Clinical trial NCT00897429: Studying Tissue Samples From Patients With Stage II Colon Cancer Treated on Clinical Trial CLB-9581
Official title: Correlative Science Studies in Colon Cancer a Companion Study to CALGB 9581 and 89803
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Colorectal Cancer
Keywords: stage IIA colon cancer
stage IIB colon cancer
stage IIC colon cancer
Lead sponsor: Alliance for Clinical Trials in Oncology
Sponsor class: OTHER
Collaborators: name: National Cancer Institute (NCI)
First posted: 2009-05-12
Enrollment: 2059
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: CASE_CONTROL
Time perspective: RETROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: Patients with colon cancer registered to CALGB 9581 or 89803

Brief summary: This research trial studies tissue samples from patients with stage II colon cancer treated on Cancer and Leukemia Group B (CALGB)-9581 or CALGB-90903. Studying samples of tissue from patients with cancer in the laboratory may help doctors learn more about changes that occur in deoxyribonucleic acid (DNA) and identify biomarkers related to cancer. It may also help doctors understand how patients respond to treatment.

Detailed description: PRIMARY OBJECTIVES:

I. To evaluate the impact of loss of p21 and mutations in p53 on the relationship between higher intake of a Western dietary pattern (manifested by higher red meat and total fat intake and lower n-3 polyunsaturated fatty acids, fruit and vegetable intake) and colon cancer recurrence/mortality. (B1)

II. To evaluate the impact of mutated v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (K-ras), mutated p53, phorphorylated (phospho)-v-akt murine thymoma viral oncogene homolog 1 (Akt) overexpression, and p27 loss on the relationship between each of obesity, physical activity and dietary glycemic intake and colon cancer recurrence/mortality. (B1)

III. To evaluate the impact of tumoral cyclooxygenase-2 (COX-2) and vascular endothelial growth factor (VEGF) overexpression, high tumor microvessel density and intact p21 on the relationship between aspirin use and colon cancer recurrence. (B1)

IV. To define the association of type and extent of genomic instability with clinical outcome in stage III colon cancers treated with resection and adjuvant chemotherapy (CALGB 89803). (B2)

V. To assess the ability of a prognostic gene expression signature to stratify stage II colorectal cancer patients into those who will experience relapse within five years post surgery (high risk) and those who will experience five-year disease free survival (low risk), without additional treatment. (B3)

VI. To determine whether there is a significant relationship between the risk of recurrence and the continuous 12-gene recurrence score (RS) as measured by the growth hormone insufficiency (GHI) assay of gene expression, using the pre-specified genes and Recurrence Score algorithm. (B4) VII. To determine whether there is a significant relationship between the risk of recurrence and the continuous 15-gene RS2 as measured by the GHI assay of gene expression, using the pre-specified genes and second-generation Recurrence Score algorithm. (B4)

VIII. To assess the methylation status of mutL homolog 1 (MLH1), o-6-methylguanine-DNA methyltransferase (MGMT), and Werner syndrome (WRN) in tumors obtained from patients enrolled in both treatment arms of CALGB 89803. (B5)

IX. Determine the expression of DNA repair pathway proteins assessed by methylation-specific polymerase chain reaction (MSP) assays as well as the expression of DNA repair proteins that are known to interact with these epigenetically silenced DNA repair proteins using validated immunostaining assays. (B5)

X. Recognition of cytosine phosphate guanine (CpG) island methylator phenotype (CIMP) genes. (B5)

XI. To understand the relationship between tumor gene methylation status and epigenetic silencing of DNA repair pathway genes. (B5)

XII. To examine newly identified prognostic biomarkers (long interspersed nucleotide element 1 \[LINE-1\] methylation, phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha \[PIK3CA\] mutation, v-raf murine sarcoma viral oncogene homolog B1 \[BRAF\] mutation, fatty acid synthase \[FASN\] expression and vitamin D receptor \[VDR\] expression) in stage III colon cancers (CALGB 89803) with detailed lifestyle, treatment and follow-up data and correlate them with survival. (B6)

SECONDARY OBJECTIVES:

I. To define the association of type and extent of genomic instability with microsatellite instability and p53 mutations, which have previously been characterized in these tumors by Drs. Warren and Bertagnolli. (B2)

II. Associations with other markers will be determined at some future time once they have been characterized by collaborators. (B2)

III. To determine whether the 12-gene RS provides significant information beyond clinical and pathologic measures, including T stage, mismatch repair system (MMR) status, number of lymph nodes examined, tumor grade, and lymphovascular invasion. (B4)

IV. To determine whether the 15-gene RS2 provides significant information beyond the clinical and pathologic measures, including T stage, MMR status, number of lymph nodes examined, tumor grade, and lymphovascular invasion. (B4)

V. To compare the risk of recurrence between the high and low recurrence risk groups based on pre-specified percentile cut-points for the 12-gene RS. (B4)

VI. To compare the risk of recurrence between the high and low recurrence risk groups based on pre-specified percentile cut-points for the 15-gene RS2. (B4)

VII. To determine, for each of a panel of selected new genes (up to 768 genes), whether there is a significant relationship between gene expression and recurrence-free interval (RFI). (B4)

VIII. To define the association of CIMP and methylated genes with other genetic alterations and tumor-specific characteristics. (B5)

IX. To study the influence of diet and other lifestyle factors on cancer recurrence and treatment-related toxicity in patients participating in this trial. (B6)

OUTLINE:

Previously collected tissue samples are analyzed for K-ras mutations; COX-2, phospho-AKT, and VEGF overexpression; microvessel density; association of genomic instability with microsatellite instability and p53 mutations; and methylation status of MLH1, MGMT, and WRN and to identify prognostic biomarkers by LINE-1 hypomethylation, PIK3CA mutation, BRAF mutation, FASN expression, and VDR expression via immunohistochemistry, polymerase chain reaction (PCR), RT-PCR, and microarray.

Eligibility criteria: Inclusion Criteria:

* Registration to CALGB 9581 or 89803
* Samples present within the CALGB Pathology Coordinating Office (PCO) or at the institutions providing treatment that are sufficient to meet study aims
* Institutional Review Board (IRB) review and approval at the institution where the laboratory work will be performed is required
* CALGB does not require that a separate consent form be signed for this study:

  * The subject population to be studied in this protocol includes patients selected from either of the following CALGB treatment protocols: CALGB 9581 or 89803; all such patients have signed (or will sign) a written informed consent document meeting all federal, state, and institutional guidelines as part of entry into those trials
  * All samples to be studied are obtained and stored as part of the patient's respective treatment trial; the material and data obtained from the patient's protocol record will be used to obtain appropriate clinical information; in no instance will the patient be contacted directly
  * There should be no physical, psychological, social, or legal risks associated with this study; no invasive procedures are recommended or requested
  * All appropriate and necessary procedures will be utilized to maintain confidentiality; all patients who have had samples submitted for analysis will have their CALGB study number used to identify specimens
  * This study does not require direct patient contact and no specific risk or benefits to individuals involved in the trial are anticipated; it is likely, however, that the information gained will substantially help similar patients in the future

Primary outcomes:
measure: Analyses of molecular models among patients who completed the diet and lifestyle questionnaire and who provided tumor blocks for analyses (B1)
timeFrame: Up to 5 years
measure: Proportion of patients who are cancer recurrence-free and alive at 4 years, approximating 4-year disease-free survival for the cohort to be 65% (B1)
timeFrame: 4 years
measure: Influence of energy balance on tumor with specific molecular features (B1)
timeFrame: Up to 5 years
measure: Influence of medications on tumors with specific molecular features (B1)
timeFrame: Up to 5 years
measure: Detection of clones associated with overall survival (OS) (B2)
timeFrame: Up to 5 years
measure: Recurrence-free interval (RFI) (B3)
timeFrame: up to 5 years
measure: Clinical validation of the GHI 12-gene recurrence score (B4)
timeFrame: Up to 5 years
measure: Clinical validation of the 15-gene second-generation recurrence score (B4)
timeFrame: Up to 5 years
measure: Determination of whether the methylated and silenced DNA repair genes, MLH1, WRN, or MGMT, or CIMP colorectal cancers are associated with OS (B5)
timeFrame: Up to 5 years
measure: Expression of newly identified prognostic biomarkers (LINE-1, PIK3CA, BRAF, FASN and VDR) on OS (B6)
timeFrame: Up to 5 years
measure: Cancer-specific mortality (B6)
timeFrame: Up to 5 years
Secondary outcomes:
measure: Detection of clones associated with disease-free survival (DFS) (B2)
timeFrame: Up to 5 years
measure: Determination of whether the methylated and silenced DNA repair genes, MLH1, WRN, or MGMT, or CIMP colorectal cancers are associated with DFS (B5)studies
timeFrame: Up to 5 years
measure: MRE11 status of MSI tumors genetic alterations and tumor-specific characteristics
timeFrame: Up to 5 years
measure: Evaluation of up to 768 new genes for their relationship with colon cancer recurrence (B4
timeFrame: Up to 5 years
Other outcomes:
Locations:
city: Boston
country: United States
facility: Brigham and Women's Hospital
state: Massachusetts
Study officials:
affiliation: Brigham and Women's Cancer Center
name: Monica Bertagnolli, MD
role: STUDY_CHAIR
References: