Stacey A Cohen1, Chen Wu2, Ming Yu3, Georgia Gourgioti4, Ralph Wirtz5, Georgia Raptou6, Chryssa Gkakou7, Vassiliki Kotoula8, George Pentheroudakis9, George Papaxoinis10, Vasilios Karavasilis11, Dimitrios Pectasides10, Konstantine T Kalogeras12, George Fountzilas7, William M Grady13. 1. Division of Oncology, University of Washington, Seattle, WA; Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA. Electronic address: shiovitz@uw.edu. 2. Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA; College of Life Sciences, Hebei University, Baoding, Hebei, People's Republic of China. 3. Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA. 4. Section of Biostatistics, Hellenic Cooperative Oncology Group, Data Office, Athens, Greece. 5. Stratifyer Molecular Pathology GmbH, Cologne, Germany. 6. Department of Pathology, Aristotle University of Thessaloniki School of Medicine, Thessaloniki, Greece. 7. Laboratory of Molecular Oncology, Hellenic Foundation for Cancer Research, Aristotle University of Thessaloniki School of Medicine, Thessaloniki, Greece. 8. Department of Pathology, Aristotle University of Thessaloniki School of Medicine, Thessaloniki, Greece; Laboratory of Molecular Oncology, Hellenic Foundation for Cancer Research, Aristotle University of Thessaloniki School of Medicine, Thessaloniki, Greece. 9. Department of Medical Oncology, Ioannina University Hospital, Ioannina, Greece. 10. Oncology Section, Second Department of Internal Medicine, "Hippokration" Hospital, Athens, Greece. 11. Department of Medical Oncology, "Papageorgiou" Hospital, Aristotle University of Thessaloniki School of Medicine, Thessaloniki, Greece. 12. Laboratory of Molecular Oncology, Hellenic Foundation for Cancer Research, Aristotle University of Thessaloniki School of Medicine, Thessaloniki, Greece; Translational Research Section, Hellenic Cooperative Oncology Group, Data Office, Athens, Greece. 13. Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA; Division of Gastroenterology, University of Washington, Seattle, WA.
Abstract
BACKGROUND: The CpG island methylator phenotype (CIMP) is a promising biomarker for irinotecan/5-fluorouracil/leucovorin chemotherapy for stage III colon cancer. In the present study, we evaluated whether CIMP is a prognostic biomarker for standard-of-care oxaliplatin-based adjuvant therapy. MATERIALS AND METHODS: The HE6C/05 trial randomized 441 patients with stage II-III colorectal adenocarcinoma to adjuvantXELOX (capecitabine, oxaliplatin) or modified FOLFOX6 (5-fluorouracil, leucovorin, oxaliplatin). The primary and secondary objectives were disease-free and overall survival, respectively. CIMP status was determined using the DNA methylation status of CACNA1G, IGF2, NEUROG1, RUNX3, and SOCS1. Cox models were used to assess the association of CIMP with survival. RESULTS: Of the 293 available tumors, 28 (9.6%) were CIMP(+). On univariate Cox regression analysis, no significant differences in survival were observed between individuals with CIMP(+) versus CIMP(-) tumors. CIMP(+) tumors were more likely to be right-sided and BRAF mutant (χ(2), P < .001). In the multivariate model, TNM stage II (vs. stage III) was associated with a reduced risk of relapse (hazard ratio [HR], 0.25; 95% confidence interval [CI], 0.11-0.55; Wald's P < .001), and a colon primary located on the left side and earlier TNM stage were associated with a reduced risk of death (HR, 0.48; 95% CI, 0.28-0.81; P = .006; and HR, 0.22; 95% CI, 0.10-0.49; P < .001, respectively). CONCLUSION: In the present exploratory analysis, CIMP did not appear to be a prognostic biomarker in oxaliplatin-treated patients with resected colorectal cancer.
RCT Entities:
BACKGROUND: The CpG island methylator phenotype (CIMP) is a promising biomarker for irinotecan/5-fluorouracil/leucovorin chemotherapy for stage III colon cancer. In the present study, we evaluated whether CIMP is a prognostic biomarker for standard-of-care oxaliplatin-based adjuvant therapy. MATERIALS AND METHODS: The HE6C/05 trial randomized 441 patients with stage II-III colorectal adenocarcinoma to adjuvant XELOX (capecitabine, oxaliplatin) or modified FOLFOX6 (5-fluorouracil, leucovorin, oxaliplatin). The primary and secondary objectives were disease-free and overall survival, respectively. CIMP status was determined using the DNA methylation status of CACNA1G, IGF2, NEUROG1, RUNX3, and SOCS1. Cox models were used to assess the association of CIMP with survival. RESULTS: Of the 293 available tumors, 28 (9.6%) were CIMP(+). On univariate Cox regression analysis, no significant differences in survival were observed between individuals with CIMP(+) versus CIMP(-) tumors. CIMP(+) tumors were more likely to be right-sided and BRAF mutant (χ(2), P < .001). In the multivariate model, TNM stage II (vs. stage III) was associated with a reduced risk of relapse (hazard ratio [HR], 0.25; 95% confidence interval [CI], 0.11-0.55; Wald's P < .001), and a colon primary located on the left side and earlier TNM stage were associated with a reduced risk of death (HR, 0.48; 95% CI, 0.28-0.81; P = .006; and HR, 0.22; 95% CI, 0.10-0.49; P < .001, respectively). CONCLUSION: In the present exploratory analysis, CIMP did not appear to be a prognostic biomarker in oxaliplatin-treated patients with resected colorectal cancer.
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