Pancreatic Cancer Stroma Subtypes Can Harm or Hinder Cancer Progression

Research may help tailor treatments to individual patients.

When it comes to pancreatic cancer, the stroma, or dense surrounding tissue, can have 1 of 2 effects on the patient. It can either prevent cancer-fighting drugs from gaining access to the tumor, or it can prevent the cancer from spreading to other areas in the body.

A recent study by UNC Lineberger Comprehensive Cancer Center revealed the 2 subtypes of pancreatic cancer stroma. The findings of the study could help tailor treatments to individual patients, something of particular importance for a disease that has a 5-year survival rate of only 7%.

“Right now, we still treat pancreatic cancers as one entity, while for some other cancers, we personalize treatment based on an individual patient’s tumor genetics or other characteristics,” said study senior author Jen Yeh, MD, a UNC Lineberger member and an associate professor and the vice chair for research in the UNC School of Medicine Department of Surgery. “We believe these results will set the groundwork for future clinical trials, allow treatments to be assigned based on the subtypes, and guide the development of new therapies.”

The study reveals the most rigorously validated classification system for pancreatic ductal adenocarcinoma to date. While previous studies have identified different subtypes of pancreatic cancer, researchers believe those attempts were confounded by the large amount of surrounding stroma that is intermixed with both normal and cancerous pancreatic tissue.

To compensate for this problem in their own study, researchers used a mathematical approach led by Richard Moffitt, PhD, a postdoctoral research associate at UNC Lineberger, to separate the tissue. The approach is called blind source separation and it allowed the researchers to separate the normal from the cancerous tissue and the stroma.

They were then able to examine gene expression patterns for each type in tissue samples from 5 different institutions. The researchers evaluated 145 primary and 61 metastatic tumors, 17 cell lines and 46 normal pancreatic samples. In addition, the researchers analyzed 88 samples of normal, non-cancerous tissue outside of the pancreas.

“This issue is that pancreatic cancer is a particularly difficult cancer to analyze because of its confounding stroma, so we needed to marry the right data analysis technique to the right problem,” Dr. Moffitt said.

Two subtypes of pancreatic stroma were identified and named “normal” and “activated,” respectively. Patients with the activated subtype had worse survival outcomes.

“This study helps make sense of researchers’ conflicting findings about stroma — that it can either promote or be a barrier to tumor spread,” Dr. Yeh said. “We are seeing 2 distinct types of stroma in patients.”

The report also revealed 2 different subtypes of pancreatic tumors called “basal-like” and “classical.” Basal-like is linked to worse outcomes for patients with 44% of patients who have the basal-like subtype living 1 year after surgery. However, those with the classical subtype had a 70% survival rate. Basal-like tumors also trended toward a better response to adjuvant therapy.

“If we know that your tumor is aggressive, then it may be important to treat your whole body first with neoadjuvant therapy, which is therapy given prior to surgery, as opposed to just trying to remove the tumor with surgery at the outset,” Dr. Yeh said. “In addition, the basal-like subtype is very similar to basal breast and bladder cancers, which respond to therapies differently than other tumor subtypes, so we are very interested in seeing whether or not this is true for pancreatic cancer as well.”

The findings suggest that a patient’s treatment regimen should be determined after their specific subtype of tumor and stroma is identified. Yeh said the researchers will be launching clinical trials to investigate how patients with the different subtypes respond to treatment.

“For pancreatic cancer in particular, it’s a race against the clock, ever therapy counts, so you want your first therapy to work,” she said. “With this cancer, you don’t have a lot of time to try different therapies. If a patient is given a therapy that is unsuccessful, that is time in which the patient’s disease has progressed. So the goal is to start patients on the right therapy from the get-go.”

With the ability to now distinguish the difference between stroma and tumor subtypes, scientists will be able to better tailor the treatment to the patient in need, with the hope of getting the right treatment administered the first time.