Androgen Receptor Expression and Association With Distant Disease-Free Survival in Triple Negative Breast Cancer: Analysis of 263 Patients Treated With Standard Therapy for Stage I-III Disease

Abstract

Background: We evaluated immunohistochemical AR expression and correlation with prognosis in a large series of homogeneously treated patients with primary TNBC. Material and Methods: Patients diagnosed with stage I-III TNBC between 2000 and 2015 at Istituto Oncologico Veneto who received treatment with surgery and neoadjuvant and/or adjuvant chemotherapy were included. Whole tissue slides were stained for AR. AR-positive expression was defined as >1% of positively stained tumor cells. Distant-disease-free survival (DDFS) was calculated from diagnosis to distant relapse or death. Late-DDFS was calculated from the landmark of 3 years after diagnosis until distant relapse or death. Results: We included 263 primary TNBC patients. Mean AR expression was 14% (range 0–100%), and 29.7% ( n = 78) of patients were AR+. AR+ vs. AR- cases presented more frequently older age ( p < 0.001), non-ductal histology ( p < 0.001), G1-G2 ( p = 0.003), lower Ki67 ( p < 0.001) and lower TILs ( p = 0.008). At a median follow up of 81 months, 23.6% of patients experienced a DDFS event: 33.3% of AR+ and 19.5% of AR- patients ( p = 0.015). 5 years DDFS rates were 67.2% and 80.6% for AR+ and AR- patients (HR = 1.82 95%CI 1.10–3.02, p = 0.020). AR maintained an independent prognostic role beyond stage, but when TILs were added to the model only stage and TILs were independent prognostic factors. AR was the only factor significantly associated with late-DDFS: 16.4% of AR+ and 3.4% of AR- patients experienced a DDFS after the landmark of 3 years after diagnosis ( p = 0.001). Late-DDFS rates at 5 years from the 3-year landmark were 75.8% for AR+ and 95.2% for AR- patients (log-rank p < 0.001; HR = 5.67, 95%CI 1.90–16.94, p = 0.002). Conclusions: AR expression is associated with worse outcome for patients with TNBC. In particular, AR+ TNBC patients are at increased risk of late DDFS events. These results reinforce the rationale of AR targeting in AR+ TNBC.

Androgen Receptor mRNA levels determine the prognosis in triple-negative breast cancer patients

“…The current study is an exploratory step to develop a similar prognostic test for TNBC. Although AR has been explored as a prognostic marker in TNBC [4][5][6][7][8]10], these IHC based studies have shown inconsistent conclusions. Some of these studies have also found no association of AR with DMFS or overall survival (OS) [5,25,26].…”

Prognostic Significance of Androgen Receptor Expression in Triple Negative Breast Cancer: A Systematic Review and Meta-Analysis

“…In some trials, patients with TNBC with AR expression had a better prognosis [12][13][14][15][16][17][18][19][20] ; however, others indicated that AR positivity was associated with poor prognosis. [21][22][23][24][25][26] In addition, in several studies, [27][28][29][30][31][32][33][34][35][36][37][38] it was illustrated that AR expression did not correlate with the prognosis of TNBC.…”

“…39,40 In a previous meta-analysis, it was confirmed that AR positivity was associated with a lower risk of disease recurrence. 41 However, studies [12][13][14][15][21][22][23]27,28,32,[34][35][36][37][38] assessing the connection of AR expression and its prognostic value have recently been published, and have added to the inconsistent evidence. According to the Cochrane Handbook for Systematic Reviews of Interventions, 42 the meta-analysis should be updated every 2 years.…”

The Clinical Importance of Androgen Receptor Status in Response to Neoadjuvant Chemotherapy in Turkish Patients with Local and Locally Advanced Breast Cancer

“…For example, in a multi-institutional study, AR-positive status was found to be a marker of good prognosis in US and Nigerian cohorts, a marker of poor prognosis in Norwegian, Irish, and Indian cohorts, and a neutral marker in the UK cohort [19]. In a trial that included 263 Italian patients who received standard treatment (NACT/adjuvant chemotherapy and surgery) for stage I-III triple-negative breast cancer (TNBC), it was found that 29.7% of patients were AR positive and that AR positivity was associated with worse outcomes, especially distant DFS [20]. However, in a study published in 2019, a retrospective pooled analysis, a total of 7,270 breast tumor mRNA profiles were evaluated for AR status, and AR positivity was related to good outcomes in the ER-positive/HER-2-negative group but with worse prog-nosis in the HER-2-positive group [21].…”