Abstract Background The mechanisms of tumour progression during anti-VEGF-A treatment are poorly understood. Patients and materials Two patients with metastatic breast cancer are described who developed new metastases while receiving anti-VEGF-A treatment. Angiogenic parameters were determined by CD34/Ki67 double staining, Chalkley counts (CC) and endothelial cell proliferation fractions (ECP). RT-PCR Taqman low-density arrays with a gene panel of 94 angiogenesis-related genes were performed on both metastases and compared to 10 unselected primary breast tumours. Results Both lesions showed a high and intermediate CC of, respectively, 7.5±0.62 and 4.8±0.2. Both lesions had elevated ECP values of 14% and 8%. Low-density array screening showed that VEGFR1 mRNA was overexpressed in both samples (z-score=7.85 and 7.81) compared to con- trol samples (out of range [min–max]). Additional analysis confirmed this finding at the protein level by immunohis- tochemistry. Conclusion These observations suggest that tumour pro- gression under continuous anti-VEGF-A continues to be angiogenesis dependent. Further exploration is needed to identify the mechanisms of anti-VEGF-A resistance in or- der to design combination-targeted therapies. Keywords Anti-VEGF-A · Bevacizumab · Refractory · Resistant · VEGFR1 · Breast cancer Background Vascular endothelial growth factor A (VEGF-A) has a criti- cal role in tumour progression, promoting angiogenesis. VEGF-A inhibitors, such as bevacizumab and VEGF-Trap, are being introduced into the treatment of breast cancer. Although these agents are able to increase progression-free survival, tumour progression eventually occurs in the ma- jority of patients. The mechanisms of tumour progression during anti-VEGF-A treatment are poorly understood. Two patients suffering from metastatic breast cancer are de- scribed as having tumour progression while being treated with single-agent bevacizumab. Both patients participated in the AVADO clinical phase III study and were shown to have received high-dose bevacizumab after unblinding [1]. Both initially responded to their treatment with the doc- etaxel and bevacizumab combination. Patient A (38 y) par- ticipated in the AVADO trial after she developed multiple lung, liver and skeletal metastases as first-line therapy for metastatic disease. She received high-dose bevacizumab and docetaxel (6 cycles) and she was on single-agent beva- cizumab (15 mg/kg/3 wk) for 4 months before her disease progressed. At that time a newly developed skin metastasis was surgically removed. Patient B developed tumour pro- gression in the mediastinum for which she participated in the AVADO trial. She initially responded to the docetaxel/ bevacizumab (9 cycles) combination. After 7 months of X.B. Trinh · P.A. van Dam · P.B. Vermeulen · S.J. Van Laere · G.G. Van den Eynden · L.Y. Dirix () Translational Cancer Research Group-Antwerp Oncology Centre St. Augustinus Hospital Oosterveldlaan 24 2610 Wilrijk-Antwerp, Belgium e-mail: luc.dirix@gza.be X.B. Trinh · W.A.A. Tjalma Department of Gynaecological Oncology Antwerp University Hospital Wilrijkstraat 10 2650 Edegem, Belgium Clin Transl Oncol (2011) 13:805-808 DOI 10.1007/s12094-011-0737-3 RESEARCH ARTICLES VEGF-A-independent and angiogenesis-dependent tumour growth in patients with metastatic breast cancer Xuan Bich Trinh · Peter A. van Dam · Peter B. Vermeulen · Steven J. Van Laere · Gert G. Van den Eynden · Wiebren A.A. Tjalma · Luc Y. Dirix Received: 14 December 2010 / Accepted: 13 February 2011