Abstract 1819: Heterogeneity of triple-negative breast cancer response to neoadjuvant treatment: tumor EGFR, HER3 and MET expressions can provide clues for therapy tailoring
Authors: Radosevic-Robin Nina , Abrial Catherine , Dauplat Marie-Melanie , Roche Matthieu , Cayre Anne , Privat Maud , Kwiatkowski Fabrice , Chalabi Nassera , Mouret-Reynier Marie-Ange , Bignon Yves-Jean , Chollet Philippe , Nabholtz Jean-Marc , Penault-Llorca Frederique 
Published: May 2015

Abstract
Background: We have recently demonstrated (AACR 2013, abstract 4669) that antibody (Ab)-based EGFR targeting, sequentially combined with cytotoxic agents, can achieve pathologic complete response in almost 50% of triple-negative breast cancer (TNBC) patients (pts). However, the pts left with a residual tumor (RT), need a modification of treatment approach. We investigated whether expression of EGFR and two of its major cooperators, HER3 and MET, can offer a simple and practical base for neoadjuvant therapy (NAT) improvement in TNBC.
Methods: The study included pts with a post-NAT RT in 2 pilot clinical trials of anti-EGFR Abs in TNBC, conducted from 2009 to 2011 by our team. One trial combined panitumumab with standard fluorouracil-epirubicin-cyclophosphamide and docetaxel (P-FEC-T) while another applied cetuximab with docetaxel (C-T). EGFR, HER3 and MET were assessed by immunohistochemistry (IHC) on pre- and post-NAT BC tissue. Expressions were evaluated by Quick score (% of positive cells x stain intensity as 0, 0.5, 1, 1.5, 2, 2.5 or 3; score range 0-300). At least 30 points of difference qualified the post-NAT score as changed, compared to the pre-NAT level.
Results: 44 pts were eligible (P-FEC-T: 26 pts, C-T: 18 pts). Using 150 (the middle of the score range) as cut-off, we separated the tumors in each study on pre-NAT EGFR-high (score ≥ 150) and EGFR-low (score &lt; 150). The P-FEC-T trial had 13 EGFR-high tumors (median score 220) and 13 EGFR-low ones (median score 0). After NAT, the pre-NAT EGFR-high BC most frequently showed EGFR decrease (9/13), HER3 increase (6/10) and MET decrease (7/12). However, the pre-NAT EGFR-low tumors showed no change in EGFR (7/13) and HER3 (6/11) post-NAT, but most of them increased MET (7/11).
The C-T trial had 7 EGFR-high (median score 210) and 11 EGFR-low cases (median score 70). The EGFR-high BC from that trial showed a similar pattern of score changes as the same group from the P-FEC-T trial: frequent EGFR decrease (4/7), HER3 increase (5/7) and MET decrease (4/7). The EGFR-low BC were more heterogeneous than in P-FEC-T: most frequently EGFR, HER3 and MET were increased (4/11, 5/11, 5/11 respectively) or unchanged (4/11, 4/11, 3/11 resp.).
Conclusion: Our results indicate that: a) there is a TNBC subgroup with relatively high EGFR expression (score ≥ 150, median around 200) which resist to anti-EGFR treatment mainly by downregulating EGFR and upregulating HER3; b) TNBC with low EGFR expression (score &lt; 150) are a heterogeneous subgroup, which will frequently upregulate HER3 and/or MET after exposure to the anti-EGFR agents. The IHC assessment of EGFR, HER3 and MET before and on-NAT can help improving TNBC treatment by introduction of currently available anti-EGFR/HER3, anti-HER3 and anti-MET agents.
Citation Format: Nina Radosevic-Robin, Catherine Abrial, Marie-Melanie Dauplat, Matthieu Roche, Anne Cayre, Maud Privat, Fabrice Kwiatkowski, Nassera Chalabi, Marie-Ange Mouret-Reynier, Yves-Jean Bignon, Philippe Chollet, Jean-Marc Nabholtz, Frederique Penault-Llorca. Heterogeneity of triple-negative breast cancer response to neoadjuvant treatment: tumor EGFR, HER3 and MET expressions can provide clues for therapy tailoring. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1819. doi:10.1158/1538-7445.AM2014-1819