Open Access Research article

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)

George Pentheroudakis115*, Vassiliki Kotoula23, Elena Fountzilas4, George Kouvatseas5, George Basdanis6, Ioannis Xanthakis4, Thomas Makatsoris7, Elpida Charalambous3, Demetris Papamichael8, Epaminontas Samantas9, Pavlos Papakostas10, Dimitrios Bafaloukos11, Evangelia Razis12, Christos Christodoulou13, Ioannis Varthalitis14, Nicholas Pavlidis1 and George Fountzilas34

Author Affiliations

1 Department of Medical Oncology, Ioannina University Hospital, Ioannina, Greece

2 Department of Pathology, Aristotle University of Thessaloniki School of Medicine, Thessaloniki, Greece

3 Laboratory of Molecular Oncology, Hellenic Foundation for Cancer Research, Aristotle University of Thessaloniki School of Medicine, Thessaloniki, Greece

4 Department of Medical Oncology, “Papageorgiou” Hospital, Aristotle University of Thessaloniki School of Medicine, Thessaloniki, Greece

5 Health Data Specialists Ltd, Athens, Greece

6 First Propaedeutic Department of Surgery, “AHEPA” Hospital, Aristotle University of Thessaloniki School of Medicine, Thessaloniki, Greece

7 Division of Oncology, Department of Medicine, University Hospital, University of Patras Medical School, Patras, Greece

8 Bank of Cyprus Oncology Center, Nicosia, Cyprus, Greece

9 Third Department of Medical Oncology, “Agii Anargiri” Cancer Hospital, Athens, Greece

10 Department of Medical Oncology, “Hippokration” Hospital, Athens, Greece

11 First Department of Medical Oncology, “Metropolitan” Hospital, Piraeus, Greece

12 Third Department of Medical Oncology, “Hygeia” Hospital, Athens, Greece

13 Second Department of Medical Oncology, “Metropolitan” Hospital, Piraeus, Greece

14 Oncology Department, General Hospital of Chania, Crete, Greece

15 Department of Medical Oncology, Medical School, University of Ioannina, Niarxou Avenue, 45500 Ioannina, Greece

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BMC Cancer 2014, 14:111  doi:10.1186/1471-2407-14-111

Published: 20 February 2014

Abstract

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 = 0.007), but not in the Control set (ORR 36.4%, p = 0.747). The Odds Ratio for response for the all-low tumor (ALDH6A1 + TFF2 + MCM5) profile versus any other ALDH6A1 + TFF2 + MCM5 profile was 15 (p = 0.018) in the Bevacizumab qPCR set but only 0.72 (p = 0.63) 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 = 0.021). The Hazard Ratio for disease progression for (KLF12-high + TFF2-low) versus any other KLF12 + TFF2 expression profile was 2.92 (p = 0.03) in the Validation and 1.29 (p = 0.39) 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.

Keywords:
Bevacizumab; Colon cancer; Gene expression; Predictive; Response rate; Survival; Biomarker