Abstract P4-10-22: Loss of androgen receptor after neoadjuvant anti-HER2 therapy in patients with locally advanced HER2-positive breast cancer
Authors: Fernandez Jose Rodrigo Espinosa , Sahin Aysegul A. , Hess Kenneth R. , Medina Raul Gerardo Ramirez , Galeana Paula Anel Cabrera , Ferrufino Alejandro Javier España , Arias Nereida Esparza , Rocha Juan Enrique Bargallo , Gordillo José Antonio García , Muñiz Gerardo Emmanuel Lopez , Ueno Naoto T 
Published: March 2020

Abstract
Background.Androgen receptor (AR) is widely expressed in different breast cancer subtypes. AR plays an important role in promoting the growth of HER2 +  breast cancer through cross-talk with HER2 signaling, including WNT7B upregulation, beta-catenin activation, stimulation of HER3 gene transcription, and promotion of HER2/HER3 heterodimerization. Preclinical data have shown that inhibiting AR with enzalutamide results in decreased HER2 phosphorylation and activation of ERK and AKT, without affecting HER2 and HER3 expression; however, the role that inhibiting HER2 with anti-HER2 therapy plays in AR expression and regulation is still unknown. In this study, we sought to identify the influence of anti-HER2 therapy on AR and estrogen receptor (ER) expression after neoadjuvant treatment in patients with locally advanced HER2+ breast cancer. Methods.We retrospectively collected data from 68 patients with locally advanced HER2+ breast cancer who received neoadjuvant treatment with trastuzumab and chemotherapy. AR and ER levels were determined by immunohistochemistry in available initial biopsy specimens and in surgical specimens of all patients with residual disease after neoadjuvant therapy. AR was assessed by Immunohistochemistry (IHC) staining using AR441 antibody from DAKO. Expression in &gt;10% of cells was considered positive. Pathological complete response (pCR) was defined as ypT0/is, ypN0. ROC curve analysis was performed to identify the correlation between AR score and pCR. Results.Twenty-five patients had pretreatment tissue available. Eighteen (72%) were positive for AR staining and 20 (80%) for ER staining. Of the 25 cases, 10 (40%) achieved a pCR and 15 (60%) did not. The median AR score for those with a pCR was higher, 20 (range 0, 80) vs 10 (range 0, 70). The area under the ROC curve was 0.59 (95% confidence interval 0.35, 0.83); we found no statistically significant relationship between AR score and pCR (p = 0.47). All nine cases positive for AR before neoadjuvant therapy who had residual tissue for staining after therapy had negative AR staining after neoadjuvant anti-HER2 therapy. Of 18 cases positive for ER before neoadjuvant therapy who had residual tissue for staining after therapy, only 6 (33%) had negative ER staining after neoadjuvant anti-HER2 therapy. Further, all patients initially positive for AR and ER remained ER positive but were AR negative after therapy. Conclusions. We found that in 100% of cases AR positivity disappeared after anti-HER2 neoadjuvant therapy in patients with residual disease, whereas ER positivity disappeared in only 33% of cases, suggesting that blocking HER2 may inhibit positive feedback with AR; however, both AR and ER receptors have independent biological interactions with HER2 that need to be explored. We plan to confirm our results with a larger sample size, and we will continue to monitor our patients to determine the influence of AR negativity after neoadjuvant anti-HER2 therapy on disease-free and overall survival.
Citation Format: Jose Rodrigo Espinosa Fernandez, Aysegul A. Sahin, Kenneth R. Hess, Raul Gerardo Ramirez Medina, Paula Anel Cabrera Galeana, Alejandro Javier España Ferrufino, Nereida Esparza Arias, Juan Enrique Bargallo Rocha, José Antonio García Gordillo, Gerardo Emmanuel Lopez Muñiz, Naoto T Ueno. Loss of androgen receptor after neoadjuvant anti-HER2 therapy in patients with locally advanced HER2-positive breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P4-10-22.