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A stroma-related lncRNA panel for predicting recurrence and adjuvant chemotherapy benefit in patients with early-stage colon cancer.

ABSTRACT: The heterogeneity in prognoses and chemotherapeutic responses of colon cancer patients with similar clinical features emphasized the necessity for new biomarkers that help to improve the survival prediction and tailor therapies more rationally and precisely. In the present study, we established a stroma-related lncRNA signature (SLS) based on 52 lncRNAs to comprehensively predict clinical outcome. The SLS model could not only distinguish patients with different recurrence and mortality risks through univariate analysis, but also served as an independent factor for relapse-free and overall survival. Compared with the conventionally used TNM stage system, the SLS model clearly possessed higher predictive accuracy. Moreover, the SLS model also effectively screened chemotherapy-responsive patients, as only patients in the low-SLS group could benefit from adjuvant chemotherapy. The following cell infiltration and competing endogenous RNA (ceRNA) network functional analyses further confirmed the association between the SLS model and stromal activation-related biological processes. Additionally, this study also identified three phenotypically distinct colon cancer subtypes that varied in clinical outcome and chemotherapy benefits. In conclusion, our SLS model may be a significant determinant of survival and chemotherapeutic decision-making in colon cancer and may have a strong clinical transformation value.

SUBMITTER: Zhou R

PROVIDER: S-EPMC7077592 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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A stroma-related lncRNA panel for predicting recurrence and adjuvant chemotherapy benefit in patients with early-stage colon cancer.

Zhou Rui R Sun Huiying H Zheng Siting S Zhang Jingwen J Zeng Dongqiang D Wu Jianhua J Huang Zhenhua Z Rong Xiaoxiang X Bin Jianping J Liao Yulin Y Shi Min M Liao Wangjun W

Journal of cellular and molecular medicine 20200127 5

The heterogeneity in prognoses and chemotherapeutic responses of colon cancer patients with similar clinical features emphasized the necessity for new biomarkers that help to improve the survival prediction and tailor therapies more rationally and precisely. In the present study, we established a stroma-related lncRNA signature (SLS) based on 52 lncRNAs to comprehensively predict clinical outcome. The SLS model could not only distinguish patients with different recurrence and mortality risks thr ...[more]

PMID: 31989761

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Project description:BackgroundDebates exist on the treatment decision of the stage II/III colorectal cancer (CRC) due to the insufficiency of the current TNM stage-based risk stratification system. Epithelial-mesenchymal transition (EMT) and tumor microenvironment (TME) have both been linked to CRC progression in recent studies. We propose to improve the prognosis prediction of CRC by integrating TME and EMT.MethodsIn total, 2382 CRC patients from seven datasets and one in-house cohort were collected, and 1640 stage II/III CRC patients with complete survival information and gene expression profiles were retained and divided into a training cohort and three independent validation cohorts. Integrated analysis of 398 immune, stroma, and epithelial-mesenchymal transition (ISE)-related genes identified an ISE signature independently associated with the recurrence of CRC. The underlying biological mechanism of the ISE signature and its influence on adjuvant chemotherapy was further explored.ResultsWe constructed a 26-gene signature which was significantly associated with poor outcome in Training cohort (p < 0.001, HR [95%CI] = 4.42 [3.25-6.01]) and three independent validation cohorts (Validation cohort-1: p < 0.01, HR [95%CI] = 1.70 [1.15-2.51]; Validation cohort-2: p < 0.001, HR [95% CI] = 2.30 [1.67-3.16]; Validation cohort-3: p < 0.01, HR [95% CI] = 2.42 [1.25-4.70]). After adjusting for known clinicopathological factors, multivariate cox analysis confirmed the ISE signature's independent prognostic value. Subgroup analysis found that stage III patients with low ISE score might benefit from adjuvant chemotherapy (p < 0.001, HR [95%CI] = 0.15 [0.04-0.55]). Hypergeometric test and enrichment analysis revealed that low-risk group was enriched in thr immune pathway while high-risk group was associated with the EMT pathway and CMS4 subtype.ConclusionWe proposed an ISE signature for robustly predicting the recurrence of stage II/III CRC and help treatment decision by identifying patients who will not benefit from current standard treatment.

Project description:ImportanceAdjuvant chemotherapy in patients with stage III colon cancer prevents recurrence by eradicating minimal residual disease. However, which patients remain at high risk of recurrence after completing standard adjuvant treatment cannot currently be determined. Postsurgical circulating tumor DNA (ctDNA) analysis can detect minimal residual disease and is associated with recurrence in colorectal cancers.ObjectiveTo determine whether serial postsurgical and postchemotherapy ctDNA analysis could provide a real-time indication of adjuvant therapy efficacy in stage III colon cancer.Design, setting, and participantsThis multicenter, Australian, population-based cohort biomarker study recruited 100 consecutive patients with newly diagnosed stage III colon cancer planned for 24 weeks of adjuvant chemotherapy from November 1, 2014, through May 31, 2017. Patients with another malignant neoplasm diagnosed within the last 3 years were excluded. Median duration of follow-up was 28.9 months (range, 11.6-46.4 months). Physicians were blinded to ctDNA results. Data were analyzed from December 10, 2018, through June 23, 2019.ExposuresSerial plasma samples were collected after surgery and after chemotherapy. Somatic mutations in individual patients' tumors were identified via massively parallel sequencing of 15 genes commonly mutated in colorectal cancer. Personalized assays were designed to quantify ctDNA.Main outcomes and measuresDetection of ctDNA and recurrence-free interval (RFI).ResultsAfter 4 exclusions, 96 eligible patients were eligible; median patient age was 64 years (range, 26-82 years); 49 (51%) were men. At least 1 somatic mutation was identified in the tumor tissue of all 96 evaluable patients. Circulating tumor DNA was detectable in 20 of 96 (21%) postsurgical samples and was associated with inferior recurrence-free survival (hazard ratio [HR], 3.8; 95% CI, 2.4-21.0; P < .001). Circulating tumor DNA was detectable in 15 of 88 (17%) postchemotherapy samples. The estimated 3-year RFI was 30% when ctDNA was detectable after chemotherapy and 77% when ctDNA was undetectable (HR, 6.8; 95% CI, 11.0-157.0; P < .001). Postsurgical ctDNA status remained independently associated with RFI after adjusting for known clinicopathologic risk factors (HR, 7.5; 95% CI, 3.5-16.1; P < .001).Conclusions and relevanceResults suggest that ctDNA analysis after surgery is a promising prognostic marker in stage III colon cancer. Postchemotherapy ctDNA analysis may define a patient subset that remains at high risk of recurrence despite completing standard adjuvant treatment. This high-risk population presents a unique opportunity to explore additional therapeutic approaches.

Project description:BackgroundSince 2004, a regimen of 6 months of treatment with oxaliplatin plus a fluoropyrimidine has been standard adjuvant therapy in patients with stage III colon cancer. However, since oxaliplatin is associated with cumulative neurotoxicity, a shorter duration of therapy could spare toxic effects and health expenditures.MethodsWe performed a prospective, preplanned, pooled analysis of six randomized, phase 3 trials that were conducted concurrently to evaluate the noninferiority of adjuvant therapy with either FOLFOX (fluorouracil, leucovorin, and oxaliplatin) or CAPOX (capecitabine and oxaliplatin) administered for 3 months, as compared with 6 months. The primary end point was the rate of disease-free survival at 3 years. Noninferiority of 3 months versus 6 months of therapy could be claimed if the upper limit of the two-sided 95% confidence interval of the hazard ratio did not exceed 1.12.ResultsAfter 3263 events of disease recurrence or death had been reported in 12,834 patients, the noninferiority of 3 months of treatment versus 6 months was not confirmed in the overall study population (hazard ratio, 1.07; 95% confidence interval [CI], 1.00 to 1.15). Noninferiority of the shorter regimen was seen for CAPOX (hazard ratio, 0.95; 95% CI, 0.85 to 1.06) but not for FOLFOX (hazard ratio, 1.16; 95% CI, 1.06 to 1.26). In an exploratory analysis of the combined regimens, among the patients with T1, T2, or T3 and N1 cancers, 3 months of therapy was noninferior to 6 months, with a 3-year rate of disease-free survival of 83.1% and 83.3%, respectively (hazard ratio, 1.01; 95% CI, 0.90 to 1.12). Among patients with cancers that were classified as T4, N2, or both, the disease-free survival rate for a 6-month duration of therapy was superior to that for a 3-month duration (64.4% vs. 62.7%) for the combined treatments (hazard ratio, 1.12; 95% CI, 1.03 to 1.23; P=0.01 for superiority).ConclusionsAmong patients with stage III colon cancer receiving adjuvant therapy with FOLFOX or CAPOX, noninferiority of 3 months of therapy, as compared with 6 months, was not confirmed in the overall population. However, in patients treated with CAPOX, 3 months of therapy was as effective as 6 months, particularly in the lower-risk subgroup. (Funded by the National Cancer Institute and others.).

Project description:BackgroundContemporary treatment of node-positive (N+) colon cancer consists of adjuvant chemotherapy; however, randomized data supporting this practice were derived from lesions T2 or greater. Minimal data exist regarding the use and need for adjuvant chemotherapy in T1N+ disease.ObjectiveThe aim of this study was to determine treatment trends and the effects of adjuvant chemotherapy on T1N+ colon cancers by using the National Cancer Database.DesignThis was a retrospective study. Baseline demographics, tumor, and cancer treatment characteristics were compared. Groups were matched on the propensity to receive chemotherapy. Adjusted long-term survival stratified by chemotherapy use was compared by using the Kaplan-Meier method with the log-rank test. Predictors of not receiving chemotherapy were identified by using a multivariable logistic regression model.SettingsData were collected from the National Cancer Database, which collects cancer data from over 1500 cancer centers.PatientsWe identified patients from 1998 to 2006 with T1N+ disease, excluding those with metastatic disease or previous cancer. Patients were stratified based on whether or not they received chemotherapy.Main outcome measuresThe primary outcome measure of this study was long-term survival.ResultsThree thousand one hundred thirty-seven patients had T1N+ disease; 70.6% (n = 2216) received chemotherapy, and utilization significantly increased from 1998 to 2011 (p < 0.001). Unadjusted analysis revealed that patients treated with chemotherapy were statistically younger and healthier, and had shorter postoperative lengths of stay (all p < 0.001). Unadjusted 5-year survival was higher in patients receiving chemotherapy (87.9% vs 63.0% in patients with no chemotherapy; p < 0.001) and this persisted after propensity matching with (83.4% and 63.0% in patients with or without chemotherapy; p < 0.001). Only age (OR, 0.29; p < 0.001) predicted not receiving chemotherapy.LimitationsLimitations include potential selection bias as well as the inability to compare disease-free survival/recurrence.ConclusionsAdjuvant chemotherapy appears to significantly improve long-term survival in patients receiving chemotherapy in T1N+ disease. Thus, the use of chemotherapy in T1N+ disease is justified and provides a highly significant survival benefit.

Dataset Information

A stroma-related lncRNA panel for predicting recurrence and adjuvant chemotherapy benefit in patients with early-stage colon cancer.

Publications

A stroma-related lncRNA panel for predicting recurrence and adjuvant chemotherapy benefit in patients with early-stage colon cancer.

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