Long-term Follow-up of Patients Having False-Positive Multitarget Stool DNA Tests after Negative Screening Colonoscopy: The LONG-HAUL Cohort Study

Abstract

Background Studies of colorectal cancer (CRC) screening by multi-target stool DNA (MT-sDNA) show false positive (FP) rates of 7–13%. It is unclear whether FP patients are at increased long-term risk of adverse outcomes. Methods We compared subsequent clinical events among patients with apparent FP MT-sDNA to those in patients reported as true negative (TN). This was a retrospective cohort study of participants in pre-FDA approval MT-sDNA studies having non-advanced or negative baseline colonoscopy findings from a single referral-center. Per-protocol and calibrated cutoffs defined FP and TN groups. From the time of stool collection, we measured differences between FP and TN groups in time to death, subsequent cancer diagnosis and onset of alarm symptoms. Results Of 1050 eligible patients, only 6 were lost to follow-up. Median age was 65.6 years (IQR, 56.8, 72.3); 54% were female. Median follow-up time was 4 years (IQR, 3.5-5.3). Eight aerodigestive (lung & gastrointestinal tract) cancers occurred. FP status by calibrated, but not per-protocol cut-offs was associated with subsequent aerodigestive cancer; however, cumulative incidence did not exceed SEER expectations from the general population. By any cut-off method, FP status was not associated with mortality or alarm symptoms. Conclusions While FP status was associated with long-term aerodigestive cancers, new cases were not temporally related and did not exceed incidence estimates from general population. Impact These observations do not justify aggressive follow-up evaluation for patients with FP MT-sDNA at this time. Larger studies are needed to confirm these early findings.

Colorectal cancer screening for average‐risk adults: 2018 guideline update from the American Cancer Society

“…Patients with positive mt‐sDNA results and a negative follow‐up colonoscopy may undergo more aggressive short‐term surveillance because of heightened concerns related to unresolved false‐positive findings. In 2 follow‐up studies of patients with false‐positive results on mt‐sDNA with median follow‐up of approximately 4 years, no excess rates of CRC or aero‐digestive malignancies were identified . In a more recent study by Cooper et al that included follow‐up mt‐sDNA, colonoscopy and upper endoscopy among 12 patients who had prior positive mt‐sDNA results and a negative colonoscopy, 7 patients had negative stool tests and colonoscopies, whereas 3 among the remaining 5 patients had positive findings on their follow‐up colonoscopy (2 advanced and 1 nonadvanced adenoma) .…”

“…In 2 follow-up studies of patients with false-positive results on mt-sDNA with median follow-up of approximately 4 years, no excess rates of CRC or aero-digestive malignancies were identified. 122,123 In a more recent study by Cooper et al that included follow-up mt-sDNA, colonoscopy and upper endoscopy among 12 patients who had prior positive mt-sDNA results and a negative colonoscopy, 7 patients had negative stool tests and colonoscopies, whereas 3 among the remaining 5 patients had positive findings on their follow-up colonoscopy (2 advanced and 1 nonadvanced adenoma). 124 Longer term follow-up will be required to provide greater reassurance and guide management, but the findings from Cooper et al are a reminder that high-quality colonoscopy is critically important, especially in the proximal colon, when following up positive findings on an mt-sDNA test.…”

A blueprint for cancer screening and early detection: Advancing screening’s contribution to cancer control

“…However, concerns have been raised about the situation in which an mt‐sDNA test is positive and colonoscopy is negative, based on the assumption that a test that is sensitive for exfoliated DNA may have detected an indication of cancer in another organ. Whereas the few follow‐up studies that have been undertaken have not identified any excess non‐CRC cancer rate or excess mortality, more reassuring evidence about unresolved positive test results comes from a recent study by Cooper et al, who retested 12 patients with prior positive mt‐sDNA and negative colonoscopy results 11 to 29 months after the initial test. During reexamination, 7 patients had negative stool tests and colonoscopy; among the remaining 5 patients, 3 had positive findings on their follow‐up colonoscopy (2 advanced adenomas and 1 nonadvanced adenoma), suggesting that the initial follow‐up colonoscopies were false‐negative findings …”

Evaluation of Patients with an Apparent False Positive Stool DNA Test: The Role of Repeat Stool DNA Testing

“…However, it is known that colonoscopy is an imperfect “gold standard”, with a quoted miss rate for advanced adenomas of up to 11% (3) and 2.6%–9.0% of cancers developing within 3 years of colonoscopy (interval cancers) (4). While neoplasms in the upper gastrointestinal tract or pancreas (5) are known to produce genetic markers that may survive passage into the stool and be detectable in stool assays, a recently published cohort study that followed more than 1000 patients with a false positive sDNA test found only 8 subsequent cancers (3 lung, 3 pancreas, 1 colon, 1 biliary) at an average 4 year follow up, which was not greater than expected in the general population (6). A similarly low estimate of extracolonic sources of sDNA test positivity was found in a case-control study (2 positive aerodigestive cancers for each 10,000 patients screened) (7).…”