Abstract 564: Identification of biomarkers predictive of response to panitumumab combined with neoadjuvant chemotherapy for primary inflammatory breast cancer
Authors: Wang Xiaoping , Matsuda Naoko , Lim Bora , Krishnamurthy Savitri , Song Juhee , Shen Yu , Wu Wenhui , Hu Jianhua , Woodward Wendy A. , Reuben James M. , Lucci Anthony , Tripathy Debu , Valero Vicente , Ueno Naoto T. 
Published: August 2018

Abstract
Inflammatory breast cancer (IBC) is the most lethal and aggressive form of breast cancer, and there are no FDA-approved targeted therapies specific for IBC. We recently completed a single-arm phase II study of neoadjuvant therapy with the humanized anti-EGFR monoclonal antibody panitumumab (PmAb), nab-paclitaxel, and carboplatin followed by 5-fluorouracil, epirubicin, and cyclophosphamide in patients with newly diagnosed HER2-negative IBC (N = 40), which produced the highest pathologic complete response (pCR) rate (47%) ever observed in patients with triple-negative IBC (TN-IBC; negative for estrogen receptor, progesterone receptor, and HER2; N = 19). In the work described here, we aimed to identify biomarkers predictive of response of IBC to this combination therapy. We used immunohistochemical staining to examine the expression of key molecules involved in EGFR signaling, which regulates cancer stem cells and epithelial-mesenchymal transition in IBC, including EGFR, phosphorylated EGFR (pEGFR), E-cadherin, vimentin, COX-2, and Nodal, in paired tumor samples obtained before and after the first dose of PmAb in our phase II trial. Our data showed that the expression of pEGFR (P = .05) and COX-2 (P = .05) in pre-PmAb tissues marginally correlated with pCR; the change of pEGFR expression (P = .09) between pre-PmAb and post-PmAb samples showed a trend toward correlation with pCR. We conducted RNA-seq on 13 pairs of tumor biopsy specimens obtained before and after the first dose of PmAb. Analysis of all samples did not identify any candidate genes with significant changes after PmAb treatment. In the TN-IBC samples, we identified 2 genes (POU3F3 and EGR1) that were significantly downregulated and 4 genes (BBOX1, GLYATL2, MUCL1, and LCN2) that were significantly upregulated after PmAb treatment, but we did not identify any gene whose change in expression predicted pCR status, possibly because the small sample size of the non-pCR group (N = 2) limits the statistical power. We validated the change in expression of EGR1, MUCL1, and LCN2 after PmAb treatment in SUM149 IBC cells. In the hormone-receptor-positive, HER2-negative tumor samples, we identified 19 genes that were significantly downregulated and 10 genes that were significantly upregulated after PmAb treatment. These genes function in cellular movement, cell morphology, cell-to-cell signaling and interaction, molecular transport, and the cell cycle. Our results suggest potential roles of pEGFR and COX-2 expression at baseline and PmAb-modulated pEGFR, EGR1, MUCL1, and LCN2 expression in predicting PmAb response. Validation of these biomarker candidates and studies of the mechanisms by which they affect IBC response are ongoing.
Citation Format: Xiaoping Wang, Naoko Matsuda, Bora Lim, Savitri Krishnamurthy, Juhee Song, Yu Shen, Wenhui Wu, Jianhua Hu, Wendy A. Woodward, James M. Reuben, Anthony Lucci, Debu Tripathy, Vicente Valero, Naoto T. Ueno. Identification of biomarkers predictive of response to panitumumab combined with neoadjuvant chemotherapy for primary inflammatory breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 564.