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

Abstract

The significance of androgen receptor (AR) in breast cancer (BC) management is not fully defined, and it is still ambiguous how the level of AR expression influences oestrogen receptor-positive (ER+) tumours. The aim of the present study was to analyse the prognostic impact of AR/ER ratio, evaluated by immunohistochemistry (IHC), correlating this value with clinical, pathological and molecular characteristics. We retrospectively selected a cohort of 402 ER+BC patients. On each tumour, IHC analyses for AR, ER, PgR, HER2 and Ki67 were performed and AR+ cases were used to calculate the AR/ER value. A cut-off of ≥2 was selected using receiver-operating characteristic (ROC) curve analyses. RNA from 19 cases with AR/ER≥2 was extracted and used for Prosigna-PAM50 assays. Tumours with AR/ER≥2 (6%) showed more frequent metastatic lymph nodes, larger size, higher histological grade and lower PgR levels than cases with AR/ER<2. Multivariate analysis confirmed that patients with AR/ER≥2 had worse disease-free interval (DFI) and disease-specific survival (DSS) (hazard ratios (HR) = 4.96 for DFI and HR = 8.69 for DSS, both ≤ 0.004). According to the Prosigna-PAM50 assay, 63% (12/19) of these cases resulted in intermediate or high risk of recurrence categories. Additionally, although all samples were positive for ER assessed by IHC, the molecular test assigned 47.4% (9/19) of BCs to intrinsic non-luminal subtypes. In conclusion, the AR/ER ratio ≥2 identifies a subgroup of patients with aggressive biological features and may represent an additional independent marker of worse BC prognosis. Moreover, the Prosigna-PAM50 results indicate that a significant number of cases with AR/ER≥2 could be non-luminal tumours.

AR/ER Ratio Correlates with Expression of Proliferation Markers and with Distinct Subset of Breast Tumors

“…The data obtained in the present paper are in line with this hypothesis, since luminal tumors (ER+) carrying AR/ER ratio ≥ 2 had higher cell proliferation gene expression ( Figures 1A and 2). Besides, our results support recent reports indicating that BC cases with AR/ER ratio ≥ 2 have both shorter disease-free interval (DFI) and overall survival (OS) [11,12]. The differences in proliferation observed between the two groups are not dependent on variable ER expression levels [42,43], because cases divided by ER% positivity alone did not show significant differences in the cellular proliferation signature ( Figure 1B).…”

“…The qPCR AR/ER ratio range was −535.6-61 (mean −24,33). Following previous reports, cases were grouped by the AR/ER ratio cut-off (<2 vs. ≥2) which better differentiate patients by prognosis [11,12]. Ten cases (10/47, 21.3%) showed higher AR/ER ratio (AR/ER ≥ 2) by both, IHC and qPCR methods, which further indicates a significant positive correlation between protein and mRNA expression levels (P < 0.0001- Figure S1).…”

“…AR and ER expression may co-localize in both, normal and tumor tissues, providing evidence for a possible crosstalk between signaling pathways of these hormone receptors [9]. Recently, we and others have demonstrated that the AR and ER expression ratio (AR/ER) could be associated with outcome in ER+ BC patients [11,12]. In fact, high AR and low ER protein expression levels (AR/ER ratio ≥ 2) are significantly associated with aggressive clinical features, tamoxifen resistance, as well as poor disease-free and overall survival [11].…”

“…In fact, high AR and low ER protein expression levels (AR/ER ratio ≥ 2) are significantly associated with aggressive clinical features, tamoxifen resistance, as well as poor disease-free and overall survival [11]. Furthermore, from a molecular point of view, ER+ tumors with higher AR protein levels, do not always result as a luminal subtype using PAM50 gene expression classifier [12].…”

Potential Novel Therapy Targets in Neuroendocrine Carcinomas of the Breast

“…4,9,20 Given the positivity for ER and/or PR, most patients with NEC are eligible for endocrine therapy against ER. AR expression has been extensively studied in breast cancer, as a diagnostic (eg, apocrine breast cancer), 21 prognostic (favorable in ER þ /AR-positive [AR þ ] breast cancers), 22 and predictive biomarker (eg, clinical trials with antiandrogens in patients with advanced/metastatic triple-negative breast cancer). 23 AR expression has been previously described in NEC of the breast and correlated with the expression of gross cystic disease fluid protein expression.…”