Abstract P6-13-01: Proteomic response in breast cancer treated with neoadjuvant chemotherapy with and without bevacizumab: Reverse phase protein array (RPPA) results from NeoAva - A randomized phase II study
Authors: Haugen MH , Lindgjærde OC , Krohn M , Zhao W , Lindholm EM , Silwal-Pandit L , Borgen E , Garred Ø , Fangberget A , Holmen MM , Schlichting E , Skjerven H , Lundgren S , Wist E , Naume B , Mælandsmo GM , Lu Y , Børresen-Dale A-L , Mills GB , Engebråten O 
Published: March 2017

BACKGROUND: Patients with HER2 negative primary tumors of ≥25 mm were treated with neoadjuvant chemotherapy (4 x FEC100 + 12 weeks of taxane-based therapy) and randomized (1:1) to receive bevacizumab or not. Mammography, ultrasound and MR imaging were used for response evaluation, in addition to the final pathology assessment after surgery.

HYPOTHESIS: RPPA proteomic analyses support identification of molecular mechanisms associated with clinical response to bevacizumab treatment.

METHODS: Tumor responses were evaluable in 132 patients; of which 66 received bevacizumab. Ratio of the tumor size at final pathology assessment, and at inclusion was calculated to obtain a continuous scale of response reflecting the percentage of tumor shrinkage in response to therapy. Tumor material was obtained at screening, 12 weeks into treatment and at surgical removal of tumors at 25 weeks. Lysates from each sample was analyzed on reverse phase protein arrays (RPPA) for expression levels of 210 proteins of which 54 were phospho-specific.

RESULTS: Several proteins were found for which expression prior to treatment reflected a better response on tumor shrinkage in the combination treatment arm (chemotherapy+bevacizumab). The proteomic response from week 0 to 12 in both treatment arms had an overall similar profile regarding up- and down-regulated proteins; however, the combination treatment (FEC100 + bevacizumab) induced a more pronounced effect on regulation of each protein. This might reflect the capability of bevacizumab therapy to potentiate the effects of the anthracyclin based chemotherapy from week 0 to 12. Conversely, from week 12-25 (taxane-based therapy + bevacizumab) this effect was lost or even reversed, except for certain phosphoproteins where potentiation imposed by bevacizumab was sustained throughout the whole treatment period. We are in the process of analyzing the impact of phosphorylation and thus protein activation states on treatment response. Furthermore, tumors with low hormone receptor pathway score demonstrated a better response in the combination treatment (chemotherapy+bevacizumab). Additionally, in these good responders the hormone signaling pathway was significantly upregulated during treatment. Further investigations are conducted to determine if this was due to selective ablation of hormone receptor negative tumor cells, or a re-programming of the molecular phenotype of cells present prior to treatment. The above mentioned results have potentially important clinical relevance and will be further investigated with respect to subtypes and the biological pathways affected by antiangiogenic therapy.

Citation Format: Haugen MH, Lindgjærde OC, Krohn M, Zhao W, Lindholm EM, Silwal-Pandit L, Borgen E, Garred Ø, Fangberget A, Holmen MM, Schlichting E, Skjerven H, Lundgren S, Wist E, Naume B, Mælandsmo GM, Lu Y, Børresen-Dale A-L, Mills GB, Engebråten O. Proteomic response in breast cancer treated with neoadjuvant chemotherapy with and without bevacizumab: Reverse phase protein array (RPPA) results from NeoAva - A randomized phase II study [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P6-13-01.