Sequencing Strategies: Metastatic Pancreatic Adenocarcinoma - Episode 1

Recent Advances in Pancreatic Cancer Research

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John L. Marshall, MD: We’ve begun to make our way in pancreatic cancer. For a long, long time, we had nothing. We had a couple of drugs that didn’t work very well. We didn’t know anything about the molecular profile of the disease. Fortunately, over the last 3 to 5 or 6 years, we’ve seen improvements in therapies, new drugs being approved, and survival being extended. At the same time, we’re learning more about the molecular characterization of the disease. We’ve uncovered the importance around BRCA. We’re studying the stromal impact and the fibrosis that occurs with pancreas cancer. Those things are giving us new targets to aim at and new therapies to come forward. We’ve learned and gotten better at surgical techniques. More and more patients are getting surgery. Our adjuvant therapy has improved. So, on all fronts, we’re beginning to make headway in this really difficult disease.

Kenneth H. Yu, MD: It has been long realized that the tumor microenvironment plays an important role in the biology of cancer. Many years ago, physicians and surgeons understood that although there was a very small number of cancer cells in a pancreatic tumor, there were a lot of other things in that tumor, which is referred to as a tumor stroma. Recent advances involve understanding the role that the tumor stroma actually plays in the biology. We used to think that the stroma acted like a barrier or a wall to prevent chemotherapy drugs and the immune system from attacking the cancer cell. But, more recently, research has uncovered that it’s a much more complicated picture. So, in addition to preventing cancer cells from being attacked, the stroma also acts as a barrier that the human body puts up to try to prevent the cancer cells from spreading. While that has important biological implications, it also has implications for therapeutics. So, increasingly, we’re trying to target those aspects of the tumor stroma, which can augment our ability to attack the cancer while not trying to impede those parts of the stroma that are important for keeping the cancer in check.

Many years ago, there was a drug targeting one of these important pathways. We initially thought it would help deplete the stroma and allow chemotherapy to work better. In fact, when clinical trials were developed targeting this pathway, which was called the “smoothened pathway,” or the “hedgehog pathway,” these drugs did not seem to have that intended effect. They may have, in fact, been potentiating the opposite—allowing the cancer to escape. So, that’s one of the important parts of the tumor microenvironment that we’re beginning to understand.

Another part is the immune system and immune cells that are present in the tumor microenvironment. We’re beginning to understand that there are cells like myeloid cells—for example, tumor macrophages, tumor-associated macrophages, and monocytes. Their presence in the tumor microenvironment suppressed the immune response. So, again, the therapeutic implication is that if we can target those cells and attack those cells, we may allow a more robust immune response against the cancer.

And then, finally, the T cells themselves. This is a really interesting and important cell type that’s being targeted in other cancer types. It’s been effectively used in checkpoint inhibitors to activate T cells. That approach remains unfulfilled in pancreatic cancer. Further research needs to be done to really understand why that is and to more effectively target those T cells.

Fadi Braiteh, MD: Pancreatic cancer’s incidence is on the rise. In fact, the mortality is also on the rise. In the next 10 to 20 years, we are expecting it to be the second most common cancer killer in men. Today, I would like to focus on pancreatic adenocarcinoma, which constitutes 95% of pancreatic cancers. It’s always very important to get tissue. I tell my patients that this is because there is a chance that it’s a pancreatic neuroendocrine tumor. Not all malignancies arising from the pancreas are pancreatic adenocarcinoma, or the cancers of the duct. Challenges exist, but it’s mainly diagnostics—recognizing if a case is resectable or borderline resectable. This is very crucial—to carve out these cases from the rest of the cases, where the disease is locally advanced or the disease is already metastatic or became metastatic since the last staging. This is really important to reiterate to patients. It’s important to discuss if you are still at that stage with the physician.

Another very important piece early on, when we see pancreatic cancer patients, is to address the complex symptoms that they have. It’s not just about the cancer. It’s the pain, the biliary obstruction, jaundice, the risk of infection, and malabsorption. Almost every pancreatic cancer patient, whether he or she has been operated on or not, has a malabsorption. So, aggressive symptom control for the patients is very crucial from day 1. This is not just palliative care at the end.

And, last but not least, another piece of information that I share with patients is, it’s very important to obtain a comprehensive family history. There are certain entities of familial predisposition to pancreatic cancer, whether it’s hereditary breast and ovarian cancer syndrome, Lynch syndrome, etc. Genetic counseling may be worth it, in certain cases, if the patients are very young and/or if they have a family history pointing to that.

Transcript Edited for Clarity