Impact of Exploratory Biomarkers on the Treatment Effect of Bevacizumab in Metastatic Breast Cancer

Nuffield Department of Clinical Laboratory Sciences, University of Oxford, Oxford, United Kingdom.
Clinical Cancer Research (Impact Factor: 8.19). 01/2011; 17(2):372-81. DOI: 10.1158/1078-0432.CCR-10-1791
Source: PubMed

ABSTRACT The addition of bevacizumab to cytotoxic chemotherapy has demonstrated a progression-free survival (PFS) benefit in the first-line and second-line treatment of advanced or metastatic breast cancer (MBC). However, the addition of bevacizumab to capecitabine in heavily pretreated MBC patients did not show a PFS benefit (AVF2119g phase III trial). The aim of this study was to evaluate the expression of novel putative biomarkers as predictors of benefit from bevacizumab in retrospective subset analyses of the AVF2119g trial.
In the AVF2119g trial, 462 patients with MBC were randomly assigned to receive capecitabine or capecitabine plus bevacizumab. Primary tumor tissue and outcome data were available for 223 patients. Biomarker expression was assessed by in situ hybridization (VEGF-A, VEGF-B, thrombospondin-2 and Flt4) or immunohistochemistry (VEGF-C, PDGF-C, neuropilin-1, delta-like ligand (Dll) 4, Bv8, p53 and thymidine phosphorylase) on formalin-fixed, paraffin-embedded tissue. PFS was associated with these variables in retrospective subset analyses.
Patients with low scores for Dll4, VEGF-C, and neuropilin-1 showed trends toward improvement in PFS associated with the addition of bevacizumab to capecitabine (P values = 0.01, 0.05, and 0.07, respectively). These observations were not statistically significant following correction for multiple hypothesis testing.
These retrospective subset analyses suggest that expression of Dll4, VEGF-C, and neuropilin-1 may predict benefit from bevacizumab. Such observations are not conclusive but warrant additional testing.

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    • "A retrospective analysis of tumour tissue samples from the AVF2119g trial of capecitabine with or without bevacizumab in heavily pretreated patients with LR/mBC showed a weak prognostic but not a predictive effect of tumour VEGF-A expression (Jubb et al, 2011). However, low expression of neuropilin-1, thymidine phosphorylase, VEGF-C, and delta-like ligand 4 showed trends towards increased PFS benefit with bevacizumab (Jubb et al, 2011). Similar findings for neuropilin-1 have been reported in two trials of bevacizumab in gastric cancer (AVAGAST) (Ohtsu et al, 2011) and colorectal cancer (NO16966) (Saltz et al, 2008), in which low neuropilin expression was associated with greater bevacizumab treatment effect (Foernzler et al, 2010; Van Cutsem et al, 2012). "
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    ABSTRACT: Background: Combining bevacizumab with first-line chemotherapy significantly improves progression-free survival (PFS) in HER2-negative metastatic breast cancer (mBC). However, identification of patients benefitting most from bevacizumab remains elusive. The AVADO trial included an extensive optional exploratory biomarker programme. Methods: Patients with HER2-negative mBC were randomised to receive docetaxel with placebo or bevacizumab. The primary end point was PFS. Plasma samples were analysed using a multiplex ELISA. Blood mRNA expression was assessed using quantitative PCR. Tumour tissue samples were analysed by immunohistochemistry. Single-nucleotide polymorphisms (SNPs) involved in the VEGF pathway were analysed in germline DNA. Results: Samples for biomarker analysis were available from 24–54% of the 736 treated patients (depending on specimen type). The most consistent potential predictive effect was observed with plasma VEGF-A and VEGFR-2; high baseline concentrations were associated with greater treatment effect. Blood mRNA analyses suggested a greater bevacizumab effect in patients with high VEGF121. No consistent predictive effect was seen for tumour neuropilin or other candidate tumour markers by immunohistochemistry, or for any of the SNPs investigated. Conclusion: Plasma VEGF-A and VEGFR-2 are potential predictive markers for bevacizumab efficacy, supporting findings in gastric and pancreatic cancers. Plasma VEGF-A is being evaluated prospectively in mBC in the MERiDiAN trial.
    British Journal of Cancer 02/2013; 108(5). DOI:10.1038/bjc.2013.69 · 4.82 Impact Factor
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    • "Given the preclinical data, there may be benefit to combination of an agent targeting DLL4 with bevacizumab. A recent retrospective analysis demonstrates that DLL4 expression, along with VEGF-C and neuropilin-1, indicated a poor response to bevacizumab treatment and may be a path of resistance in human disease (Jubb et al., 2011). "
    Tumor Angiogenesis, 02/2012; , ISBN: 978-953-51-0009-6
  • Article: Bevacizumab
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    ABSTRACT: Bevacizumab (Avastin™) is a humanized monoclonal antibody directed against vascular endothelial growth factor. In patients with human epidermal growth factor receptor type 2 (HER2)-negative metastatic breast cancer, bevacizumab is indicated as first-line therapy in combination with paclitaxel, or in combination with capecitabine when treatment with other chemotherapy options, including taxanes or anthracyclines, is not considered appropriate. This article reviews the efficacy and tolerability of these combination therapies in the first-line treatment of patients with metastatic breast cancer, and summarizes the pharmacological properties of bevacizumab. In randomized, controlled, phase III trials in patients with predominantly HER2-negative metastatic or locally recurrent breast cancer, the addition of bevacizumab to paclitaxel or capecitabine significantly prolonged progression-free survival (PFS; investigator assessment) by a median of 5.9 and 2.9 months, respectively, relative to paclitaxel or capecitabine alone. It also significantly increased the objective response rate, but not overall survival. Independent reviews of data supported the results of the primary analyses of investigator-assessed PFS. However, as the efficacy of bevacizumab in combination with capecitabine appears to be less than that of other available options, it should be used only if treatment with other chemotherapy options are not considered appropriate. The addition of bevacizumab to paclitaxel had no significant adverse effects on health-related quality of life. Efficacy data from two routine clinical practice studies were generally consistent with those from the phase III trials. Bevacizumab had generally acceptable tolerability when administered in combination with paclitaxel or capecitabine as first-line therapy in these studies, and adverse events were consistent with the known tolerability profiles of the individual agents. The most common adverse events associated with bevacizumab combination therapy in phase III trials were sensory neuropathy and grade ≥3 hypertension, occurring more frequently with combination therapy than with chemotherapy alone. Potentially life-threatening events, such as venous thromboembolism, gastrointestinal perforation, arterial thromboembolism, haemorrhage and left ventricular dysfunction, occurred in ≤5% of patients receiving combination therapy in these trials. In conclusion, bevacizumab administered in combination with paclitaxel, or in combination with capecitabine if other chemotherapy regimens are not appropriate, may be considered as an option for the first-line treatment of patients with HER2-negative metastatic breast cancer.
    American Journal of Cancer 01/2011; 3(3). DOI:10.2165/00024669-200403030-00005
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