Updated SimpleScreen CRC Blood Test Improves Precancerous Lesion Detection

An updated version of the SimpleScreen CRC blood test detected advanced precancerous lesions (APLs) with 18.2% sensitivity, up from 13.7% with the previous version, while maintaining 80.4% sensitivity for colorectal cancer (CRC). The late-breaking results come from a clinical validation study presented at the American College of Gastroenterology (ACG) 2026 Annual Scientific Meeting in Nashville, Tennessee.1

SimpleScreen CRC, developed by Freenome, received US Food and Drug Administration (FDA) approval based on the PREEMPT CRC study. In that study, the original test achieved 79.2% CRC sensitivity, but its 12.5% APL sensitivity missed the prespecified acceptance criterion.1,2

Aasma Shaukat, MD, MPH, of NYU Grossman School of Medicine, told HCPLive APL detection is central to CRC prevention, and current blood tests fall short of stool-based tests on this measure.

“It’s really important that we see an improvement in that advanced precursor lesion because in their current form they don’t confer the same amount of protection or prevention as tests that have higher detection of advanced precursor lesions,” she explained.

Assay and Algorithm Updates to the SimpleScreen CRC Blood Test

Shaukat said the updated version incorporates two changes: assay modifications to improve the signal-to-noise ratio, and algorithm refinements trained on prior results to detect circulating tumor DNA at the base-pair level. Validation drew on PREEMPT CRC, which enrolled 48,995 average-risk adults aged 45 to 85 years undergoing screening colonoscopy.1

The validation cohort included all previously untested CRC (n = 26) and APL (n = 1142) samples. As prespecified and aligned with the FDA, investigators added previously tested samples with sufficient volume: 70 CRCs, 517 randomly selected APLs, and 70 additional APLs with high-grade dysplasia (HGD).1

The evaluable cohort comprised 9001 participants, including 89 with CRC, 1570 with APLs, and 7342 without advanced neoplasia, with a mean age of 60.0 years. The positivity threshold targeted 90% specificity among participants with no colonoscopic findings, and sensitivity estimates were adjusted to the US Census age-sex distribution.1

Updated Blood Test Sensitivity for CRC and Advanced Precancerous Lesions

The updated test achieved CRC sensitivity of 80.4% (95% CI, 70.2%-87.7%).¹ Sensitivity was 52.0% for stage I cancers (T1, 39.9%; T2, 81.2%), 100% for stage II, 97.3% for stage III, and 100% for stage IV. The stage I estimate was numerically lower than with the previous version, with overlapping confidence intervals.1

APL sensitivity was significantly higher with the updated test (18.2%; 95% CI, 16.3%-20.4%) than with the previous version (13.7%; 95% CI, 12.4%-15.0%), with improvements across APL subtypes.¹ Sensitivity for APLs with HGD was 41.9% (95% CI, 34.0%-50.3%) among 157 evaluable cases.1

Specificity was 90.0% (95% CI, 89.0%-91.0%) among participants with no colonoscopic findings and 89.7% (95% CI, 89.0%-90.4%) among those without advanced neoplasia.1

Modeled Impact and Role of Blood-Based CRC Screening

In a validated microsimulation model of screening every 3 years from ages 45 to 75, the updated test was projected to prevent 426 more CRC cases (9.5%) and 143 more CRC deaths (9.5%) per 100,000 adults, and to add 1582 life-years (7.7%), compared with the previous version.1

Shaukat said blood tests are better than no screening but currently inferior to colonoscopy and stool-based testing, and she still prefers patients complete one of those options. She expects blood test sensitivity for APLs to reach parity with stool tests over time. She added the goal is to reach patients who decline or cannot complete colonoscopy, with follow-up colonoscopy after any abnormal result.

“So we’re looking for that addition and not substitution, which is obviously a big concern,” said Shaukat.

Editors’ note: Shaukat reports relevant disclosures with Freenome, Geneoscopy, and UniversalDx.

References

1. Shaukat A, Burke CA, Gupta S, et al. Improved sensitivity for advanced precancerous lesions demonstrated in clinical validation of an updated colorectal cancer screening blood test in an average-risk population. Presented at: American College of Gastroenterology 2026 Annual Scientific Meeting; October 9-14, 2026; Nashville, TN.

2. Shaukat A, Burke CA, Chan AT, et al. Clinical validation of a circulating tumor DNA-based blood test to screen for colorectal cancer. JAMA. 2025;334(1):56-63. doi:10.1001/jama.2025.7515