Concepts for Targeting the Metastatic Process in Pancreatic Cancer

When cancer becomes metastatic, the chances of patients developing complications or succumbing to their disease are heightened. Metastatic disease appears to be more prevalent in pancreatic cancer compared with other malignancies, and researchers have, therefore, begun to study metastases more closely.

Liver metastases are among the most common of metastases found in pancreatic cancer but are not the only sites in which patients can become metastatic. According to Gregory L. Beatty, MD, PhD, lung metastases are also common, and metastases can also spread through the body. In pancreatic tumors, metastases have been known to spread to areas like the brain. The ongoing questions related to metastatic pancreatic cancer are which patient characteristics increase the risk of local or distant metastasis, and which comorbidities may advance pancreatic cancer to metastatic pancreatic cancer.

In terms of preventing the development and spread of metastases in the pancreas, little is known to oncologists, although it is an area of active research. Specifically, the association with interleukin 6 (IL-6) activated by comorbidities like cardiovascular and endocrine diseases, is being tested with the help of, C-reactive protein (CRP), a blood-based biomarker.

In an interview with Targeted Oncology, Beatty, associate professor, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, discussed the science behind the development of metastases in pancreatic tumors, including how metastases differ in various sites in the body. He also reviewed the treatment options for this disease.

TARGETED ONCOLOGY: Can you explain the process of targeting the metastatic evolution in pancreatic cancer?

Beatty: Metastasis ends up being one of the main causes of morbidity and mortality for cancer in general. This is particularly true for pancreatic cancer. The reasons why pancreas cancer so prone to a metastatic spread have been the focus of many different laboratories recently. Oncologists have now started to look at that process as well. We focused on the liver because the liver ends up being the most common site of metastasis in pancreatic cancer, and we uncovered that there is what appears to be a normal physiologic process that is co-opted by the cancer to help it seed and colonize the liver. That process involves activation of the chief functional cells of the liver, called hepatocytes, which become activated by factors that are released from the pancreatic tumors, in this , IL-6. That redirects the hepatocytes to release acute phase reactants that then facilitate the formation of niche environments in the liver. It helps cancer cells to seed and metastasize.

TARGETED ONCOLOGY: Can you expand of the spread of disease by discussion liver metastasis risk in patients with metastatic pancreatic cancer? What characteristic in a patients can make this spread more likely?

Beatty: One of the things that we found in our studies it’s that not just the cancer that might be conditioning the liver for increased susceptibility to metastasis. Just having the high levels of expression of a cytokine called IL6 was sufficient to drive all the steps that are needed in the liver to form a niche environment that is pro-metastatic. What that means is that other conditions that are non-malignant, and are comorbidities for patients, like cardiovascular disease and diabetes, that are associated with high levels of IL-6, which could be detected by looking simply at a blood-based marker C-reactive protein. That may be a risk factor. We don't know that for sure.

Further studies are needed to really clarify how other comorbidities may place a patient at risk for liver metastases, but I think it leads us down a path towards not just treating the cancer but actually caring for the patient's overall. That may be a determinant of how patients do.

We know that those patients who are in better shape and have a performance status that it is good, tend to do better. All of that may just feed into the host environments playing a role in the outcomes of patients with pancreatic cancer.

TARGETED ONCOLOGY: Can you discuss prevention of liver metastases in patients with pancreatic cancer?

Beatty: What we know is that's not everybody will develop liver metastases. A particularly important observation in some patients who have localized pancreatic cancer and have it surgically resected is that there is a subset of patients for which they will not have recurrent whether it's local or metastatic.

Those patients, based on work from colleagues and others, have suggested that having a presence of an effective immune response against the cancer is associated with a less likelihood for recurrence and as a result a long-term survival.

In fact, even those patients who redo recur, 30% of the percent of them will recur locally, and they won't recur with metastases. At this point, we don't know the recipe for defining whether patients recur locally, don't recur, or they recur distantly. In fact, when you recurred distantly you could recur in the lung and not the liver.

The outcomes for those patients appear to be different too. In general, patients with lung metastases tend to do a little bit better than those patients who have liver metastases. Empirically were able to begin compiling subsets patients. What we don’t understand is the genetics of the cancer that helped to define those subsets of patients.

TARGETED ONCOLOGY: Are there any other metastases that you would consider common with this malignancy?

Beatty: Yes. It's not just the liver. The peritoneum is also very common, as are lung metastases. In general, though, as no patients live longer, pancreas cancer can go to other places as well.Cancer has been found out of the brain. It's been found to go to the skin. It has been found to go to the brain, skin, bone, and many other places that we might not typically think of.

TARGETED THERAPY: In terms of treating pancreatic cancers, what promise is being shown with therapies aside from chemotherapy?

Beatty: The standard therapy for the last 20 years and beyond has been chemotherapy for pancreatic cancer and metastatic pancreatic cancer, and we have not been able to identify another treatment that can improve upon the efficacy seen with chemotherapy.

A few things are in the pipeline. Some studies have shown some promise. The challenge with the studies is the inability to identify the patient populations that might be most impacted in because it may be not be all patients. Those studies have been a bit difficult.

There is also and one other unique patient population that appears to benefit from a targeted therapy, which is very exciting, and those patients harbor genomic alterations and pathways that are involved in damage repair. At this point, there a hint that patients may be able to come off of chemotherapy and go on a PARP inhibitor, which sensitizes cancer cells.

TARGETED ONCOLOGY: What is an area of unmet need for treating this disease?

Beatty: Beyond understanding and being able to treat metastasis or being able to control the spread of cancer, there is an unmet need around being able to manage the supportive care issues the patients face. Pancreatic cancer, more so than some other malignancies, carries issues like pain, cachexia, and depression. Managing comorbidities with pancreas cancer is very challenging and can impact outcomes. Finding ways to control these comorbidities in the setting of pancreas cancer could in and of itself, be a breakthrough for the treatment of this disease and allow npatients to live longer with their disease.