ctDNA Blood Test Showed High Sensitivity, Specificity for Colorectal Cancer but Poor Sensitivity for Advanced Precancerous Neoplasia

A large diagnostic accuracy study to evaluate the performance of a circulating tumor DNA (ctDNA) blood test for colorectal cancer (CRC) found the test had a sensitivity of 79.2% for CRC and specificity of 91.5% for advanced colorectal neoplasia in a diverse cohort of asymptomatic adults at average risk for the disease.

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While all primary endpoints in the prospective study met prespecified criteria, however, the ctDNA test's performance for advanced precancerous lesions fell short of expectations, achieving only 12.5% sensitivity (95% CI, 11.3%-13.8%), failing to meet the predefined acceptance threshold, according to the study authors. Findings of the population-based, observational study were published in JAMA.
Colorectal cancer is the third most common cancer in the US but just more than half of screening-eligible adults (59%) are up-to-date with the assessment. Although the gold standard for CRC screening remains the colonoscopy, noninvasive modalities, including 2 stool-based and 1 blood-based test, have been approved by the FDA, offering options for shared decision making between clinicians and eligible patients.

As the former home-based tests become more widely available and more popular, efforts to increase their sensitivity and specificity continue. With one blood-based biomarker test approved and several in mid-to-late stages of clinical development, the challenge to enhance sensitivity for early detection of advanced precancerous neoplasia also continues, as findings of the current study attest.

The study enrolled asymptomatic adults aged 45 to 85 years at average risk for CRC between May 2020 and April 2022 across 201 centers in US states and the United Arab Emirates. Study inclusion required participants to complete a standard of care screening colonoscopy and laboratory testing. Study staff and pathologists and participants all were blinded to to results of blood tests, and laboratory studies were performed blinded to findings on colonoscopy.

The primary outcomes included sensitivity for CRC, specificity for advanced colorectal neoplasia, and both positive and negative predictive values. As a secondary endpoint, investigators evaluated sensitivity for advanced precancerous lesions.

The mean age among the 27,010 participants in the evaluable cohort was 57 years and half (55.8%) were women, according to the study. The blood-based ctDNA test demonstrated a sensitivity of 79.2% (95% CI, 68.4% - 86.9%) for detecting CRC and a specificity of 91.5% (95% CI, 91.2% - 91.9%) for advanced colorectal neoplasia. The investigational test had a negative predictive value of 90.8% (95% CI, 90.7% - 90.9%) and a positive predictive value of 15.5% (95% CI, 14.2% - 16.8%) for advanced colorectal neoplasia, authors reported.

Among the study's limitations the authors note the focus on one-time diagnostic accuracy of the test without comparing patient acceptance or long-term effectiveness against other screening methods. The impact on colorectal cancer incidence and mortality, along with optimal screening intervals, requires further investigation through future studies and modeling analyses, they added.

In assessing the study's strengths, however, the authors pointed to the large and diverse population with participants enrolled across urban and rural areas in the US and from a range of practice settings. They also explained that the decentralized trial platform combined direct-to-participant and site-based enrollment, which helped increase participation from underrepresented regions and also address COVID-19–related operational challenges.

“In an average-risk colorectal cancer screening population, a blood-based test demonstrated acceptable accuracy for [CRC] detection, but detection of advanced precancerous lesions remains a challenge, and ongoing efforts are needed to improve test sensitivity,” wrote the researchers.

In an editorial accompanying the study, a group of physicians from gastroenterology divisions of major US academic medical centers augment the need with this lament:

"The ideal CRC screening test would be noninvasive and acceptable to those being screened, be highly sensitive for both early cancer and advanced precancerous lesions, have excellent specificity, and be widely accessible. All of the currently available CRC screening test options fall short of this ideal in at least 1 way, limiting their effectiveness. Thus, there is an ongoing search for more agreeable screening test options."

Blood-Based Colorectal Cancer Screening: The Illusion of Simplicity and the Cancer Prevention Paradox

Jason A. Dominitz, MD, MHS^1,2; Swati G. Patel, MD^3,4; David A. Lieberman, MD⁵