A highly sensitive blood test that detects traces of tumor DNA in patients with localized pancreatic cancer identified substantially more patients with residual disease than conventional liquid biopsy testing, according to a prospective study published in Clinical Cancer Research. The findings suggest that more sensitive detection of circulating tumor DNA (ctDNA) could improve risk stratification after chemotherapy and surgery and help identify patients who remain at high risk for recurrence despite reassuring imaging results.
Researchers at Northwestern Medicine evaluated digital droplet polymerase chain reaction (ddPCR), a liquid biopsy approach that detects specific KRAS mutations, against standard next-generation sequencing (NGS), which surveys hundreds of cancer-associated genes but with lower sensitivity. Because KRAS mutations drive more than 90% of pancreatic cancers, the investigators hypothesized that focusing on this single, biologically important target would allow detection of extremely low levels of circulating tumor DNA that broader sequencing approaches often miss.
“We’re able to detect very high sensitivity in the blood for pancreas cancer,” said senior author Akhil Chawla, MD, clinical associate professor of surgery at Northwestern University Feinberg School of Medicine and a complex surgical oncologist at Northwestern Medicine. “We’re looking for extremely low levels of the DNA in the plasma.”
The prospective study followed 106 patients with localized pancreatic cancer from diagnosis through chemotherapy and surgical resection. Blood samples were collected before treatment, after chemotherapy, and following surgery to determine whether changes in KRAS ctDNA reflected treatment response and predicted patient outcomes.
At diagnosis, ddPCR detected tumor-derived KRAS DNA in 65% of patients, compared with just 17% using conventional NGS. The differences became even more striking after treatment. Following chemotherapy, ddPCR detected ctDNA in 60% of patients, while NGS detected it in only 5%. After surgery, ddPCR remained positive in 56% of patients compared with 9% using standard sequencing.
“What this publication is going to show is that yes, we can detect it with both, but we are missing a significant number of patients with standard sequencing,” Chawla said.
According to the study, patients whose disease was detected only by ddPCR represented a previously hidden intermediate-risk group. These patients had a median overall survival of 27 months after diagnosis, compared with 41 months among patients who tested negative by both assays. The findings suggest that standard liquid biopsy testing may underestimate the presence of minimal residual disease in many patients who appear to have responded well to therapy.
“We’re missing up to 60% of patients,” Chawla said. “Even at the time of diagnosis, and after treatment—particularly where we think it looks like on a CT scan after a patient’s undergone chemotherapy and had their surgical resection—everything looks great, and even the blood test that looks at ctDNA looks great. In sixty percent of patients we were still able to detect low levels.”
He adds, “Our goal is to get rid of that disease forever. Unfortunately, even with the work that we’ve done, we’ve shown that 60% to 70% of patients have recurrence of that disease after chemotherapy and surgery.”
The study also demonstrated that ctDNA dynamics over the course of treatment carried important prognostic information. Rather than relying solely on whether ctDNA was present or absent, investigators found that changes in ctDNA levels reflected treatment response.
“We’ve been able to see it even with chemotherapy and surgery,” Chawla said. “Patients that have that significant decline in the marker—not just the presence or absence, but even if they go from a high level to a medium to low level—those patients actually are benefiting from that treatment.”
Conversely, patients whose ctDNA levels remained stable or increased during treatment experienced substantially worse outcomes.
Unlike broad NGS panels, which search for hundreds of genetic alterations simultaneously, ddPCR focuses on a limited number of mutations with far greater analytical sensitivity. Chawla emphasized that the innovation was not a new laboratory technology but rather a new application of an established one.
“DDPCR can detect a single mutation with 1,000 times more sensitivity,” he said. “When we do that deep dive in pancreas cancer, what we’re really trying to do is identify whether this biomarker can, number one, be detectable in a high percentage of patients; number two, is it prognostic… and number three, can it really tell us how well a treatment is working?”
Because the assay targets the same KRAS mutations that are the focus of emerging targeted therapies, Chawla believes the approach could become increasingly valuable as those therapies enter clinical practice.
“I think there’s a lot of value in this test, particularly as we enter the age of KRAS-targeted treatments,” he said. “Our biomarker actually targets the exact same gene.”
Currently, surveillance after surgery relies primarily on CT imaging performed every few months, leaving clinicians with limited tools for detecting microscopic residual disease before recurrence becomes radiographically apparent.
“What the standard of care today is, is we just get CT scans every three months to give us an idea of when this comes back—we’re just kind of sitting on our hands and waiting,” Chawla said. “This blood test gives us an opportunity to be more active in that surveillance, potentially be more adaptive in our treatment.”
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