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Jump to Key Points NASHVILLE — Results from fecal immunochemical tests (FITs) showed significant differences in the detection of colorectal cancer (CRC) between men and women, raising the question of a need for gender-based thresholds, according to the results of a new study.
The findings show that sensitivity for CRC and advanced precancerous lesions (APLs) is higher in males, particularly for proximal lesions, said first author Thomas Imperiale, MD, of the Indiana University School of Medicine, in Indianapolis, who presented the findings at the American College of Gastroenterology (ACG) 2026 Annual Scientific Meeting.
But whether these results support the use of different FIT thresholds for men and women “depends on the goal of screening,” Imperiale told Medscape Medical News.
“If the goal is to ensure equal detectability between males and females, then yes, the thresholds should differ,” he said. “However, the downstream consequences of having two thresholds to equalize sensitivity for CRC must be considered.”
- FIT sensitivity for CRC/APLs higher in men vs women at 100 ng/mL.
- CRC sensitivity: men 77.4% vs women 62.0%; APL 25.8% vs 20.2%.
- 95% specificity thresholds differed: men 120 ng/mL; women 94 ng/mL.
- Proximal lesion detection markedly lower in women; CRC 50.0% vs 80.8% in men.
- Male sex independently associated with advanced neoplasia sensitivity; smoking, obesity, lesion size also ↑.
These include potentially more positive FIT tests and the capacity of systems to take on increased colonoscopy referrals, Imperiale explained.
Analysis of Data From DeeP-C and BLUE-C
Notable differences in the prevalence and distribution of CRC are well known to exist between genders, but data are lacking on their implications in FIT testing thresholds and results.
To investigate, Imperiale and colleagues conducted a retrospective analysis of prospective cross-sectional data from the DeeP-C and BLUE-C clinical validation studies for the multitarget stool DNA (mt-sDNA) and next-generation mt-sDNA FIT tests.
Each test utilized the same independent, quantitative comparator FIT, with a positivity threshold of 100 ng/mL [20 µg/g]).
Of 30,165 participants in the studies combined — overall mean age 63.4 years and 46.6% male — 163 (0.54%) were identified as having CRC and 2901 (9.6%) had APLs, overall.
Of note, men had higher mean or median fecal hemoglobin levels than women, in addition to higher FIT sensitivities for CRCs vs women at the 100 ng/mL threshold (77.4% vs 62.0%; P = .03) and higher APL sensitivity (25.8% vs 20.2%; P < .001).
The thresholds yielding FIT specificities of 95% were also notably different: 120 ng/mL for males (with a CRC sensitivity of 77.1%) compared with 94 ng/mL for females (with a CRC sensitivity of 63.3%, P < .001).
While no significant differences were observed in CRC or APL size distribution based on gender, distal CRCs were more common in males than in females (69.0% vs 51.9%), as were distal APLs (46.4% for males vs 38.8% for females). However, females had a higher proportion of proximal CRCs (48.1% vs 31% for males) and proximal APLs (61.2% vs 53.6% for males).
For proximal location, CRC sensitivity was significantly higher in males than in females (80.8% vs 50.0%; P = .01), as was APL sensitivity (17.7% vs 12.8%; P = .01).
Overall, male gender was independently associated with a higher risk for advanced neoplasia sensitivity, with an odds ratio (OR) of 1.22. Other risk factors included being a current or former smoker (OR, 1.36); having a BMI ≥ 30 (OR, 1.39); having a larger lesion size (10-19 mm: OR, 1.70; 20-29 mm: OR, 3.21; ≥ 30 mm: OR, 4.27); distal/rectal location (OR, 2.41); CRC (OR, 4.61); high-grade dysplasia (OR, 2.19); villous adenomas (OR, 1.40); and serrated lesions ≥ 10 mm (OR, 0.23).
Complications of Addressing Different Thresholds
Commenting on the study, Michael Dougherty, MD, an attending gastroenterologist at University of North Carolina (UNC) REX Digestive Healthcare, in Chapel Hill, noted that previous smaller studies have also shown the threshold used in FIT to be positive at a lower rate and miss more cancers in women.
However, “this is a much larger, modern, and diverse cohort that is able to give more robust and granular quantification of just how different the test characteristics are in men and women,” Dougherty, who is also an adjunct clinical assistant professor at the UNC School of Medicine, told Medscape Medical News.
That being said, he agreed that efforts to address different thresholds could be complicated.
“If you have to have different versions of the test for each sex, and/or a different interpretation from the clinician, that's added complexity to a process we would prefer to be as simple and streamlined as possible, to maximize uptake,” Dougherty said.
Ultimately, based on the findings, “I wouldn't suggest that women 'not use' the current iterations of FIT as a CRC screening test, [but] it's something to keep in mind,” he noted.
“When faced with a negative FIT in a particular patient, if something doesn't add up, or they later develop symptoms, then maybe a negative test isn't quite as reassuring,” he said. “You still need to take any alarm symptoms very seriously.”
Imperiale’s disclosures include consultancy for Cook Medical and research/grant support from Exact Sciences Corp. Dougherty had no disclosures to report.
