Presentation of the Team Science Award to the Hopkins team

When she presented the award to the team at the opening ceremonies of the annual AACR meeting in Washington D.C., Dr. Willman said that the Hopkins team was selected “because of the tremendous impact it has made on understanding of the fundamental genetic changes that characterize pancreatic cancer, research that has immediate clinical implications.”
While it is wonderful for the pancreatic cancer research team to be recognized in this way, the award also highlights something we firmly believe in here at Johns Hopkins- the power of collaborative science. While there is great power in individual scientist initiated research, we need to recognize that pancreatic cancer is a complex disease, and that this complexity can best be studied by collaborative teams- teams in which each member has a shared vision- alleviating the suffering caused by pancreatic cancer, and teams in which each member of the team brings their own unique expertise to the research and each selflessly gives their time and effort to the cause.

We obviously still have a long way to go in the war against pancreatic cancer, but it is nice on this occasion to recognize the collaborative science being conducted by the pancreatic cancer research team at Hopkins.

Because staging is so very important, we have updated our web pages that describe the proper staging of pancreatic cancer (http://pathology.jhu.edu/pc/DiagStaging.php). These updated pages provide new illustrations (an example of which is shown above) of the Seventh Edition Staging from the American Joint Committee on Cancer (AJCC). Details on staging can be found at: http://www.cancerstaging.org/

The staging of tumors of the pancreas uses the TNM staging system.
“T” in this system designates the extent of the primary tumor in the pancreas.
T0 No evidence of a primary tumor
Tis Carcinoma in situ (a precancerous lesion, such as an intraductal papillary mucinous neoplasm with high-grade dysplasia)
T1 Tumor limited to the pancreas and 2 cm or less in size
T2 Tumor limited to the pancreas and greater than 2 cm in size
T3 Tumor extends beyond the pancreas but it does not involve the blood vessels of the celiac axis or the superior mesenteric artery (two arteries that run close to the pancreas)
T4 Tumor involves the blood vessels of the celiac axis or the superior mesenteric artery (two blood vessels that run close to the pancreas)

“N” in the staging system designates whether or not the cancer has spread (metastasized) to lymph nodes in the region of the pancreas (regional lymph nodes)
NX Regional lymph nodes cannot be assessed
N0 No regional lymph node metastases (cancer has not spread to the lymph nodes)
N1 Regional lymph node metastases (cancer has spread to the lymph nodes, as shown above)

The “M” of TNM designates spread to other organs beyond the pancreas, also known as distant metastasis.

M0 No distant spread (no distant metastasis)
M1 Distant spread (distant metastasis, shown below)

Once the T, the N and the M designations are established for a given patient, they can be combined to determine the stage of the patient’s cancer using the chart below.
Stage 0 Tis N0 M0
Stage IA T1 N0 M0
Stage IB T2 N0 M0
Stage IIA T3 N0 M0
Stage IIB T1, T2 or T3 N1 M0
Stage III T4 Any N M0
Stage IV Any T Any N M1

While it is important to recognize that not all pancreatic cysts or lesions become pancreatic cancer, the study is important because it suggests that potentially curable precancerous lesions can be detected by screening high risk individuals. As Dr. Canto said, “We now know that although these high-risk patients often tend to develop pancreatic lesions, we can detect the lesions, track them over time and remove them before they become cancer.”

Not that long ago, there was no hope.  Pancreatic surgery was a dangerous affair, with operative mortality rates approaching 20 percent.  In the research labs there were no leads. The research that was being done was mostly mundane, offering little hope for significant advances.  Then, in the last decade, in what seemed like a blink of an eye, things changed dramatically.  Where there was no hope in patient care, surgery became safe.  Where there were no leads in research, new discoveries, particularly in cancer genetics, provided many new leads.

Having witnessed the exciting discoveries made in the last few years, particularly the sequencing of the entire pancreatic cancer genome by scientists in The Sol Goldman Pancreatic Cancer Research Center here at Johns Hopkins, I am now profoundly excited about what lies ahead. Perhaps most exciting are the new opportunities to integrate research discoveries into improved patient care.  Let me give just three examples.

First, from the sequencing we have discovered rare genetic changes that can increase a person’s risk of developing pancreatic cancer (just as we inherit our eye and hair color from our parents, so to do some individuals inherit an increased risk of developing pancreatic cancer).   The discovery of genes that increase the risk of a person developing pancreatic cancer means that we can now test members of families in which there is a clustering of pancreatic cancer and, in some cases, we can determine which family members are at risk, and which are not.  Those at risk may which to participate in research trials of screening for early pancreatic cancer, while those not at increased risk would be relieved of their anxiety.

Second, from the sequencing we have learned that it takes years, if not decades for a pancreatic cancer to develop. This exciting discovery means that there likely is a large window of opportunity to detect and treat curable precancerous lesions in the pancreas before patients develop incurable advanced disease. Just as colonoscopy can be used to detect and treat colon polyps before a colon cancer develops, so too do we foresee a future in which the early detection of curable pancreatic tumors will save many lives.

Third, from the sequencing we have discovered genetic changes, mutations in specific genes, that characterize precancerous cysts in the pancreas.  Cysts (small fluid-filled sacs) are fairly common.  The problem has been that doctors haven’t been able to determine which cysts are potentially harmful (precancerous) and which are harmless. Now, with this advance, there is hope that doctors will be able to tell when a cyst needs to be removed and when it is safe to leave it in place.

These are but just a few of the many exciting discoveries made in the research lab that will be applied, in the not too distant future, to patient care.  The pace of discovery is mind boggling.  As Mario Andretti said, “if everything seems under control you just aren’t driving fast enough.”

We sincerely thank all of you who have supported our research over the years.  You have made a profound difference.

Dr. Hruban

Dr. Hruban

In the March 2011 issue of the journal Science, Y. Jiao and C. Shi at Johns Hopkins reported that when they sequenced the DNA in PanNETs they found that the genes mutated (changed) in PanNETs are completely different from the genes mutated in ductal adenocarcinomas.  The genes TP53, KRAS, p16 and SMAD4 are targeted in ductal adenocarcinomas, while the genes MEN-1, DAXX, ATRX, PTEN and TSC2 are mutated in PanNETs.  This provided the first clue that the clinical differences observed in these two tumors may have their roots in the genetic (DNA) changes in these tumors.

Recently, in the    June 30th, 2011 on-line edition of the journal Science, Christopher Heaphy, Roeland De Wilde and Yuchen Jiao in the laboratory of Alan Meeker in the Sol Goldman Pancreatic Cancer Research Center at Johns Hopkins reported that they have discovered that pancreatic neuroendocrine tumors also have unique chromosome changes called “Alternative Lengthening of Telomeres.” Alternative Lengthening of Telomeres affects the ends of chromosomes, the part of the chromosomes called telomeres. The team then showed that Alternative Lengthening of Telomeres in pancreatic neuroendocrine tumors (also known as “islet cell tumors”) is likely caused by mutations (DNA changes) in two specific genes- the DAXX and ATRX genes. This finding is important because it uncovers an entirely new cancer pathway, and it helps define the fundamental differences between ductal adenocarcinoma and neuroendocrine tumors.  Now that this new pathway has been discovered, the team hopes that this pathway can be exploited diagnostically and therapeutically.

Dr. Hruban

Afinitor was approved for the treatment of patients with progressive pancreatic neuroendocrine tumors that are not resectable surgically,that are  locally advanced or metastatic.  This approval by the FDA was based on a phase III clinical trial of Afinitor, in which the drug was shown to prolong progression free survival in patients with advanced PanNETs.  This phase III trial was reported in the New England Journal of Medicine (N Engl J Med. 2011 Feb 10;364(6):514-23.). The research team at Johns Hopkins has played a role in understanding the likely mechanism by which Afinitor works (http://pathology.jhu.edu/pancreas/news.php).  The team sequenced all of the known human genes in a series of pancreatic neuroendocrine tumors and found that one in six of these tumors harbors an activating mutation (DNA change) in the mTOR pathway. (Jiao, Shi, Edil, de Wilde, Klimstra, Maitra, Schulick, Tang, Wolfgang, Choti, Velculescu, Diaz, Jr., Vogelstein, Hruban & Papadopoulos, Science, 2011).    This is the very pathway that Afinitor targets, and it is likely that Afinitor will be most effective in patients with a tumor with an mTOR pathway gene mutation. 

Sunitinib belongs to the class of drugs called “tyrosine kinase inhibitors,” and it has both effects against blood vessels in tumors (antiangiogenic) and effects against the tumor itself (antitumor properties).   In a phase III clinical trial treatment with Sunitinib has been shown to significantly improve progression free survival in patients with metastatic pancreatic neuroendocrine tumors (PNETs) (Reviewed in: Cancer Metastasis Rev, 2011, Suppl 1:19-26). 

We are excited by these new agents and look forward to new advances in the treatment of patients with pancreatic neuroendocrine tumors.  To learn more about pancreatic neuroendocrine tumors visit: http://pathology.jhu.edu/pancreas/TreatmentEndocrine.php

This important study demonstrates exciting progress in the treatment of pancreatic cancer.  Our hope is that these promising initial results with FLORFIRINOX will be validated in follow-up studies, and that other more potent agents with fewer side effects will be developed.  Until then, it looks like FLORFIRINOX will be another agent in the pancreatic cancer oncologist’s armamentarium.

For more information on the multidisciplinary treatment of patients with pancreatic cancer at johns Hopkins visit:  http://pathology.jhu.edu/pancreas/

The location of the pancreas deep within the abdomen places it close to numerous large blood vessels that are necessary for life (see “Where is the pancreas?” post).  As a result, cancers of the pancreas do not need to grow very large before invading these vessels and this poses a significant treatment problem. There are two main arteries in the area of the pancreas and these are called the celiac artery and the superior mesenteric artery. The celiac artery gives rise to the splenic artery and the hepatic artery and supplies blood to the liver, pancreas, spleen and stomach. The superior mesenteric artery gives rise to numerous branches that supply the small bowel, part of the colon and the pancreas. The venous system in this area is the portal vein and its tributaries. It drains blood from most of the gastrointestinal track back to the liver and ultimately to the heart through the hepatic veins. Pancreatic cancers that invade these major blood vessels are classified as Stage III which includes two subcategories – “border-line resectable” and “locally advanced, unresectable”.

Cancers that are found to completely surround one of the main arteries as determined by CT scan (“encasement”) are typically considered to not be operable (locally advanced, unresectable). An attempt at removal of such cancers has a very high probability of leaving a portion of the tumor behind (R2 resection) and thus the surgery will confer no survival benefit while potentially subjecting the person to debilitating side effects. Patients with locally advanced, unresectable pancreatic cancer will often undergo radiation and chemotherapy in hopes of shrinking the tumor away from the artery. Unfortunately, significant shrinkage of the tumor that converts it to removable occurs only 10% of the time. A tumor that grows next to one of the main arteries but does not surround it (“abutment”) is considered borderline resectable. In this case there is a good chance it can be removed without cutting though the tumor and, at worst, leaving only a few tumor cells behind (R1 resection). In most centers, including ours, patients with borderline resectable pancreatic cancer will receive radiation therapy prior to surgery in order to kill the cancer cells in the periphery of the tumor. This takes about 6 weeks and increases the likelihood of leaving no cancer behind at the margins (R0 resection). Unlike Stage III locally advanced pancreatic cancer, most patients with Stage III borderline resectable cancer will go on to have their tumor removed by surgery. The main exception to proceeding to surgery in borderline resectable patients is in the event the cancer grows further or develops distant metastases while receiving the chemotherapy and radiation therapy.

The assessment of whether or not a tumor is removable based on invasion of the main veins is very different than that of the arteries. Basically, any degree of involvement of the vein from abutment to encasement is considered to be borderline resectable as long as the tumor involves a portion of the vein that can be reconstructed once that section is removed. For example, if the tumor grows in the mid-portion of the vein (called the portal vein – superior mesenteric vein confluence), the tumor must be taken out with the vein attached and the two end of the vein can be reconnected to restore flow. If the same size tumor grows lower down on this vein (towards the feet), it will involve the portion of the vein that braches like numerous limbs of a tree. Removal of the vein in this area would leave the surgeon with one main “trunk” at the top and numerous “small braches” at the bottom. There would be no way to reconnect the ends. Thus for venous involvement, if it grows at a location in which the surgeon can technically remove the tumor and reconstruct the vein it is called Stage III borderline resectable. If removal and reconstruction is not possible it is called Stage III locally advanced. As described above for the arteries, patients with stage III cancers will most likely receive radiation therapy and most of those in the borderline resectable category will go on to surgery, while only 10% locally advanced will have significant tumor shrinkage.

There are numerous exceptions to this general algorithm based on feature that are unique to each individual patient. The complexity of the many treatment options underscores the need to be evaluated by an experienced team of specialists. We have found that this is best accomplished through a multidisciplinary clinic where patients are evaluated by all of the specialists in a single day. If you would like to learn more about this clinic please feel free to contact us at 410-933-PANC. We will be able to answer your questions and schedule a clinic appointment for you at your request.

Christopher Wolfgang, MD, PhD
Johns Hopkins Hospital