Diagnosing and Treating Metastatic Pancreatic Cancer

Diane Simeone, MD

CancerNetwork discusses the treatment and diagnosis of metastatic pancreatic cancer with Dr. Diane Simeone, professor in the department of surgery at the University of Michigan where she is the director of the pancreatic tumor program. Dr. Simeone is involved in both pancreatic cancer clinical trials as well as research to better characterize important pancreatic cancer pathways and identify biomarkers for the disease. Pancreatic cancer is one of the most lethal cancers with an extremely poor prognosis-a median 6 to 10 months for metastatic disease. It is the fourth most common cause of cancer deaths but represents only 3% of all cancer diagnoses. Most pancreatic cancers, about 95%, are adenocarcinomas that arise within the exocrine part of the pancreas. The minority are neuroendocrine tumors that arise from pancreatic islet cells.

-Interviewed by Anna Azvolinsky, PhD

CancerNetwork: Dr. Simeone, what are the current advances in the molecular characterization of pancreatic cancer? Do we know what the major driver mutations are for either of the two pancreatic cancer types?

Dr. Simeone: There has been a lot of work done to try to understand the genomic mutational profile in pancreatic tumors. The major drivers, if you will, are common genetic mutations, and in pancreatic adenocarcinomas have actually been known for some time. There has been some recent work that has validated what those dominant mutations are. There are four dominant mutations that are well known. They include mutations in a gene called KRAS, which is an oncogene in pancreatic cancer and in fact is the most common mutation in any human cancer. Almost all pancreatic cancers have a mutation in KRAS. There are other mutations in three different tumor-suppressor genes that are common in most pancreatic cancers. So while we know the genetic mutations, that is different than actually understanding how to treat the cancers. So, understanding the mutations is just one step. One thing we don’t understand is how similar or different, different pancreatic cancers are in their response to treatment.

So really the next phase is going to be looking at the compilation of different genetic mutations within a person’s tumor and figuring out, with all of that information, how can we best treat that patient’s tumor? With regard to other less common types of tumors of the pancreas, there have also been some inroads into understanding the genetic mutations. We now have some understanding of the genetic mutations that are present in pancreatic cystic tumors and we see those with increasing frequency in the clinic. Between 2% to 4% of the people have such cystic tumors. We don’t know what the best predictors are for the cystic tumors that go on and progress to cancer. And so that is an important piece that is missing that will need further work. Lastly, there is a subtype of pancreatic cancer called pancreatic neuroendocrine tumors, and we now are beginning to have an understanding of the genetic mutations that are important in promoting those tumor types, but we still lack an understanding of which of those neuroendocrine tumors are going to become the “bad actors” in how those genetic mutations help inform us of how to treat those patients in the best manner.

CancerNetwork: Are there current techniques to screen for pancreatic cancer? Do most patients who come in already have advanced form of the disease?

Dr. Simeone: Most patients who present in the clinic with pancreatic cancer already have advanced disease. Only about 15% of patients who present to the clinic are candidates for surgical resection which is currently the only way to potentially cure the disease. So why is it discovered at such a late stage? I think there are a number of issues involved. One, is we don’t have a good early screening test. We don’t have a good blood test to figure out if one is at high risk for the development of pancreatic cancer or for the presence of early pancreatic cancer. Additionally, the pancreas is hard to get to. It sits in the back of the abdomen and is not easily accessible with a scope like the colon is. And thirdly, we think, just from a biologic standpoint, pancreatic cancers are inherently more aggressive and metastasize earlier than other cancer types and so that, again, makes these cancers not only harder to detect, but when we do detect them, harder to treat.

CancerNetwork: And are there any symptoms of early-stage pancreatic cancer? And do these maybe coincide with symptoms of other diseases and that may be why the cancer is partly difficult to diagnose?

Dr. Simeone: Unfortunately, I think that is part of the issue. A lot of the early symptoms are fairly nondescript, and so patients may have some symptoms but they are chalked up to be gastritis or dyspepsia or unrelated diagnoses. Really in many patients we see the symptoms have persisted for many months before someone drills down on the fact that the patient may have something as serious as a pancreatic cancer going on. There is some interesting new work that shows that the presence of or the development of types of type II diabetes, especially in people over 50 who otherwise wouldn’t be in a high-risk category, may be a marker for early pancreatic cancer. So that is something we are trying to figure out, how might that best be integrated into the clinic? How do we decide which patients who develop diabetes might go on to have screening for pancreatic cancer.

CancerNetwork: You are giving a talk at the upcoming pancreatic cancer American Association of Cancer Research conference on a cancer stem cell approach for pancreatic cancer. Are there specific pancreatic cancer stem cell markers that are currently in development?

Dr. Simeone: There certainly are. Our laboratory did the initial work in identifying cancer stem cells within human pancreatic cancers. What that means is that there is a small subset of cancer cells within a cancer that are stem cell–like that are more primitive and seem to be the drivers of the development of pancreatic cancer and importantly, we think, in the development of metastases. We have described cell surface markers that define what cancer stem cells are, and we are continuing to refine what those markers are as we move forward. Importantly, what we would like to do is beyond knowing what the cell-surface markers are, but understanding the key signaling pathways that regulate the function of cancer stem cells because we know from our work, that these cancer stem cells are quite resistant to chemotherapy and radiation. So we think understanding these cells in a deeper way will allow us to develop targeted therapies to eradicate these cancer stem cells from the tumor which we think will be an important part of a cancer cure.

CancerNetwork: Do you see the cancer stem cell approach more as way to identify therapeutic targets and maybe not so much in terms of a diagnostic tool?

Dr. Simeone: Well, I think the diagnostic piece is still a question mark. I think that remains to be seen. But, certainly, from a therapeutic standpoint, it seems to be an important piece of the puzzle.

CancerNetwork: Do some of the characteristics of pancreatic cancer stem cells, do they overlap with the characteristics that have been identified for breast cancer stem cells, for example, and other tumor types?

Dr. Simeone: It is interesting. There is definitely some overlap with cancer stem cells in other cancer types. But there are also significant differences. And so there is a lot of talk of, “If we understand signaling pathways in one cancer, it will be relevant across all other cancers.” I actually don’t think that that is necessarily true. Significant inroads have been made into treating other cancers that have not happened for pancreatic cancer, and I think pancreatic cancer is its own unique entity, and we need to study it as an individual cancer. This doesn’t mean that we can’t learn from other cancers, but I think to really understand how to treat pancreatic cancer, we will have to study the disease specifically.

CancerNetwork: Could you describe what the major treatment options are now for advanced pancreatic adenocarcinomas?

Dr. Simeone: So the main treatment options now for advanced pancreatic cancer are combination chemotherapy and the standard backbone of chemotherapy for advanced pancreatic cancer has traditionally been a drug called gemcitabine (Gemzar). That has had some benefit to patients, although there are newer regimens that seem to have a higher level of efficacy. In particular, a regimen called FOLFIRINOX. The trade-off there is that the side effect profile is much more significant so patients have a much harder time tolerating that regimen. There are also a lot of other promising treatments that are being tested both in laboratories, in preclinical model systems and also in very early phase clinical trials that I think hold promise. I suspect in the next few years we will have a good understanding of a number of these new approaches and what role they will play in treating pancreatic cancer. But, importantly, I think we are now having more people in the field and really trying to drill down and understanding how pancreatic cancer works and how we might best treat it.

CancerNetwork: Two new treatments were approved last year, specifically for pancreatic neuroendocrine tumors. One is sunitinib (Sutent), which is a receptor tyrosine kinase and also everolimus (Afinitor), an mTOR inhibitor. How do you put this in the context of pancreatic neuroendocrine treatments and do you see these as major advances?

Dr. Simeone: So I think these are advances. Anytime we can take an advanced disease and have some impact on improving progression-free survival, that is definitely an advance. And both of these agents were found to significantly improve progression-free survival in phase III, randomized trials. However, one of the issues with neuroendocrine tumors is that some of the tumors are very indolent and others are much more biologically aggressive, and we don’t have a good understanding currently of which tumors are the more aggressive ones. And even though these treatments have provided advances, they haven’t really resulted in cures. I think it moves things one step closer to where we want to be, but I still think that we have a long way to go.

CancerNetwork: Thank you so much for joining us, Dr. Simeone.

Dr. Simeone: You’re welcome, thank you.