Prognostic Significance of Multiple Molecular Markers for Patients With Stage II Colorectal Cancer Undergoing Curative Resection

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Abstract
The aim of this study was to determine whether our constructed high-sensitivity colorimetric membrane-array method could detect circulating tumor cells (CTCs) in the peripheral blood of stage II colorectal cancer (CRC) patients and so identify a subgroup of patients who are at high risk for relapse. Adjuvant chemotherapy is not routinely recommended in patients diagnosed with UICC stage II CRC. However, up to 30% of patients with stage II disease relapse within 5 years of surgery from recurrent or metastatic disease. The identification of reliable prognostic factors for high-risk stage II CRC patients is imperative. Membrane-arrays consisting of a panel of mRNA markers that included human telomerase reverse transcription (hTERT), cytokeratin-19 (CK-19), cytokeratin-20 (CK-20), and carcinoembryonic antigen (CEA) mRNA were used to detect CTCs in the peripheral blood of 194 stage II CRC patients who underwent potentially curative (R0) resection between January 2002 and December 2005. Digoxigenin (DIG)-labeled cDNA were amplified by RT-PCR from the peripheral blood samples, which were then hybridized to the membrane-array. All patients were followed up regularly, and their outcomes were investigated completely. Overall, 53 of 194 (27.3%) stage II patients were detected with the expression of all 4 mRNA markers using the membrane-array method. After a median follow up of 40 months, 56 of 194 (28.9%) developed recurrence/metastases postoperatively. Univariately, postoperative relapse was significantly correlated with the depth of invasion (P < 0.001), the presence of vascular invasion (P < 0.001), the presence of perineural invasion (P = 0.048), the expression of all 4 mRNA markers (P < 0.001), and the number of examined lymph nodes (P = 0.031). Meanwhile, using a multivariate logistic regression analysis, T4 depth of tumor invasion (P = 0.013), the presence of vascular invasion (P = 0.032), and the expression of all 4 mRNA markers (P < 0.001) were demonstrated to be independent predictors for postoperative relapse. Combination of the depth of tumor invasion, vascular invasion, and all 4 mRNA markers as predictors of postoperative relapse showed that patients with any 1 positive predictor had a hazard ratio of about 27-fold to develop postoperative relapse (P < 0.001; 95% CI = 11.42-64.40). The interval between the detection of all 4 positive molecular markers and subsequently developed postoperative relapse ranged from 4 to 10 months (median: 7 months). Furthermore, the expression of all 4 mRNA markers in all stage II CRC patients, or either stage II colon or rectal cancer patients were strongly correlated with poorer relapse-free survival rates by survival analyses (all P < 0.001). The pilot study suggests that the constructed membrane-array method for the detection of CTCs is a potential auxiliary tool to conventional clinicopathological variables for the prediction of postoperative relapse in stage II CRC patients who have undergone curative resection.

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