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Higher ETV5 Expression Associates With Poor 5-Florouracil-Based Adjuvant Therapy Response in Colon Cancer.

ABSTRACT: Discovery of markers predictive for 5-Fluorouracil (5-FU)-based adjuvant chemotherapy (adjCTX) response in patients with locally advanced stage II and III colon cancer (CC) is necessary for precise identification of potential therapy responders. PEA3 subfamily of ETS transcription factors (ETV1, ETV4, and ETV5) are upregulated in multiple cancers including colon cancers. However, the underlying epigenetic mechanism regulating their overexpression as well as their role in predicting therapy response in colon cancer are largely unexplored. In this study, using gene expression and methylation data from The Cancer Genome Atlas (TCGA) project, we showed that promoter DNA methylation negatively correlates with ETV4 expression (? = -0.17, p = 5.6 × 10^-3) and positively correlates with ETV5 expression (? = 0.22, p = 1.43 × 10^-4) in colon cancer tissue. Further, our analysis in 1,482 colon cancer patients from five different cohorts revealed that higher ETV5 expression associates with shorter relapse-free survival (RFS) of adjCTX treated colon cancer patients (Hazard ratio = 2.09-5.43, p = 0.004-0.01). The present study suggests ETV5 expression as a strong predictive biomarker for 5-FU-based adjCTX response in stage II/III CC patients.

SUBMITTER: Giri AK

PROVIDER: S-EPMC7917823 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Higher ETV5 Expression Associates With Poor 5-Florouracil-Based Adjuvant Therapy Response in Colon Cancer.

Giri Anil K AK

Frontiers in pharmacology 20210209

Discovery of markers predictive for 5-Fluorouracil (5-FU)-based adjuvant chemotherapy (adjCTX) response in patients with locally advanced stage II and III colon cancer (CC) is necessary for precise identification of potential therapy responders. PEA3 subfamily of ETS transcription factors (ETV1, ETV4, and ETV5) are upregulated in multiple cancers including colon cancers. However, the underlying epigenetic mechanism regulating their overexpression as well as their role in predicting therapy respo ...[more]

PMID: 33658938

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Project description:Background & aimsThe CpG island methylator phenotype (CIMP), defined by a high frequency of aberrantly methylated genes, is a characteristic of a subclass of colon tumors with distinct clinical and molecular features. Cohort studies have produced conflicting results on responses of CIMP-positive tumors to chemotherapy. We assessed the association between tumor CIMP status and survival of patients receiving adjuvant fluorouracil and leucovorin alone or with irinotecan (IFL).MethodsWe analyzed data from patients with stage III colon adenocarcinoma randomly assigned to groups given fluorouracil and leucovorin or IFL after surgery, from April 1999 through April 2001. The primary end point of the trial was overall survival and the secondary end point was disease-free survival. DNA isolated from available tumor samples (n = 615) was used to determine CIMP status based on methylation patterns at the CACNA1G, IGF2, NEUROG1, RUNX3, and SOCS1 loci. The effects of CIMP on survival were modeled using Kaplan-Meier and Cox proportional hazards; interactions with treatment and BRAF, KRAS, and mismatch repair (MMR) status were also investigated.ResultsOf the tumor samples characterized for CIMP status, 145 were CIMP positive (23%). Patients with CIMP-positive tumors had shorter overall survival times than patients with CIMP-negative tumors (hazard ratio = 1.36; 95% confidence interval: 1.01-1.84). Treatment with IFL showed a trend toward increased overall survival for patients with CIMP-positive tumors, compared with treatment with fluorouracil and leucovorin (hazard ratio = 0.62; 95% CI: 0.37-1.05; P = .07), but not for patients with CIMP-negative tumors (hazard ratio = 1.38; 95% CI: 1.00-1.89; P = .049). In a 3-way interaction analysis, patients with CIMP-positive, MMR-intact tumors benefited most from the addition of irinotecan to fluorouracil and leucovorin therapy (for the interaction, P = .01). CIMP was more strongly associated with response to IFL than MMR status. Results for disease-free survival times were comparable among all analyses.ConclusionsPatients with stage III, CIMP-positive, MMR-intact colon tumors have longer survival times when irinotecan is added to combination therapy with fluorouracil and leucovorin.

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.

Project description:BackgroundThe role of adjuvant chemotherapy in stage II colon cancer continues to be debated. The presence of circulating tumor DNA (ctDNA) after surgery predicts very poor recurrence-free survival, whereas its absence predicts a low risk of recurrence. The benefit of adjuvant chemotherapy for ctDNA-positive patients is not well understood.MethodsWe conducted a trial to assess whether a ctDNA-guided approach could reduce the use of adjuvant chemotherapy without compromising recurrence risk. Patients with stage II colon cancer were randomly assigned in a 2:1 ratio to have treatment decisions guided by either ctDNA results or standard clinicopathological features. For ctDNA-guided management, a ctDNA-positive result at 4 or 7 weeks after surgery prompted oxaliplatin-based or fluoropyrimidine chemotherapy. Patients who were ctDNA-negative were not treated. The primary efficacy end point was recurrence-free survival at 2 years. A key secondary end point was adjuvant chemotherapy use.ResultsOf the 455 patients who underwent randomization, 302 were assigned to ctDNA-guided management and 153 to standard management. The median follow-up was 37 months. A lower percentage of patients in the ctDNA-guided group than in the standard-management group received adjuvant chemotherapy (15% vs. 28%; relative risk, 1.82; 95% confidence interval [CI], 1.25 to 2.65). In the evaluation of 2-year recurrence-free survival, ctDNA-guided management was noninferior to standard management (93.5% and 92.4%, respectively; absolute difference, 1.1 percentage points; 95% CI, -4.1 to 6.2 [noninferiority margin, -8.5 percentage points]). Three-year recurrence-free survival was 86.4% among ctDNA-positive patients who received adjuvant chemotherapy and 92.5% among ctDNA-negative patients who did not.ConclusionsA ctDNA-guided approach to the treatment of stage II colon cancer reduced adjuvant chemotherapy use without compromising recurrence-free survival. (Supported by the Australian National Health and Medical Research Council and others; DYNAMIC Australian New Zealand Clinical Trials Registry number, ACTRN12615000381583.).

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Higher ETV5 Expression Associates With Poor 5-Florouracil-Based Adjuvant Therapy Response in Colon Cancer.

Publications

Higher ETV5 Expression Associates With Poor 5-Florouracil-Based Adjuvant Therapy Response in Colon Cancer.

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