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Predictive value of VEGF gene polymorphisms for metastatic colorectal cancer patients receiving first-line treatment including fluorouracil, irinotecan, and bevacizumab

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International Journal of Colorectal Disease Aims and scope Submit manuscript

Abstract

Purpose

The aim of this study is to evaluate the influence of germline vascular endothelial growth factor (VEGF) gene polymorphisms (VGPs) on the efficacy of the anti-VEGF antibody bevacizumab (Bev) in metastatic colorectal cancer (MCRC) patients.

Methods

Forty MCRC patients eligible for a first-line therapy were enrolled in this prospective trial and treated with FOLinate/Fluorouracil/Irinotecan (FOLFIRI) + Bev (male/female = 22:18, age (median) = 61 years). Eight VGPs within the promoter/5’UTR region were evaluated in patient blood samples. Primary endpoint was association between VGPs and median progression-free survival (mPFS). Overall radiological response rate (ORR), overall survival (OS), and toxicity were assessed as secondary outcomes.

Results

VGPs −2578, −1512, −1451, −1411, and −460 were in complete linkage disequilibrium and therefore analyzed as haplotype (two variants: Haplo1: A-18 bp insertion-T-4G-C and Haplo2: C-18 bp deletion-C-5G-T, respectively). Seventeen patients Haplo2/Haplo2 had significantly shorter mPFS compared to 23 patients Haplo1/Haplo1 or Haplo1/Haplo2 (mPFS, 9 vs. 15.4 months, respectively, p = 0.02; hazard ratio (HR), 2.64). Also, VGPs −152 (G/G vs. G/A + A/A) and −1154 (G/G vs. G/A + A/A) were significantly associated with PFS (mPFS, 8.9 vs. 15.4 months, p = 0.007; HR, 3.53 and 9.8 vs. 16 months, p = 0.03, HR, 2.32, respectively). In the multivariate analysis including also biochemical variables known to influence prognosis, VGP −1154 retained an independent predictive value for mPFS (G/G over G/A + A/A = HR, 4.43; p = 0.02). With regard to ORR, only VGP −634 was significantly associated with response (G/G vs. G/C + C/C = 64% vs. 14%, p = 0.03). No significant influence on OS and toxicity by the investigated VGPs was observed.

Conclusions

Although these data need to be confirmed in larger trials, investigation of germline VGPs may help identify patients who are more sensitive to anti-VEGF agents.

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Acknowledgments

The authors wish to thank Barbara Leone for her excellent technical assistance. This study was partially supported by the Italian Ministry of Health Research Grant RFPS-2006-7-342220 and ACC-WP 3/1b and carried out within the Experimental Physiopathology–Oncology Rehabilitation PhD program, ‘Tor Vergata’ University of Rome.

Conflict of interest statement

The authors declare that they have no conflict of interest in connection with this paper.

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Authors and Affiliations

  1. Medical Oncology Unit, Internal Medicine Department, ‘Tor Vergata’ Clinical Center University of Rome, Viale Oxford, 0133, Rome, Italy

    Vincenzo Formica, Italia Grenga, Michele Schirru & Mario Roselli

  2. IRCCS San Raffaele, Via della Pisana 235, 00163, Rome, Italy

    Vincenzo Formica & Mario Roselli

  3. Department of Laboratory Medicine and Advanced Biotechnologies, IRCCS San Raffaele, Via della Pisana 235, 00163, Rome, Italy

    Raffaele Palmirotta, Annalisa Savonarola, Giorgia Ludovici, Maria Laura De Marchis & Fiorella Guadagni

  4. San Raffaele Rocca di Papa Clinical Center, via Ariccia 16-00040, Rocca di Papa, Rome, Italy

    Girolamo Del Monte

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  1. Vincenzo Formica
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Correspondence to Vincenzo Formica.

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Formica, V., Palmirotta, R., Del Monte, G. et al. Predictive value of VEGF gene polymorphisms for metastatic colorectal cancer patients receiving first-line treatment including fluorouracil, irinotecan, and bevacizumab. Int J Colorectal Dis 26, 143–151 (2011). https://doi.org/10.1007/s00384-010-1108-1

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