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

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.

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.

Eligibility Criteria:
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.