Cancer Genetics and Epigenetics, 2025, Vol.13, No.6, 287-299 http://medscipublisher.com/index.php/cge 295 treatment, and such changes often occur earlier than imaging results, regardless of whether the condition improves or worsens (Holz et al., 2025; Van Steijn et al., 2025). If ctDNA significantly decreases or turns negative in the early stage of treatment, it generally indicates that the progression-free survival or overall survival may be longer. Conversely, a persistently high or continuously rising ctDNA level often indicates poor therapeutic effect and a more likely premature deterioration of the condition, providing a reference for doctors to judge the therapeutic effect more quickly and whether to adjust the treatment plan. In clinical practice, doctors can arrange treatment more individually based on changes in ctDNA: when ctDNA turns negative, they have more confidence in continuing the original treatment plan; When ctDNA remains consistently positive, it is advisable to consider adjusting or enhancing treatment as early as possible before significant deterioration in imaging or symptoms. Based on these results, appropriate clinical trials or new treatment methods should be selected for the patient. With the advancement of detection technology, the role of ctDNA in guiding treatment adjustment after recurrence of colorectal cancer is expected to be further enhanced. 7 Current Challenges and Future Prospects 7.1 The necessity of standardizing and unifying ctDNA detection methods Although circulating tumor DNA (ctDNA) holds great promise as a highly breakthrough biomarker in the treatment and management of colorectal cancer (CRC), the lack of a unified standard for detection methods is currently the most significant issue. The current ctDNA detection technologies vary greatly. For instance, there are detection platforms for specific tumors and those for non-specific tumors, and the sample processing procedures and detection sensitivity standards also differ (Negro et al., 2025). This difference makes it difficult to compare the results of different studies and also makes the research conclusions hard to replicate and generalize. For instance, different detection sensitivities may affect the detection results of minimal residual disease (MRD), thereby interfering with clinical treatment decisions - especially when the ctDNA content in the bodies of early-stage cancer patients is extremely low. In addition, there is no consensus on key issues such as "how to collect samples, how to process samples, and how to report test results", which also hinders ctDNA testing from entering the routine clinical process (Chen et al., 2025). Experts and research teams suggest establishing a unified ctDNA testing standard, which includes sample collection, testing procedures, and result interpretation, etc. It is generally believed that technologies with a sensitivity of over 95% and the ability to simultaneously detect multiple genes should be selected, along with consistent positive determination criteria and multi-center data sharing, to enhance the comparability and stability of the results. With the development of ctDNA technology, only by constantly improving these norms and reaching a consensus within the industry can the test results serve clinical diagnosis and treatment more reliably. 7.2 False negatives, challenges in cost and accessibility False negatives are a very obvious problem when ctDNA is used to guide the treatment and care of colorectal cancer, which may be related to the characteristics of the tumor itself or caused by deficiencies in the detection technology. For example, if the number of tumor cells is very small, or the cancer cells have metastasized to the lungs, peritoneum and other places, or the detection method is not sensitive enough, even if there are still residual cancer cells in the patient's body, the ctDNA test result may still be negative. Research has found that for patients with cancer cells metastasizing to the lungs or peritoneum, the credibility of ctDNA test results is relatively low, which may delay early treatment. In addition, when conducting tests, a balance needs to be struck between sensitivity and accuracy: too high sensitivity may lead to false positives, while too low sensitivity will increase the risk of false negatives. In either case, it will have a negative impact on the treatment of patients (Chen et al., 2025; Henriksen et al., 2023). The high cost of testing and the difficulty in promotion are also among the important reasons why ctDNA testing is not widely used at present. High-sensitivity ctDNA testing using next-generation sequencing technology is often expensive, and many hospitals do not yet have the equipment and conditions to carry out such tests. As a result, patients in areas with relatively scarce medical resources find it more difficult to have the opportunity to undergo this examination, which has also led people to start paying attention to and discussing the issue of
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