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

Abstract

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

Vascular Endothelial Growth Factor Pathway Polymorphisms as Prognostic and Pharmacogenetic Factors in Cancer: A Systematic Review and Meta-analysis

“…Among those investigating bevacizumab response, Schneider and colleagues (N ¼ 341) reported that the C allele of VEGF À2578C>A and G allele of VEGF À1154G>A (alternatively known as À116G>A) were independently associated with poorer OS in patients treated with bevacizumab (9). Similarly, a smaller study investigating 9 polymorphisms, by Formica and colleagues (N ¼ 40), reported the same finding for VEGF À1154G>A with respect to PFS (corrected for multiple comparisons) and also found the C allele for VEGF þ405G>C (alternatively known as þ634G>C) associated with improved overall radiologic RR (12). Another small study by Argiris and colleagues (N ¼ 28), found the C/-genotypes of VEGF þ405G>C significantly associated with OS and TTP in multivariate analysis, but only 1 patient was present in the G/G genotype group (14).…”

Tumor characteristics and metastatic sites may predict bevacizumab efficacy in the first-line treatment of metastatic colorectal cancer

“…Angiogenesis is a critical step in the metastatic cascade of CRC and the development of anti-angiogenic approaches, particularly anti-VEGF therapy, was shown to be promising in the treatment of patients with metastases, particularly those arising from CRC and, to a lesser degree, neuroendocrine carcinoma (18). Bevacizumab is a humanized immunoglobulin G1 monoclonal antibody that selectively binds to and neutralizes the biological activity of human VEGF (13). The neutralization of the biological activity of VEGF results in inhibition of the outgrowth of new blood vessels and a subsequent reduction in tumor growth.…”

“…Numerous markers, including CD133 (11), circulating tumor cell count (12), lactate dehydrogenase level (22), carbonic anhydrase 9 (23), CA 125 (24), CA 19.9 (25), visceral fat area (26), SHMT1 polymorphism (27), VEGF gene polymorphisms and baseline VEGF circulating level (13,28,29), were reported as potential predictors of angiogenesis blockade. Although the biology of tumor angiogenesis is complex, there is a biological rationale to support such observations.…”

“…Several studies and genetic analyses were conducted in order to identify a biomarker predictive of bevacizumab treatment (10)(11)(12). However, unlike the EGFR-targeted therapies, no clinical or biological factors clearly predictive of the response or resistance to bevacizumab treatment have been identified thus far (13). Furthermore, despite nearly a decade of experience with bevacizumab, its optimal use, ideal patient population and predictive biomarkers are yet to be determined.…”

Molecular biomarkers of colorectal cancer: prognostic and predictive tools for clinical practice

“…Recent studies have investigated the influence of VEGF gene polymorphisms (VGPs) on the response to bevacizumab in breast and ovarian cancer (Schneider et al, 2008;Schultheis et al, 2008). Formica et al (2011) first reported a predictive value for PFS of VGPs located in the promoter/5′ UTR in bevacizumab-treated mCRC patients. They investigated eight VGPs showing the highest polymorphic rates and found a statistically significant association between germline −2 578, −1 512, −1 451, −1 411, −460, −152, and −1 154 VGPs and PFS.…”