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  • br Results br Patient Characteristics and

    2020-08-14


    Results
    Patient Characteristics and Irinotecan-Based Chemotherapy
    In total, 102 patients were included in this study (Supplementary material 2). The patient characteristics are described in Table 1. According to the inclusion criteria, all patients had undergone resection of the primary tumor. All surgical specimens used for this study were collected from the primary tumors before the 18 α-Glycyrrhetinic acid of irinotecan treatment and therefore do not reflect the potential effects from subsequent treatments. Twenty-one patients (20.6%) exhibited proximal (cecum to transverse colon) lesions, and 81 (79.4%) exhibited distal lesions. In total, 73 patients (71.6%) presented with synchronous metastatic disease and 29 (28.4%) with metachronous metastasis. Irinotecan-based chemotherapy was administered as first-line therapy in 51 patients (50.0%), second-line in 38 (37.3%), and ≥third-line in 13 patients (12.7%). The irinotecan-containing chemotherapy regimens include FOLFIRI in 44 patients (43.1%), IFL in 15 (14.7%), XELIRI in 21 (20.6%), and irinotecan as a single agent in 22 patients (21.6%). Bevacizumab or cetuximab was added for five and four patients, respectively. The TTP following irinotecan therapy was 5.57 months (95% CI, 3.61-7.52) in the entire population. At the time of last follow-up (March 2018), all 102 patients had died. The median OS after the initiation of irinotecan-based chemotherapy was 20.4 months (95% CI, 18.0-22.8).
    CHFR Methylation and Irinotecan Treatment Outcomes
    Promoter methylation in CHFR, WRN, and SULF2 was observed in 16 (15.7%), 24 (23.5%), and 33 (32.4%) patients, respectively. Twenty-two (21.6%) patients exhibited at least three methylated CIMP-specific loci and were defined as CIMP-positive. Among the five CIMP-specific loci, NEUROG1 was the most frequently methylated locus (63 patients; 61.8%), followed by CACNA1G (41; 40.2%), IGF2 (28; 27.5%), SOCS1 (16; 15.7%), and RUNX3 (16; 15.7%). In our analysis, CHFR and WRN methylation was significantly associated with CIMP positivity, whereas SULF2 methylation was not (Supplementary Material 3). CHFR methylation was closely associated with the WRN methylation as well. We confirmed a significant increase in CHFR methylation level according to CIMP subtypes using the TCGA dataset (Supplementary material 3). The CHFR-methylated group showed more frequent mutations in KRAS, NRAS, or BRAF compared to the unmethylated group (62.5% vs. 31.2%; P = .024). However, other clinicopathological characteristics including tumor location, BRAF mutation, and MMR status were not associated with methylation of CHFR, WRN, SULF2, or the CIMP status in our analysis (Table 1).
    TTP after the initiation of irinotecan-containing chemotherapy was significantly different according to CHFR methylation status (P = 
    Table 1. Patient Characteristics and CHFR Methylation
    Total (%) CHFR CHFR P
    Methylated (%) Unmethylated (%)
    Age
    Sex
    Location
    Histology
    Differentiation
    KRAS/NRAS
    BRAF status
    hMLH1/hMSH2
    Presentation
    No. metastatic organs
    CEA
    No. prior treatment(s)
    Irinotecan regimen
    P = .024 for KRAS/NRAS/BRAF mutation frequency and CHFR methylation (62.5% vs. 31.2% for CHFR methylated and unmethylated groups, respectively)
    150 CHFR Promoter Methylation in Metastatic Colorectal Cancer Cha et al. Neoplasia Vol. 21, No. 1, 2019
    Figure 1. (A-B) Kaplan-Meier curves for TTP and OS of irinotecan treatment according to CHFR methylation. (C-D) Kaplan-Meier curves for TTP and OS of irinotecan treatment according to CHFR methylation and CIMP status.
    Table 2. Multivariate Analyses for TTP and OS According to CHFR Status
    TTP
    OS
    Covariates in the Final Model Adjusted HR (95% CI) P
    Covariates in the Final Model Adjusted HR (95% CI) P
    No. prior treatments
    Multivariate analyses were performed by Cox regression analysis with forward conditional selection method adjusted for age (continuous), sex, differentiation (well to moderately differentiated vs. poorly differentiated), tumor location (right vs. left), metastatic organs (1-2 vs. ≥3), CEA level (≤5 vs. N5.0 ng/ml), BRAF mutation, hMLH1/hMSH2, number of prior treatment(s), promoter methylation, and CIMP status.
    CHFR Promoter Methylation in Metastatic Colorectal Cancer Cha et al. 151
    Table 3. Multivariate Analyses for TTP and OS According to CHFR and CIMP Status
    TTP
    OS
    Covariates in the Final Model Adjusted HR (95% CI) P Covariates in the Final Model Adjusted HR (95% CI) P
    CHFR/CIMP status
    b.001 CHFR/CIMP status
    Multivariate analyses were performed by Cox regression analysis with forward conditional selection method adjusted for age (continuous), sex, differentiation (well to moderately differentiated vs. poorly differentiated), tumor location (right vs. left), metastatic organs (1-2 vs. ≥3), CEA level (≤5 vs. N5.0 ng/ml), BRAF mutation, hMLH1/hMSH2, number of prior treatment(s), and CHFR/CIMP status.