Clinical Outcome Of First - Line Chemotherapy For Advanced Colorectal Cancer And Preliminary Screening Of Therapeutic MicroRNAs

Part I Efficacy of first-line chemotherapy and prognostic factors in patients with advanced colorectal cancerObject:To assess the efficacy of standard first-line chemotherapy and investigate the prognostic factors related to survival in patients with advanced colorectal cancer.Methods:A total of 210 patients who had received standard FOLFOX/XELOX or FOLFIRI as first-line chemotherapy regimen between January 2009 and May 2013 at Fudan University Cancer Hospital were retrospectively analyzed. Clinical characteristics including age, gender, primary tumor site, timing of metastases, radical resection of primary lesion, number of metastatic organs and first-line regimen were identified. All statistical analyses were performed using the SPSS software package 19.0. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method with log-rank test in univariate analysis. Cox regression model was used in PFS and OS multivariate analysis. A subgroup analysis was also used. Early response rate was estimated by chi-square test or Fisher exact test for univariate analysis and logistic regression model for multivariate analysis. Differences with a P value of less than 0.05 were considered to be statistically significant.Results:210 patients were enrolled in this retrospective study.125 patients(59.0%) of them received FOLFOX/XELOX as first-line chemotherapy and 85 patients (41.0%) received FOLFIRI regimen. The median PFS of the 210 patients was 8.1 months (95%CI:7.31～8.89 months) and the median OS was 25.3 months (95%CI:22.08～28.53months). Multivariate analysis demonstrated that radical resection of primary lesion (P=0.022) and number of metastatic organs (P=0.010) were independent prognostic factors related to PFS. In terms of OS, multivariate analysis showed that radical resection of primary lesion (P=0.000) and number of metastatic organs (P=0.001) were also independent prognostic factors. No prognostic factors were found to be significant for first-line response in univariate analysis. Subgroup analysis showed that among the 170 patients who underwent radical resection of primary lesion, number of metastatic organs (P=0.039) was still the independent prognostic factor related to PFS. In 125 patients treated with FOLFOX/XELOX, radical resection of primary lesion was prognostic factor influencing PFS (P=0.018) but multivariate analysis showed no significant difference. Gender was independent prognostic factor related to early response rate in this group of patients (P=0.022). In 85 patients treated with FOLFIRI, radical resection of primary lesion (P=0.003) was independent prognostic factor related to PFS in multivariate analysis.Conclusion:FOLFOX/XELOX and FOLFIRI achieved similar efficacy as first line chemotherapy regimen for patients with advanced colorectal cancer. Radical resection of primary lesion and number of metastatic organs are independent factors for both PFS and OS. Number of metastatic organs is independent factor for PFS in patients treated with FOLFIRI regimen. 85 patients (41.0%) received FOLFIRI regimen. The median PFS of the 210 patients was 8.1 months (95%CI:7.31～8.89 months) and the median OS was 25.3 months (95%CI:22.08～28.53months). Multivariate analysis demonstrated that radical resection of primary lesion (P=0.022) and number of metastatic organs (P=0.010) were independent prognostic factors related to PFS. In terms of OS, multivariate analysis showed that radical resection of primary lesion (P=0.000) and number of metastatic organs (P=0.001) were also independent prognostic factors. No prognostic factors were found to be significant for first-line response in univariate analysis. Subgroup analysis showed that among the 170 patients who underwent radical resection of primary lesion, number of metastatic organs (P=0.039) was still the independent prognostic factor related to PFS. In 125 patients treated with FOLFOX/XELOX, radical resection of primary lesion was prognostic factor influencing PFS (P=0.018) but multivariate analysis showed no significant difference. Gender was independent prognostic factor related to early response rate in this group of patients (P=0.022). In 85 patients treated with FOLFIRI, radical resection of primary lesion (P=0.003) was independent prognostic factor related to PFS in multivariate analysis.Conclusion:FOLFOX/XELOX and FOLFIRI achieved similar efficacy as first line chemotherapy regimen for patients with advanced colorectal cancer. Radical resection of primary lesion and number of metastatic organs are independent factors for both PFS and OS. Number of metastatic organs is independent factor for PFS in patients treated with FOLFIRI regimen.Part Ⅱ Preliminary exploration of miRNA expression related to efficacy of first-line chemotherapy in advanced colorectal cancerObject:To explore the miRNA expression related to efficacy of first-line chemotherapy in advanced colorectal cancer using the technology of miRNA microarray and real-time PCR. We hope to find some candidate miRNAs for further study.Methods:(1)In the present study, we chose paired cases from patients with advanced colorectal cancer who received standard FOLFOX/XELOX or FOLFIRI as first-line chemotherapy and had plasma sample which was obtained before chemotherapy. In those treated with FOLFOX/XELOX, we selected 3 pairs of cases including 3 patients with long PFS and 3 patients with short PFS. In those treated with FOLFIRI, we selected 5 pairs of cases including 5 patients with long PFS and 5 patients with short PFS. TaqMan Human MicroRNA Array was used to screen miRNA from the above samples. (2) In those treated with FOLFOX/XELOX. we selected 10 pairs of cases including 10 patients with long PFS and 10 patients with short PFS. The same amount of patients was selected as above in patients treated with FOLFIRI. Real-time PCR was used to further validate the microarray data in the above samples.Results:(1) Using 2-fold expression difference as a threshold, comparing patients with different efficacy (long PFS vs short PFS), we identified 25 miRNAs differently expressed in the paired patients treated with FOLFOX/XELOX. Of the 25 differentially expressed miRNAs,15 miRNAs expression levels were down-regulated and 10 miRNAs were up-regulated. In the FOLFIRI group, 30 miRNAs differently expressed in the paired patients treated with FOLFOX/XELOX. 21 miRNAs expression levels were down-regulated and 9 miRNAs were up-regulated. (2)RT-PCR was used to detect the microarray data using 2-fold expression difference as a threshold.6 miRNAs showed different expression in the paired patients treated with FOLFOX/XELOX.4 miRNAs expression levels were down-regulated and 2 miRNAs were up-regulated. In the FOLFIRI group, 4 miRNAs showed different expression.3 miRNAs expression levels were down-regulated and 1 miRNA was up-regulated.Conclusion:MiRNA microarray and real-time PCR were effective technology to detect circulating miRNA. Using these methods, we found the different expressing profile of miRNA related to first-line chemotherapy efficacy.