Dr Afghani explains how increased understanding of the genetic epidemiology of pancreatic cancer is creating an evolving landscape that holds hope for earlier detection and targeted treatment of this highly lethal disease.

Elham Afghani, MD, is an assistant professor of medicine at the Johns Hopkins University School of Medicine in Baltimore, Maryland.

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Hi, my name is Elham Afghani, and I'm Assistant Professor of Medicine at Johns Hopkins Hospital in the Department of Medicine, Division of Gastroenterology. I'm here at DDW 2023 in Chicago, and I just gave a lecture on the genetic epidemiology of pancreatic cancer, recent innovations in an evolving landscape.

Just to summarize my talk, I spoke about the evolution of our knowledge on the genomic landscape of pancreatic cancer, that has really revolutionized our knowledge of tumor genesis. This has mainly been through the technological advancements in sequencing. As you all may know, pancreatic cancer is one of the most lethal cancers, and currently, is the third most common cause of cancer related mortality in the United States, but it's slated to be the second most common by 2030. It has a very poor survival, and that's really due to a lack of early detection and the lack of efficacious therapies that we have available, as well as the aggressive behavior.

What we have been able to determine through all the research that has been done on genomics is that mutations are what's driving the cancer. There are somatic mutations and germline mutations, with somatic mutations being the most common mutation seen in most cancers, including in pancreatic cancer. The four most common somatic mutations are KRAS, CDKN2A, TP53, and SMAD4 mutations. There's a list of others that are less frequent, but still have been studied.

In regards to germline mutations, there is about 10 that have been well studied, and have been shown to have an increased risk of pancreatic cancer. The most common one is the BRCA2 mutation. Then we have the others that are in that same category where they affect the DNA double strand breaks, repairing system. The other ones are BRCA1, PALB2, and ATM mutations.

The other mutations are not as commonly seen in familial pancreatic cancer or in pancreatic adenocarcinoma in the sporadic, but they do account for a small portion. Those are CDKN2AA, which is associated with familial atypical multiple mole melanoma, the MLH1, MSH2, MSH5, and PMS2, which are associated with Lynch syndrome, STK11, which is associated with Peutz-Jegher, and the PRSS1 which is associated with hereditary pancreatitis.

Through everything that we've really been able to determine with what's going on with the genomic landscape of pancreatic cancer, is that there is not only the somatic and germline mutations that are occurring, some of them co-occurring at the same time, but there's also chromosomal structural variations that lead to chromosomal instability that are also driving tumor genesis. So it's a very complex process, but through this, we've been able to determine ways of screening at least some high risk individuals, such as those who do have germline mutations. The major GI societies have adopted screening guidelines for that. Through our knowledge of the genomic landscape, we've been able to determine if there's any molecular changes that happen in pre-cancerous lesions, such as IPMNs and MCNs, which may tell us if there is malignant progression of these pre-cancerous lesions.

Last is that we've been able to develop more targeted therapy, which has been found in some studies to be more effective than the standard chemotherapy that's given, especially in patients who have certain mutations. Patients who have a BRCA2, a BRCA1 mutation, or any mutation that's really affecting their DNA double-stranded repair system, they will most likely benefit more from PARP inhibitors. Then there's others that are currently being used like those that have deficiencies in the mismatch repair system, which is the MSH2, MLH1, MSH6 genes. They may benefit from immune checkpoint inhibitors.

As we're learning more and more about the genetics, and how to really risk stratify patients, we are able to hopefully get to an era where we'll have adequate screening that is cost-effective, and we'll hopefully be able to improve the mortality of pancreatic cancer, not only by being able to detect it early, but by also being able to provide more efficacious therapies.

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