Cell-Free DNA Blood-Based Assay Is Not Superior to Colonoscopy in Colorectal Cancer

A cell-free DNA (cfDNA) blood-based test demonstrated an 83.1% (95% CI, 72.2%-90.3%) sensitivity rate for detecting colorectal cancer (CRC), data from the observational ECLIPSE study (NCT04136002) revealed. Nonetheless, colonoscopy is still considered the “gold standard” for CRC diagnosis compared with the cfDNA blood-based assay, according to Sewit Teckie, MD.

“A colonoscopy is still better than the blood-based test at both detecting CRC—as colonoscopy [finds] more true positive cases and fewer false positives—and identifying precancerous lesions. Colonoscopy [is associated with] significantly more true positives,” Teckie explained in an email interview with OncLive® for CRC Awareness Month, which is observed in March. “Given its noninvasive nature, this [cfDNA] assay could increase screening participation, but colonoscopy remains the gold standard for early-stage and precancerous lesion detection.”

Among participants in the study (n = 7861), 83.1% had confirmed CRC via colonoscopy and subsequently demonstrated a positive cfDNA test. However, 16.9% of participants with confirmed CRC via colonoscopy demonstrated a negative cfDNA test. Of note, the lower boundary of the 95% CI for the assay’s sensitivity rate exceeded the acceptance criteria of 65% that was established in other FDA-approved CRC screening tests.

In the interview, Teckie discussed the detection of CRC with the cfDNA blood-based assay, how this test compares with other assays, its potential role in improving CRC diagnoses, and the current treatment paradigm for CRC.

Teckie is the system chief of Radiation Oncology and director of Head and Neck Radiation Oncology at NYC Health + Hospitals.

OncLive: How does the blood-based assay from ECLIPSE work to detect CRC?

Teckie: The ECLIPSE study investigated the results of a commercially available blood-based test for CRC detection. This specific test relies on the analysis of circulating cfDNA, which is shed into the bloodstream by tumor cells. This assay uses methylation-based biomarkers that detect specific DNA methylation patterns that are characteristic of CRC and precancerous lesions. The test differentiates between noncancer and cancerous methylation patterns by using next-generation sequencing or other molecular techniques. Therefore, the blood-based test is a noninvasive way to detect CRC.

How does this cfDNA assay differ from other similar assays?

This cfDNA blood-based assay differs from other similar assays in a few ways. First, unlike conventional stool-based CRC screening tests, such as fecal immunochemical tests or stool DNA tests—like Cologuard, this assay requires only a blood sample. Compared with some other liquid biopsy approaches, this assay focuses specifically on DNA methylation markers, which may provide a more reliable signature for CRC detection compared with general mutation-based cfDNA assays.

With a rise in CRC cases in recent years, how might this assay help improve diagnosis rates?

The increase in CRC incidence, particularly among younger adults, highlights the need for improved screening methods. This blood-based cfDNA test is a less invasive and more accessible alternative to traditional colonoscopies and stool-based tests. Its ease of use could increase screening adherence, particularly among people who are hesitant to undergo colonoscopy. However, the ECLPISE study results show that this test has much lower sensitivity for detecting advanced precancerous lesions than colonoscopy, as well as slightly lower sensitivity for detecting cancer than colonoscopy. This test may be effective for CRC detection in people who cannot otherwise undergo a colonoscopy, but it cannot be used to replace colonoscopy for early prevention of cancer, because it doesn’t do a good job picking up pre-cancerous lesions.

What does the current CRC treatment paradigm look like?

CRC management typically includes multiple treatments, depending on the stage of the cancer and its molecular markers. These treatments include surgical resection for stage I to III localized disease; adjuvant chemotherapy for higher-risk early-stage and stage III disease; combination chemotherapy regimens, such as FOLFOX [folinic acid, 5-fluorouracil, and oxaliplatin] or FOLFIRI [folinic acid and irinotecan], for advanced disease; targeted therapy for metastatic stage IV disease; immunotherapy for microsatellite instability-high or mismatch repair-deficient disease; and radiation therapy for rectal cancer.

What new and novel CRC management approaches are you interested in?

Innovations and areas of ongoing investigation in CRC management include circulating tumor DNA monitoring for minimal residual disease detection and treatment response assessment; CAR T-cell therapy and bispecific antibodies, which are being explored in clinical trials; personalized mRNA-based vaccines targeting CRC-specific mutations; next-generation immunotherapy approaches, such as TGF-β inhibitors to enhance checkpoint blockade therapy; and microbiome-based therapeutics, which are investigating how gut bacteria influence CRC progression and treatment response.

What is your main message for colleagues about the incorporation of the cfDNA diagnostic assay into the CRC treatment paradigm?

The cfDNA test is acceptable for CRC detection but fails in early precancerous lesion detection. Given its low sensitivity for precancerous lesions, the cfDNA test cannot replace colonoscopy for CRC prevention; it may only serve as an alternative for CRC detection in individuals who otherwise cannot complete traditional screening.

Reference

Chung DC, Gray DM 2nd, Singh H, et al. A cell-free DNA blood-based test for colorectal cancer screening. N Engl J Med. 2024;390(11):973-983. doi:10.1056/NEJMoa2304714