Novel Colorectal Cancer Screening Tests Under Development

When it comes to colorectal cancer, a lot of emphasis has been placed on early detection of the disease. The straightforward reason, despite treatment being anything but straightforward, is that colorectal cancer is highly treatable if it is detected early.

It may take years for a small polyp to grow to a significant size and develop into a malignant tumor. As such, many cases of sporadic colorectal cancer do not show any symptoms until the disease has progressed significantly.

For most individuals, colorectal cancer screening is usually recommended from age 50 onwards, though the invasive procedure often instills fear in patients and many may be reluctant to undergo a colonoscopy. Nonetheless, it remains the most sensitive test for colorectal cancer detection. While other screening tests such as stool-based tests are non-invasive and can be completed at home, they are one-time tests with lower sensitivity and specificity and need- to be repeated yearly or every other year. If the stool test is abnormal, a follow-up colonoscopy is required to confirm the presence or absence of colorectal cancer.

Patient compliance is a key hurdle in improving early cancer detection rates, and has been key in driving research in more novel screening techniques that are not only minimally or non-invasive but are also more specific and sensitive.

In this article, we explore some of the colorectal cancer screening tests that are currently under development and may soon be available for clinical use.

Clinical Genomics is currently engaged in an expansive investigation involving the utilization of both stool-based and blood-based biomarkers as part of a comprehensive study (registered as NCT00843375) aimed at the early identification of colorectal cancer and advanced neoplasia.

This evaluation focuses on the examination of a specific methylated circulating tumor DNA (ctDNA) marker. To accomplish its objectives, the study intends to enlist a substantial cohort of 1,800 individuals who fall within the average risk category, encompassing participants aged 18 years and above, residing within the United States. The projected timeline for the study's completion is slated for the year 2028.

Freenome is currently assessing an innovative method for early cancer detection, which involves analyzing cell-free methylated DNA and protein samples using an artificial intelligence-based machine learning classifier test. This approach aims to identify specific patterns of cell-free biomarkers in the blood that can indicate the presence of cancer at an early stage.

To evaluate the effectiveness of this technique, Freenome initiated the PREEMPT trial (NCT04369053) in 2020. This prospective multicenter study aims to enroll 25,000 individuals in the United States who are at an average risk of developing cancer and are between the ages of 45 and 85, and participants will be undergoing colonoscopy screening. The primary objectives of the trial are to assess the sensitivity and specificity of the method in detecting colorectal cancer (CRC). The trial was expected to conclude in 2023, providing valuable insights into the potential of this novel approach for early cancer detection.

Currently pending US Food and Drug Administration (FDA) approval, Shield^™ is a liquid biopsy that detects the ctDNA fragments in a blood sample to screen for colorectal cancer. Guardant Health, the company behind Shield™, recommends the test to asymptomatic and average-risk adults.

Guardant Health’s ECLIPSE (Evaluation of ctDNA LUNAR Assay In an Average Patient Screening Episode) clinical trial (NCT04136002) of 20,000 patients reported an overall 83% sensitivity. While 83% might not sound impressive — it does mean that 17% of colorectal cancer cases were not detected — the results, at more a granular level, have greater implications.

When the results are stratified by cancer stages 1 to 4, local stage 1 cancers had a reported sensitivity of 55%, while the sensitivity was 100% for stages 2, 3 and 4. This means that all the patients who had regional or advanced metastatic cancer were correctly identified. In addition, the study also reported a 90% overall specificity (i.e. 10% false positive results).

Compared to a fecal immunochemical test (FIT), which is considered the leading non-invasive colorectal cancer screening test, the overall results of the ECLIPSE study prove that Shield™is potentially comparable.

As of December 2023, the FDA is scheduled to review the premarket approval application for Shield^™ on 28 March 2024.

Magnetic resonance (MR) colonography is an innovative and non-invasive technique that has been developed to assess the colon for colorectal polyps and colorectal cancer (CRC). Additionally, it allows for the evaluation of extracolonic findings and the presence of cancer metastases. One significant advantage of MR colonography over computed tomography colonography (CTC) is the absence of ionizing radiation, making it a safer alternative. However, similar to CTC, MR colonography does require patients to undergo bowel preparation. Before the procedure, patients must be screened for general contraindications to magnetic resonance imaging (MRI), such as the presence of metallic implants or severe claustrophobia.

During the MR colonography procedure, the colon is inflated using either water, air, or carbon dioxide. Additionally, patients are required to change positions throughout the examination, similar to what is done during CTC. A comprehensive systematic review encompassing 14 trials involving a total of 1,305 patients demonstrated a high rate of CRC detection, reaching 98.2%. The pooled sensitivity for the detection of large polyps was found to be 82%, while for any polyps, it was 38%. The majority of the studies included in the review utilized a dark lumen technique (11 out of 14 trials), employing rectal administration of warm tap water (5 trials), air (4 trials), a combination of warm tap water and air (1 trial), or a fat enema (1 trial) as a contrast agent.

A few adverse events were reported during the MR colonography procedures, including instances of water spillage or incontinence. Moreover, one case documented painful constipation after the administration of highly concentrated barium sulfate. Although the technology shows promise, further large-scale studies are required to fully evaluate its effectiveness and determine its potential benefits, while also considering potential side effects.