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.

  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Neo-angiogenesis is a critical process for tumor growth and invasion and has become a promising target in cancer therapy. This manuscript reviews three currently relevant anti-angiogenic agents targeting the vascular endothelial growth factor system: bevacizumab, ramucirumab and sorafenib. The efficacy of anti-angiogenic drugs in adjuvant therapy or as neo-adjuvant treatment has been estimated in clinical trials of advanced breast cancer. To date, the overall observed clinical improvements are unconvincing, and further research is required to demonstrate the efficacy of anti-angiogenic drugs in breast cancer treatments. The outcomes of anti-angiogenic therapy have been highly variable in terms of tumor response. New methods are needed to identify patients who will benefit from this regimen. The development of biomarkers and molecular profiling are relevant research areas that may strengthen the ability to focus anti-angiogenic therapy towards suitable patients, thereby increase the cost-effectiveness, currently estimated to be inadequate.
    International Journal of Molecular Sciences 12/2014; 15(12):23024-23041. DOI:10.3390/ijms151223024 · 2.46 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The evaluation of therapeutic efficacy is necessary to predict the outcome of patients with metastatic colorectal cancer (CRC). In these patients, there is a critical need for predictive chemosensitivity assays and biomarkers to optimize efficacy and minimize toxicity. The introduction of targeted agents has improved the progression-free survival and overall survival of patients with metastatic disease. However, approximately 50% of patients do not show a positive response to chemotherapy and the selection of patients likely to respond to a specific regimen remains challenging. Cell culture-based chemosensitivity tests use autologous viable tumor cells to evaluate susceptibility to specific agents in vitro and predict their direct effects. Adenosine triphosphate-based assays and methyl thiazolyl-diphenyl-tetrazolium bromide-based assays are used widely as sensitivity tests because of their short assay period, technical simplicity, and the requirement of small amount of specimen. Among protein- and gene-based chemosensitivity assays, assessment of KRAS mutation status predicts the response to epidermal growth factor receptor-targeted therapy in CRC patients. The validation of predictive and prognostic markers enables the selection of therapeutic regimens with optimal efficacy and minimal toxicity for each patient, which has been termed personalized treatment. This review summarizes currently available predictive and prognostic chemosensitivity tests for metastatic CRC.
    World Journal of Gastroenterology 11/2014; 20(44):16398-16408. DOI:10.3748/wjg.v20.i44.16398 · 2.43 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: This multicentre, single arm, phase II study was aimed to assess the efficacy and safety of pazopanib as second-line treatment after failure of sunitinib in patients with metastatic renal cell carcinoma (mRCC) and explore biomarkers for pazopanib response. Patients received pazopanib 800mgperday. The primary end-point was progression-free survival (PFS). Secondary end-points included objective response rate (ORR), overall survival (OS) and safety. Serum proteins (Delta-like ligand (DLL4), Notch1, hypoxia inducible factor-1α (HIF-1α), HIF-2α, vascular endothelial growth factor A (VEGFA) and platelet-derived growth factor receptor β (PDGFRB)) levels were measured using enzyme-linked immunosorbent assay (ELISA). 86 patients with clear cell mRCC were enrolled from December 2009 to March 2012 from three centres in Southern China. Of 85 evaluable patients, the median PFS was 5.6months (95% confidence interval (CI), 4.1-6.7months) by independent review. No complete response (CR) was observed in all patients. 13 (15.3%; 95% confidence interval [CI], 11.2-23.9%) patients achieved partial responses (PR) (ORR 15.3%). Median OS was 18.1months (95% CI, 13.2-19.8months). The most common adverse events (AEs) were mild to moderate and clinically manageable, including hypertension (37.6%), diarrhoea (36.5%), increased AST (51.8%), and anaemia (60%). AEs resulted in dose reduction in 24.7% of patients. Multivariable analysis showed that higher baseline levels of DLL4 and VEGFA and lower baseline level of HIF-2α were associated with shorter PFS; only lower baseline level of HIF-2α was correlated with shorter OS. The lower expression level of DLL4 after pazopanib treatment was associated with higher response rate probability. In conclusion, pazopanib was clinically active and well tolerated as second-line treatment after sunitinib in mRCC patients. Baseline levels of serum DLL4, VEGFA and HIF-2α may have potential utility as biomarkers of clinical efficacy in this setting (chiCTR-TRC-13004016). Copyright © 2015 Elsevier Ltd. All rights reserved.
    European journal of cancer (Oxford, England: 1990) 01/2015; 51(5). DOI:10.1016/j.ejca.2015.01.005 · 4.82 Impact Factor


Available from