Multitargeted DNA Test Bests Fecal Immunochemical Test With Higher Sensitivity for CRC

Thomas F. Imperiale, MD

A next-generation, multitarget stool DNA test demonstrated higher sensitivity for colorectal cancer (CRC) and advanced precancerous lesions compared with a commercially available fecal immunochemical test (FIT), but lower specificity was observed, according to findings from a prospective study published in The New England Journal of Medicine.¹

The study which included 20,176 participants with CRC (n = 98), advanced precancerous lesions (n = 2144), nonadvanced adenomas (n = 6973), and nonneoplastic findings or a negative colonoscopy (n = 10,961), showed that the sensitivity for CRC was 93.9% (95% CI, 87.1%-97.7%) with the next-generation test vs 67.3% (95% CI, 57.1%-76.5%) with the FIT. The sensitivity for advanced precancerous lesions was 43.4% (95% CI, 41.3%-45.6%) compared with 23.3% (95% CI, 21.5%-25.2%), respectively.

Although the next-generation test displayed superior sensitivity for CRC (P < .001) and advanced precancerous lesions (P < .001) compared with FIT, it had lower specificity for advanced neoplasia (P < .001); specificity for advanced neoplasia was 90.6% (95% CI, 90.1%-91.0%) with the next-generation test vs 94.8% (95% CI, 94.4%-95.1%) with FIT. Additionally, the specificity for nonneoplastic findings or negative colonoscopy was 92.7% (95% CI, 92.2%-93.1%) vs 95.7% (95% CI, 95.3%-96.1%), respectively.

“We found that the next-generation stool DNA test had a good balance of sensitivity—detecting disease—and specificity–low false positive results,” Thomas F. Imperiale, MD, distinguished professor, Lawrence Lumeng Professor of Gastroenterology and Hepatology, and a professor of medicine at Indiana University School of Medicine, in Indianapolis, said in a press release.² “Compared to the FIT, the next-[generation] test had superior sensitivity for both CRC and advanced precancerous polyps, especially the subgroup of advanced polyps containing high-grade dysplasia. And even though a direct comparison between the current version of the test and this newer version wasn’t made, the numerical values for sensitivity were the same or actually a little better for the next-[generation] test and the specificity was approximately 30% better with this new version of the test, with significantly fewer false positives compared (indirectly) with the current version.”

Investigators conducted their study at 186 sites across the US. Data collection and monitoring were performed by the independent clinical research organization and the data were analyzed by the second author of the study.¹

The study population was made up of individuals at least 40 years old who were scheduled or planned to undergo a screening colonoscopy. Those with a history of CRC, advanced precancerous lesions, inflammatory bowel disease or Cronkhite–Canada syndrome, positive results on a first-generation multitarget stool DNA test within the previous 2 years or on a FIT or fecal occult blood test within the previous 6 months, who had received a colonoscopy within the previous 9 years, or had rectal bleeding within the previous 30 days were excluded. Individuals with a medical or family history of familial adenomatous polyposis, hereditary nonpolyposis CRC syndrome, or other hereditary cancer syndromes were also deemed to be ineligible for the study.

The study was conducted between November 15, 2019, and January 5, 2023. Patients in the overall population were a mean age of 63 years and most were women (53.2%) and White (60.1%). Study authors noted that the study population was generally representative of the racial and ethnic group distribution of the US of those who are eligible for screening.

The primary objective of the study was to identify the sensitivity of the multitarget stool DNA test for CRC and specificity for advanced neoplasia. Secondary outcomes consisted of sensitivity for advanced precancerous lesions, specificity for nonneoplastic findings or negative colonoscopy, and comparison of results between the multitarget stool DNA test and the commercial FIT.

Additional findings from the study revealed that the next-generation DNA test displayed a sensitivity of 92.7% (95% CI, 84.8%-97.3%) for patients with stage I, II, or III CRC compared with 64.6% (95% CI, 53.3%-74.9%) among those who underwent FIT. The next-generation test was also superior to FIT in terms of sensitivity in those with high-grade dysplasia, at 74.6% (95% CI, 65.6%-82.3%) vs 47.4% (95% CI, 37.9%-56.9%), respectively. However, FIT was superior in terms of specificity for those who had a negative colonoscopy at 96.0% (95% CI, 95.5%-96.4%) vs 93.4% (95% CI, 92.8%-93.9%) for the next-generation test.

“Primary care providers drive colon cancer screening in this country,” Imperiale said in the press release.² “While our study establishes superior sensitivity of the next-[generation] DNA stool test to FIT, it does not indicate which screening modality is ‘best’ for a particular patient. That should be discussed in a conversation between the clinician and the patient that explores various factors including disease risk and likelihood that the patient will complete the chosen test, among other factors. The best candidates for this test are average risk persons aged 45 to 60-to-65 years old who lack conditions that increase the chances of CRC, including a personal history of inflammatory bowel disease, previous CRC or pre-cancerous polyps, and a strong family history of CRC. A strong family history is defined as 2 first degree relatives (parent, sibling, child) with CRC or a single first degree relative with CRC diagnosed before the age of 60.”

References

1. Imperiale TF, Porter K, Zella J, et al. Next-generation multitarget stool DNA test for colorectal cancer screening. N Engl J Med. 2024;390:984-939. doi:10.1056/NEJMoa2310336
2. Next generation stool DNA test has best detection rate of noninvasive colorectal cancer screening tools. News release. Regenstrief Institute. March 13, 2024. Accessed March 13, 2024. https://www.regenstrief.org/article/stool-dna-test-best-detection-rate/