Predictive Biomarkers for Bevacizumab: Are We There Yet?

Pathology, The University of Texas MD Anderson Cancer Center.
Clinical Cancer Research (Impact Factor: 8.72). 04/2013; DOI: 10.1158/1078-0432.CCR-12-3409
Source: PubMed


Therapy targeting VEGF has become the standard of care in several solid malignancies. Early investigations attempting to identify predictive markers for the efficacy of therapy failed to identify any predictive markers that could help oncologist decide who should, and more importantly, who should not receive VEGF-targeted therapies. However, there has been renewed interest in predictive biomarkers for VEGF-targeted therapies especially in light of the fact that the US Food and Drug Administration withdrew approval for use of bevacizumab, an antibody to VEGF, in patients with metastatic breast cancer. In a recent publication in the Journal of Clinical Oncology, investigators identified circulating VEGF and tumor neuropilin-1 expression as potential predictive biomarkers for bevacizumab. In this perspective, we provide a critical evaluation of the utility of these markers, and the need for validation in prospective clinical trials.

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    • "These markers include levels of baseline circulating endothelial cells, circulating angiogenesis-related cytokines such as interleukin- 8 and PlGF 16 (Jayson et al, 2005; Dellapasqua et al, 2008; Willett et al, 2009; Kopetz et al, 2010), and SNPs in VEGF-A, VEGFR-1, and interleukin-8 (Schneider et al, 2008; Schultheis et al, 2008; Zhang et al, 2009; Jubb and Harris, 2010; Loupakis et al, 2011; Lambrechts et al, 2012; Collinson et al, 2013; Maru et al, 2013; Miles et al, 2013). Technical measurement difficulties and lack of validation in large randomised trials have limited their translation into routine clinical use (Furstenberger et al, 2005; Rowand et al, 2007; Mancuso et al, 2009; Maru et al, 2013). SNPs studies have produced conflicting findings and are compromised by multiple analyses that limit interpretation of apparently significant published P-values (Schneider et al, 2008; Schultheis et al, 2008; Zhang et al, 2009; Jubb and Harris, 2010; Lambrechts et al, 2012). "
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    ABSTRACT: background: Bevacizumab prolongs progression-free survival (PFS) in patients with metastatic colorectal cancer. We analysed the protein expression levels of vascular endothelial growth factor (VEGF) ligands and receptors to determine their prognostic and predictive effects. methods: We graded expression of VEGF-A, VEGF-B, VEGF-C, VEGF-D, VEGF-R1, and VEGF-R2 to assess whether overexpression predicted bevacizumab resistance in samples from 268 of 471 patients randomised to capecitabine (C), capecitabine and bevacizumab (CB), or CB and mitomycin (CBM) in the MAX trial and extended the analysis to the CAIRO-2 population. results: Patients with low expression of VEGF-D (0, 1+) benefited from bevacizumab treatment (PFS hazard ratio (HR) (C vs CB+CBM), 0.21; 95% CI, 0.08–0.55; overall survival (OS) HR, 0.35; 95% CI, 0.13–0.90). Patients with higher VEGF-D expression received less benefit (VEGF-D 2+ PFS HR, 0.67; 95% CI, 0.45–1.00; OS HR, 0.82; 95% CI, 0.52–1.30; VEGF-D 3+ PFS HR, 0.77; 95% CI, 0.50–1.17; OS HR, 1.28; 95% CI, 0.79–2.09) (P interaction <0.05). In CAIRO-2, there was no difference in PFS or OS according to VEGF-D expression. conclusions: The predictive value of VEGF-D expression for bevacizumab may depend on the chemotherapy backbone used. Further evaluation is required before clinical utilisation.
    British Journal of Cancer 06/2015; 113(1). DOI:10.1038/bjc.2015.209 · 4.84 Impact Factor
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    • "Previous studies have reported the clinical impact of some genes, including VEGF splice isoforms or neuropilin-1 (NRP-1) [27]. However, to date, no biomarkers have been identified in randomized controlled trials on the clinical response of anti-angiogenic treatments in colorectal cancer [28]. Further prospective studies on HOXB9 and IL6 in different specimens such as serum samples are important to clarify the utility of these molecules as biomarkers. "
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    ABSTRACT: Background Homeobox B9 (HOXB9), a transcriptional factor, regulates developmental processes and tumor progression and has recently been recognized as one of important transcriptional factors related to angiogenesis. This study aimed to investigate the role of HOXB9 in tumorigenesis and angiogenesis. Methods We examined the expression of HOXB9 in colorectal cancer using qPCR and in situ hybridization. We also examined the effect of HOXB9 overexpression in colorectal cancer using a proliferation assay, ELISA, a multiplex assay, and xenograft models. The clinical significance of HOXB9 was statistically evaluated in resected specimens. Results HOXB9 was expressed in colorectal cancer specimens. HOXB9 induced angiogenesis and tumor proliferation in vitro, which resulted in high tumorigenicity in vivo and poor overall survival. Bevacizumab, an anti-vascular endothelial growth factor (VEGF) antibody, remarkably suppressed tumor proliferation by inhibiting angiogenesis in HOXB9-overexpressing xenografts, and it improved overall survival and provided prolonged progression-free survival in HOXB9-overexpressing patients. A comprehensive multiplex assay of the supernatant of cancer cells co-cultured with human vascular endothelial cells and fibroblasts indicated significantly higher interleukin-6 (IL6) levels than those in the supernatant of monocultured cells. HOXB9 overexpression in clinical specimens was significantly correlated with increased IL6 expression. An IL6-neutralizing antibody inhibited VEGF secretion and tumor proliferation in the co-culture system. Conclusions HOXB9 promotes the secretion of angiogenic factors, including VEGF, to induce tumor proliferation through microenvironmental production of cytokines including IL6 signaling. Moreover, silencing of VEGF or IL6 terminates cytokine release in tumor microenvironment. Thus, HOXB9 and IL6 may be potential biomarkers for bevacizumab treatment.
    Molecular Cancer 05/2014; 13(1):102. DOI:10.1186/1476-4598-13-102 · 4.26 Impact Factor
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    • "Despite the significant number of studies based on GBM treatment with bevacizumab, alone or in combination with other drugs, in vivo modifications induced by treatment are poorly defined [3]. Moreover, although the highly variable response to bevacizumab, currently there are no prospectively validated predictive or prognostic biomarkers for it [4]. "
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    ABSTRACT: Perfusion weighted imaging (PWI) can be used to measure key aspects of tumor vascularity in vivo and recent studies suggest that perfusion imaging may be useful in the early assessment of response to angiogenesis inhibitors. Aim of this work is to compare Parametric Response Maps (PRMs) with the Region Of Interest (ROI) approach in the analysis of tumor changes induced by bevacizumab and irinotecan in recurrent glioblastomas (rGBM), and to evaluate if changes in tumor blood volume measured by perfusion MRI may predict clinical outcome. 42 rGBM patients with KPS ≥50 were treated until progression, as defined by MRI with RANO criteria. Relative cerebral blood volume (rCBV) variation after 8 weeks of treatment was calculated through semi-automatic ROI placement in the same anatomic region as in baseline. Alternatively, rCBV variations with respect to baseline were calculated into the evolving tumor region using a voxel-by-voxel difference. PRMs were created showing where rCBV significantly increased, decreased or remained unchanged. An increased blood volume in PRM (PRMCBV+) higher than 18% (first quartile) after 8 weeks of treatment was associated with increased progression free survival (PFS; 24 versus 13 weeks, p = 0.045) and overall survival (OS; 38 versus 25 weeks, p = 0.016). After 8 weeks of treatment ROI analysis showed that mean rCBV remained elevated in non responsive patients (4.8±0.9 versus 5.1±1.2, p = 0.38), whereas decreased in responsive patients (4.2±1.3 versus 3.8±1.6 p = 0.04), and re-increased progressively when patients approached tumor progression. Our data suggest that PRMs can provide an early marker of response to antiangiogenic treatment and warrant further confirmation in a larger cohort of GBM patients.
    PLoS ONE 03/2014; 9(3):e90535. DOI:10.1371/journal.pone.0090535 · 3.23 Impact Factor
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