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Circulating Tumor DNA Methylation Guided Postoperative Adjuvant Chemotherapy for High-risk Stage II/III Colorectal Cancer

ABSTRACT: Colorectal cancer (CRC) is one of the most common gastrointestinal tumors. According to the latest cancer report, the incidence and mortality rates of CRC are both ranked top 5 among malignant tumors worldwide and continue to rise. Patients who receive treatment in the early stage (stage I) have a 5-year survival rate of approximately 90%. However, for high-risk stage II and III colorectal cancer patients, the 5-year survival rate is only 40%-70%, and almost half of the patients experience postoperative recurrence and metastasis. Evidence suggests that Stage III CRC patients can benefit from standard adjuvant chemotherapy. It is worth noting that some high-risk stage II patients, especially those with T4N0, have a poorer prognosis compared to stage IIIA (T1-2N+). Adjuvant chemotherapy is now also recommended for postoperative cases of high-risk stage II CRC. Given the high effectiveness of the three-drug FOLFOXIRI regimen in treating metastatic CRC and the success of adjuvant chemotherapy in treating pancreatic cancer, the combination of 5-fluorouracil, oxaliplatin, and irinotecan may have a synergistic effect. Extensive study results have shown that: (a) The status of ctDNA methylation after surgery is significantly correlated with patient prognosis, and patients who are positive for ctDNA methylation in the first 1-4 weeks after surgery (before adjuvant chemotherapy) have a poor prognosis. (b) Patients who are ctDNA methylation positive in the first 1-4 weeks after surgery (before adjuvant chemotherapy) can benefit from adjuvant chemotherapy, and achieving ctDNA methylation negativity through adjuvant chemotherapy significantly improves patient prognosis. This project focuses on exploring the optimized mode of postoperative adjuvant chemotherapy for high-risk stage II and III CRC guided by ctDNA methylation, which has high scientific and innovative value. This multicenter, prospective, and randomized controlled cohort study uses a single-tube methylation-specific quantitative PCR (mqMSP) detection, which detects 10 different methylation markers and can quantitatively analyze plasma samples containing tumor DNA as low as 0.05%. This study will use this ctDNA methylation detection technology to perform quantitative detection of ctDNA methylation in the plasma of enrolled patients, and explore the effect of different chemotherapy regimens on ctDNA clearance rate and the prognostic value for ctDNA positive patients. We hope to screen out high-risk populations for recurrence through postoperative ctDNA testing, and administer more intensive chemotherapy regimens (chemotherapy upgrading) as early as possible to improve ctDNA clearance rate and patient prognosis.

DISEASE(S): High-risk Stage Ii Colorectal Cancer,Circulating Tumor Dna Methylation,Stage Iii Colorectal Cancer,Colorectal Neoplasms

PROVIDER: 67142 | ecrin-mdr-crc |

REPOSITORIES: ECRIN MDR

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Project description:Distant metastasis is the major causes of death in colorectal cancer (CRC) patients. In order to identify genes influencing the prognosis of patients with CRC, we compared gene expression in primary tumors with and without distant metastasis using an oligonucleotide microarray. We also examined the expression of the candidate gene in 100 CRC patients by quantitative real-time reverse transcription PCR and studied the relationship between its expression and the prognosis of patients with CRC. As a result, we identified MUC12 as a candidate gene involved in metastasis processes by microarray analysis. Quantitative real-time reverse transcription PCR showed that MUC12 expression was significantly lower in cancer tissues than in adjacent normal tissues (P < 0.001). In stage II and stage III CRC, patients with low expression showed worse disease-free survival (P = 0.038). Multivariate analysis disclosed that MUC12 expression status was an independent prognostic factor in stage II and stage III CRC (relative risk, 9.532; 95% confidence interval, 2.303-41.905; P = 0.002). This study revealed the prognostic value of MUC12 expression in CRC patients. Moreover, our result suggests MUC12 expression is a possible candidate gene for assessing postoperative adjuvant therapy for CRC patients. Total of 111 microarray datasets (77 for LCM samples, and 17 pairs for homogenized samples from tumor and adjacent tissues) were normalized using robust multi-array average (RMA) method under R 2.6.2 statistical software together with BioConductor package, as described previously. Then, the gene expression levels were log2-transformed, and 62 control probe sets were removed for further analysis. In order to identify a set of genes associated with development of metastatic recurrence, we performed Wilcoxon rank-sum test for gene expression differences of 54,613 probe sets between recurrence and non-recurrence groups. Similarly, Wilcoxon singed-rank test was conducted to select genes which showed significant expression difference between tumor and adjacent tissue. Then, we selected a set of genes that satisfied both of above two criteria.

Project description:Colorectal cancer (CRC) is one of the most common gastrointestinal tumors. According to the latest cancer report, the incidence and mortality rates of CRC are both ranked top 5 among malignant tumors worldwide and continue to rise. Patients who receive treatment in the early stage (stage I) have a 5-year survival rate of approximately 90%. However, for high-risk stage II and III colorectal cancer patients, the 5-year survival rate is only 40%-70%, and almost half of the patients experience postoperative recurrence and metastasis. Circulating tumor DNA (ctDNA) is a small fraction of total cell-free DNA (cfDNA) in peripheral blood circulation, carrying tumor-specific genetic and epigenetic information. It can usually be detected in the serum or plasma of tumor patients in peripheral blood. Studies have shown that methylation detection of plasma ctDNA can be used for predicting the efficacy and prognosis of tumor postoperatively, as well as for dynamic monitoring. Current methods for monitoring CRC recurrence include testing for carcinoembryonic antigen (CEA) in blood and periodic computed tomography (CT) scans. However, due to the low sensitivity of CEA and the radiation and cost limitations of CT examination, the disease status of postoperative CRC patients cannot be well-monitored. ctDNA is a promising biomarker for monitoring the recurrence and metastasis of CRC. Research results have shown that ctDNA can be detected in all subjects before surgery, and the changes in ctDNA levels are related to the extent of surgical resection. The detection of ctDNA after surgery generally indicates recurrence within one year. ctDNA may be a more reliable and sensitive indicator than the current standard biomarker CEA, providing a window for early intervention. This multicenter, prospective, and randomized controlled cohort study uses a single-tube methylation-specific quantitative PCR (mqMSP) detection, which detects 10 different methylation markers and can quantitatively analyze plasma samples containing tumor DNA as low as 0.05%. This study will use the ctDNA methylation detection technology to conduct quantitative detection of ctDNA methylation in the plasma of enrolled patients, hoping to predict the recurrence and metastasis risk of patients at an earlier stage through ctDNA changes, and to explore the value of ctDNA detection in guiding postoperative follow-up for high-risk stage II and III CRC.

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Circulating Tumor DNA Methylation Guided Postoperative Adjuvant Chemotherapy for High-risk Stage II/III Colorectal Cancer

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