What factors or circumstances led to your initial research in pancreatic cancer?

My interest in pancreatic cancer really began between 1987 and 1989, when our clinical volume at the Johns Hopkins Hospital started to increase, and I was involved as a junior faculty member with taking care of this rising number of pancreatic cancer patients. At the time, we happened to see an NIH prospectus requesting applications for grants to pursue pancreatic cancer research. NIH had recognized that pancreatic cancer was an understudied tumor at the time, and so, with the help of some very bright, very hard-working colleagues at Hopkins—people like Scott Kern, Ralph Hruban, and Constance Griffith—we put together an RO1 grant, sent it in to NIH and, lo and behold, got the best score and got it funded. That was about 1990 or ‘91, and that was when things really took off.

  One of your highly cited papers is, "The importance of hospital volume in the overall management of pancreatic cancer," (Sosa JA, et al., Ann. Surg. 228[3]: 429-38, 1998). What did that paper show?

That was a remarkable study. Julianne Sosa was a resident at that time and was critical in pulling that together. What that study basically showed—and it has been seen in many other studies since then—was that there is a benefit to what you might call a team effort, the institutional volume, the assembly-line process. There’s a benefit to patients, particularly for these very complex procedures. As far as the patients go, they undergo treatment by experienced surgeons, oncologists, and nurses. They fit into the critical pathway—the care map—post-operatively in a way that is well orchestrated. There is an expectation that the patient will hit certain progress points on a day-to-day basis.

“In the 17 or so years we’ve been studying pancreatic cancer, our understanding of the genetics of these tumors basically went from zero to almost entirely known.”

This means that the patient and their families, when they come to the hospital for these big operations, understand the average length of stay; they understand when the patient is expected to be up and walking around; they understand, on a day-to-day basis, when drains we placed in the operating room will be removed. And so the patient and the family and the whole team taking care of that individual are made accustomed to the different points along this care map, or critical pathway. And everyone is pushing the patient toward recovery in a unified way. This study showed that patients’ morbidity and mortality rates were far lower at a high-volume institution using this kind of approach (i.e., Johns Hopkins) than compared with other lower-volume institutions in the state of Maryland. We have recently pushed this concept even further at Jefferson, targeting hospital discharge on post-op days six or seven.

  Is this why it has been so influential over the years?

It was influential because it crossed several different lines. It dealt with high-volume pancreas surgery, so some people have cited it for that. It is also basically a medical economics paper. It shows what can be accomplished with team building and critical pathways. It’s used as an example of how to put together a team approach to a specific operative procedure. And it’s also cited because of one of the amazing things about this paper: it showed a decrease in statewide mortality and morbidity rates when pancreaticoduodenectomy—the "Whipple procedure"—is centralized in one tertiary care institution. In this case, the overall mortality and morbidity rate for the entire state of Maryland fell because of what was being done at Hopkins. That was a pretty dramatic result.

  What do you mean by "tertiary" care?

That means a referral center—a center of excellence—as opposed to a small community hospital.

  How has the state of our knowledge about pancreatic cancer evolved in the years that you’ve been involved in this research?

It’s been quite dramatic. In the 17 or so years we’ve been studying pancreatic cancer, our understanding of the genetics of these tumors basically went from zero to almost entirely known. We went from not really having a clue how to sub-classify pancreas cancer to now recognizing there are certain molecular alterations which clearly affect the patient. We now understand the pathway from precursor lesions—pre-malignant lesions—to pancreatic cancer. In other words, we didn’t have a clue about how pancreatic cancer got to be pancreatic cancer, and now we completely understand it—not just histologically, but molecularly.

We have also gone from having very little in effective chemotherapy to having drugs that are effective. I wouldn’t say they are highly effective, but they are effective. And that brings some excitement to the field of pancreas cancer treatment.

What’s also happened in these two decades is that the number of patients who have undergone major surgical procedures has risen dramatically, as we have trained more and more young surgeons to do these complex operations safely. There have really been many, many different areas where progress has been dramatic. It’s been remarkable.

  Was the NIH the driving force in this evolution?

I would say that, at least for us, the NIH and their RFA (Request For Applications) was very important. It opened our eyes to the fact that there was money available for good science to approach this problem. Over the years, the NIH has continuously funded research on this tumor. With the initial success we had, we started a Special Program Of Research Excellence—the acronym is SPORE. There had been programs like that in breast cancer and prostate cancer. Probably 10 years ago now, they began the SPORE process for gastrointestinal malignancies, of which pancreatic tumors are now among the most heavily studied tumors. So, yes, I would credit NIH for making these funds available and stimulating interest for people to do this research.

  What are the hottest areas of research in pancreatic cancer today?

There are several areas on which people are now focusing, on which there is much ongoing work. One is strategies for early detection, using either blood tests or novel imaging—X-rays, CAT scans, PET scans, etc.—or even using invasive testing, like endoscopic ultrasound. You put a lighted scope down the mouth, and image the pancreas through the back wall of the stomach.

A second area would be the whole issue of improvements in therapy, meaning chemotherapy, radiation, or immunotherapy. There’s some very exciting data on the chemotherapy front: different combinations of drugs and, particularly, individualized therapy. A patient’s tumor is biopsied and studied, and drugs are used that are particularly effective for the genetics of that tumor. Some of that research is going on here at Jefferson, done by a brilliant scientist named Jonathan Brody.

Immunotherapy is hot now: using the patient’s own immune system to recognize tumor cells and turn on the patient’s own killer T cells and helper T cells, and these cells go out and chew up cancer cells. Wonderful work has been done on that by Elizabeth Jaffee and Dan Laheru at Hopkins and their collaborators. These scientists designed a vaccine that is derived from patients’ cancers that we resected at Hopkins 10 years ago. It is a vaccine derived from real human pancreatic cancer. They irradiate the tumor cells, and then plasmid transfected the tumor cells so that the immune system is better able to recognize them. They have incredibly exciting data, with the best survivals ever reported in patients who have had this vaccine after surgery in which their tumors have been resected.

Another hot area would be better understanding of the molecular genetics of these tumors, particularly the progenitors or stem cells involved.

  If you had an unlimited source of funds, what one experiment would you want to do to push forward our understanding of the cause and treatment of pancreatic cancer?

I would say that, with unlimited resources, probably the best chance to make an impact and improve survival for pancreatic cancer would be to do the following: harvest every individual’s tumor to quickly define its genetics. Put the tumor DNA through machines that would lead you to the proper sequences. Then, in a high-throughput-type system, test various chemotherapeutic agents against the specific genetic alterations in these tumors, then get the patients themselves immediately on the chemotherapeutic regimen that is best tailored to the molecular features in the patients tumor. I realize that this process entails more than one experiment. But the broad concept is very, very important. Stem cells play a role in that. Certain predictable genetic abnormalities play a role, certain subgroups of pancreas cancers.

A great example of what this approach can give us is that we now know that certain tumors that have mutations in Fanconi anemia genes make up perhaps five to eight percent of all pancreatic cancers. It turns out that in those particular patients their tumors are highly susceptible to drugs that we have had on our shelves for decades. These drugs are highly toxic at the doses needed to have an effect on tumors without mutations in that pathway. But if a tumor has that mutation, then it will be highly susceptible to those drugs.

An example drug would be mitomycin C. Certain tumors are highly susceptible to mitomycin C at doses that are incredibly safe. For patients with those tumors, we can step down the dose ten-fold and the patients tolerate the drug beautifully. This is nowhere near a dose that will cause major complications, but it will kill their tumor. This is where the ability to study the tumor better, to sub-classify tumors, to find specific drugs that are best for each individual tumor, holds remarkable promise for the future of pancreatic cancer therapy.

  What would you like to convey to the general public about your work?

At Thomas Jefferson University, where I now work, we’re focused on many different projects to better understand the molecular genetics of pancreatic cancer and to better understand the abnormalities of the cell signaling pathways involved in pancreatic cancer—all ultimately with the hope of deriving better approaches to individualized chemotherapy and treatment.

Charles J. Yeo, M.D., FACS
Jefferson Medical College
Thomas Jefferson University
Philadelphia, PA, USA