Pancreatic Cancer Research Discoveries

By: IU Simon Comprehensive Cancer Center
February 16, 2024

In terms of complexity, few cancers hold a candle to pancreatic tumors. Pancreas lesions develop in seclusion, tucked away in millimeters-wide ducts that impede early detection, interfere with confident diagnosis, and complicate the possibility of surgical cure.

Recommending pancreas surgery is a serious decision: If a removed lesion turns out to be early cancer, surgery saved the patient’s life. If the lesion is benign, the patient went through an intense and invasive procedure that ultimately was not beneficial.

People who’ve never had a cancer scare might say they’d rather take their chances with surgery to gain peace of mind. But faced with a vague diagnosis—“this lesion has the potential to become pancreatic cancer”—many patients who’ve been there likely would have chosen surveillance, if they could have been confident in that choice.

Giving patients and providers the confidence to make informed decisions is key to our clinical and research missions at Indiana University Melvin and Bren Simon Comprehensive Cancer Center.

Over three decades, C. Max Schmidt, MD, professor of surgery and of biochemistry and molecular biology, and colleagues such as Michele T. Yip-Schneider, PhD, senior research professor of surgery, have made significant research contributions that have informed international treatment guidelines and help reduce the burden of pancreatic cancer worldwide.

In our practice, an average of 30% of patients have a cancer that just started, which we can cure with surgery, or that is about to start, which we can prevent. These are obvious cases where surgery is the best choice. But for the other 70% of patients who may have difficult-to-access tumors or complex comorbidities, the risk/benefit ratio of surgery is steeper and treatment options are less clearly defined.

Approaches and technologies developed in our labs are focused on the early detection and prevention of pancreatic cancer in patients at high risk, as well as better defining which patients may benefit from pancreatic cancer surgery.

Intraductal papillary mucinous neoplasms (IPMNs) are a type of pancreatic lesion that develops in the lining of the pancreatic ducts, similar to polyps that grow in the colon. As IPMNs progress, the surrounding ducts produce more mucus and swell like a stuffy nasal sinus passage, becoming visible on imaging.

Like most colon polyps, most pancreas lesions are unlikely to become cancer in the patient’s lifetime. However, we cannot always know with full confidence which lesions will or won’t become cancer. When we biopsy the lesion and look at its biochemical composition, genetic markers, and cytology, sometimes the DNA suggests an aggressive phenotype and sometimes the cytology suggests a high-grade risk or cancer.

IPMNs are not benign—while they can be benign-acting, they are by definition precancerous. So, why aren’t all pancreas lesions removed like colon polyps, to be on the safe side? It comes down to logistics and long-term benefit: If we had a low-risk way to get rid of them, we would.

Colons are relatively simple structures—though lengthy, these organs are smooth and spacious. Specialists can easily spot and remove most benign and suspicious polyps during a colonoscopy, which is a very low-risk tool to cast a wide net and prevent colon cancer.

Pancreatic lesion removal is a significant logistical challenge. The pancreas is complex and ductal, like a pine tree—it’s a large “trunk” of an organ with sprawling branches that diverge into sub-branches mere millimeters wide where microscopic lesions hide.

There is not yet a low-risk screening tool like colonoscopy for IPMNs, and until recently, there have been no promising markers for whether a lesion is unlikely to cause cancer until it was pathologically assessed after major surgery to remove it.

So, finding reliable markers of both cancer and of benign-ness are main areas of focus in Dr. Schmidt’s research in his Pancreatic Cyst and Cancer Early Detection Center. IU Health surgeons perform more pancreatic cancer surgeries than any other team in the nation—our researchers have access to a diverse collection of banked pancreatic tissue and fluid, which has led to practice-changing discoveries.

Up until about 15 years ago, everyone thought the bigger IPMNs were worse, so they need to come out, no matter where in the pancreas they are found. It was a natural assumption because that is generally the process for other cancers. But “size” is more nuanced:

• Main pancreas ducts are long, and the IPMNs found there tend to be cylindrical like a sausage link, getting longer and a little wider as they progress. In general, we start to worry when the lesion grows to more than 7mm in diameter, depending on where it is located within the head or tail of the main duct.
• Branch pancreas ducts are short, and these IPMNs tend to be round like a grape swelling on a vine. These tend to look alarming on imaging, seeming very large compared to their branch duct location.

Surgeons historically focused on removing branch duct IPMNs when they got to 2-3cm because the lesion diameter looks hulking and insidious compared to the millimeters-wide surrounding duct. But the combined data of main and branch duct IPMNs showed this strategy wasn’t catching more cancers.

Dissatisfied, our experts separated our IPMN data based on lesion location, not relative size to the duct. The data were illuminating: Through our “sausage to sausage, grape to grape” analysis, we learned that diameter cannot be generalized across all IPMNs. Location matters when it comes to IPMN size. While diameter doesn’t predict cancer incidence in the branch ducts, diameter does predict cancer incidence in the main ducts. 

For example, a main duct lesion with a diameter of 10mm has nearly a 50% risk that it is cancer or near-cancer. A branch duct of the same size is almost never cancerous upon removal. This finding proved to be a key criterion for removing IPMNs in most cases. 

IU was among the first cancer centers to adopt this paradigm-shifting protocol in pancreatic cancer treatment. With this knowledge, our experts can more confidently determine which patients may benefit most from pancreatic surgery.

Serous cystic neoplasms (SCNs) are fluid-filled growths that are benign but can mimic suspicious pancreatic lesions on imaging. Some contain solid components or may present as multiple tiny, crammed together cysts that can draw concern, even from seasoned pancreas specialists. Often, SCNs are recommended for removal, only for the pathologist to determine after surgery that the cyst was benign.

In 2014, while our team was analyzing fluid from pancreatic cysts, they serendipitously discovered an isoform of a protein called vascular endothelial growth factor A (VEGF-A) that was 97% diagnostically accurate for SCNs.

That means the level of VEGF-A in 10 microliters of cystic fluid tells us with 97% certainty that the cyst is very unlikely to become cancerous and does not need to be removed or surveilled unless it is causing symptoms. Very few tests in medicine offer that level of certainty, particularly when it comes to sparing patients from surgery.

Imaging provides a high level of detail about the suspicion or benign-ness of pancreas lesions. However, it sometimes contributes to the “size matters” misperception.

But what if doctors could see beyond the lesion, finding hidden clues in the pancreas that could lead to more streamlined management?

Our scientists are partnering with Fiona Kolbinger, MD, a clinical researcher at Purdue University, who is developing an artificial intelligence tool that could help us reveal previously unidentified outcome-predicting patterns within the pancreas. Combining such a tool with lesion-focused imaging may one day allow us to double-down on detection of benign, precancerous, and cancerous lesions.

Tiny pieces of DNA from pancreatic cancer cells can circulate throughout the body and can show up in bloodwork. IU radiation oncologist Tim Lautenschlaeger, MD, is studying whether circulating tumor DNA can also be detected in urine samples.

Dr. Lautenschlaeger compares his analysis of patients’ pre-surgery urine samples with those of our pathologist after the tumor is biopsied to confirm accuracy. While this assessment is not yet ready for prime time, it could in the future help us determine which patients could most benefit from pancreas surgery.

Gastroenterologist John M. DeWitt, MD, is a primary investigator of CHARM II, a randomized double-blinded clinical trial in which previously-detected IPMNs are injected with alcohol and/or chemotherapy to ablate them.

Patients whose cysts are known to be either benign or cancerous are not eligible for this study.

Preliminary data suggest that some patients who were not surgical candidates are seeing reductions in cysts.