Angiogenic escape and tumour progression in two patients with metastatic breast cancer receiving bevacizumab treatment.
Authors: Trinh B , Van Dam P , Prové A , Maes H , Van Laere S , Tjalma W , Huget P , Vermeulen P , Dirix L 
Published: December 2010

Abstract
Abstract #1029
Background: Vascular endothelial growth factor A (VEGF-A) has an important role in tumour progression by promoting angiogenesis. VEGF-A inhibitors, such as bevacizumab (Bev) and VEGF-Trap are being introduced into the treatment of breast cancer in order to target angiogenesis by inhibiting VEGF-A.&#x2028; Material and Methods: Two patients with metastatic breast cancer are described having tumour progression while being treated with single agent Bev. Both patients participated in the AVADO clinical phase III study, where shown to have received Bev in combination with docetaxel (D) as first line treatment for metastatic breast cancer. The first patient (A) had received 6 cycles of D and Bev and was for 4 months on single agent Bev (15mg/kg/3wk) before progressing. Pt B had received 9 cycles of D and Bev and was on 7 months of single agent Bev (15mg/kg/3wk) before disease progression. Tumour biopsies of progressing lesions were obtained after informed consent. Routine histological assessment and a CD34/Ki67 double staining were performed on their primary tumour as well as on the newly developed metastasis (A+B). Chalkley counts (CC) and endothelial cell proliferation fractions (ECP) were assessed by two independent observers. RT-PCR Taqman low density arrays with a gene panel of 94 angiogenesis related genes were performed in triplicate on both metastasis and compared to 10 other primary breast tumours.&#x2028; Results: Both lesions showed a high CC, respectively 7.5±0.62 (A) and 4.8±0.2 (B). Both lesions had elevated ECP values of 14% (A) and 8% (B).&#x2028; Using the 2 (-__CT) method and 18S as an internal control, the VEGFR1 mRNA was highly overexpressed in both A (25.18±0.12 fold change) and B (38.60±0.07 fold change) compared to the mean of 10 unselected primary breast tumours serving as controls (p&lt;10-7). Similarly, in metastasis B, VEGF-B, TGFB1 and PDGFRA were found to be overexpressed, i.e. out of range [min-max] of the 10 primary breast tumours. A had out of range overexpression of VEGF-C. The gene expression of VEGF-A, VEGF-D, VEGFR2, VEGFR3, PDGFB and PDGFRB in both A and B were found to be in the range of the 10 controls.&#x2028; Conclusion: We describe two patients with progressive disease while being treated with Bev after an initial response on the combination of D and Bev. These new sites of disease showed a highly angiogenic and apparently vascular dependent growth pattern, in spite of high dosed anti-VEGF-A regimen. This suggests the existence of an important VEGF-A independent alternative modality of the tumour to promote angiogenesis. VEGFR1 was remarkably overexpressed in both metastases compared to controls. The expression of placental growth factor, a VEGFR1 specific ligand is further being explored. Knowledge of the biology of Bev resistance is essential since it could be useful in designing well considered combinations of targeted therapies.
Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 1029.