Abstract
This analysis uses data from 2 studies to explore whether lowering the threshold for fecal immunochemical test positivity can achieve comparable levels of sensitivity and specificity as multitarget stool RNA testing for colorectal cancer screening.
Fecal immunochemical tests (FITs) for hemoglobin are the most widely used screening tests for colorectal cancer (CRC) globally.1 However, they have limited sensitivity in detecting early-stage CRC and CRC precursors.2 In 2023, the CRC-PREVENT study, a blinded, prospective, cross-sectional study that enrolled the target population for CRC screening, demonstrated increased sensitivity for CRC of a multitarget stool RNA (mt-sRNA) test compared with FIT alone (94% vs 78%). The mt-sRNA test incorporated a commercially available FIT (iFOBT OC-Auto; positivity threshold, 20 μg hemoglobin per gram of feces), concentration of 8 RNA transcripts, and participant-reported smoking status.3 However, this increase in sensitivity came at a substantial loss of specificity for no lesions compared with FIT alone (88% vs 96%). This analysis evaluated whether comparable levels of sensitivity and specificity could be achieved by lowering the FIT positivity threshold, without additional stool RNA testing and smoking assessment.
Methods
Our analyses are based on data from the ongoing German BLITZ study. Details of the BLITZ study design have been reported elsewhere.4,5 Briefly, participants undergoing screening colonoscopy are recruited in gastroenterology practices located in various cities of southern Germany, complete a short questionnaire, and provide a fecal sample prior to bowel preparation for the evaluation of noninvasive CRC screening tests, including the FIT evaluated in this analysis. All participants provide written informed consent. The BLITZ study was approved by the ethics committees of the Heidelberg Medical Faculty of Heidelberg University and the state medical chambers of Baden-Württemberg, Saarland, Rhineland-Palatinate, and Hesse.
Participants for this analysis were recruited from 2008 to 2020 and received the same quantitative FIT (FOB Gold, Sentinel Diagnostics). We excluded participants who had a history of CRC or inflammatory bowel disease, a colonoscopy in the past 5 years, inadequate bowel preparation, incomplete colonoscopy, not further specified polyps reported in the colonoscopy record, or who obtained their fecal sample after colonoscopy. The FIT analyses were conducted at a central accredited laboratory (Limbach Laboratory) on Abbott Architect c8000 machines (analytical range: 0.03 to 142 μg hemoglobin per gram of feces) by experienced laboratory personnel who were blinded to the colonoscopy results.
The main characteristics of the study participants of the CRC-PREVENT and BLITZ studies were summarized by descriptive statistics. Sensitivities of the FIT for detecting CRC or advanced adenoma 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) yielding the same positivity rate as reported for the mt-sRNA test in the CRC-PREVENT study (17%). All analyses were conducted using R version 4.1.3 (R Foundation).
Results
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% vs 40.2%) and participants with CRC (0.8% vs 0.4%) and advanced adenomas (10.5% vs 6.8%) (Table 1).
Table 1. Main Characteristics of the CRC-PREVENT and BLITZ Study Populations.
| Characteristics | CRC-PREVENTa | BLITZ |
|---|---|---|
| Total No. of participants | 8920 | 7607 |
| Country, date range | United States, 2021-2022 | Germany, 2008-2020 |
| Sex | ||
| Male, No. (%) | 3584 (40.2) | 3687 (48.5) |
| Female, No. (%) | 5326 (59.7) | 3920 (51.5) |
| Age, y | ||
| Mean (SD) [range], y | 55.0 (7.8) [45-90] | 61.5 (7.1) [45-90] |
| 45-49, No. (%) | 2071 (23.2) | 130 (1.7) |
| 50-54, No. (%) | 2937 (32.9) | 480 (6.3) |
| 55-59, No. (%) | 1139 (12.8) | 3125 (41.4) |
| 60-64, No. (%) | 1413 (15.8) | 1435 (18.9) |
| ≥65, No. (%) | 1360 (15.2) | 2437 (32.0) |
| Most advanced finding at colonoscopy | ||
| CRC, No. (%) | 36 (0.4) | 59 (0.8) |
| Advanced adenoma, No. (%)b | 606 (6.8) | 795 (10.5) |
| Any advanced neoplasia, No. (%)c | 642 (7.2) | 854 (11.2) |
| No advanced neoplasia, No. (%) | 8278 (92.8) | 6753 (88.8) |
Abbreviation: CRC, colorectal cancer.
Data extracted from Barnell et al.3
Defined as adenomas ≥1 cm, >10 adenomas, tubulovillous or villous adenomas, or adenomas with high-grade dysplasia.
Includes CRC or advanced adenomas.
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% [95% CI, 86.1%-98.3%] vs 94.4% [95% CI, 81.9%-98.5%] for CRC and 44.7% [95% CI, 41.2%-48.1%] vs 45.9% [95% CI, 41.9%-49.9%] for advanced adenoma) and specificities (86.9% [95% CI, 86.1%-87.7%] vs 85.5% [95% CI, 84.7%-86.2%]) (Table 2).
Table 2. Sensitivities and Specificities of mt-sRNA Test in the CRC-PREVENT Study and FIT in the BLITZ Study, After Lowering Cutoff to Yield a Comparable Positivity Rate.
| Metric | Outcome | CRC-PREVENTa | BLITZ | ||
|---|---|---|---|---|---|
| mt-sRNA test | FIT (FOB Gold) (cutoff, 8.83 μg/g) | ||||
| No./total No. | % (95% CI) | No./total No. | % (95% CI) | ||
| Positivity rate | 1516/8920 | 17.0 (16.2-17.8) | 1293/7607 | 17.0 (16.2-17.9) | |
| Sensitivity | CRC | 34/36 | 94.4 (81.9-98.5) | 56/59 | 94.9 (86.1-98.3) |
| Advanced adenoma | 278/606 | 45.9 (41.9-49.9) | 355/795 | 44.7 (41.2-48.1) | |
| Any advanced neoplasia | 312/642 | 48.6 (44.8-52.5) | 411/854 | 48.1 (44.8-51.5) | |
| Specificity | No advanced neoplasia | 7074/8278 | 85.5 (84.7-86.2) | 5867/6753 | 86.9 (86.1-87.7) |
Data extracted from Barnell et al.3
Discussion
This study found that comparable levels of sensitivity and specificity as reported for the mt-sRNA test in the CRC-PREVENT study could be achieved by lowering the FIT positivity threshold, without additional mt-sRNA testing. The findings are similar to previous observations for multitarget stool DNA testing.6 Limitations of the study include the indirect comparison based on different study populations with different sex and age composition and different prevalences of CRC and advanced adenoma. Future comparisons of novel stool-based screening tests with FITs should incorporate comparisons of sensitivities at the same positivity rate or specificity.
Section Editors: Kristin Walter, MD, and Jody W. Zylke, MD, Deputy Editors; Karen Lasser, MD, MPH, Senior Editor.
Data Sharing Statement
References
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Supplementary Materials
Data Sharing Statement