A study of gene expression markers for predictive significance for bevacizumab benefit in patients with metastatic colon cancer: a translational research study of the Hellenic Cooperative Oncology Group (HeCOG)
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- 作者：George Pentheroudakis (27) (28)
Vassiliki Kotoula (16) (28)
Elena Fountzilas (17)
George Kouvatseas (18)
George Basdanis (19)
Ioannis Xanthakis (17)
Thomas Makatsoris (20)
Elpida Charalambous (16)
Demetris Papamichael (21)
Epaminontas Samantas (22)
Pavlos Papakostas (23)
Dimitrios Bafaloukos (24)
Evangelia Razis (25)
Christos Christodoulou (26)
Ioannis Varthalitis (27)
Nicholas Pavlidis (27)
George Fountzilas (16) (17) - 关键词：Bevacizumab ; Colon cancer ; Gene expression ; Predictive ; Response rate ; Survival ; Biomarker
- 刊名：BMC Cancer
- 出版年：2014
- 出版时间：December 2014
- 年：2014
- 卷：14
- 期：1
- 全文大小：330 KB
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37. The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2407/14/111/prepub - 作者单位：George Pentheroudakis (27) (28)
Vassiliki Kotoula (16) (28)
Elena Fountzilas (17)
George Kouvatseas (18)
George Basdanis (19)
Ioannis Xanthakis (17)
Thomas Makatsoris (20)
Elpida Charalambous (16)
Demetris Papamichael (21)
Epaminontas Samantas (22)
Pavlos Papakostas (23)
Dimitrios Bafaloukos (24)
Evangelia Razis (25)
Christos Christodoulou (26)
Ioannis Varthalitis (27)
Nicholas Pavlidis (27)
George Fountzilas (16) (17)
27. Oncology Department, General Hospital of Chania, Crete, Greece
28. Department of Medical Oncology, Medical School, University of Ioannina, Niarxou Avenue, 45500, Ioannina, Greece
16. Laboratory of Molecular Oncology, Hellenic Foundation for Cancer Research, Aristotle University of Thessaloniki School of Medicine, Thessaloniki, Greece
17. Department of Medical Oncology, “Papageorgiou-Hospital, Aristotle University of Thessaloniki School of Medicine, Thessaloniki, Greece
18. Health Data Specialists Ltd, Athens, Greece
19. First Propaedeutic Department of Surgery, “AHEPA-Hospital, Aristotle University of Thessaloniki School of Medicine, Thessaloniki, Greece
20. Division of Oncology, Department of Medicine, University Hospital, University of Patras Medical School, Patras, Greece
21. Bank of Cyprus Oncology Center, Nicosia, Cyprus, Greece
22. Third Department of Medical Oncology, “Agii Anargiri-Cancer Hospital, Athens, Greece
23. Department of Medical Oncology, “Hippokration-Hospital, Athens, Greece
24. First Department of Medical Oncology, “Metropolitan-Hospital, Piraeus, Greece
25. Third Department of Medical Oncology, “Hygeia-Hospital, Athens, Greece
26. Second Department of Medical Oncology, “Metropolitan-Hospital, Piraeus, Greece - ISSN：1471-2407
文摘
Background Bevacizumab, an antibody neutralizing Vascular Endothelial Growth Factor (VEGF), is licensed for the management of patients with advanced colon cancer. However, tumor biomarkers identifying the molecular tumor subsets most amenable to angiogenesis modulation are lacking. Methods We profiled expession of 24526 genes by means of whole genome 24?K DASL (c-DNA-mediated, Annealing, Selection and Ligation) arrays, (Illumina, CA) in 16 bevacizumab-treated patients with advanced colon cancer (Test set). Genes with correlation to 8-month Progression-free status were studied by means of qPCR in two independent colon cancer cohorts: 49 patients treated with bevacizumab-?chemotherapy (Bevacizumab qPCR set) and 72 patients treated with chemotherapy only (Control qPCR set). Endpoints were best tumor response before metastasectomy (ORR) and progression-free survival (PFS). Results Five genes were significantly correlated to 8-month progression-free status in the Test set: overexpression of KLF12 and downregulation of AGR2, ALDH6A1, MCM5, TFF2. In the two independent datasets, irinotecan- or oxaliplatin-based chemotherapy was administered as first-line treatment and metastasectomies were subsequently applied in 8-14% of patients. No prognostically significant gene classifier encompassing all five genes could be validated in the Bevacizumab or Control qPCR sets. The complex gene expression profile of all-low tumor (ALDH6A1-?TFF2-?MCM5) was strongly associated with ORR in the Bevacizumab qPCR set (ORR 85.7%, p--.007), but not in the Control set (ORR 36.4%, p--.747). The Odds Ratio for response for the all-low tumor (ALDH6A1-?TFF2-?MCM5) profile versus any other ALDH6A1-?TFF2-?MCM5 profile was 15 (p--.018) in the Bevacizumab qPCR set but only 0.72 (p--.63) in the Control set. The tumor expression profile of (KLF12-high-?TFF2-low) was significantly associated with PFS only in the Bevacizumab qPCR set: bevacizumab-treated patients with (KLF12-high-?TFF2-low) tumors had superior PFS (median 14?months, 95% CI 2-21) compared to patients with any other (KLF12-?TFF2) expression profile (median PFS 7?months, 95% CI 5-10, p--.021). The Hazard Ratio for disease progression for (KLF12-high-?TFF2-low) versus any other KLF12-?TFF2 expression profile was 2.92 (p--.03) in the Validation and 1.29 (p--.39) in the Control set. Conclusions Our ?three-stage? hypothesis-generating study failed to validate the prognostic significance of a five-gene classifier in mCRC patients. Exploratory analyses suggest two gene signatures that are potentially associated with bevazicumab benefit in patients with advanced colon cancer.