Impact of exploratory biomarkers on the treatment effect of bevacizumab in metastatic breast cancer

Adrian M. Jubb, Kathy Miller, Hope S. Rugo, Adrian L. Harris, Dafeng Chen, James D. Reimann, Melody A. Cobleigh, Maike Schmidt, Virginia K. Langmuir, Kenneth J. Hillan, Daniel S. Chen, Hartmut Koeppen

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Abstract

Purpose: 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. Experimental Design: 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. Results: 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. Conclusion: 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.

Original languageEnglish
Pages (from-to)372-381
Number of pages10
JournalClinical Cancer Research
Volume17
Issue number2
DOIs
StatePublished - Jan 15 2011

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Biomarkers
Neuropilin-1
Breast Neoplasms
Vascular Endothelial Growth Factor C
Disease-Free Survival
Vascular Endothelial Growth Factor B
Therapeutics
Thymidine Phosphorylase
Paraffin
Formaldehyde
Vascular Endothelial Growth Factor A
In Situ Hybridization
Bevacizumab
Research Design
Immunohistochemistry
Drug Therapy
Capecitabine
Neoplasms

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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Impact of exploratory biomarkers on the treatment effect of bevacizumab in metastatic breast cancer. / Jubb, Adrian M.; Miller, Kathy; Rugo, Hope S.; Harris, Adrian L.; Chen, Dafeng; Reimann, James D.; Cobleigh, Melody A.; Schmidt, Maike; Langmuir, Virginia K.; Hillan, Kenneth J.; Chen, Daniel S.; Koeppen, Hartmut.

In: Clinical Cancer Research, Vol. 17, No. 2, 15.01.2011, p. 372-381.

Research output: Contribution to journalArticle

Jubb, AM, Miller, K, Rugo, HS, Harris, AL, Chen, D, Reimann, JD, Cobleigh, MA, Schmidt, M, Langmuir, VK, Hillan, KJ, Chen, DS & Koeppen, H 2011, 'Impact of exploratory biomarkers on the treatment effect of bevacizumab in metastatic breast cancer', Clinical Cancer Research, vol. 17, no. 2, pp. 372-381. https://doi.org/10.1158/1078-0432.CCR-10-1791
Jubb, Adrian M. ; Miller, Kathy ; Rugo, Hope S. ; Harris, Adrian L. ; Chen, Dafeng ; Reimann, James D. ; Cobleigh, Melody A. ; Schmidt, Maike ; Langmuir, Virginia K. ; Hillan, Kenneth J. ; Chen, Daniel S. ; Koeppen, Hartmut. / Impact of exploratory biomarkers on the treatment effect of bevacizumab in metastatic breast cancer. In: Clinical Cancer Research. 2011 ; Vol. 17, No. 2. pp. 372-381.
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AU - Reimann, James D.

AU - Cobleigh, Melody A.

AU - Schmidt, Maike

AU - Langmuir, Virginia K.

AU - Hillan, Kenneth J.

AU - Chen, Daniel S.

AU - Koeppen, Hartmut

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N2 - Purpose: 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. Experimental Design: 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. Results: 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. Conclusion: 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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