Significant effect of VEGFA polymorphisms on the clinical outcome of metastatic colorectal cancer patients treated with FOLFIRI-cetuximab
Abstract
Aim: The efficacy of a cetuximab-based regimen used to treat metastatic colorectal cancer (mCRC) could be influenced by VEGFA polymorphisms. Materials & methods: We studied the effects of five polymorphisms in the VEGFA gene (-2549D/I, -1154G/A, -460T/C, +405G/C and +936C/T) on the outcome of 98 mCRC patients treated with FOLFIRI plus cetuximab. Results: Patients homozygous for the -2549D, -1154G and -460T alleles did exhibit higher response rates to treatment and longer progression-free survival compared with others. In addition, the DGTGC and IGCGC haplotypes were significantly associated with a lower risk of disease progression. Conclusion: These findings suggest that VEGFA genetic variations might influence response/resistance of FOLFIRI plus cetuximab treatment in mCRC patients.
Papers of special note have been highlighted as: • of interest; •• of considerable interest
References
- 1 . Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int. J. Cancer 127, 2893–2917 (2010).
- 2 . The biological properties of cetuximab. Crit. Rev. Oncol. Hematol. 68(2), 93–106 (2008).
- 3 Fluorouracil, leucovorin, and irinotecan plus cetuximab treatment and RAS mutations in colorectal cancer. J. Clin. Oncol. 33, 692–700 (2015).
- 4 . Prognostic and predictive biomarkers for epidermal growth factor receptor-targeted therapy in colorectal cancer: Beyond KRAS mutations. Crit. Rev. Oncol. Hematol. 85, 45–81 (2013).
- 5 Anti-epidermal growth factor receptor antibody C225 inhibits angiogenesis in human transitional cell carcinoma growing orthotopically in nude mice. Clin. Cancer Res. 5, 257–265 (1999).• Demonstrated for the first time in mice model that cetuximab treatment has a significant antitumoral effect mediated in part by inhibition of angiogenesis by decreasing VEGF expression in tumor.
- 6 Epidermal growth factor receptor blockade with C225 plus gemcitabine results in regression of human pancreatic carcinoma growing orthotopically in nude mice by antiangiogenic mechanisms. Clin. Cancer Res. 6, 1936–1948 (2000).
- 7 . The antiepidermal growth factor receptor monoclonal antibody cetuximab/C225 reduces hypoxia-inducible factor-1 alpha, leading to transcriptional inhibition of vascular endothelial growth factor expression. Oncogene 24, 4433–4441 (2005).
- 8 Circulating VEGF reduction, response and outcome in advanced colorectal cancer patients treated with cetuximab plus irinotecan. Pharmacogenomics 8, 319–327 (2007).•• These data represent the first evidence that suggests a role of VEGF reduction in the prediction of efficacy of treatment with cetuximab plus weekly irinotecan in heavily pretreated advanced colorectal cancer patients.
- 9 Biomarkers for cetuximab-based neoadjuvantradiochemotherapy in locally advanced rectal cancer. Clin. Cancer Res. 17, 3469–3477 (2011).•• High intratumoral EGFR and VEGF mRNA expressions were significantly associated with complete response of patient with locally advanced rectal cancer treated by cetuximab-based chemoradiation.
- 10 . Clinical implications of genetic variations in the VEGF system in relation to colorectal cancer. Pharmacogenomics 12, 1681–1693 (2011).
- 11 VEGF gene sequence variation defines VEGF gene expression status and angiogenic activity in non-small cell lung cancer. Lung Cancer 46, 293–298 (2004).
- 12 Polymorphisms of the vascular endothelial growth factor and susceptibility to diabetic microvascular complications in patients with type 1 diabetes mellitus. J. Diabetes Complications 17, 1–6 (2003).
- 13 A common 936 C/T mutation in the gene for vascular endothelial growth factor is associated with vascular endothelial growth factor plasma levels. J. Vasc. Res. 37, 443–448 (2000).
- 14 Cetuximab pharmacokinetics influences progression-free survival of metastatic colorectal cancer patients. Clin. Cancer Res. 17, 6329–6337 (2011).
- 15 . Novel polymorphisms in the promoter and 5’ UTR regions of the human vascular endothelial growth factor gene. Hum. Immunol. 60, 1245–1249 (1999).
- 16 VEGF polymorphisms are associated with an increasing risk of developing renal cell carcinoma. J. Urol. 184, 1273–1278 (2010).
- 17 Specific haplotypes of the P-selectin gene are associated with myocardial infarction. Hum. Mol. Genet. 11, 2015–2023 (2002).
- 18 . Cox proportional hazards survival regression in haplotype-based association analysis using the stochastic-EM algorithm. Eur. J. Hum. Genet. 12, 971–974 (2004).
- 19 . Analysis of VEGF polymorphisms, tumor expression of VEGF mRNA and colorectal cancer susceptibility in a Swedish population. Mol. Med. Rep. 2, 435–439 (2009).
- 20 . Vascular endothelial growth factor polymorphisms -1154 G/A and -460 C/T are not associated with VEGF mRNA expression and susceptibility to sporadic colon cancer. DNA Cell. Biol. 27, 569–574 (2008).
- 21 Cyclin D1 and epidermal growth factor polymorphisms associated with survival in patients with advanced colorectal cancer treated with Cetuximab. Pharmacogenet. Genomics 16, 475–483 (2006).
- 22 . Association between polymorphisms in vascular endothelial growth factor gene and response to chemotherapies in colorectal cancer: a meta-analysis. PLoS ONE 10, e0126619 (2015).
- 23 Vascular endothelial growth factor gene polymorphisms are associated with acute renal allograft rejection. J. Am. Soc. Nephrol. 13, 260–264 (2002).
- 24 . Haplotype analysis of the polymorphic human vascular endothelial growth factor gene promoter. Cancer Res. 63, 812–816 (2003).
- 25 . Molecular determinants of cetuximab efficacy. J. Clin. Oncol. 23, 3536–3544 (2005).• Suggests that gene-expression levels of EGFR and VEGF in patients with metastatic colorectal cancer may be useful markers of clinical outcome in single-agent cetuximab treatment.
- 26 Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer. N. Engl. J. Med. 360, 1408–1417 (2009).