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    Evaluation of efficacy and safety markers in a phase II study of metastatic colorectal cancer treated with aflibercept in the first-line setting.

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    Author
    Lambrechts, D; Thienpont, B; Thuillier, V; Sagaert, X; Moisse, M; Peuteman, G; Pericay, C; Folprecht, G; Zalcberg, J; Zilocchi, C; ...
    Date
    2015-09-29
    Source Title
    British Journal of Cancer
    Publisher
    Springer Science and Business Media LLC
    University of Melbourne Author/s
    Zalcberg, John
    Affiliation
    Medicine and Radiology
    Metadata
    Show full item record
    Document Type
    Journal Article
    Citations
    Lambrechts, D., Thienpont, B., Thuillier, V., Sagaert, X., Moisse, M., Peuteman, G., Pericay, C., Folprecht, G., Zalcberg, J., Zilocchi, C., Margherini, E., Chiron, M. & Van Cutsem, E. (2015). Evaluation of efficacy and safety markers in a phase II study of metastatic colorectal cancer treated with aflibercept in the first-line setting.. Br J Cancer, 113 (7), pp.1027-1034. https://doi.org/10.1038/bjc.2015.329.
    Access Status
    Open Access
    URI
    http://hdl.handle.net/11343/257187
    DOI
    10.1038/bjc.2015.329
    Open Access at PMC
    http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4651136
    Abstract
    BACKGROUND: Aflibercept (ziv-aflibercept) is an anti-angiogenic agent recently approved in combination with FOLFIRI for the treatment of metastatic colorectal cancer (mCRC) patients previously treated with oxaliplatin. Despite heterogeneity in response to aflibercept, no biomarkers for efficacy or adverse effects have been identified. Here we present biomarker data from the randomised phase II AFFIRM trial assessing aflibercept in combination with mFOLFOX6 first line in mCRC. METHODS: Ninety-six somatic mutations in key oncogenic drivers of mCRC and 133 common single-nucleotide polymorphisms (SNPs) in vascular endothelial growth factor (VEGF) pathway genes were analysed, and 27 plasma markers measured at baseline, during and after treatment. We assessed correlations of these three classes of biomarkers with progression-free survival (PFS) and adverse events (AEs). RESULTS: Somatic mutations identified in KRAS, BRAF, NRAS, PIK3CA and PIK3R1 did not significantly correlate with PFS (multiple testing-adjusted false discovery rate (FDR) or multiple testing-adjusted FDR>0.3). None of the individual SNPs correlated with PFS (multiple testing-adjusted FDR>0.22), but at the gene level variability in VEGFB significantly correlated with PFS (multiple testing-adjusted FDR=0.0423). Although none of the plasma markers measured at baseline significantly correlated with PFS, high levels of circulating IL8 at baseline together with increased levels of IL8 during treatment were significantly associated with reduced PFS (multiple testing-adjusted FDR=0.0478). No association was found between biomarkers and AEs. CONCLUSIONS: This represents the first biomarker study in mCRC treated with aflibercept. High IL8 plasma levels at baseline and subsequent increases in IL8 were associated with worse PFS, suggesting that IL8 may act as a potentially predictive biomarker of aflibercept treatment outcome.

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