Map of Pancreatica Walks and Runs

FOLFIRINOX as Neoadjuvant Therapy for Cancer of the Pancreas

The idea behind treating surgically unresectable and borderline resectable pancreatic cancer with chemotherapy or chemoradiation is that some minority of cases will thereupon improve to the point of now being deemed amenable to surgery, with its typically more favorable outcome.  This is generally the point then of so-called neoadjuvant therapy.

As the 5-FU based four-drug FOLFIRINOX regimen appears to show improved outcomes for advanced pancreatic cancer over gemcitabine alone, Bahary and colleagues at the University of Pittsburgh used FOLFIRINOX as neoadjuvant therapy in unresectable and borderline resectable pancreatic cancer.  The results were published in the September edition of the Journal of Surgical Oncology.

The researchers treated 21 such pancreatic cancer patients with the drug combination; seven patients were then able to progress to surgery (two of these patients were initially found to have been unresectable).  An additional two patients were deemed fit for surgery who were treated with both FOLFIRINOX and stereotactic body radiation therapy.

The authors found the results of FOLFIRINOX neoadjuvant treatment for surgically unresectable and borderline resectable pancreatic cancer as encouraging.   This approach is certainly worthy of further study.

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Dale O’Brien, MD

 

Cancer Diversity: Enemy of Personalized Medicine ?

In what appears to be a season of blockbuster conceptual research results in the cancer medical literature, comes a recent study involving leukemia cells but which has implications for the entire spectrum of cutting edge cancer treatment. The general current prevailing thought on the origin of cancer is that a pattern of gene mutations or epigenetic changes emerge – that initiates signaling miscues to the normal orderly growth pathways of a cell – thus launching subsequent rapid and erratic cellular division and growth: cancer.

The present study takes the above as a starting point, but in a heretofore unknown (to this author) minor strain of research over the last few years – asks the questions: are these genetic mutations physically uniform throughout a tumor, and does the mutation profile of the tumor remain uniform over time?   Of course, their answers are no and no.  They cite research primarily from the last two years, but going back until 2008 demonstrating that there exists genetic diversity within a single tumor – and they indicate that “intraclonal genetic and phenotypic diversity is an inherent feature of [cancer].”

The implications of this concept are large, in that much of the idea of personalized medicine and targeted therapy is aimed at specific genetic patterns.  If such a pattern is not uniform throughout a tumor then the results of the therapy may not be effective, or could possibly be ameliorated.

Greaves and colleagues primarily from The Institute of Cancer Research in London E-published the results of their research on November 6th in the journal Genomics Research that offers an in-depth view of genetic diversity in leukemia cells. In a multi-stage procedure the authors used state-of-the-art technologies to undertake single cell whole genome DNA sequencing, repeated in approximately three hundred cells. This was done for an individual with leukemia, and later for two other leukemia patients. The results showed not merely the expected mutations, but a large range of genetic mutations, and which were seen to be distributed in a manner which suggested sub-clonal populations (as identified by mutation patterns).  These data were sorted and placed into a tree-and-branch clonal phylogeny by algorithm which physically demonstrated the relationships and temporal evolution of the DNA mutation patterns.  In effect, these results showed that the individual patients did not have “leukemia” but in fact (rather astoundingly) had between two and ten genetically distinct leukemias.

Interestingly, the authors refer to their research process in such terms as “interrogating” clonal genetic complexity, in the sense that the DNA profile might perhaps be coaxed (through similar observation) to tell the story of what has happened to the cell over time. The researchers make the point that the beginning of disorderly cell division and growth due to DNA mutations in cancer increases the likelihood of subsequent DNA mutations in the same tumor / cell line. They indicate that leukemia is less likely to be complex in these matters than carcinoma (one might insert here adenocarcinoma of the pancreas).  Finally, with all of the potential problems that these results confer to the idea of “personalized medicine” (treatments aimed at a patient’s tumor profile) the authors offer some promise in the sense that future doctors on understanding a more complex picture of the underpinnings of a given tumor, may be more likely to treat the “founder lesion” rather than a clonal branch or even a more minor clone – thus conferring more likely success in therapy.

This is large concept work – shown in meticulous, brilliant detail. It is actually rather breathtaking science that reveals again the unexpected at the cutting edge of medicine; plaudits to these researchers.           

                       

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Dale O’Brien, MD

 

Biomarker miR-10b for Cancer of the Pancreas: earlier diagnosis and/or therapeutic target?

As alluded to in another recent blog entry, the study of microRNA has been a source of great interest as to the possible development of biomarkers that may screen or aid on the diagnosis of pancreatic cancer.  MicroRNAs (or sometimes abbreviated miR) are small (18 to 25 nucleotide) non-coding RNA molecules that are involved in genetic regulation – that were first discovered and better characterized in the decade of the 1990s and since.

A number of microRNAs tend to be overexpressed in pancreatic cancer including miR-10b, miR-21, miR-196a, miR-203, miR-155, miR-210 and miR-221.  But at an approximately four-fold increase, in this and earlier research by the researchers in the present study (below), microRNA-10b has been found to be one of the most frequently overexpressed microRNAs in pancreatic cancer.

We addressed this area of biomarker research involving miR-27a-3p by Chinese researchers in our June 17 Pancreatica Blog posting. And now comes further interesting research on the subject as published by Korc and colleagues from the University of Indiana as E-published on October 7, 2013 in the journal Oncogene.  The authors again verify that miR-10-b is overexpressed in adenocarcinoma of the pancreas, correlate increasing levels of 10-b with increased aggressiveness of cancer activity, and better characterize some of 10-b’s biochemical and growth pathway role and interactions.

Thus interestingly, the authors point to miR-10b’s potential as both a possible biomarker for pancreatic cancer, and as a possible therapeutic target.

This is provocative thoughtful research that represents early work in the promising area.

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Dale O’Brien, MD

 

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