Genetic and Epigenetic Determinants of Response to Fluorouracil-based Adjuvant Chemotherapy in Patients With Stage III Colorectal Cancer

Not yet recruiting

• Conditions: Stage III Colorectal Cancer
• Interventions: Genetic: Gene mutations analysis; Genetic: Gene methylation analysis; Genetic: Gene expression analysis; Genetic: SNP analysis; Genetic: Protein expression analysis

• Registration Number: NCT03127111
• Lead Sponsor: Renmin Hospital of Wuhan University

Brief Summary

The goal of this laboratory research is to look for genetic and epigenetic markers that can predict which patients with stage III colorectal cancer will benefit from fluorouracil-based adjuvant chemotherapy.

Detailed Description

This is a prospective project in collecting and assessing clinical outcomes data related to molecular profiling of tumors based on samples from peripheral blood, primary tumor, and adjacent normal colorectal tissue.

Objectives:

1. Validation of predictive value of known markers CpG island methylator phenotype (CIMP) and microsatellite instability (MSI) in the response to 5-fluorouracil-based chemotherapy in patients with stage III colorectal cancer.

2. Exploratory evaluation of the potential predictive values of known genetic variations including, but not limited to, KRAS mutations, BRAF mutations, PIK3A mutations, and EGFR mutations, etc.

3. Exploratory identification and evaluation of the predictive value of novel methylation aberrations identified by whole-genome bisulfite sequencing.

4. Exploratory identification and evaluation of the predictive value of novel genetic aberrations discovered by RNA-sequencing (RNA-seq) or genome-wide association study (GWAS).

Outline:

Blood is collected at baseline and examined for single-nucleotide polymorphisms (SNPs) and expression level of specific gene. Tumor and corresponding normal tissue at surgical resection and assessed for gene methylations, mutations, and expressions.

Study Timeline

• Study First Submitted: 2017-04-16
• Study First Submitted QC: 2017-04-23
• Study First Posted: 2017-04-25
• Status Verified: 2022-03
• Last Update Submitted: 2022-03-12
• Last Update Posted: 2022-03-15
• Study Start: 2022-12-01
• Primary Completion: 2025-12-31
• Study Completion: 2026-12-31

Recruitment & Eligibility

• Status: NOT_YET_RECRUITING
• Sex: All
• Target Recruitment: 300

Inclusion Criteria

1. Requirements for tumor parameters

   1. Histologically confirmed colorectal adenocarcinoma.
   2. Stage III disease (any pT, N1-2, M0).
   3. Tumors must have been curatively resected (R0).
   4. No evidence of residual involved lymph node disease or metastatic disease at the time of registration.

2. Requirements for patient characteristics

   1. Patient is ≥ 18 years of age on the day of consenting to the study.
   2. Eastern Cooperative Oncology Group Performance Status (ECOG PS) 0 or 1 at the time of screening.
   3. Fertile patients must use effective contraception.
   4. Patients must demonstrate ability to understand and the willingness to sign a written informed consent document.
   5. Patients must demonstrate ability to complete study questionnaires.
   6. Patients must provide written informed consent prior to performance of study-specific procedures or assessments and must be willing to comply with treatment and follow up.

3. Required initial laboratory values

   1. Leukocytes ≥ 3,000/mm^3
   2. Absolute neutrophil count ≥ 1,500/mm^3
   3. Platelet count ≥ 100,000/mm^3
   4. Creatinine ≤ 1.5 times upper limit of normal (ULN)
   5. Total Bilirubin ≤ 1.5 times ULN
   6. Aspartate aminotransferase (AST) ≤ 2.5 times ULN
   7. Alanine aminotransferase (ALT) ≤ 2.5 times ULN

Exclusion Criteria

1. Patients with a known history of allergic reactions attributed to compounds of similar chemical or biologic composition to fluorouracil.
2. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection-requiring intravenous antibiotics, or psychological, familial, sociological, or geographical condition that would limit compliance with study requirements
3. Following cardiovascular conditions within the past 6 months: Myocardial infarction, unstable angina, symptomatic congestive heart failure, serious uncontrolled cardiac arrhythmia, cerebrovascular accident or transient ischemic attack, deep vein thrombosis, other significant thromboembolic event.
4. Known human immunodeficiency virus (HIV)-positive patients and those with known hepatitis B or C.
5. Patients with evidence of other primary malignancies within the past 5 years, excluding adequately treated basal cell carcinoma of the skin or carcinoma in situ of the cervix.
6. Pregnant or nursing.

Study & Design

• Study Type: OBSERVATIONAL
• Study Design: Not specified

Arm && Interventions

Group	Intervention	Description
Adjuvant chemotherapy	Gene expression analysis	Samples from patients with stage III colorectal cancer who are going to receive fluorouracil-based adjuvant chemotherapy will be used for gene mutations analysis, gene methylation analysis, gene expression analysis, SNP analysis, and protein expression analysis.
Adjuvant chemotherapy	SNP analysis	Samples from patients with stage III colorectal cancer who are going to receive fluorouracil-based adjuvant chemotherapy will be used for gene mutations analysis, gene methylation analysis, gene expression analysis, SNP analysis, and protein expression analysis.
Adjuvant chemotherapy	Protein expression analysis	Samples from patients with stage III colorectal cancer who are going to receive fluorouracil-based adjuvant chemotherapy will be used for gene mutations analysis, gene methylation analysis, gene expression analysis, SNP analysis, and protein expression analysis.
Adjuvant chemotherapy	Gene mutations analysis	Samples from patients with stage III colorectal cancer who are going to receive fluorouracil-based adjuvant chemotherapy will be used for gene mutations analysis, gene methylation analysis, gene expression analysis, SNP analysis, and protein expression analysis.
Adjuvant chemotherapy	Gene methylation analysis	Samples from patients with stage III colorectal cancer who are going to receive fluorouracil-based adjuvant chemotherapy will be used for gene mutations analysis, gene methylation analysis, gene expression analysis, SNP analysis, and protein expression analysis.

Primary Outcome Measures

Name	Time	Method
Time to recurrence (TTR)	3 years after surgery	Time to any event, except non-cancer-related death. All recurrences, treatment-related deaths, second same or other primary cancers, and deaths from other cancers are considered to be events. Loss to follow-up and non-cancer-related deaths are censored. Associations between TTR and genetic and epigenetic markers will be analyzed.

Secondary Outcome Measures

Name	Time	Method
Disease-free survival (DFS)	3 years, 5 years after surgery	Time to any event, irrespective of cause. All events are included, except loss to follow-up. Associations between DFS and genetic and epigenetic markers will be analyzed.
Cancer-specific survival (CSS)	3 years, 5 years after surgery	Time to death caused by the same cancer, whether due to the original tumor or to a second primary same cancer. The only event is death from the same cancer, without taking into account whether the death is caused by the primary tumor or a second same cancer. Locoregional recurrence, distant metastases, second primary same cancers, and second other primary cancers are ignored. Deaths from other cancers, non-cancer-related deaths, treatment-related deaths, and loss to follow-up are censored. Associations between CSS and genetic and epigenetic markers will be analyzed.
Overall survival (OS)	3 years, 5 years after surgery	Time to death, irrespective of cause. There is no need to specify whether the death was due to cancer. Locoregional recurrence, distant metastases, second primary colorectal cancers, and second other primary cancers are ignored. Loss to follow-up is censored. Associations between OS and genetic and epigenetic markers will be analyzed.

Trial Locations

Locations (1)

Department of Gastrointestinal Surgery II, Renmin Hospital of Wuhan University; 🇨🇳 Wuhan, Hubei, China