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

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:

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

Inclusion criteria

• Requirements for tumor parameters

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

• Patient is ≥ 18 years of age on the day of consenting to the study.
• Eastern Cooperative Oncology Group Performance Status (ECOG PS) 0 or 1 at the time of screening.
• Fertile patients must use effective contraception.
• Patients must demonstrate ability to understand and the willingness to sign a written informed consent document.
• Patients must demonstrate ability to complete study questionnaires.
• 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.
• Required initial laboratory values

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

Exclusion criteria

• Patients with a known history of allergic reactions attributed to compounds of similar chemical or biologic composition to fluorouracil.
• 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
• 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.
• Known human immunodeficiency virus (HIV)-positive patients and those with known hepatitis B or C.
• 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.
• Pregnant or nursing.