CHICAGO — Once a multi-target stool DNA (mt-sDNA) test is identified as a false positive, it is often considered reassuring for patients and providers concerned about colorectal cancer. However, new research links these false positives to a small but significant increase in head and neck, lung, and gastric aerodigestive cancers, pointing to a need to further evaluate these patients.

“It has been shown previously a false positive result is not clinically significant and does not warrant further diagnostic evaluation,” said Kaitlyn J. Kelly, MD, a surgical oncologist and associate professor of surgery at the University of Wisconsin-Madison School of Medicine and Public Health.

However, “we have seen several patients who have had upper endoscopy due to false positive mt-sDNA testing and were found to have gastric cancer. This prompted us to investigate further,” she said at Digestive Disease Week (DDW) 2026.

Large Study Population

Kelly and colleagues retrospectively assessed 54,361 people screened for colorectal cancer using mt-sDNA test kits at University of Wisconsin between 2014 and 2024.

An mt-sDNA positive result is triggered by occult blood, somatic KRAS genetic mutations, or abnormal DNA methylation (BMP3, NDRG4). Of the study population, 84% yielded negative results. Of the remaining 16% that were positive, 6.2% (3353) were false positive findings.

The false positive group was significantly older at baseline than the negative group (63 years vs 58 years; P < .001). The cohorts were well matched for sex, with about 60% women in both. The study population was 95% White individuals, 2% Black individuals, 1% Pacific Islander individuals, and less than 1% Alaskan/Native American individuals and the remainder unknown or not reported.

Median follow-up in the false-positive group was slightly longer than in the negative group (36 months vs 33 months).

Key Findings

The incidence of noncolorectal cancers was higher in the false-positive group than in the negative group (4.3% vs 1.5%; P < .001).

Specifically, lung and bronchus cancers were significantly more common in the false-positive group, with an incidence of 1.5% compared with 0.4% in the negative group. Similarly, gastrointestinal (GI) cancers were also significantly higher in the false-positive patients (2.2% vs 0.6%; P < .001 for both).

Head and neck cancers also were higher in the false positive group than in in the negative group (0.6% vs 0.3%), but this difference was not statistically significant.

Kelly and colleagues also found a statistically lower cancer-free survival rate among those in the false-positive group than among those in the negative group (P < .001). Overall survival did not differ significantly between groups.

However, the researchers identified Black race, male sex, and advanced age as independent risk factors associated with lower cancer-free and overall survival.

On a positive note, there were no new cases of colorectal cancer in the false-positive cohort, “showing that colonoscopy really works,” Kelly said. 

Strengths, Limitations, and Implications

Strengths of the study included comprehensive assessment of patients and a large cohort. Limitations included a retrospective design, no information on symptom status at the time of testing, and the possibility that some cancer diagnoses were missed.

Because early GI cancers rarely cause symptoms, providers should evaluate risk factors to guide possible further workup, Kelly said.

In addition, based on these findings, she added, “a stool-based DNA test may hold potential for a multicancer diagnostic and may be able to detect early stage disease better than a blood test for cancers that come up in the GI tract.”

In response to attendee questions, Kelly said they did not account for smoking as a risk factor, nor were they able to identify whether the fecal immunochemical test or DNA component of the mt-sDNA testing was linked to more false positive results.

Another attendee questioned if the billing code findings were verified by a chart review. Kelly responded that they verified the positive patients but not the others.

‘Intriguing Data’

“When bleeding is detected in the lower GI tract, it is usually colorectal cancer, and mt-sDNA testing will come out positive. But really, what’s happening?” asked session co-moderator Andrew T. Chan, MD, MPH, a gastroenterologist at Mass General Brigham in Boston, when asked to comment.

“The data are intriguing. I know as a clinician we all struggle about how to handle these situations,” he added.

“False positive mt-sDNA testing is really an indicator of a cancer that’s missed because it’s biologically shedding DNA or bleeding,” said Chan. “The data suggests that you should try to understand the risk factors better.”

This study was independently supported. Kelly disclosed she is a consultant for AstraZeneca. Chan reported being a consultant for Pfizer and Boehringer Ingelheim and was an investigator on a study evaluating a circulating tumor-based DNA test for colorectal cancer sponsored by Freenome Holdings.

Damian McNamara is a freelance contributor to Medscape Medical News. He worked full-time for Medscape and WebMD from 2018 to 2024. Damian has a BA in chemistry and an MA in science, health and environmental reporting/journalism.