Advancing Early Detection and Therapeutic Innovation Remain Critical in Pancreatic Ductal Adenocarcinoma

Early detection, coordinated multidisciplinary care, and progress in targeted therapeutics remain defining challenges and opportunities in pancreatic ductal adenocarcinoma (PDAC) management. In an interview with OncLive®, Jose Trevino, MD, underscored persistent gaps in early recognition and the high proportion of patients who present with unresectable disease—both of which represent major unmet needs across the PDAC treatment continuum. He noted that subtle disruptions in endocrine or exocrine pancreatic function, a significant family history of the disease, and modifiable lifestyle risk factors should trigger earlier clinical assessment, especially in individuals at elevated risk.

Trevino emphasized that clinical trajectories differ sharply once PDAC is detected. Patients with early-stage disease may still benefit from a multimodality approach involving medical, surgical, and radiation oncology, whereas those with advanced disease—who make up most new diagnoses—often depend solely on systemic therapy and face substantially poorer outcomes.

He emphasized that sustained investment in translational and clinical research is crucial for overcoming therapeutic resistance and developing combination approaches that improve outcomes beyond standard chemotherapy. In recognition of Pancreatic Cancer Awareness Month, observed annually in November, Trevino noted that continued progress in early detection and therapeutic innovation remains essential to advancing survival for this aggressive disease.

Trevino serves as the chair of the Division of Surgical Oncology at the Virginia Commonwealth University (VCU) School of Medicine and is surgeon-in-chief at the VCU Massey Cancer Center in Richmond. He is also the Walter Lawrence, Jr., Distinguished Professor of Oncology at Massey and is an associate professor in the Department of Surgery at the VCU College of Medicine.

OncLive: What do you identify as the most critical unmet needs in both the early and advanced disease settings for patients with pancreatic ductal adenocarcinoma regarding early detection and therapeutic resistance?

Trevino: When it comes to trying to make changes, or really making an impact on pancreatic adenocarcinoma, one of the key things we [need to] realize is that early detection is key, right? [Decades ago], we were, as I would say, really behind the eight ball on a level where most of the time we saw a patient with pancreatic ductal adenocarcinoma, they were at a much more advanced stage than we could help. Typically, the overall kind of message that we send people is that if you have pancreatic symptoms, or if you have any issues with pancreatic insufficiency, those typically are ways where the pancreas is telling you something is wrong.

The pancreas has two main functions, [endocrine and exocrine], and I tell people, that’s pretty much, in a simplified form, sugar control and helping digest foods. And I think that if you focus in on early detection, which is again very important. If you start showing changes in your pancreas that affect any one of these two areas where sugar control and/or digestion can become affected, it is incredibly important that these be red flags, not only to the [patient themselves], but also to the [treating] physician.

There are some key areas where we discuss early detection protocols for patients that come to VCU and [also] act on it, right? That’s the point. Additionally, on top of the fact that there are certain areas where you have issues with pancreatic function that can be red flags toward the development of pancreatic cancer: family history is important. Right? If mom had pancreatic cancer, and grandpa on mom’s side had pancreatic cancer, and your brother and sister had pancreatic cancer, you start to worry that there could be a genetic predisposition. In other words, are we passing genes [across] generations of a family that could predispose you or have you at a higher risk for developing pancreatic cancer?

Very important components—again, things we think about when we consider: how do we detect, or early detect, changes in the pancreas that could ultimately lead to pancreatic cancer? On top of the simple things, right? Don’t smoke. Don’t take carcinogens that are going to affect the pancreas. Don’t heavily drink. Don’t chronically heavily drink that can cause pancreatitis and changes in the pancreas. There are a ton of things that we can do that we as physicians are now starting to implement to try to detect the changes in the pancreas before you get pancreatic adenocarcinoma, which can be deadly.

How do treatment goals and clinical priorities differ between early-stage and advanced pancreatic ductal adenocarcinoma, and what roles do multidisciplinary care and emerging therapeutic strategies play across these settings?

Once you develop cancer, if you detect it at an early stage, sure—therapies work better, and surgeries are potentially an option. At this point in the year 2025 it is incredibly important that you consider a multidisciplinary approach with medical oncologists, surgeons, [and] potentially radiation oncologists that can help control the disease and ultimately lead to a longer survival and a potential cure.

But as you start to get to the later stages of pancreatic ductal adenocarcinoma—which is one of the questions you asked—that’s when it becomes incredibly difficult. And that’s where the therapies are critical for us to understand. People study pancreatic cancer [all over] the world, including this country, and there is a lot of funded [work]—NIH-funded individuals who really, really focus on how do we beat this disease at a later stage where surgery might not be an option, and the only thing we can do is systemic chemotherapy to try to control this disease from killing people.

The way we address that is really some novel and innovative research that great investigators—basic science investigators, translational investigators, clinical investigators—get together [to pursue]. They say, ‘Hey, there’s a great drug out there that’s going to target a particular part of this cancer that we know is overrun or upregulated, and we’re going to do our best to try to develop these novel combinations that will ultimately, you know, cure or try to control this disease and maybe one day lead to a cure.’

That’s probably the hardest aspect of treating pancreatic cancers when it’s at its advanced stage, but I think it’s probably one of the more critical ones. So really, your question is dead on in the sense of asking about early versus late stage. And I would say: let’s not talk about early cancer. Let’s talk about ways to avoid development of that cancer. In other words, really early screening of patients who are high risk, and when we start detecting these changes that we know are going to ultimately lead to the development of [pancreatic ductal adenocarcinoma], treat it then. And I think the future lies there, and also the future lies in development of novel therapies for patients with more advanced disease.

How might emerging KRAS-directed therapies—such as inhibitors for KRAS G12D and G12V—and other pathway-targeted approaches like RAS–MAPK or DNA damage response inhibitors reshape the treatment landscape?

[When] we’re talking about [advanced disease] at the end of the day, that’s key—[especially] when we’re thinking about more advanced cancers that aren’t surgically [amenable] to resection. And that’s, to be honest with you, the more advanced cancers—[which] are approximately 80% of these patients. And so 80% of people, can you imagine, that come with a diagnosis of pancreatic ductal adenocarcinoma are not given theopportunity for surgical resection. In other words, they’re not given the opportunity for cure.

These targeted therapies that you discuss are incredibly important. And while we’re not going to get into the weeds too much as to why certain KRAS mutations are going to be more susceptible to our therapeutics, the idea is that people are thinking of this, right? People are thinking about what is changing in that cancer, what is upregulated, what is really driving this cancer that is going to lead to a better therapy.

My personal opinion on why these KRAS inhibitors might have a significant impact in the future—I truly believe that we can’t look at just one potential signaling pathway that’s driving this, because it’s not that simple. And at the end of the day, KRAS in and of itself has been targeted for many, many years and has been unsuccessful on its own. Therefore this is the idea, right? We think, ‘Okay, we’re going to target this one pathway,’ but we have to make sure that there aren’t other things within that cancer cell that are going to take over from us blocking one pathway.

Cancer, at the end of the day, is incredibly smart. We know that cancer absolutely has evolved to a level way beyond our understanding to some degree, but it’s up to us to figure out what’s going on within that cell when we block a certain pathway such as KRAS. Is another pathway—like you mentioned, a MAP kinase pathway—is there an AKT/PI3 kinase/AKT pathway that’s being [activated], a STAT3 pathway, upstream, downstream? You have to get in front of this, and so this is where all the real exciting research is being done.

The people that are proposing all these particular pathway inhibitors are incredibly smart and incredibly [ahead] in trying to be in front of this particular cancer and really try to control it. At the end of the day, while it is great to think about these novel targeted therapies, we have to think bigger on a combination level. That’s the way we’re really going to make a difference.

Never forget that as we work with certain chemotherapies—systemic chemotherapies that are provided by our medical oncologists—they have to align with some of these targeted components. [It’s] complex, right? At the end of the day, there are a lot of great people doing great work behind this and hopefully [will] make a difference

References

1. Yamada R, Tsuboi J, Yumi Murashima, Tanaka T, Nose K, Nakagawa H. Advances in the Early Diagnosis of Pancreatic Ductal Adenocarcinoma and Premalignant Pancreatic Lesions. Biomedicines. 2023;11(6):1687-1687. doi: 10.3390/biomedicines11061687
2. Demir T, Moloney C, Mahalingam D. Threading the Needle: Navigating Novel Immunotherapeutics in Pancreatic Ductal Adenocarcinoma. Cancers. 2025;17(5):715-715. doi:10.3390/cancers17050715