Pancreatic Cancer Tumor and Stroma Subtypes Discovered

Using a novel approach in the largest gene expression analysis to-date of pancreatic cancer (PC), researchers have identified subtypes of PC tumors and of surrounding stroma tissue, potentially paving the way for more personalized therapeutics.

Dense surrounding stroma tissue can block drugs from reaching PC tumors, but can also help prevent the cancer from spreading. A new multi-institutional collaborative study, led by researchers of the Lineberger Comprehensive Cancer Center, University of North Carolina (UNC) School of Medicine (Chapel Hill, NC, USA) sheds light on the conflicting role of the stroma by revealing subtypes of PC stroma and tumors based on molecular characteristics.

“We still treat PCs as one entity, while for some other cancers we personalize treatment based on an individual patient’s tumor genetics or other characteristics,” said senior author Jen Jen Yeh, MD, associate professor and vice chair for research, Surgery Dept., UNC School of Medicine, “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 provides the most rigorously validated classification system for pancreatic ductal adenocarcinoma to-date. Previous studies that identified PC subtypes were likely confounded by the large amount of surrounding stroma intermixed with both normal and cancerous pancreatic tissue. To solve this problem, the team, led by Richard Moffitt, PhD, postdoctoral research associate at UNC Lineberger, used a mathematics-based approach called blind-source-separation. “PC 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,” said Dr. Moffitt.

The approach allowed the researchers to separate normal from cancerous and stroma tissues. They were then able to examine gene expression patterns for each type in tissue samples from five different institutions: analyzing 145 primary and 61 metastatic tumors, 17 cell lines, as well as 46 normal pancreatic samples and 88 samples of normal, non-cancerous tissue outside of the pancreas.

They discovered 2 subtypes of pancreatic stroma, which they named “normal” and “activated.” 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,” said Prof. Yeh, “We are seeing 2 distinct types of stroma in patients.”

Their analysis also revealed 2 subtypes of PC tumors. The subtype they called “basal-like” is linked to worse outcomes for patients: only 44% of patients with basal-like subtype lived 1 year after surgery, compared to 70% survival for patients with the other subtype, called “classical.”

Basal-like tumors 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 neo-adjuvant therapy, which is therapy given prior to surgery, as opposed to just trying to remove the tumor with surgery at the outset,” said Prof. Yeh, “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 PC as well.”

The findings suggest that treatment decisions should be based on both a patient’s stroma and tumor subtype. Clinical trials will investigate how patients with the different subtypes respond to treatment. “For pancreatic cancer in particular, it’s a race against the clock,” said Prof. Yeh, “you don’t have a lot of time to try different therapies.”

The study, by Moffitt RA et al, was published online September 7, 2015, in the journal Nature Genetics.

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