Cancer Genetics and Epigenetics, 2025, Vol.13, No.6, 287-299 http://medscipublisher.com/index.php/cge 294 of traditional regimens, providing a basis for reducing the treatment intensity of ctDNA-negative patients. The DYNAMIC-III and Dynamic-rectal studies extended this strategy to stage III colon cancer and locally advanced rectal cancer, further demonstrating the value of ctDNA in predicting recurrence and guiding treatment; Although the intensive treatment of DYNAMIC-III did not significantly improve the survival rate, the overall results still indicated that ctDNA was an important tool for risk stratification and individualized treatment. The GALAXY, VEGA and ALTAIR trials under the CIRCULATION-JAPAN project systematically evaluated ctDNA-based therapeutic enhancement or reduction strategies on the same platform. The GALAXY study found that positive ctDNA after surgery is a key indicator for predicting recurrence, and such patients benefit the most from adjuvant chemotherapy. Subsequent studies focused on evaluating whether ctDNA-negative patients could safely reduce or abandon adjuvant therapy, and exploring whether new drugs or intensive regimens could improve the prognosis of CTDNA-positive patients (Kotani et al., 2023; Nakamura et al., 2024). These international studies and ongoing trials are driving the development of colorectal cancer treatment towards ctDNa-based precision intervention models, which are expected to improve survival rates while minimizing unnecessary toxic and side effects. 6 The Role of ctDNA in the Treatment After Recurrence 6.1 Early detection of recurrence and assistance in locating the recurrence site circulating tumor DNA (ctDNA) is a relatively sensitive biomarker. Regular detection can capture recurrence signals at the molecular level, usually several months earlier than imaging examinations or clinical symptoms. On average, the risk of postoperative recurrence of colorectal cancer can be indicated approximately 3 to 10 months earlier (Mo et al., 2023; Gu et al., 2025). Studies have shown that ctDNA has high sensitivity and accuracy in diagnosing recurrence, and the results are relatively stable during multiple sampling tests. As a dynamic monitoring method, it can, to a certain extent, make up for or even surpass cancer embryo antigen detection and imaging examinations, enabling doctors to detect recurrence signs earlier (Hisamatsu et al., 2025). ctDNA can also help determine the specific location of recurrence. When ctDNA is positive but no lesions have been found by conventional imaging, doctors can arrange more detailed examinations such as liver-specific enhanced MRI or PET-CT based on the ctDNA results to more accurately identify hidden metastases and recurrence sites. To provide a basis for subsequent precise treatment (Hisamatsu et al., 2025). 6.2 Monitor gene mutations related to drug resistance ctDNA analysis has a distinct advantage, which is that it can reflect in real time the molecular-level changes of recurrent or metastatic colorectal cancer. Tissue biopsy can only reflect the static situation at a certain point in time, while ctDNA can continuously reveal the genetic differences and changes of tumor cells, including the problem of drug resistance caused by RAS gene family mutations (Kagawa et al., 2025; Kim et al., 2025; Massaro et al., 2025). Monitoring of RAS mutations through ctDNA revealed that drug-resistant mutations may occur during or after targeted therapy, disappear, and then reappear. This situation is referred to as "new-onset RAS wild-type". This change has significant guiding significance for treatment: If the RAS mutation previously detected in the patient's ctDNA disappears, the patient may become sensitive to EGFR-targeted therapy again, which provides a new direction for adjusting the treatment plan and achieving individualized treatment. ctDNA can not only detect the RAS gene, but also discover other gene changes related to drug resistance, such as abnormal BRAF and EGFR, etc. These changes may all lead to drug resistance problems (Kagawa et al., 2025). This relatively comprehensive and repeatable genetic monitoring is particularly important for metastatic colorectal cancer. It helps to detect new genetic abnormalities earlier during systemic treatment, enabling doctors to adjust medication based on the patient's current genetic information rather than relying solely on previous tissue biopsy results, thereby making treatment more flexible and precise. 6.3 Real-time evaluation of treatment effect to guide personalized treatment adjustment ctDNA is a useful tool for real-time assessment of the treatment of patients with recurrent or metastatic colorectal cancer. During systemic treatment, changes in its level can directly reflect tumor activity and response to
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