Study compares efficacy of lowering FIT positivity threshold to multitarget stool RNA testing for colorectal cancer screening

The study, published in the Journal of the American Medical Association (JAMA), found comparable sensitivity and specificity levels as reported for the multitarget stool RNA (mt-sRNA) test in the CRC-PREVENT study could be achieved by lowering the FIT positivity threshold, without additional mt-sRNA testing. The results are similar to the previous observations for multitarget stool DNA testing.

The screening tests most widely used for colorectal cancer globally are fecal immunochemical tests for hemoglobin. However, they have limited sensitivity in early-stage CRC and CRC precursors detection.

In 2023, the CRC-PREVENT study, a blinded, prospective, cross-sectional study that enrolled the target population for CRC screening, showed increased sensitivity for CRC of a mt-sRNA test compared with FIT alone (94% versus 78%). The mt-sRNA test involved a commercially available FIT (iFOBT OC-Auto; positivity threshold, 20 μg hemoglobin per gram of feces), participant-reported smoking status, and concentration of 8 RNA transcripts. However, this rise in sensitivity came at a substantial specificity loss for no lesions versus FIT alone (88% vs 96%).

The analysis by Tobias Niedermaier, German Cancer Research Center, Heidelberg, Germany, and colleagues evaluated whether comparable specificity and sensitivity levels could be achieved by lowering the FIT positivity threshold, without additional stool RNA testing and smoking assessment.

The analyses were based on ongoing German BLITZ study data. Participants undergoing screening colonoscopy are recruited in gastroenterology practices located in various southern German cities, complete a short questionnaire, and provide a fecal sample before bowel preparation for evaluating noninvasive CRC screening tests, including the FIT evaluated in this analysis. All participants provide written informed consent.

The main characteristics of the study participants of the BLITZ and CRC-PREVENT studies were summarized by descriptive statistics. Sensitivities of the FIT for CRC or advanced adenoma detection and specificity for the absence of advanced neoplasia were determined for the FIT in the BLITZ study after lowering the positivity threshold recommended by the manufacturer (17 μg hemoglobin per gram of feces) to a lower level (8.8 μg/g) providing the same positivity rate as reported for the mt-sRNA test in the CRC-PREVENT study (17%).

The study led to the following findings:

• Of 10 061 BLITZ participants recruited from 2008 to 2020, 2454 were excluded, leaving 7607 participants for analysis.
• Compared with CRC-PREVENT, the study population in BLITZ was older (mean age, 61.5 vs 55.0 years) and included higher proportions of men (48.5% versus 40.2%) and participants with CRC (0.8% versus 0.4%) and advanced adenomas (10.5% versus 6.8%).
• Lowering the FIT positivity threshold in BLITZ to achieve the same positivity rate as reported for the mt-sRNA test in CRC-PREVENT achieved similar sensitivities (94.9% versus 94.4% for CRC and 44.7% versus 45.9% for advanced adenoma) and specificities (86.9% versus 85.5%)

The limitations include the indirect comparison based on different study populations with varying compositions of age and sex and different prevalences of CRC and advanced adenoma.

"There is a need for future comparisons of novel stool-based screening tests with FITs, which should incorporate comparisons of sensitivities at the same positivity rate or specificity," the researchers concluded.

Reference:

Niedermaier T, Seum T, Hoffmeister M, Brenner H. Lowering Fecal Immunochemical Test Positivity Threshold vs Multitarget Stool RNA Testing for Colorectal Cancer Screening. JAMA. Published online June 01, 2024. doi:10.1001/jama.2024.9289