Androgen Receptor Expression In Breast Cancer Research Articles

Core Needle Biopsy Accuracy for Androgen Receptor Expression in Invasive Breast Cancer.

Breast cancer (BC) biomarkers, such as hormone receptors expression, are crucial to guide therapy in BC patients. Antiandrogens have been studied in BC; however, limited data are available on androgen receptor (AR) expression test methodology. We aim to report the core needle biopsy (CNB) accuracy for AR expression in BC. Patients diagnosed with stage I-III invasive BC from a single institution were included. Androgen receptor expression was evaluated by immunohistochemistry (IHC) using 1 and 10% cutoff and the AR expression in surgical specimens (SS) was the gold standard. Kappa coefficients were used to evaluate the intraprocedural agreement. A total of 72 patients were included, with a mean age of 61 years old and 84% were Luminal A or B tumors. The prevalence of AR expression in all BC samples was 87.5% using a cutoff ≥ 10% in SS. With a cutoff value ≥ 1%, CNB had an accuracy of 95.8% (Kappa value = 0.645; 95% confidence interval [CI]: 0.272-1.000; p < 0.001) and 86.1% (Kappa value = 0.365; 95% CI: 0.052-0.679; p < 0.001) when ≥ 10% cutoff was used for AR positivity. Androgen receptor expression in CNB (cutoff ≥ 1%) had a sensitivity of 98.5%, specificity of 60%, positive predictive value of 97.0%, and a negative predictive value of 76.9% in the detection of AR expression in SS. Core needle biopsy has good accuracy in evaluating AR expression in BC. The accuracy of CNB decreases with higher cutoff values for AR positivity.

Comprehensive characterization of androgen receptor expression in breast cancer.

1035 Background: The androgen receptor ( AR) is a hormone-regulated transcription factor that plays an important role in breast cancer (BC) pathogenesis. While estrogen receptor inhibitors are well-studied in BC, the role of AR on prognosis and therapy is less well-known. Here we aim to characterize the clinicopathologic and molecular features of AR expression in BC. Methods: 27,169 BC samples were tested by NGS (592, NextSeq; WES, NovaSeq), WTS (NovaSeq) (Caris Life Sciences, Phoenix, AZ). Microsatellite-instability (MSI) was tested by IHC and NGS. Tumor mutational burden (TMB) totaled somatic mutations per tumor (high≥10 mt/MB). Tumors with AR-high(H) and AR-low(L) expression were classified by top and bottom quartile, respectively. Real world overall survival (OS) and treatment-associated survival was obtained from insurance claims and calculated from tissue collection or treatment start to last contact using Kaplan-Meier estimates. Statistical significance was determined by chi-square and Mann-Whitney U test with p-values adjusted for multiple comparisons (q&lt;0.05). Results: Median AR expression was higher in lobular compared to ductal carcinoma (2.2-fold) and in HR+/HER2- compared to TNBC (13.9-fold). Compared to AR-L, AR-H BC had higher frequency of PIK3CA (50.6% vs 12.7%), CDH1 (20% vs 2.2%), ESR1 (12.8% vs 1.4%), MAP3K1 (9.4% vs 1.4%), GATA3 (11.2% vs 2.7%), AKT1 (5.7% vs 1.4%), NF1 (8.6% vs 3.6%), ARID1A (6.9 vs 3.6), SPEN (2.8% vs 1.5%), and PTEN (7.9% vs 6.2%) mutations and TMB high (9.5% vs 7.7%), but lower frequency of dMMR/MSI-H (0.6% vs 1.7%) and PD-L1 (18.7% vs 45.3%) positivity (all p&lt;0.05). AR-H tumors also showed enrichment of the IL2-STAT5 pathway (NES: 1.33, FDR: 0.24). Further, AR-H BC had higher expression of immune checkpoint genes ( CD274, PDCD1LG2, LAG3, HAVCR2, FOXP3, FC: 1.1-1.4, all p&lt;0.05) and T cell inflamed scores (32.5% vs 26.2%, p&lt;0.05). AR-H BC had increased immune cell infiltration of B cells (6% vs 4%), M2 Mφ (5% vs 2%), and NK cells (3% vs 2%), but decreased infiltration of M1 Mφ (2% vs 3%) (all p&lt;0.05). AR-H BC had upregulation of M2 Mφ related genes ( ARG1, IL10, CCL17, CXCR1, FC: 1.2-1.8, all p&lt;0.05) and downregulation of M1 Mφ related genes ( CCL2, CCL5, CXCL9, CXCL10, FC: 1-1.5, all p&lt;0.05). AR-H BC was associated with improved OS compared to AR-L BC (mOS: 1843 vs 1096 days; HR 0.6, 95% CI 0.5-0.7, p&lt;0.00001), and with doxorubicin (2294 vs 2054 days; HR 0.7, 95% CI 0.5-0.9, p&lt;0.001) , paclitaxel (2239 vs 1967 days; HR 0.7, 95% CI 0.5-0.9, p&lt;0.001) and trastuzumab (inf vs 2351 days; HR 0.6, 95% CI 0.4-0.9, p&lt;0.01) treatment. Conclusions: Our data suggest a strong association between AR expression and increased mutations in several cancer related genes, immune checkpoint markers, the IL2-STAT5 pathway, differential immune cell infiltration, and improved overall survival.

AR pathway activity correlates with AR expression in a HER2-dependent manner and serves as a better prognostic factor in breast cancer.

Androgen receptor (AR) antagonists are currently tested in multiple clinical trials for different breast cancer (BC) subtypes, which emphasizes the need for clarifying the role of AR in this type of cancer. Previous studies showed that AR expression was associated with a favorable prognosis in ER-positive BC. However, the true biological effect of AR signaling in BC is not clear. An AR pathway signature was generated to compute AR pathway activity in BCs (n=6439) from 46 microarray datasets. Associations of AR pathway activity and AR expression with BC prognosis were compared by survival analysis. AR pathway activity showed moderate positive and negative correlations with AR expression in HER2-positive and HER2-negative BCs, respectively. AR pathway activity increased while AR expression decreased in ER-negative BCs. Like ER and progesterone receptor (PR) expression, AR expression was also negatively associated with tumor grade, neoadjuvant response, and recurrence risk in BC. By contrast, AR pathway activity was positively, and more significantly, associated with these clinical features. Moreover, the AR pathway, but not AR expression, was significantly associated with recurrence risk in BC patients treated with endocrine therapy. These data suggest that, although AR expression probably reflects well-differentiated states of BC and is thus associated with favorable prognosis in BC, the biological effects of AR signaling confers worse outcomes in BC. Our findings encourage the continued evaluation of AR antagonists for BC treatment and support that AR pathway activity serves as a better prognostic factor than AR expression in BC.

Prognostic Role of Androgen Receptor Expression in Surgically Resected Early Breast Cancer Patients.

PurposeEndocrine therapy is a standard treatment for hormone receptor-positive breast cancer, which accounts for 60%–75% of all breast cancer. Hormone receptor positivity is a prognostic and predictive biomarker in breast cancer. Approximately 50%–80% of breast cancer is also positive for androgen receptor (AR), but the prognostic and predictive value of AR expression in breast cancer is controversial. Here, we investigated AR expression and its prognostic value in patients with surgically resected breast cancer in Korea.MethodsWe retrospectively reviewed the medical records of patients who had surgically resected breast cancer to collect AR expression data and other clinicopathological data. The optimal cut-off for AR positivity was determined using a receiver operating characteristic curve analysis.ResultsWe reviewed 957 patients with surgically resected breast cancer from June 2012 to April 2013. The median follow-up was 62 months, and relapse events occurred in 101 (10.6%) patients. Unlike the cut-off value of 1% or 10% in previous reports, 35% was determined to be best for predicting relapse-free survival (RFS) in this study. At the cut-off value of 35%, 654 (68.4%) patients were AR-positive. AR expression was more prevalent in luminal A (87.6%) and luminal B (73.1%) types than in human epidermal growth factor receptor 2-positive (56.2%) or triple-negative (20.6%) types. AR expression of ≥ 35% was significantly related to longer RFS in a multivariate analysis (hazard ratio, 0.430; 95% confidence interval, 0.260–0.709; p = 0.001).ConclusionWe propose a cut-off value of 35% to best predict RFS in patients with surgically resected breast cancer. AR expression was positive in 68.4% of patients, and AR positivity was found to be an independent prognostic factor for longer RFS.

Abstract 2295: Influence of endocrine therapy on the ratio of androgen receptor (AR) to estrogen receptor (ER) positive circulating epithelial tumor cells (CETCs) in breast cancer

Abstract Background: The androgen receptor (AR) is expressed in the majority of breast cancers and across the main breast cancer subtypes. Despite the high frequency of AR expression in breast cancer its appraisal remains controversial because its role is complex, dependent on the hormonal milieu. The aim of the current study was to investigate the frequency of AR and ER positive CETCs in breast cancer patients. Material and Methods: The number of vital CETCs was determined from blood of 66 patients suffering from breast cancer and the expression of AR and ER on these cells was investigated using the maintrac method. Results: Numbers of CETCs/ml blood were significantly higher in patients with advanced disease as compared to patients with early stage disease. The fraction of AR positive CETCs was significantly higher than the fraction of ER positive CETCs (90% vs. 50%; p&amp;lt;0.001). Patients with positive lymph nodes had less AR positive CETCs as compared to patients with negative lymph node status. The AR:ER ratio was higher in patients receiving tamoxifen therapy as compared to patients without tamoxifen therapy whereas treatment with aromatase inhibitor had no influence on AR:ER ratio. Conclusions: The ratio of AR to ER positive CETCs, obviously, is influenced by endocrine therapy, more specifically therapy with tamoxifen. Since AR expression seems to be responsible to resistance to endocrine therapy this may provide a new biomarker to select patients who might benefit from combination treatment of ER and AR inhibitors. Note: This abstract was not presented at the meeting. Citation Format: Monika Pizon, Dorothea Schott, Daniel Lux, Ulrich Pachmann, Katharina Pachmann. Influence of endocrine therapy on the ratio of androgen receptor (AR) to estrogen receptor (ER) positive circulating epithelial tumor cells (CETCs) in breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2295.

Influence of endocrine therapy on the ratio of androgen receptor (AR) to estrogen receptor (ER) positive circulating epithelial tumor cells (CETCs) in breast cancer

BackgroundThe androgen receptor (AR) is expressed in the majority of breast cancers and across the main breast cancer subtypes. Despite the high frequency of AR expression in breast cancer its appraisal remains controversial because its role is complex, dependent on the hormonal milieu. The aim of the current study was to investigate the frequency of AR and ER positive CETCs in breast cancer patients.MethodsThe number of vital CETCs was determined from blood of 66 patients suffering from breast cancer and the expression of AR and ER on these cells was investigated using the maintrac method.ResultsNumbers of CETCs/mL blood were significantly higher in patients with advanced disease as compared to patients with early stage disease. The fraction of AR positive CETCs was significantly higher than the fraction of ER positive CETCs (90% vs. 50%; P < 0.001). Patients with positive lymph nodes had less AR positive CETCs as compared to patients with negative lymph node status. The AR:ER ratio was higher in patients receiving tamoxifen therapy as compared to patients without tamoxifen therapy whereas treatment with aromatase inhibitor had no influence on AR:ER ratio.ConclusionsThe ratio of AR to ER positive CETCs, obviously, is influenced by endocrine therapy, more specifically therapy with tamoxifen. Since AR expression seems to be one of the possible mechanism of resistance to endocrine therapy this may provide a new biomarker to select patients who might benefit from combination treatment of ER and AR inhibitors.

Differential microRNA expression is associated with androgen receptor expression in breast cancer.

The androgen receptor (AR) is frequently expressed in breast cancer; however, its prognostic value remains unclear. AR expression in breast cancer has been associated with improved outcomes in estrogen receptor (ER)-positive breast cancer compared with ER-negative disease. Eliminating AR function in breast cancer is critically important for breast cancer progression. However, the mechanism underlying AR regulation remains poorly understood. The study of microRNAs (miRNAs) has provided important insights into the pathogenesis of hormone-dependent cancer. To determine whether miRNAs function in the AR regulation of breast cancer, the present study performed miRNA expression profiling in AR-positive and -negative breast cancer cell lines. A total of 153 miRNAs were differentially expressed in AR-positive compared with AR-negative breast cancer cells; 52 were upregulated and 101 were downregulated. A number of these have been extensively associated with breast cancer cell functions, including proliferation, invasion and drug-resistance. Furthermore, through pathway enrichment analysis, signaling pathways associated with the prediction targets of the miRNAs were characterized, including the vascular endothelial growth factor and mammalian target of rapamycin signaling pathways. In conclusion, the results of the present study indicated that the expression of miRNAs may be involved in the mechanism underlying AR regulation of breast cancer, and may improve understanding of the role of AR in breast cancer.

Targeting the androgen receptor in breast cancer.

The androgen receptor (AR) is expressed in the majority of breast cancer and across the three main breast cancer subtypes. Historically, the oncogenic role of AR has best been described in molecular apocrine breast cancers, an estrogen receptor (ER)-/AR+ subtype which has a steroid response signature similar to that in the ER-positive breast cancer. The signalling effect of AR is likely to be different across breast cancer subtypes, and particularly important is its interaction with ER signalling. Despite the high frequency of AR expression in breast cancer, it is still not a standard clinical practice to use AR antagonists as therapy. Older trials of AR-directed therapies in breast cancer have had generally been disappointing. More recently, more potent, next-generation, AR-directed therapies have been developed in the context of prostate cancer. Here, we will review the emerging literature dissecting the role of AR signalling in a context-dependent manner in breast cancer and the renewed interest and wave of clinical trials targeting the AR in breast cancer.

Reduced Androgen Receptor Expression Accelerates the Onset of ERBB2 Induced Breast Tumors in Female Mice

Androgen receptor (AR) is commonly expressed in both the epithelium of normal mammary glands and in breast cancers. AR expression in breast cancers is independent of estrogen receptor alpha (ERα) status and is frequently associated with overexpression of the ERBB2 oncogene. AR signaling effects on breast cancer progression may depend on ERα and ERBB2 status. Up to 30% of human breast cancers are driven by overactive ERBB2 signaling and it is not clear whether AR expression affects any steps of tumor progression in this cohort of patients. To test this, we generated mammary specific Ar depleted mice (MARKO) by combining the floxed allele of Ar with the MMTV-cre transgene on an MMTV-NeuNT background and compared them to littermate MMTV-NeuNT, Arfl/+ control females. Heterozygous MARKO females displayed reduced levels of AR in mammary glands with mosaic AR expression in ductal epithelium. The loss of AR dramatically accelerated the onset of MMTV-NeuNT tumors in female MARKO mice. In this report we show that accelerated MMTV-NeuNT-dependent tumorigenesis is due specifically to the loss of AR, as hormonal levels, estrogen and progesterone receptors expression, and MMTV-NeuNT expression were similar between MARKO and control groups. MMTV-NeuNT induced tumors in both cohorts displayed distinct loss of AR in addition to ERα, PR, and the pioneer factor FOXA1. Erbb3 mRNA levels were significantly elevated in tumors in comparison to normal mammary glands. Thus the loss of AR in mouse mammary epithelium accelerates malignant transformation rather than the rate of tumorigenesis.

Androgen resistance in female mice increases susceptibility to DMBA-induced mammary tumors.

Hormones, notably estrogens, are pivotal in the origins of breast cancer but androgenic effects, while supported by persistence of AR expression in breast cancers, remain controversial. This study determined the role of the androgen actions via androgen receptor (AR) in experimental mammary cancer. Androgen-resistant female and male mice (ARKO) were generated using Cre/loxP technique and featured a global AR inactivation. The effect of AR inactivation and influence of genetic background on 7,12-dimethylbenz[a]anthracene (DMBA)-induced tumorigenesis was confirmed using two separate ARKO models with different genetic backgrounds. The onset of palpable mammary tumors was significantly faster in ARKO females (median time 22 vs 34weeks, respectively; (p = 0.0024; multivariate Cox regression) compared to WT and independent of the mouse genetic background. The cumulative incidence at 9months was 81 ± 10% [mean ± SE] for ARKO compared to 50 ± 13% in WT females. The increased DMBA susceptibility of ARKO females was associated with a higher epithelial proliferation index but not with major structural or receptor (estrogen or progesterone) expression differences between the virgin WT or ARKO female mammary glands. AR inactivation allowed substantial ductal extension in ARKO males while WT males displayed only rudimentary epithelial branches or complete regression of epithelial structures. Yet, DMBA did not induce epithelial mammary tumors in WT or ARKO males, demonstrating that AR inactivation alone is insufficient to promote mammary tumors. These results demonstrate that AR inactivation accelerates mammary carcinogenesis in female mice exposed to the chemical carcinogen DMBA regardless of mouse genetic background but require prior exposure to endogenous ovarian hormones.