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

NCT03127111 | Not Yet Recruiting

• 1 other identifier: GEDEREFAC-CRC
• Study Type: observational
• Target: 300
• Locations: 1 country
• Sites: 1

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.

Conditions

Stage III Colorectal Cancer

Outcome Measures

Primary Outcomes (1)

• Time to recurrence (TTR)

  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.

  3 years after surgery

Secondary Outcomes (3)

• Disease-free survival (DFS)

  3 years, 5 years after surgery

• Cancer-specific survival (CSS)

  3 years, 5 years after surgery

• Overall survival (OS)

  3 years, 5 years after surgery

Study Arms (1)

Adjuvant chemotherapy

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.

Genetic: Gene mutations analysis; Genetic: Gene methylation analysis; Genetic: Gene expression analysis; Genetic: SNP analysis; Genetic: Protein expression analysis

Interventions

Gene mutations analysis GENETIC

Genomic DNA extracted from paired fresh-frozen tumor and normal tissues is used for KRAS mutations, BRAF mutations, PIK3A mutations, and EGFR mutations, etc., by sequencing and for MSI analysis by PCR and capillary electrophoresis.

Adjuvant chemotherapy

Gene methylation analysis GENETIC

Genomic DNA extracted from paired fresh-frozen tumor and normal tissues is used for specific gene methylation or CIMP status analysis by MethyLight or bisulfite sequencing. Whole-genome bisulfite sequencing will be used to identify novel candidate set of predictive markers.

Adjuvant chemotherapy

Gene expression analysis GENETIC

RNA extracted from paired fresh-frozen tumor and normal tissues or serum is used for specific gene expression analysis by real-time reverse-transcription PCR (RT-qPCR). RNA-seq will be used to identify novel candidate set of predictive markers.

Adjuvant chemotherapy

SNP analysis GENETIC

Genomic DNA extracted from serum is used for specific SNP analysis by using sequencing. GWAS with SNPs array will be used to identify novel candidate set of predictive markers.

Adjuvant chemotherapy

Protein expression analysis GENETIC

Tissue microarray made from formalin-fixed paraffin-embedded (FFPE) paired tumor and normal tissues is used for specific protein expression analysis by immunohistochemistry staining.

Adjuvant chemotherapy

Eligibility Criteria

• Age: 18 Years - 70 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)
• Sampling Method: Probability Sample

Study Population

Patients with histologically confirmed colorectal adenocarcinoma consecutively enrolled at the Department of Gastrointestinal Surgery II, Renmin Hospital, Wuhan University between Jan 2020 and Jan 2025.

You may qualify if:

• 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

You may not qualify if:

• 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.

Sponsors & Collaborators

• Renmin Hospital of Wuhan University: lead

Study Sites (1)

Department of Gastrointestinal Surgery II, Renmin Hospital of Wuhan University

Wuhan, Hubei, 430060, China

Location

Related Publications (17)

• Jover R, Nguyen TP, Perez-Carbonell L, Zapater P, Paya A, Alenda C, Rojas E, Cubiella J, Balaguer F, Morillas JD, Clofent J, Bujanda L, Rene JM, Bessa X, Xicola RM, Nicolas-Perez D, Castells A, Andreu M, Llor X, Boland CR, Goel A. 5-Fluorouracil adjuvant chemotherapy does not increase survival in patients with CpG island methylator phenotype colorectal cancer. Gastroenterology. 2011 Apr;140(4):1174-81. doi: 10.1053/j.gastro.2010.12.035. Epub 2010 Dec 24.

  PMID: 21185836 BACKGROUND

• Carethers JM, Smith EJ, Behling CA, Nguyen L, Tajima A, Doctolero RT, Cabrera BL, Goel A, Arnold CA, Miyai K, Boland CR. Use of 5-fluorouracil and survival in patients with microsatellite-unstable colorectal cancer. Gastroenterology. 2004 Feb;126(2):394-401. doi: 10.1053/j.gastro.2003.12.023.

  PMID: 14762775 BACKGROUND

• Gamazon ER, Huang RS, Cox NJ, Dolan ME. Chemotherapeutic drug susceptibility associated SNPs are enriched in expression quantitative trait loci. Proc Natl Acad Sci U S A. 2010 May 18;107(20):9287-92. doi: 10.1073/pnas.1001827107. Epub 2010 May 4.

  PMID: 20442332 BACKGROUND

• Dai J, Gu J, Huang M, Eng C, Kopetz ES, Ellis LM, Hawk E, Wu X. GWAS-identified colorectal cancer susceptibility loci associated with clinical outcomes. Carcinogenesis. 2012 Jul;33(7):1327-31. doi: 10.1093/carcin/bgs147. Epub 2012 Apr 12.

  PMID: 22505654 BACKGROUND

• Xing J, Myers RE, He X, Qu F, Zhou F, Ma X, Hyslop T, Bao G, Wan S, Yang H, Chen Z. GWAS-identified colorectal cancer susceptibility locus associates with disease prognosis. Eur J Cancer. 2011 Jul;47(11):1699-707. doi: 10.1016/j.ejca.2011.02.004. Epub 2011 Mar 12.

  PMID: 21402474 BACKGROUND

• Lin M, Gu J, Eng C, Ellis LM, Hildebrandt MA, Lin J, Huang M, Calin GA, Wang D, Dubois RN, Hawk ET, Wu X. Genetic polymorphisms in MicroRNA-related genes as predictors of clinical outcomes in colorectal adenocarcinoma patients. Clin Cancer Res. 2012 Jul 15;18(14):3982-91. doi: 10.1158/1078-0432.CCR-11-2951. Epub 2012 Jun 1.

  PMID: 22661538 BACKGROUND

• O'Donnell PH, Stark AL, Gamazon ER, Wheeler HE, McIlwee BE, Gorsic L, Im HK, Huang RS, Cox NJ, Dolan ME. Identification of novel germline polymorphisms governing capecitabine sensitivity. Cancer. 2012 Aug 15;118(16):4063-73. doi: 10.1002/cncr.26737. Epub 2012 Jan 3.

  PMID: 22864933 BACKGROUND

• Yoon HH, Tougeron D, Shi Q, Alberts SR, Mahoney MR, Nelson GD, Nair SG, Thibodeau SN, Goldberg RM, Sargent DJ, Sinicrope FA; Alliance for Clinical Trials in Oncology. KRAS codon 12 and 13 mutations in relation to disease-free survival in BRAF-wild-type stage III colon cancers from an adjuvant chemotherapy trial (N0147 alliance). Clin Cancer Res. 2014 Jun 1;20(11):3033-43. doi: 10.1158/1078-0432.CCR-13-3140. Epub 2014 Mar 31.

  PMID: 24687927 BACKGROUND

• Roepman P, Schlicker A, Tabernero J, Majewski I, Tian S, Moreno V, Snel MH, Chresta CM, Rosenberg R, Nitsche U, Macarulla T, Capella G, Salazar R, Orphanides G, Wessels LF, Bernards R, Simon IM. Colorectal cancer intrinsic subtypes predict chemotherapy benefit, deficient mismatch repair and epithelial-to-mesenchymal transition. Int J Cancer. 2014 Feb 1;134(3):552-62. doi: 10.1002/ijc.28387. Epub 2013 Sep 13.

  PMID: 23852808 BACKGROUND

• Dalerba P, Sahoo D, Paik S, Guo X, Yothers G, Song N, Wilcox-Fogel N, Forgo E, Rajendran PS, Miranda SP, Hisamori S, Hutchison J, Kalisky T, Qian D, Wolmark N, Fisher GA, van de Rijn M, Clarke MF. CDX2 as a Prognostic Biomarker in Stage II and Stage III Colon Cancer. N Engl J Med. 2016 Jan 21;374(3):211-22. doi: 10.1056/NEJMoa1506597.

  PMID: 26789870 BACKGROUND

• Sinicrope FA, Mahoney MR, Smyrk TC, Thibodeau SN, Warren RS, Bertagnolli MM, Nelson GD, Goldberg RM, Sargent DJ, Alberts SR. Prognostic impact of deficient DNA mismatch repair in patients with stage III colon cancer from a randomized trial of FOLFOX-based adjuvant chemotherapy. J Clin Oncol. 2013 Oct 10;31(29):3664-72. doi: 10.1200/JCO.2013.48.9591. Epub 2013 Sep 9.

  PMID: 24019539 BACKGROUND

• Sinicrope FA, Shi Q, Smyrk TC, Thibodeau SN, Dienstmann R, Guinney J, Bot BM, Tejpar S, Delorenzi M, Goldberg RM, Mahoney M, Sargent DJ, Alberts SR. Molecular markers identify subtypes of stage III colon cancer associated with patient outcomes. Gastroenterology. 2015 Jan;148(1):88-99. doi: 10.1053/j.gastro.2014.09.041. Epub 2014 Oct 8.

  PMID: 25305506 BACKGROUND

• Toiyama Y, Hur K, Tanaka K, Inoue Y, Kusunoki M, Boland CR, Goel A. Serum miR-200c is a novel prognostic and metastasis-predictive biomarker in patients with colorectal cancer. Ann Surg. 2014 Apr;259(4):735-43. doi: 10.1097/SLA.0b013e3182a6909d.

  PMID: 23982750 BACKGROUND

• Calon A, Lonardo E, Berenguer-Llergo A, Espinet E, Hernando-Momblona X, Iglesias M, Sevillano M, Palomo-Ponce S, Tauriello DV, Byrom D, Cortina C, Morral C, Barcelo C, Tosi S, Riera A, Attolini CS, Rossell D, Sancho E, Batlle E. Stromal gene expression defines poor-prognosis subtypes in colorectal cancer. Nat Genet. 2015 Apr;47(4):320-9. doi: 10.1038/ng.3225. Epub 2015 Feb 23.

  PMID: 25706628 BACKGROUND

• Kap EJ, Seibold P, Scherer D, Habermann N, Balavarca Y, Jansen L, Zucknick M, Becker N, Hoffmeister M, Ulrich A, Benner A, Ulrich CM, Burwinkel B, Brenner H, Chang-Claude J. SNPs in transporter and metabolizing genes as predictive markers for oxaliplatin treatment in colorectal cancer patients. Int J Cancer. 2016 Jun 15;138(12):2993-3001. doi: 10.1002/ijc.30026. Epub 2016 Feb 19.

  PMID: 26835885 BACKGROUND

• Dienstmann R, Vermeulen L, Guinney J, Kopetz S, Tejpar S, Tabernero J. Consensus molecular subtypes and the evolution of precision medicine in colorectal cancer. Nat Rev Cancer. 2017 Mar 23;17(4):268. doi: 10.1038/nrc.2017.24. No abstract available.

  PMID: 28332502 BACKGROUND

• Punt CJ, Buyse M, Kohne CH, Hohenberger P, Labianca R, Schmoll HJ, Pahlman L, Sobrero A, Douillard JY. Endpoints in adjuvant treatment trials: a systematic review of the literature in colon cancer and proposed definitions for future trials. J Natl Cancer Inst. 2007 Jul 4;99(13):998-1003. doi: 10.1093/jnci/djm024. Epub 2007 Jun 27.

  PMID: 17596575 BACKGROUND

Biospecimen

Retention: SAMPLES WITH DNA

Blood, serum, tumor tissue, normal colorectal tissue

MeSH Terms

Conditions

Colorectal Neoplasms

Interventions

Gene Expression Profiling

Condition Hierarchy (Ancestors)

Intestinal Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Rectal Diseases

Intervention Hierarchy (Ancestors)

Genetic Techniques; Investigative Techniques

Study Design

• Study Type: observational
• Observational Model: COHORT
• Time Perspective: PROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Head of Department of GI Surgery II

Study Record Dates

• First Submitted: April 16, 2017
• First Posted: April 25, 2017
• Study Start: December 1, 2022
• Primary Completion: December 31, 2025
• Study Completion (Estimated): December 31, 2026
• Last Updated: March 15, 2022

Record last verified: 2022-03

Data Sharing

• IPD Sharing: Will not share

Locations

CN (1)