Cell-free DNA (cfDNA) blood-based test screening for colorectal cancer (CRC)

The ECLIPSE (Evaluation of the ctDNA LUNAR Test in an Average Patient Screening Episode) study was designed to evaluate the performance of the cfDNA blood-based test (Shield, Guardant Health) to detect asymptomatic and early-stage colorectal cancer in a screening-relevant population (1).

The study assessed the performance characteristics of a cell-free DNA (cfDNA) blood-based test in a population eligible for colorectal cancer screening

• coprimary outcomes were sensitivity for colorectal cancer and specificity for advanced neoplasia (colorectal cancer or advanced precancerous lesions) relative to screening colonoscopy
• secondary outcome was sensitivity to detect advanced precancerous lesions

Study population:

• eligible persons were 45 to 84 years of age at the time of consent, at average risk for colorectal cancer and undergoing routine screening with colonoscopy
  • key exclusion criteria were a history of cancer, a known diagnosis of inflammatory bowel disease, a hereditary predisposition to colorectal cancer, a history of colorectal cancer in a first-degree relative, and recent receipt of screening for colorectal cancer (colonoscopy within the preceding 9 years, positive faecal immunohistochemical test [FIT] or faecal occult blood test within the preceding 6 months, or completion of the multitarget stool DNA test or methylated Septin9 blood test within the preceding 3 years)
  • study sample size was calculated on the basis of a prevalence of colorectal cancer of 0.5 to 0.7%

Study Results:

• clinical validation cohort included 10,258 persons, 7861 of whom met eligibility criteria and were evaluable
• a total of 83.1% of the participants with colorectal cancer detected by colonoscopy had a positive cfDNA test and 16.9% had a negative test, which indicates a sensitivity of the cfDNA test for detection of colorectal cancer of 83.1% (95% confidence interval [CI], 72.2 to 90.3)
• sensitivity for stage I, II, or III colorectal cancer was 87.5% (95% CI, 75.3 to 94.1), and sensitivity for advanced precancerous lesions was 13.2% (95% CI, 11.3 to 15.3)
• a total of 89.6% of the participants without any advanced colorectal neoplasia (colorectal cancer or advanced precancerous lesions) identified on colonoscopy had a negative cfDNA blood-based test, whereas 10.4% had a positive cfDNA blood-based test, which indicates a specificity for any advanced neoplasia of 89.6% (95% CI, 88.8 to 90.3)
• false positive rate of this cfDNA blood-based test was 10.1% (i.e., 10.1% of the patients who did not have any neoplasia on colonoscopy had a positive cfDNA blood-based test)
• specificity for negative colonoscopy (no colorectal cancer, advanced precancerous lesions, or nonadvanced precancerous lesions) was 89.9% (95% CI, 89.0 to 90.7)

Conclusions:

• study authors concluded that, in an average-risk screening population, this cfDNA blood-based test had 83% sensitivity for colorectal cancer, 90% specificity for advanced neoplasia, and 13% sensitivity for advanced precancerous lesions

Additional comments:

• sensitivity of this blood-based test for colorectal cancer was 83.1%, whereas reported sensitivity of other noninvasive screening tests ranges from 67.3% (95% CI, 57.1 to 76.5) with FIT and 68% (95% CI, 53 to 80) with the methylated Septin9 test19 to 93.9% (95% CI, 87.1 to 97.7) with the multitarget stool DNA test
• sensitivity of this blood-based test for advanced precancerous lesions was 13.2% (95% CI, 11.3 to 15.3), whereas reported sensitivity of other noninvasive screening tests ranges from 22% (95% CI, 18 to 24) with the methylated Septin9 test19 and 23.3% (95% CI, 21.5 to 25.2) with FIT15 to 43.4% (95% CI, 41.3 to 45.6) with the multitarget stool DNA test

In comparison to the use of FIT in the English Bowel Screening programme (2):

• a study investigated the sensitivity for diagnosis of colorectal cancer using FIT at a threshold of 120 μg/g
  • study stated that the current programme threshold used in England of 120 μg/g was estimated to identify 47.8% of CRC and 25.0% of high-risk adenomas (HRA)
  • the lower the FIT threshold the more likely an individual is to have a positive FIT screening result (and the proportion of false positive results increases)
  • in the analysis by Li et al:
    • for FIT values 80-119 μg/g 1 in 7 individuals with a positive FIT would either have a colorectal cancer or a high risk adenoma
    • for FIT values 40-79 μg/g 1 in 10 individuals with a positive FIT would either have a colorectal cancer or a high risk adenoma
    • for FIT values 20-39 μg/g 1 in 25 individuals with a positive FIT would either have a colorectal cancer or a high risk adenoma
    • for FIT values 10-19 μg/g 1 in 171 individuals with a positive FIT would either have a colorectal cancer or a high risk adenoma
    • comparing different FIT levels with different sensitivities for CRC
      • if a FIT at a level of 20 μg/g was used then the sensitivity would be 82.2% for colorectal cancer
      • if a FIT at a level of 40 μg/g was used then the sensitivity would be 71.1% for colorectal cancer
      • if a FIT at a level of 80 μg/g was used then the sensitivity would be 57.8% for colorectal cancer
      • if a FIT at a level of 120 μg/g was used then the sensitivity would be 47.8% for colorectal cancer

Reference:

1. Chung DC, Gray DM 2nd, Singh H, Issaka RB, Raymond VM, Eagle C, Hu S, Chudova DI, Talasaz A, Greenson JK, Sinicrope FA, Gupta S, Grady WM. A Cell-free DNA Blood-Based Test for Colorectal Cancer Screening. N Engl J Med. 2024 Mar 14;390(11):973-983.
2. Li SJ, Sharples LD, Benton SC, Blyuss O, Mathews C, Sasieni P, Duffy SW. Faecal immunochemical testing in bowel cancer screening: Estimating outcomes for different diagnostic policies. J Med Screen. 2021 Sep;28(3):277-285.