FIT Misses More CRCs in Women; Could Sex-Specific Thresholds Help?

Fecal immunochemical test (FIT) sensitivity for colorectal cancer (CRC) and advanced precancerous lesions (APLs) was lower in women than in men at the standard positivity threshold, according to findings from an analysis of > 30,000 screening participants presented at the American College of Gastroenterology (ACG) 2026 Annual Scientific Meeting in Nashville, Tennessee.1

Thomas Imperiale, MD, of Indiana University School of Medicine, and colleagues concluded the data support different FIT thresholds for men and women, depending on the goals of screening.1

FIT performance varies by brand and threshold, but whether it differs by sex has been less clear. CRC and APL prevalence and anatomic distribution differ between men and women, raising the question of whether a single threshold serves both groups equally.1

How Does FIT Sensitivity Differ Between Men and Women?

The retrospective analysis used cross-sectional data from DeeP-C and BLUE-C, the pivotal validation studies for the original and next-generation multitarget stool DNA (mt-sDNA) tests. Both studies included the same quantitative comparator FIT (OC-FIT-CHEK) at a positivity threshold of 100 ng/mL, approximately 20 µg/g feces, with screening colonoscopy as the reference standard.11,2,3

The cohort included 30,165 participants with a mean age of 63.4 years; 46.6% were men. Overall, 163 participants (0.54%) had CRC and 2901 (9.6%) had APLs.1

At 100 ng/mL, FIT sensitivity for CRC was 77.4% in men vs 62.0% in women (P = .03). Sensitivity for APLs was 25.8% vs 20.2% (P <.001), and specificity was 94.2% in men and 95.3% in women (P <.001).1

Why is FIT Less Sensitive for Colorectal Cancer in Women?

Men had higher fecal hemoglobin concentrations than women for both CRC (median, 1037 vs 276 ng/mL; P = .03) and APLs (median, 13 vs 7 ng/mL; P <.001). Levels did not differ significantly by sex among participants with nonadvanced neoplasia, nonneoplastic findings, or normal colonoscopies.1

Lesion size distributions were similar by sex, but location differed. Distal or rectal CRCs accounted for 69.0% of cancers in men vs 51.9% in women (P = .03), and distal APLs for 46.4% vs 38.8% (P <.001). FIT sensitivity for proximal CRC was 80.8% in men vs 50.0% in women (P = .01), while sensitivity for distal CRC was similar (75.9% vs 73.2%; P = .76).1

In multivariable analysis, male sex (odds ratio [OR], 1.22; 95% CI, 1.02-1.47), current or former smoking (OR, 1.36; 95% CI, 1.14-1.63), and BMI of 30 or higher (OR, 1.39; 95% CI, 1.17-1.67) were independently associated with FIT sensitivity for advanced neoplasia. Distal or rectal location (OR, 2.41; 95% CI, 2.01-2.89), lesion size ≥ 30 mm (OR, 4.27; 95% CI, 2.55-7.27), and CRC histology (OR, 4.61; 95% CI, 3.02-7.08) were also associated with detection. Serrated lesions of 10 mm or larger were less likely to be detected than tubular adenomas of similar size (OR, 0.23; 95% CI, 0.14-0.36).1

Should FIT Positivity Thresholds Vary by Sex?

A 95% specificity was reached at thresholds of 120 ng/mL in men and 94 ng/mL in women. At these sex-specific cutoffs, CRC sensitivity was 77.1% in men vs 63.3% in women, a difference falling short of statistical significance (P = .054).1

Matching male CRC sensitivity in women would require lowering the female threshold to 12 ng/mL, which reduced specificity to 75.7%.¹ Matching male APL sensitivity would require a female threshold of 65 ng/mL, with a resulting specificity of 92.8%. The investigators noted the optimal threshold depends on whether screening programs prioritize sensitivity or specificity.1

Investigators noted the analysis was limited to a single FIT brand, a single threshold, and a single test application.1

References

1. Imperiale TF, Porter K, Limburg P. Performance characteristics of fecal immunochemical tests in males and females: should the threshold vary? Presented at: American College of Gastroenterology 2026 Annual Scientific Meeting; October 9-14, 2026; Nashville, TN.

2. Imperiale TF, Ransohoff DF, Itzkowitz SH, et al. Multitarget stool DNA testing for colorectal-cancer screening. N Engl J Med. 2014;370(14):1287-1297. doi:10.1056/NEJMoa1311194

3. Imperiale TF, Porter K, Zella J, et al. Next-generation multitarget stool DNA test for colorectal-cancer screening. N Engl J Med. 2024;390(11):984-993. doi:10.1056/NEJMoa2310336