Lu Cao1, Guomin Xiang1, Fang Liu1, Cong Xu1, Jing Liu1, Qingxiang Meng1, Shuhua Lyu2, Shuling Wang3, Yun Niu4. 1. Department of Breast Cancer Pathology and Research Laboratory, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Ministry of Education, Tianjin Medical University Cancer Institute and Hospital, Tianjin Medical University, Tianjin, 300060, China. 2. Department of Pathology, Tianjin Union Medical Center, Tianjin People's Hospital, Tianjin, 300121, China. 3. Department of Breast Oncology, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Ministry of Education, Tianjin Medical University Cancer Institute and Hospital, Tianjin Medical University, Tianjin, 300060, China. 4. Department of Breast Cancer Pathology and Research Laboratory, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Ministry of Education, Tianjin Medical University Cancer Institute and Hospital, Tianjin Medical University, Tianjin, 300060, China. yunniu2017@163.com.
Abstract
PURPOSE: Approximately 30% oestrogen receptor alpha (ERα)-positive breast cancer (BC) patients exhibit intrinsic or recurrent resistance to adjuvant endocrine therapy with tamoxifen. The androgen receptor (AR) is expressed in about 90% of ERα-positive patients, with particularly high expression in tamoxifen-resistant tumours. Prostate-derived Ets factor (PDEF), which is a co-regulator of AR, plays a role in tamoxifen resistance in ERα-positive BC. The purpose of this research was to analyse the potential roles of AR, PDEF and ERα levels in the response to tamoxifen resistance in ERα-positive BC. METHODS: The nuclear AR:ERα and PDEF:ERα ratios were examined immunohistochemically in a cohort of 225 ERα-positive pre-menopausal BC patients who had received adjuvant tamoxifen therapy. RESULTS: For both AR:ERα and PDEF:ERα ratios, the optimal cutoff value was 2.0. Patients receiving adjuvant tamoxifen treatment who had a high AR:ERα (≥ 2.0) (HR = 3.90) or PDEF:ERα ratio (≥ 2.0) (HR = 2.77) had a beyond twofold increased risk of failure. Both the AR:ERα ratio (P = 0.001) and PDEF:ERα ratio (P = 0.002) were independently associated with the risk of tamoxifen treatment failure. Furthermore, both a high ratio of AR:ERα (≥ 2.0) and PDEF:ERα (≥ 2.0) were associated with shorter disease-free survival (DFS) and shorter disease-specific survival (DSS). In addition, both the AR:ERα ratio and PDEF:ERα ratio were independent predictors of DFS (both P < 0.0001) and DSS (P = 0.001 and P < 0.0001, respectively). CONCLUSIONS: AR:ERα and PDEF:ERα ratios are independent predictors of the response to conventional ERα-directed tamoxifen endocrine therapy.
PURPOSE: Approximately 30% oestrogen receptor alpha (ERα)-positive breast cancer (BC) patients exhibit intrinsic or recurrent resistance to adjuvant endocrine therapy with tamoxifen. The androgen receptor (AR) is expressed in about 90% of ERα-positive patients, with particularly high expression in tamoxifen-resistant tumours. Prostate-derived Ets factor (PDEF), which is a co-regulator of AR, plays a role in tamoxifen resistance in ERα-positive BC. The purpose of this research was to analyse the potential roles of AR, PDEF and ERα levels in the response to tamoxifen resistance in ERα-positive BC. METHODS: The nuclear AR:ERα and PDEF:ERα ratios were examined immunohistochemically in a cohort of 225 ERα-positive pre-menopausal BC patients who had received adjuvant tamoxifen therapy. RESULTS: For both AR:ERα and PDEF:ERα ratios, the optimal cutoff value was 2.0. Patients receiving adjuvant tamoxifen treatment who had a high AR:ERα (≥ 2.0) (HR = 3.90) or PDEF:ERα ratio (≥ 2.0) (HR = 2.77) had a beyond twofold increased risk of failure. Both the AR:ERα ratio (P = 0.001) and PDEF:ERα ratio (P = 0.002) were independently associated with the risk of tamoxifen treatment failure. Furthermore, both a high ratio of AR:ERα (≥ 2.0) and PDEF:ERα (≥ 2.0) were associated with shorter disease-free survival (DFS) and shorter disease-specific survival (DSS). In addition, both the AR:ERα ratio and PDEF:ERα ratio were independent predictors of DFS (both P < 0.0001) and DSS (P = 0.001 and P < 0.0001, respectively). CONCLUSIONS:AR:ERα and PDEF:ERα ratios are independent predictors of the response to conventional ERα-directed tamoxifen endocrine therapy.
Authors: Suriyan Ponnusamy; Sarah Asemota; Lee S Schwartzberg; Fouzia Guestini; Keely M McNamara; Mariaelena Pierobon; Alba Font-Tello; Xintao Qiu; Yingtian Xie; Prakash K Rao; Thirumagal Thiyagarajan; Brandy Grimes; Daniel L Johnson; Martin D Fleming; Frances E Pritchard; Michael P Berry; Roy Oswaks; Richard E Fine; Myles Brown; Hironobu Sasano; Emanuel F Petricoin; Henry W Long; Ramesh Narayanan Journal: iScience Date: 2019-10-23