TO THE EDITOR
Colorectal cancer is a malignant tumor with the third and second highest incidence and mortality rates worldwide, and its mortality rate is increasing annually[1]. Although the clinical prognosis of colorectal cancer is gradually improving, 30%-50% of patients still experience recurrence and progression after radical surgery, with approximately 80% occurring in the second to third year after surgical resection and up to 95% occurring in the first five years[2,3]. Recently, the continuous development of surgical methods, radiotherapy, chemotherapy, and other treatment methods had gradually decreased the recurrence and metastasis rates of colorectal cancer. However, it still significantly impacts the 5-year survival rate of patients and remains an important challenge in colorectal treatment and monitoring. Therefore, early tumor screening and timely intervention play important roles in prolonging patient survival and improving their prognosis[4,5]. Commonly used methods for screening colorectal cancer include colonoscopy, colon capsule endoscopy, sigmoidoscopy, plasma circulating tumor DNA (ct-DNA), computed tomography (CT), magnetic resonance imaging (MRI), and positron emission tomography/CT (PET/CT). Colonoscopy is the most reliable modality for screening colorectal tumors and provides pathological support. However, as an invasive procedure, it requires intestinal preparation as an invasive procedure and may result in surgical failure and complications, such as intestinal perforation, bleeding, and infection, making it less acceptable for patients. Although capsule endoscopy advantageously reduces pain, its inability to obtain a biopsy after lesion discovery necessitates colonoscopy for clarification. Considering its cost-effectiveness, it is currently not recommended for routine screening for colorectal cancer. Sigmoidoscopy is widely performed in Western countries. However, because of its natural defects, sigmoidoscopy cannot detect the proximal side of the sigmoid colon, which may lead to a missed diagnosis of proximal colorectal cancer. CT is also widely used for the early screening of colorectal cancer because it is easy to perform and can be compared with previous data. However, its ability to distinguish small lesions is poor; therefore, it cannot sensitively detect early tumors, delaying patient treatment. Although the early detection rate of local recurrence is higher for PET/CT than that for CT and MRI, it causes strong radiation damage and is not routinely recommended. Therefore, the current clinical focus is on finding a non-invasive and effective examination method.
In recent years, the rapid development of biotechnology has increased the non-invasive screening methods for colorectal cancer. Common screening methods include the fecal occult blood test (FOBT), fecal immunochemical test (FIT), stool DNA test, blood circulating tumor cell (CTC) testing, and plasma ct-DNA. These screening methods with the characteristics of low cost, easy operation and non-invasiveness have been widely used in current clinical practice. In a recent publication titled “Colorectal cancer screening: Modalities and adherence”, the authors provided a detailed introduction to common screening methods and summarized the populations for which they are suitable[6]. However, we still need more relevant experiments to confirm its effectiveness and safety.
Summary of commonly used non-invasive screening modalities for colorectal cancer
The FOBT is the most used screening method for early colorectal cancer. A relevant study showed that FOBT can reduce mortality in patients with colorectal cancer[7]. Among these, guaiac-based FOBT (gFOBT) is the frequently used method. However, its inability to reduce the incidence rate of colorectal cancer because of low colorectal cancer sensitivity and the high susceptibility of its detection results to dietary interference have led to elevated false- positive rates. Therefore, gFOBT has gradually been replaced by FIT. FIT uses the principle of antibody-antigen reactions in human hemoglobin, which can overcome the disadvantages of gFOBT and avoid the influence of food and other factors. This significantly improves the specificity and sensitivity, making it more suitable for mass screening. According to relevant studies, the sensitivity and specificity of the FIT in diagnosing colorectal cancer are 74% and 96%, respectively[8]. However, its sensitivity in detecting advanced colorectal adenoma is low (24%)[9]. Fecal DNA tests mainly target gene mutations and methylation in colorectal cells and can be used together with FIT. It has been used in several countries for colorectal cancer screening, and its sensitivity is higher than that of conventional FIT. Moreover, its sensitivity to precancerous lesions was significantly improved[10]. The genes currently being tested include FIT, KRAS mutations, NDRG4 methylation, and BMP3 methylation. Although this method has high sensitivity and specificity, its high inspection cost makes it difficult for use in large-scale applications, such as mass screening. Liquid biopsy overcame the many limitations of tissue biopsies and has been used to analyze CTCs in patients with cancer. The continuous development of detection technologies has gradually expanded the detection of circulating tumor factors. Furthermore, most of the relevant research are focused on ct-DNA. Currently, the common blood-based methods for colorectal cancer (CRC) screening include blood CTCs detection and plasma ct-DNA detection. Compared with traditional tissue biopsies, CTCs detection is advantageous in that it is less invasive, have high sensitivity and specificity and can provide information about the disease status of patients with CRC, aiding in early screening of CRC. A relevant study showed that the sensitivity of detecting CRC using CTCs reached 95%, which is significantly higher than the effectiveness of FOBT, which ranges from 62% to 79%[11]. However, at this stage, CTCs still lack standardized interpretation criteria, and the cost of detection remains high. Therefore, whether CTCs testing can be used for the early screening of CRC remains debatable. As an important tumor-derived factor, ct-DNA plays a crucial role in early screening, prognostic assessment, and tumor recurrence. Although one of the targets for plasma ct-DNA detection is gene mutations, the mutation rate of CRC -related individual genes is usually less than 60%, making it difficult to diagnose the disease by detecting a single gene mutation. Next-generation sequencing can simultaneously detect multiple gene mutations. However, because of its high cost, it is currently not suitable for the screening and diagnosis of CRC. Another ideal target for plasma ct-DNA detection is gene methylation; methylated SEPT9 is the most commonly used target. Results from a clinical trial indicated that the sensitivity and specificity of mSEPT9 for detecting CRC reached 74.8% and 87.4%, respectively, which were significantly higher than those of FIT. However, the sensitivity of mSEPT9 for detecting precancerous lesions was relatively low (27.4%)[12]. In addition to mSEPT9, SEPT9, SEPT9 region2, BCAT1, IKZF1, BCAN, and VAV3 can be used for ct-DNA detection. Compared with the mSEPT9 single-gene methylation test, the combination of the six genes mentioned above can cover a broader range of tumor epigenetic heterogeneity with a sensitivity and specificity of 86% and 92%, respectively[13]. Currently, ct-DNA examination is recommended because of its high cost for screening high-risk populations for CRC or those in good economic conditions among the general risk population. Additionally, it can be used as a secondary screening method for individuals who test positive in the initial FIT to improve screening accuracy and population compliance.
CONCLUSION
A study conducted by Metaxas discussed the importance of CRC screening and the current state of screening practices worldwide. This emphasizes the importance of improving screening methods to enhance early diagnosis rates and reduce mortality. And they also summarize various screening methods, including noninvasive techniques such as liquid biopsies and biomarkers, stress the importance of raising awareness and making screening accessible, especially in high-risk and low-resource areas. Finally, they called for more tailored approaches for CRC screening to meet the needs of different populations. Considering the invasiveness of colonoscopy and the radiation exposure from CT and digital radiography, blood and stool tests still play an irreplaceable role in CRC screening. With the development of new screening modalities for CRC, examinations such as CTCs and ct-DNA are playing an increasingly important role in CRC screening. However, the research is still in its early stages, and its clinical applications are limited. However, large-scale clinical studies and trials are required to validate the efficacy and safety of these markers. Furthermore, no single biomarker that can be stably detected in all types of CRC has been identified. Therefore, a multi-target strategy combining multiple markers of the same or different types has become a CRC screening option, as advocated by experts. Further research is needed to identify the optimal microbiome markers and biomarker combinations and evaluate their detection accuracy and cost.
