Abstract P4-11-14: Molecular response in breast cancer treated with neoadjuvant chemotherapy with and without bevacizumab: Results from NeoAva - a randomized phase II study
Authors: Engebraaten Olav , Silwal-Pandit Laxmi , Krohn Marit , Møller Elen K , Nord Silje , Fleischer Thomas , von der Lippe Gythfelt Hedda , Borgen Elin , Garred Øystein , Fangberget Anne , Holmen Marit Muri , Schlichting Ellen , Skjerven Helle , Lundgren Steinar , Kristensen Vessela N , Lingjaerde Ole Christian , Wist Erik , Naume Bjørn , Børresen-Dale Anne-Lise 
Published: May 2015

Abstract
The NeoAva study is a phase II clinical trial of patients with HER2 negative primary tumors of ≥25 mm treated with neoadjuvant chemotherapy (4 x FEC100 + 12 weeks of taxane-based therapy) and randomized (1:1) to receive bevacizumab or no bevacizumab. Mammography, ultrasound and MR imaging were used for response evaluation, in addition to final pathology assessment.
Tumor response were evaluable in 131 patients; of which 66 received bevacizumab in addition to chemotherapy. Tumor material was obtained at screening, 12 weeks into treatment and at surgical removal of tumors at 25 weeks. mRNA expression profiling was performed on Agilent 8x60K platform and the tumors were classified into LuminalA, LuminalB, Her2-enriched, Basal and Normal-like subtypes using the PAM50 classifier. Ratio of the tumor size at final pathology assessment, and at inclusion (by radiology assessment) was calculated to obtain a continuous scale of response reflecting the percentage of tumor shrinkage in response to therapy. Genomic Grade Index (GGI scores) based on expression profiles of 97 genes (including cell-cycle and proliferation genes) were calculated.
There were no significant differences in the tumor size, lymph node, hormone receptor status or PAM50 subtypes between the treatment arms. pCR in breast and axilla were obtained in 14 (21.1%) patients in the chemo+bev arm, and in 7 (10.6%) patients in the chemo-only arm. Tumors that obtained pCR were in higher number ER negative and TP53 mutated and exhibited Basal-like phenotype. The overall pCR rates were higher in the ER negative tumors compared to ER positive tumors {39.1% (9 of 23) vs 11.1% (12 of 108)}. However, addition of bevacizumab seemed to improve pCR in the ER positive patient group (9 vs 3) and not in ER negative patient group (5 vs 4).
On evaluating the continuous response variable, ER status, TP53 mutation status and PAM50 subtypes were significantly associated to response (p &lt; 0.001). GGI scores were highly correlated to response (p&lt; 0.001), i. e tumors with higher GGI scores showed better response. Importantly, when the chemo+bev and the chemo-only arms were evaluated separately, although similar trend of associations was observed in both arms, the associations were found to be enhanced in the chemo+bev arm.
Next, we evaluated a shift in PAM50 subtypes across the timepoints. A shift towards a better prognosis group, i.e Luminal A or Normal-like profile was observed in response to therapy. Distribution of Luminal A and Normal-like tumors at week 25, (and not at screening or week 12) was significantly different in the chemo+bev vs chemo-only group (p = 0.026, Fisher’s exact test).
GGI scores regressed across timepoints reflecting the loss of aggressive and proliferating component of the tumors in response to therapy. GGI scores in the chemo+bev group became significantly lower (p &lt; 0.01) already at week 12. This suggests that the removal of the proliferating component of the tumors by chemotherapy is accelerated and improved by addition of bevacizumab.
These results, with potentially important clinical relevance will be further investigated with respect to subtypes and the molecular changes induced by antiangiogenic therapy.
Citation Format: Olav Engebraaten, Laxmi Silwal-Pandit, Marit Krohn, Elen K Møller, Silje Nord, Thomas Fleischer, Hedda von der Lippe Gythfelt, Elin Borgen, Øystein Garred, Anne Fangberget, Marit Muri Holmen, Ellen Schlichting, Helle Skjerven, Steinar Lundgren, Vessela N Kristensen, Ole Christian Lingjaerde, Erik Wist, Bjørn Naume, Anne-Lise Børresen-Dale. Molecular response in breast cancer treated with neoadjuvant chemotherapy with and without bevacizumab: Results from NeoAva - a randomized phase II study [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P4-11-14.