NEW YORK – New research from Germany comparing results from two different patient cohorts suggests that low-cost fecal immunochemical test (FIT)-based colorectal cancer (CRC) screening may reach similar sensitivity and specificity as pricier stool DNA testing with Exact Sciences' Cologuard and Cologuard Plus tests by lowering its positivity cutoff.
"Our study demonstrates that the same detection rates of colorectal cancer and its precursor as reported for the multitarget stool DNA test (MSDT) [Cologuard] and the novel next-generation multitarget stool DNA test (NG MSDT) [Cologuard Plus] can be achieved by lowering the positivity cutoff of a commercial fecal immunochemical test (FIT)," Hermann Brenner, head of the clinical epidemiology and aging research division of the German Cancer Research Center (DKFZ), said in an email.
In a research letter published in JAMA Internal Medicine on Monday, Brenner and colleagues at DKFZ, Heidelberg University, and Ludwig Maximilian University of Munich analyzed data from a screening colonoscopy study known as BLITZ that was conducted in Germany between 2008 and 2020, focusing on 7,190 individuals tested with the commercially available FOB Gold FIT from Sentinel Diagnostics.
In particular, the team evaluated the sensitivity and specificity of the FIT approach at a range of positivity thresholds, comparing them to results from a different study, known as BLUE-C, that tested the performance of NG-MSDT (Cologuard Plus) and was funded by Exact Sciences. Findings from BLUE-C, a multi-center prospective study that included 20,176 individuals tested with the Cologuard Plus test and with FIT between 2019 and 2023, were published in the New England Journal of Medicine in March.
"It was previously shown that lowering the positivity threshold of a commercial quantitative FIT could enhance diagnostic performance to be comparable to a multitarget stool ribonucleic acid (RNA) test," the authors explained, "prompting an evaluation of whether the same approach could yield similar outcomes with the NG-MSDT."
To explore this further, the researchers changed the sensitivity of the FIT test in the BLITZ study by using different positivity thresholds, ranging from the manufacturer-recommended cutoff of 17 μg of hemoglobin per gram of stool to 11.7 μg/g to 10 μg/g.
Consistent with prior research, the team saw higher specificity but lower sensitivity for FOB Gold FIT when they used a positivity threshold of 17 μg/g and compared their results with those from Cologuard Plus in the BLUE-C study.
But that started to change when the investigators began bumping down the positivity threshold for the FIT test. At a cutoff of 11.7 μg/g, sensitivity went up to 94.7 percent — slightly higher than the 93.9 percent sensitivity reported for Cologuard Plus in the NEJM study, while specificity was similar.
In contrast, FIT sensitivity remained lower for finding advanced precancerous lesions, coming in at 38.3 percent compared to 43.4 percent for Cologuard Plus.
Sensitivity for finding advanced neoplasia rose to 45.4 percent in the BLITZ study when the team turned down the FIT test cutoff still further, to 10 μg/g. At that positivity threshold, sensitivity for detecting CRC increased slightly, to 96.5 percent, with specificity dipping to 89 percent, slightly below that of Cologuard Plus.
Together, despite the limitations of an indirect study, the results suggested that "a commercial FIT can achieve similar diagnostic results to the newer stool DNA test" and that "lowering the positivity threshold of a high-quality FIT may be a much more economical way to increase sensitivity of noninvasive CRC screening," the authors wrote, adding that "further research to enhance both sensitivity and specificity of noninvasive CRC screening tests is highly desirable."
Brenner noted that FIT comes with a price tag of around $25 a test compared to $500 or more for MSDTs or NG-MSDTs.
In a commentary in JAMA Internal Medicine, Thomas Imperiale of Indiana University School of Medicine, the lead author of the earlier NEJM study, who was not involved in the German study, called the new analyses "provocative."
Even so, Imperiale pointed to the need for further "rigorous and valid comparisons of noninvasive CRC screening tests, which require that the tests are compared not just in the same cohort, but on the same specimens (stool or blood) from that cohort."
Paul Limburg, chief medical officer for screening at Exact Sciences, said in an email that he agrees with Imperiale's call for direct comparisons between its Cologuard tests and specific FITs in the same cohort. "Exact Sciences supports rigorous research to fully understand noninvasive colorectal cancer (CRC) screening options and how they perform to ensure we can help close the CRC screening gap," he wrote, adding that "[w]e are very confident in the findings from the BLUE-C study, which directly compared results for the next-generation Cologuard test and an independent FIT from the same participants and specimens, providing strong support for our recent FDA approval of the Cologuard Plus test."