Next, I'd like to invite Dr. Nicolette Rodriguez, who's coming to us from Brigham and Women's Hospital, and she's going to be talking to us about pancreatic cancer screening. Hi, everyone. I am thrilled to be able to talk to you all today about screening for pancreas cancer in individuals with genetic susceptibility. I have no disclosures. So a family history of pancreatic ductal adenoparsinoma, also known as PDAC, increases one's risk of developing PDAC. Approximately 5 to 10% of individuals with PDAC have a pathogenic germline variant in a cancer susceptibility gene. However, most carriers do not have a classic family history. The term familial pancreatic cancer, what I want to highlight here is a relevant teaching And essentially, this term is used somewhat variably to define familial clustering. As I said previously, approximately 5 to 10% of PDAC patients have a pathogenic germline variant. However, this 5 to 10% is made up of a lot of different genes and syndromes. And so among individuals with a pathogenic germline variant, early cancer prevention strategies and surveillance can lead to early cancer detection and interception, not only for PDAC, but other cancers as well. The NCCN guidelines recommend germline genetic testing for all individuals with PDAC, regardless of age and personal or family history of cancer. However, given the poor prognosis among PDAC patients, the rates for genetic counseling and testing are generally low, preventing many family members from understanding their genetic cancer risk. And so as a result, the NCCN guidelines now also recommend offering multi-gene panel testing to individuals with a family history of PDAC and a first-degree relative when it's actually not possible to test the index pancreatic cancer case. So what I want to talk about in this talk is the seven W's of PDAC surveillance, and I'm going to walk through all of these one by one. So who do we screen and when do we screen? So this slide has a lot of information, but what I want to highlight here is that there are a wide array of syndromes and pathogenic germline variants in PDAC cancer susceptibility genes that increase an individual's risk for pancreatic cancers and other cancers. And as a result, syndrome-specific germline testing is really not adequate, and if you're going to offer this, it really needs to be multi-gene panel testing that should be performed. I do also want to highlight that the longer you look at this table, the more you're going to notice that the cumulative PDAC incidence and the pancreatic cancer risk seem very different in some cases, and this is really because these numbers are drawn from multiple studies with many that have wide confidence intervals. So hereditary pancreatitis is also associated with PDAC risk. However, these are not cancer genes, but rather pancreatitis genes that predispose individuals to chronic pancreatitis, which can then predispose them to PDAC. And so it's really unclear what a pathogenic germline variant means when there's actually no clinical phenotype of hereditary pancreatitis. So it's really important to only start screening after counseling about the risks and benefits of PDAC screening, including the cost as well as the high incidence of incidental lomas, such as benign or indeterminate pancreatic abnormalities. Additionally, the overall goal of surveillance is try to improve mortality outcomes while also trying to balance that against the costs and potential harms of surveillance. So when do we actually screen patients? Among individuals with pathogenic germline variants in these genes, we recommend to begin screening at age 50 or 10 years younger than the youngest PDAC in the family, whichever is earlier. In individuals with a pathogenic germline variant in CDKN2A or STK11, PDAC screening is recommended earlier and regardless of family history, given the high PDAC risk. I do want to go ahead and take the time to highlight one difference when it comes to recommendations for BRCA1 and 2 carriers, as well as PALB2 carriers. So while ASCO, NCCN, and the CAHPS Guidelines recommend PDAC surveillance among individuals with pathogenic germline variants and PDAC cancer susceptibility genes who have a family history of PDAC, the ASGE Guidelines recommend screening for all pathogenic germline carriers, regardless of a family history of PDAC, if they have a pathogenic germline variant in BRCA1 or 2. And so it's just important to note that this is a conditional recommendation given the low quality evidence, and this is likely because, in general, there is limited data on PDAC risk and surveillance when there's no PDAC family history. This is also the same for PALB2 carriers, and again, as a reminder, we want to go ahead and start screening for PDAC in these cases at age 50. So among individuals with familial pancreatic cancer, screening is recommended beginning at age 50 or 10 years younger than the youngest PDAC in the family. Again, what I want to remind everyone here is that familial pancreatic cancer is a term that's used somewhat variably to define familial clustering. And so as you can see here, there's a different definition from the NCCN Guidelines compared to the CAHPS Consortium compared to ASG. When we're talking about hereditary pancreatitis, again, I want to emphasize that the clinical significance of these pathogenic germline variants in individuals without a clinical history of pancreatic – of pancreatitis is not entirely clear. And so for patients with a hereditary pancreatitis gene and a clinical phenotype of hereditary pancreatitis, screening is recommended depending on which guideline you're looking at, either beginning at age 20 years after start of pancreatitis or at age 40 years. So importantly, when we're considering who to screen, we need to ascertain, are they a candidate for resection if there is something that is found, and would they want a resection? We also need to understand when we want to discontinue screening, and it's really recommended to discontinue screening when an individual is more likely to die from other causes or is no longer a surgical candidate. So when to screen these individuals? We recommend screening on an annual basis, and you can consider shorter intervals based on either clinical judgments or patients that are found to have concerning abnormalities on screening. In addition, we recommend screening in high-volume centers with experience, and this is really given the nuances of imaging interpretation and the variability in the technique and quality of imaging studies. Furthermore, we recommend screening either with MRI, MRCP, or an EUS. And depending on patient preference, you can either alternate, or if they're really against having one or the other, going with one option is absolutely okay. So why do we screen for PDAC, and what are the data? The goal of PDAC screening is really to target detectable pancreatic lesions that are resectable, including stage 1 PDAC and higher precursor neoplasms. And so I want to go ahead and, over the next few slides, discuss two specific studies. So in this study by Claudia et al., it was a prospective study that evaluated PDAC surveillance and outcomes over 20 years among 347 individuals with germline pathogenic variants in CDKN2A. They collected data, including outcomes such as patients developing PDAC, surgical resection rates, and survival rates. This table from the study shows a summary of PDAC cases, with 31 patients being diagnosed with PDAC, with a mean age of primary PDAC diagnosed at age 60.4 years old. Importantly, the majority of participants undergoing PDAC surveillance in this study were diagnosed with PDAC at stage 1 or 2. In the Cancer of Pancreas Screening 5 study, also known as CAHPS 5, they report on pancreas surveillance outcomes among 1,731 high-risk individuals. So this slide has a lot of information, but I want to go ahead and walk you through the key points. In the CAHPS cohort, which spanned about five studies, there were 1,731 patients that were included, with 19 PDAC cases that were diagnosed during routine PDAC surveillance, as noted in the left-hand pie chart labeled with the letter A. Of those 19 patients diagnosed with PDAC, 11 were diagnosed with stage 1 disease, and 3 were diagnosed with stage 2 disease. Conversely, among the 7 PDAC cases that were diagnosed outside surveillance, meaning they either presented with concerning symptoms or they presented between surveillance intervals, seven of these patients were diagnosed with PDAC. Six patients were diagnosed with stage 4 disease specifically. The five-year survival among patients with screen-detected PDAC in the surveillance program was 73.3 percent, with a median overall survival of 9.8 years. On the other hand, the five-year survival for PDACs detected outside of surveillance was 0 percent, with a median overall survival of 1.5 years. On the next slide, we will see the Kaplan-Meier curve showing survival of all screen-detected PDACs and PDACs diagnosed outside surveillance. And what I want to highlight here is that patients undergoing PDAC surveillance have earlier stage disease and longer survival outcomes. One piece to highlight from this comparison chart of the two studies in particular is the five-year survival rate. And so this comparison chart was created by Matt Yergelin and has a really good summary of both studies. But what I want to show you guys is here. So as you can see, there is a really distinct difference between the five-year survival rate between the two studies. And one consideration for the lower five-year survival rate in the Claudia et al. study is whether having a CDKN2A pathogenic germline variant actually, in general, just pretends worse outcomes, or whether this was actually due to the fact that the study included both screen-detected and non-screen-detected cases in their series with actually not subdividing this further. Other potential explanations could include differences in the quality of surveillance. So now I want to go ahead and move on to how do we interpret the results and when do we actually call for help. So there are common findings that don't typically require follow-up, as many of us know, including anatomic variants such as pancreatic divisims and other nonspecific findings that can be seen in chronic pancreatitis. Furthermore, in terms of how do we interpret the results, I really want to take a moment to highlight the FUQUOCA guidelines, which many of us know. However, to be clear, this algorithm is not specifically delineated for high-risk individuals, which we're discussing. I just really like the way in which it actually risk stratifies patients with things that actually highlight high-risk stigmata versus worrisome features, as well as features that prompt concern and then delineate a specific surveillance interval. However, how do we actually interpret these results when it comes to high-risk individuals specifically? And so the CAHPS Cohort Study team actually looked at data from 354 individuals at high risk for PDAC and delineated surveillance findings that predicted either high-grade dysplasia or PDAC, as listed here. The boxes that are highlighted in orange or red are similar to FUQUOCA guidelines, but they also added other high-risk worrisome features as delineated here in red, including a solid mass, 5 millimeters or greater, cytology suspicious for PDAC if it's actually available, and also having multiple cysts. So when do we call for help? Really it's whenever we're in doubt. Call in your multidisciplinary colleagues, radiology, advanced endoscopists, surgeons, and have a discussion about the findings and the patients. You can always also consider shorter interval follow-up and or evaluation with alternate imaging. So I said we had seven Ws of PDAC surveillance, but really there's also an eighth too. Where do we go from here and what are the waves of the future? So additional advancements include blood-based biomarkers, circulating tumor DNA for PDAC, and also a multi-cancer detection test, including how risk factors are also considered in the context of genetic susceptibility. And the importance is that these tests and advancements should really be complementary to screening. So this is a summary slide of what we actually do for PDAC surveillance. So we want to screen individuals who have a hereditary predisposition or familial risk on an annual basis and can consider shorter intervals based on findings. We want to make sure we're doing this in high-volume centers with experience, given the nuances of interpreting and actually undergoing these imaging studies with either MRI, MRCP, or EUS. The goal really is to diagnose earlier stage disease and improve longer survival outcomes. And we need to know how to interpret these results in the setting of high-risk individuals. When in doubt, always also call in your colleagues. And there are many advancements for the future. However, how do we actually make this scalable and equitable? And so from an equity perspective, we have to ask ourselves these questions. How do we get folks in for multi-gene panel testing when we're actually recommending it? If someone is found to be a high-risk individual in need of PDAC surveillance, how do we get them to high-volume centers, particularly given that imaging interpretation requires a lot of nuance to perform and interpret surveillance findings with a real potential for harm? Can these benefits be reproduced outside of tertiary care centers? And how do we make sure that in advancing detection efforts, we are including historically marginalized communities, particularly given the known barriers on the individual, provider, and system level? We know that PDAC surveillance seems to work, but in moving forward, we also need to continue to consider how to make it scalable and equitable. Thank you very much. Thank you.

pancreatic cancer screening

genetic susceptibility

genetic testing

screening guidelines

early detection