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Expressions of 10 genes as candidate predictors of recurrence in stage III colon cancer patients receiving adjuvant oxaliplatin-based chemotherapy.

ABSTRACT: Approximately 30% patients with stage III colon cancer (CC) develop local recurrence and/or distant metastasis, even if postoperative adjuvant chemotherapy with oxaliplatin plus 5-fluorouracil and leucovorin (5-FU/LV) has been completed. In the present study, molecular analysis was performed to identify molecular markers of tumor recurrence in patients with stage III CC receiving oxaliplatin-based adjuvant chemotherapy. The FACOS study was conducted as a phase II study to evaluate the safety and efficacy of oxaliplatin-based treatment for stage III CC patients. Of the 132 CC patients enrolled in the present study, gene expression analysis using a microarray was conducted in 51 patients. Of these 51 patients, 6 developed recurrence within 5 years. The topmost 5% genes that showed differential expressions between cases that developed/did not develop recurrence were selected, and a set of predictive molecular markers for recurrence was identified. Of the 34,694 genes in the microarray, 1,734 genes were extracted as topmost 5% genes showing differential expressions between cases with and without recurrence. Among these, 10 genes, includingADH1A, ADH1C, CA12, CHP2, HMGCS2, SNAR-A1, TPI1, MS4A12, PLA2G10 and PTPRO, were identified as markers that could clearly divide patients with and without recurrence. Although several prediction models of tumor recurrence have been reported for CC, the set of 10 genes that the present study identified may be useful to predict the risk of recurrence in stage III CC patients receiving oxaliplatin-based adjuvant chemotherapy. Based on these results, high-risk patients with CC should be carefully observed to detect tumor recurrence during the follow-up period.

SUBMITTER: Kumamoto K

PROVIDER: S-EPMC6607086 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

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Expressions of 10 genes as candidate predictors of recurrence in stage III colon cancer patients receiving adjuvant oxaliplatin-based chemotherapy.

Kumamoto Kensuke K Nakachi Yutaka Y Mizuno Yosuke Y Yokoyama Masaru M Ishibashi Keiichiro K Kosugi Chihiro C Koda Keiji K Kobayashi Michiya M Tanakaya Kohji K Matsunami Toshio T Eguchi Hidetaka H Okazaki Yasushi Y Ishida Hideyuki H

Oncology letters 20190605 2

Approximately 30% patients with stage III colon cancer (CC) develop local recurrence and/or distant metastasis, even if postoperative adjuvant chemotherapy with oxaliplatin plus 5-fluorouracil and leucovorin (5-FU/LV) has been completed. In the present study, molecular analysis was performed to identify molecular markers of tumor recurrence in patients with stage III CC receiving oxaliplatin-based adjuvant chemotherapy. The FACOS study was conducted as a phase II study to evaluate the safety and ...[more]

PMID: 31423202

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Project description:BackgroundThe addition of oxaliplatin to adjuvant 5-fluorouracil (5-FU) improves survival of patients with stage III colon cancer in randomized clinical trials (RCTs). However, RCT participants are younger, healthier, and less racially diverse than the general cancer population. Thus, the benefit of oxaliplatin outside RCTs is uncertain.Subjects and methodsPatients younger than 75 years with stage III colon cancer who received chemotherapy within 120 days of surgical resection were identified from five observational data sources-the Surveillance, Epidemiology, and End Results registry linked to Medicare claims (SEER-Medicare), the New York State Cancer Registry (NYSCR) linked to Medicaid and Medicare claims, the National Comprehensive Cancer Network (NCCN) Outcomes Database, and the Cancer Care Outcomes Research & Surveillance Consortium (CanCORS). Overall survival (OS) was compared among patients treated with oxaliplatin vs non-oxaliplatin-containing adjuvant chemotherapy. Overall survival for 4060 patients diagnosed during 2004-2009 was compared with pooled data from five RCTs (the Adjuvant Colon Cancer ENdpoinTs [ACCENT] group, n = 8292). Datasets were juxtaposed but not combined using Kaplan-Meier curves. Covariate and propensity score adjusted proportional hazards models were used to calculate adjusted survival hazard ratios (HR). Stratified analyses examined effect modifiers. All statistical tests were two-sided.ResultsThe survival advantage associated with the addition of oxaliplatin to adjuvant 5-FU was evident across diverse practice settings (3-year OS: RCTs, 86% [n = 1273]; SEER-Medicare, 80% [n = 1152]; CanCORS, 88% [n = 129]; NYSCR-Medicaid, 82% [n = 54]; NYSCR-Medicare, 79% [n = 180]; and NCCN, 86% [n = 438]). A statistically significant improvement in 3-year overall survival was seen in the largest cohort, SEER-Medicare, and in the NYSCR-Medicare cohort (non-oxaliplatin-containing vs oxaliplatin-containing adjuvant therapy, adjusted HR of death: pooled RCTs: HR = 0.80, 95% CI = 0.70 to 0.92, P = .002; SEER-Medicare: HR = 0.70, 95% CI = 0.60 to 0.82, P < .001; NYSCR-Medicare patients aged ?65 years: HR = 0.58, 95% CI = 0.38 to 0.90, P = .02). The association between oxaliplatin treatment and better survival was maintained in older and minority group patients, as well as those with higher comorbidity.ConclusionThe addition of oxaliplatin to 5-FU appears to be associated with better survival among patients receiving adjuvant colon cancer treatment in the community.

Project description:BackgroundMethylation levels of long interspersed nucleotide elements (LINE-1) are representative of genome-wide methylation status and crucial in maintaining genomic stability and expression. Their prognostic impact on colon cancer patients receiving adjuvant chemotherapy has not been well established. We evaluated the association between LINE-1 methylation status and clinicopathologic features and postoperative oncological outcomes in stage III colon cancer patients.Materials and methods129 UICC stage III colon cancer patients who had received radical resection and FOLFOX adjuvant chemotherapy were enrolled. Global methylation was estimated by analyzing tumor LINE-1 methylation status using bisulfite-polymerase chain reaction (PCR) and pyrosequencing assay. Demographics, clinicopathological data, and postoperative outcomes were recorded by trained abstractors. Outcome measurements included postoperative recurrence and disease-free survival. Univariate, multivariate, and survival analyses were conducted to identify prognostic factors of oncological outcomes.ResultsThe LINE-1 methylation of all 129 patients was measured on a 0-100 scale (mean 63.3; median 63.7, standard deviation 7.1), LINE-1 hypomethylation was more common in patients aged 65 years and above (61.7%±7.6% vs. 64.6±6.4, p=0.019) and those with post-therapeutic recurrence (61.7±7.4 vs 64.3±6.7, p=0.041). Considering risk adjustment, LINE-1 hypomethylation was found to be an independent risk factor of post-therapeutic recurrence (Adjusted OR=14.1, p=0.012). Kaplan-Meier analysis indicated that patients in the low methylation group had shorter period of disease free survival (p=0.01). In a stratified analysis that included 48 patients with post-therapeutic recurrence, it was found that those who experienced shorter period of disease free survival (?6 months) appeared to have lower LINE-1 methylation levels than patients who reported of recurrence after 6 months (56.68±15.75 vs. 63.55±7.57, p=0.041).ConclusionThere was a significantly greater risk of early postoperative recurrence and a shorter period of disease-free survival in Stage III colon cancer patients exhibiting LINE-1 hypomethylation status after being treated with radical resection and FOLFOX chemotherapy.

Project description:Response to oxaliplatin-based adjuvant chemotherapy varies among patients with stage II and III colon cancer; however, genetic alterations associated with this response remain incompletely characterized. A three-stage analytical framework, including the discovery, validation, and replication stages, was designed to explore genetic alterations modulating response to oxaliplatin-based chemotherapy in adjuvant setting among patients with stage II and III colon cancer receiving complete resection of tumor. Except for several somatic mutated genes, such as ARSD and ACE, showing less definitive associations with response to oxaliplatin-based adjuvant chemotherapy, we found stable associations of rs6891545C > A polymorphism in SLF1 gene, a key component of DNA damage response system, with the response across all three stages. Patients with rs6891545 A allele had significantly lower risk of poor responsiveness to oxaliplatin-based adjuvant chemotherapy at both discovery and validation stages, compared with ones possessing wild homozygous genotype CC (discovery stage: odds ratio, 0; 95% CI, 0-0.48; P = .005; validation stage: odds ratio, 0.33; 95% CI, 0.11-0.99; P = .048). In the replication cohort, rs6891545 A allele was confirmed to be strongly associated with improved DFS (hazard ratio, 0.43; 95% CI, 0.23-0.81; P = .007). Notably, the improvement persisted after controlling for sex, age, tumor location, differentiation, and stage (hazard ratio, 0.42; 95% CI, 0.22-0.80; P = .009). Moreover, in silico analysis unraveled strong impact of rs6891545 A allele on local secondary structure of SLF1 mRNA, possibly leading to low SLF1 protein expression. We conclude that the rs6891545C > A polymorphism may serve as an independent marker of response to oxaliplatin-based adjuvant chemotherapy in patients with stage II and III colon cancer, with improved clinical benefit observed in patients with the A allele possibly attributable to low expression of SLF1 protein resulting in deficient DNA repair capacity.

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Expressions of 10 genes as candidate predictors of recurrence in stage III colon cancer patients receiving adjuvant oxaliplatin-based chemotherapy.

Publications

Expressions of 10 genes as candidate predictors of recurrence in stage III colon cancer patients receiving adjuvant oxaliplatin-based chemotherapy.

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