A cell-free DNA colorectal cancer screening test promising enhanced accessibility and early detection

Abstract

Colorectal cancer (CRC) remains a significant global health challenge, with approximately 1.9 million new cases and 930,000 deaths reported in 2020. The highest incidence rates are observed in Australia/New Zealand and Europe, while lower rates are found in Africa and Southern Asia. Projections for 2040 indicate a rise to 3.2 million new cases and 1.6 million deaths, particularly in high development index regions, underscoring the need for improved prevention and detection. Despite advancements in screening methods and polyp removal, CRC mortality remains high in the United States due to non-adherence to recommended tests. Barriers such as cost and lack of insurance contribute to this issue. Cell-free DNA (cfDNA) blood-based testing offers a promising alternative, with studies showing 83.1% sensitivity for CRC and 89.6% specificity for advanced neoplasia, comparable to traditional screening methods but with reduced risk of adverse events. The recent FDA approval of the Shield blood test, which has demonstrated 83% efficacy in detecting late-stage CRC, represents a significant advancement. Incorporating cfDNA testing into screening protocols could improve accessibility and compliance, especially for those unwilling or unable to undergo more invasive procedures. Regular evaluation of cfDNA testing, including Shield, is essential for enhancing CRC screening strategies and patient outcomes.

Dear Editor,

Colorectal cancer (CRC) is the third most common cancer in the global population; there are approximately 1.9 million new cases and 930,000 global deaths in the year 2020. With regard to the overall incidence rates, the highest was recorded in the areas within Australia/New Zealand and Europe with a record of 40.28 per 100,000 males, and the lowest rate was in the African regions and Southern Asia, with 4.4 per 100,000 females. Estimations for the year 2040 reveal it to be 3.2 million new cases and 1.6 million deaths, especially in high developmental index regions, countries pointing to the imperative for better prevention and detection mechanisms. [1] Thus, it is important for us to draw attention to the fact that cell-free DNA (cfDNA) blood-based testing of colorectal cancer could be one of the promising directions that may be incorporated into current studies of screenings.

As far as colorectal cancer screening gaps are concerned, there has been an enhancement in the screening and polyp removal. However, the colorectal cancer mortality rate is still high in the United States, as highlighted by the American Cancer Society; a third of people who should have taken the colorectal cancer test have never taken it. Reasons for non-adherence include ignorance, high costs, and insurance barriers [2]. The mentioned hurdles could be alleviated through cfDNA testing; hence, more people could be screened and diagnosed early.

According to The American Society of Clinical Oncology (ASCO) guidelines, there are many possibilities of screening for colorectal cancer such as guaiac fecal occult, blood tests, fecal immunochemical testing, flexible sigmoidoscopy, and colonoscopy [3]. Of course, these procedures remain to be fundamental but when it comes to sensitivity and strictly following the guidelines, the established procedures portray some drawbacks.

A study comparing cfDNA testing shows 83.1% sensitivity for colorectal cancer, 89.6% specificity for advanced neoplasia, and 13.2% sensitivity for advanced precancerous lesions [4]. This includes the findings that the sensitivity of the cfDNA test for colorectal cancer is as effective as that of colonoscopy while it has a specificity that competes with that of other screening tests. On the other hand, an observational cohort study conducted by Tomaszewski et al. of the British Columbia Colon Screening Program observed 350 serious adverse events including perforations, bleeding, and deaths, in 96,192 colonoscopies [5]. This just goes to show that there are more risks involved in the procedure and that other choices such as cfDNA testing should be employed for the initial screenings to eliminate such risks. Integrating cfDNA testing into the treatment plan can increase compliance since it is not as invasive as other procedures, especially where the traditional approaches are unavailable or not accessible.

The task of colorectal cancer (CRC) screening has been made more effective because of the progress made lately in the testing of free DNA (cfDNA) in the body for better detection and measurement of tumors. A circulating tumor DNA (ctDNA)-derived study recently showed the potential of ctDNA as a prognostic marker in the case of locally advanced rectal cancer (LARC). This review expresses the relevance of ctDNA in assessing LARC cases with regard to disease progression, treatment response, and recurrence. The ctDNA test proved to be a highly predictive factor for the likelihood of tumor recurrence, with hazard ratios of 8.87 in the post-neoadjuvant and 15.15 in the post-operative periods, respectively, showing that it was positive ctDNA. These results lend weight to the application of ctDNA testing in standard follow-up procedures in LARC patients since it is very informative in the case of disease recurrence and could even help in the creation of more personalized therapy plans [6].

Additionally, a paper presents a comparative study of cfDNA and carcinoembryonic antigen (CEA) levels in the prediction of disease recurrence after surgery for colon cancer. The study revealed that perioperative cfDNA levels, especially at 48 h, postoperative day 3 and day 5, were strongly correlated with early recurrence showing an area under the curve (AUC) of 0.947. On the other hand, ΔCEA levels were only significantly associated with recurrence when macroscopically apparent. The results indicate that cfDNA fluctuations are so sensitive that they can detect the recurrence 6 months earlier than CEA changes, thus bringing the potential of cfDNA as a more timely and accurate biomarker for early detection of recurrence [7]. Similarly, a meta-analytic review caught the prognostic value of ctDNA in colorectal cancer recurrence. The research project included data from eight studies with 879 CRC patients, and in this manner, it was shown that ctDNA positivity postoperation was strongly correlated with higher recurrence rates among patients with a pooled hazard ratio of 5.41. The review arrived at the general conclusion that continuous ctDNA monitoring, along with imaging techniques like CT and MRI, could be a good way to detect cancer recurrence early after surgery. In accordance with that, the cfDNA testing is to be incorporated into follow-up care to ensure prompt detection and management of CRC recurrences. The evidence infers that cfDNA testing is an integral part of CRC recurrence follow-up care which promotes early detection and management [8].

Considering the limitations of the present screening practices, their incorporation into the ASCO guidelines in terms of cfDNA approaches can negate these issues. For patients who do not adhere to endoscopic screening or for those who are uncomfortable with some of the invasive tests, cfDNA testing can be advised to act as a first-line screen or a backup, depending on patients’ preferences.

To address these challenges, it should be considered to incorporate new screening gadgets like the Shield blood test, recently approved by the FDA for the CRC screening program with an efficacy of 83%, especially the late-stage ones. Shield’s access will be enhanced by Medicare and private insurance patients in the future. However, a pathologic test result of a Shield must be complemented by a colonoscopy to establish the diagnosis as well as staging of the cancer. It is important to raise awareness about Shield among healthcare providers and patients and establish the need for further procedures. Thus, integrating the evaluation of Shield on screening rate and patients’ outcomes regularly would be crucial for the enhancement of the models of screening for colorectal cancer assessment and reporting.

Author contribution

All co-authors wrote the main manuscript text. All authors reviewed the manuscript.

Data availability

No datasets were generated or analysed during the current study.

Declarations

Conflict of interest

The authors declare no competing interests.