The Prognostic Role of Androgen Receptor in Patients with Early-Stage Breast Cancer: A Meta-analysis of Clinical and Gene Expression Data

Abstract

Purpose: Androgen receptor (AR) expression has been observed in about 70% of patients with breast cancer, but its prognostic role remains uncertain.Experimental Design: To assess the prognostic role of AR expression in early-stage breast cancer, we performed a metaanalysis of studies that evaluated the impact of AR at the protein and gene expression level on disease-free survival (DFS) and/or overall survival (OS). Eligible studies were identified by systematic review of electronic databases using the MeSH-terms "breast neoplasm" and "androgen receptor" and were selected after a qualitative assessment based on the REMARK criteria. A pooled gene expression analysis of 35 publicly available microarray data sets was also performed from patients with early-stage breast cancer with available gene expression and clinical outcome data.Results: Twenty-two of 33 eligible studies for the clinical meta-analysis, including 10,004 patients, were considered as evaluable for the current study after the qualitative assessment. AR positivity defined by IHC was associated with improved DFS in all patients with breast cancer [multivariate (M) analysis, HR 0.46; 95% confidence interval (CI) 0.37-0.58, P < 0.001] and better OS [M-HR 0.53; 95% CI, 0.38-0.73, P < 0.001]. Thirty-five datasets including 7,220 patients were eligible for the pooled gene expression analysis. High AR mRNA levels were found to confer positive prognosis overall in terms of DFS (HR 0.82; 95% CI 0.72-0.92;P ¼ 0.0007) and OS (HR 0.84; 95% CI, 0.75-0.94; P ¼ 0.02) only in univariate analysis.Conclusions: Our analysis, conducted among more than 17,000 women with early-stage breast cancer included in clinical and gene expression analysis, demonstrates that AR positivity is associated with favorable clinical outcome. Clin Cancer Res; 23(11); 2702-12. Ó2016 AACR.

VEGF-A/Neuropilin 1 Pathway Confers Cancer Stemness via Activating Wnt/β-Catenin Axis in Breast Cancer Cells

“…Breast cancer is the most frequent cancer in women [23]. Although endocrine therapy, targeting therapy and chemotherapeutics have greatly improved the overall survival of breast cancer patients, the drug resistance is the main clinical problem [24].…”

The Magnitude of Androgen Receptor Positivity in Breast Cancer Is Critical for Reliable Prediction of Disease Outcome

“…A recent meta-analysis in which AR mRNA expression was correlated with various gene signatures in large combined breast cancer cohorts strongly supports this concept (26). Functionally, AR and ERa are hormone-activated nuclear transcription factors that regulate gene expression and are commonly coexpressed in normal and malignant breast epithelial cells (37,56), indicating the potential for direct cross-talk between these two sex hormone receptor signaling pathways.…”

“…Disparate results among studies may be attributed to heterogeneity of breast cancer cohorts and differences in methodology, including the use of different cut-points for AR positivity. Although several meta-analyses commonly conclude that AR is associated with better outcomes in ERa-positive disease (26)(27)(28)(29), these analyses used population-level rather than individual patient-level data. Moreover, most studies included in the meta-analyses of AR as a prognostic biomarker used cut-points that are typically those used for ERa and progesterone receptor (PR) as a predictive biomarker (30,31).…”

The role of the AR/ER ratio in ER-positive breast cancer patients

“…The prognostic role of AR in ER+ BC has been extensively studied. Several authors have reported that AR expression in luminal cancers is associated with a better outcome compared to AR negative BCs (Park et al 2011, Castellano et al 2013, Kim et al 2015, Bozovic-Spasojevic et al 2016. However, some reports suggest that AR could be related to BC progression (Grogg et al 2015), as it is detected in a significantly higher percentage of ductal carcinomas 'in situ' (DCIS) that are adjacent to invasive carcinomas than in pure DCIS (Yu et al 2011).…”

“…AR positivity has been detected in up to 61% of primary and metastatic BC lesions (Park et al 2010, Hu et al 2011, Yu et al 2011) and approximately 75% of ER-positive (ER+) BCs are also AR positive (AR+). Several studies have shown that AR expression in luminal tumours (ER+) is associated with lower tumour grade, smaller tumour size, lower proliferative index (Ki67 level) and more importantly, AR expression in ER+ tumours is an independent prognostic factor of a good outcome (Castellano et al 2010, Niemeier et al 2010, Aleskandarany et al 2016, Bozovic-Spasojevic et al 2016). On the other hand, up to 31% of ER-negative (ER−) BCs are reported to be AR+ (Niemeier et al 2010, Park et al 2010, but the prognostic impact of AR expression in this subset of BCs is not clear (Luo et al 2010, Hu et al 2011, Park et al 2011, Pistelli et al 2014, Vera-Badillo et al 2014, Hilborn et al 2016, Jiang et al 2016, Asano et al 2017.…”