or a simple diagnostic indicator. The two biomarkers most often used with pancreatic cancer are CA19-9 and carcinoembryonic antigen (CEA). However these assays are not very specific or sensitive in the early stages of the disease progression.
There have been a number of recent forays in terms of diagnostic biomarkers for adenocarcinoma of the pancreas based on specific gene mutations that tend to be seen in pancreatic cancer. And this has extended to the realm of MicroRNAs (or MiRNAs), small non-coding RNA strands that regulate the expression of specific referent genes. There have been a number of recent published studies demonstrating that certain members of the family of MiRNAs are affected by or affect many aspects of the natural history pancreatic cancer.
Now comes a study led by Danish researcher Johansen of Herlev Hospital near to Copenhagen (and her colleagues) which evaluates MiRNA panels as potential diagnostic markers for pancreatic cancer. The study, published in the Journal of the American Medical Association on January 22, 2014, is a case control study including 409 patients diagnosed with pancreatic cancer from six Danish hospitals from 2008 until 2012. The researchers looked at MiRNA in the whole blood of the patients with pancreatic cancer, in 25 with pancreatitis, and in 312 healthy controls. They evaluated 754 MiRNas, discovering 38 that appeared to identify pancreatic cancer. 19 of these MiRNAs were validated by a different method. Then two diagnostic panels (indices) consisting of these miRNAs were developed.
The area under the curve (AUC) for both MiRNa indices were higher than the AUC for CA19-9 (except in the validation cohort). This is an indication that these panels held improved diagnostic ability for pancreatic cancer over CA19-9. Also, and perhaps importantly, including the CA19-9 together with the MiRNA indices gave better results than using CA19-9 alone.
There are serious limitations of this study. First, the differences between the AUC of the MiRNA indices and that of CA19-9 were quite small – and may not be clinically significant. Also, the age of the healthy control subjects was younger than those with pancreatic cancer.
Nevertheless, this is an intriguing finding in a clever study that requires validation and additional scientific investigation.
Dale O’Brien, MD
The K-Ras gene is found to be mutated in 30% of all tumors (human), but this rises to 90% or more in pancreatic cancer (ductal adenocarcinoma of the pancreas). It is considered an “oncogene” meaning a gene whose mutation typically initiates a cascade of proteins that signal for rapid cell growth and division – in this case by promoting an increased binding of the referent protein to GTP (guanosine triphosphate) and a reduced ability to convert GTP to GDP – thus potentiating cell proliferation and ameliorating signals for programmed cell death. As such the K-Ras mutation is one of the most powerful divers of cancer in human beings. And this is assumed to be especially true in pancreatic cancer. Though the K-Ras involvement in pancreatic cancer has been known for decades, direct approaches at altering this mechanism have largely proved elusive.
However, this past June the U.S. National Cancer Institute revealed that it will offer substantive ($10M) grants for scientists to target K-Ras. Also, a piece of exquisite research by Kevan Shokat and colleagues from the Howard Hughes Medical Institute at the University of California in San Francisco has given impetus to this mission. On November 20, 2013 in the journal Nature these researchers E-published an article on their work detailing their discovery of a specific compound that binds to the K-Ras protein known as G12C which tends to inhibit the effects of the mutated protein. G12C is the most common mutation of K-Ras whereby cysteine replaces glycine at position 12 of the protein – this mutation is found for example in more than 20,000 patients with lung and colorectal cancer annually in the U.S.
The investigators screened more than five hundred compounds – finally discovering one that binds to a previously unrecognized pocket (identified by crystallographic means) near G12C on the physical structure of the protein. The effect of the binding of this compound to the K-Ras protein appears to reduce the affinity of G12C for GTP, but not for GDP, thus allowing for reinstatement of the more normal (non-mutated) action of K-Ras.
This is a fascinating study that offers future promise for the treatment of pancreatic cancer.
Dale O’Brien, MD
Hawkins and colleagues at Barnes-Jewish Hospital and Washington University School of Medicine in St. Louis, Missouri E-published an article on November 19, 2013 in the journal Annals of Surgery which examined regional lymph node status and the medical disposition of 136 of their patients who had received surgery for pancreatic neuroendocrine tumors from 1994 through 2012.
In this retrospective study the authors found that lymph node metastases were associated with bigger tumors. They also found increased regional lymph node presence in those tumors that were found in the head of the pancreas (not in the tail, for instance), those with high Ki-67 levels, and those with lymphatic vascular invasion. But perhaps the key finding was that at a p < 0.0001 level, the median survival was lower for those patients who evidenced lymph node metastases. The median survival duration for those without these metastases was 14.6 years versus 4.5 years for those with metastases.
The researchers conclude that these data suggest that regional lymphadenectomy may be an important additional step for patients with pancreatic neuroendocrine tumors who undergo pancreatic resection.
This research contains the inherent limitations of retrospective studies in general, and the primary conclusion (that lyphadenectomy may significantly prolong survival) does not necessarily strictly translate. Nevertheless, it is an interesting finding that may well be true. Thus, it is deserving of further inquiry – including perhaps a prospective study.
Dale O’Brien, MD