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

Ricciardelli, Carmela; Bianco‐Miotto, Tina; Jindal, Shalini; Butler, Lisa M.; Leung, Samuel; McNeil, Catriona M.; O’Toole, Sandra A.; Ebrahimie, Esmaeil; Millar, Ewan K.A.; Sakko, Andrew J.; Ruiz, Alexandra I.; Vowler, Sarah L.; Huntsman, David G.; Birrell, Stephen N.; Sutherland, Robert L.; Palmieri, Carlo; Hickey, Theresa E.; Tilley, Wayne D.

doi:10.1158/1078-0432.ccr-17-1199

Cited by 63 publications

(72 citation statements)

References 98 publications

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“…Many studies defined AR positivity according to the proportion score with a cut-off value of 10% using immunohistochemistry, but other studies used cut-off values of 75%, 45%, 5%, 3% or 1% [3,4,6]. Ricciardelli et al investigated to determine the optimal cut-off value for AR positivity as an independent predictor of breast cancer survival by ROC analysis with a comprehensive review of the literature [25]. They reported that prognostication was most robust with a high cut-off value of 78%, but not robust with lower (1%-10%) cut-off points.…”

Section: Discussionmentioning

confidence: 99%

Influence of Androgen Receptor on the Prognosis of Breast Cancer

Hwang

Kim

et al. 2020

JCM

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We investigated the prognostic influence of androgen receptor (AR) on breast cancer. AR status was assessed using immunohistochemistry with tissue microarrays from 395 operable primary breast cancer patients who received curative surgery. The Kaplan–Meier estimator was used to analyze the survival rates and a log-rank test was used to determine the significance of the differences in survival. The Cox proportional hazards model was used to calculate the hazard ratio (HR) and the 95% confidence interval (CI) of survival. There were 203 (51.4%) subjects with a low expression of AR, and 192 patients (48.6%) with a high expression rate. The high AR expression group showed superior overall survival (p = 0.047) and disease-free survival (p = 0.004) when compared with the low AR expression group. The high AR expression group showed superior systemic recurrence-free survival when compared with the low AR expression group (p = 0.027). AR was an independent prognostic factor for both overall survival (HR, 0.586; 95% CI, 0.381–0.901; p = 0.015) and disease-free survival (HR, 0.430; 95% CI, 0.274–0.674; p < 0.001). A high AR expression was a significant favorable prognostic factor only in the subgroups with positive hormone receptors (HRc) and negative human epidermal growth factor receptor 2 (HER2) when considering disease-free survival (p = 0.026). The high AR expression group was significantly associated with superior overall survival and disease-free survival when compared with the low AR expression group with breast cancer patients. AR was a significant independent prognostic factor for both overall survival and disease-free survival. The prognostic impact of AR was valid in the HRc(+)/HER2(−) subtype when considering disease-free survival. These findings suggest the clinical usefulness of AR as a prognostic marker of breast cancer in clinical settings.

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Section: Discussionmentioning

confidence: 99%

Influence of Androgen Receptor on the Prognosis of Breast Cancer

Hwang

Kim

et al. 2020

JCM

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“…Numerous studies have reported that approximately 80% of breast cancers are positive for AR, furthermore AR protein is detectable across luminal A (ERα+ve, PR+ve, Her2-ve), Luminal B (ERα+ve, PR+ve, Her2+ve), triple-negative/basal (ER-ve, PR-ve and Her2-ve) and Her2 amplified (Her2+) ( 13 , 44 ). The majority of AR positive tumors are ERα positive (~90%); however AR is also detectable in a significant proportion of triple-negative and basal tumors (~35–50%) ( 10 , 45 , 46 ).…”

Section: Ar and Androgens In Normal Breast Tissue And Breast Cancermentioning

confidence: 99%

“…The majority of AR positive tumors are ERα positive (~90%); however AR is also detectable in a significant proportion of triple-negative and basal tumors (~35–50%) ( 10 , 45 , 46 ). AR expression has been associated with good patient outcome in a large number of clinical datasets ( 44 , 47 ). Preclinical studies have surmised that AR may enact its protective role by blocking ERα gene transcription ( 48 ), however, other studies in triple-negative and apocrine breast cancers indicate that AR may act as a pseudo- ERα in this setting ( 49 , 50 ).…”

Section: Ar and Androgens In Normal Breast Tissue And Breast Cancermentioning

confidence: 99%

“…Immunohistochemical studies of breast cancers have shown that whilst the majority of tumors express some degree of AR protein (>1%) there is also a huge diversity in the percentage of cells within a tumor expressing the protein and also the relative abundance of the protein present (Figure 3 ). A recent meta-analysis by Ricciardelli et al ( 44 ) highlighted the importance of evaluating the abundance of the AR when determining its impact on breast cancer outcome.…”

Section: Ar and Androgens In Normal Breast Tissue And Breast Cancermentioning

confidence: 99%

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The Divergent Function of Androgen Receptor in Breast Cancer; Analysis of Steroid Mediators and Tumor Intracrinology

Bleach

McIlroy

2018

Front. Endocrinol.

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Androgen receptor (AR) is the most widely expressed steroid receptor protein in normal breast tissue and is detectable in approximately 90% of primary breast cancers and 75% of metastatic lesions. However, the role of AR in breast cancer development and progression is mired in controversy with evidence suggesting it can either inhibit or promote breast tumorigenesis. Studies have shown it to antagonize estrogen receptor alpha (ERα) DNA binding, thereby preventing pro-proliferative gene transcription; whilst others have demonstrated AR to take on the mantle of a pseudo ERα particularly in the setting of triple negative breast cancer. Evidence for a potentiating role of AR in the development of endocrine resistant breast cancer has also been mounting with reports associating high AR expression with poor response to endocrine treatment. The resurgence of interest into the function of AR in breast cancer has resulted in various emergent clinical trials evaluating anti-AR therapy and selective androgen receptor modulators in the treatment of advanced breast cancer. Trials have reported varied response rates dependent upon subtype with overall clinical benefit rates of ~19–29% for anti-androgen monotherapy, suggesting that with enhanced patient stratification AR could prove efficacious as a breast cancer therapy. Androgens and AR have been reported to facilitate tumor stemness in some cancers; a process which may be mediated through genomic or non-genomic actions of the AR, with the latter mechanism being relatively unexplored in breast cancer. Steroidogenic ligands of the AR are produced in females by the gonads and as sex-steroid precursors secreted from the adrenal glands. These androgens provide an abundant reservoir from which all estrogens are subsequently synthesized and their levels are undiminished in the event of standard hormonal therapeutic intervention in breast cancer. Steroid levels are known to be altered by lifestyle factors such as diet and exercise; understanding their potential role in dictating the function of AR in breast cancer development could therefore have wide-ranging effects in prevention and treatment of this disease. This review will outline the endogenous biochemical drivers of both genomic and non-genomic AR activation and how these may be modulated by current hormonal therapies.

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“…These values were used to derive mean percentage positivity in the tumour area examined 20 . AR, ERα, progesterone receptor, HER‐2/ neu and Ki67 were stained and scored as previously described 18,21,22 …”

Section: Methodsmentioning

confidence: 99%

Elevated levels of tumour apolipoprotein D independently predict poor outcome in breast cancer patients

Jankovic‐Karasoulos¹,

Bianco‐Miotto

Butler³

et al. 2020

Histopathology

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Aims: Apolipoprotein D (ApoD) is a protein that is regulated by androgen and oestrogen, and is a major constituent of breast cysts. Although ApoD has been reported to be a marker of breast cancer, its prognostic importance in invasive breast cancer is unclear. The aim of this study was to investigate the relationship between ApoD protein expression, oestrogen receptor-a (ERa) expression and androgen receptor (AR) expression in predicting breast cancer outcome. Methods and results: ApoD levels were measured by the use of immunohistochemistry and video image analysis on tissue sections from a breast cancer cohort (n = 214). We assessed the associations of ApoD expression with disease-free survival (DFS), metastasis-free survival (MFS), and overall survival (OS). We also assessed the relationship between ApoD expression, AR expression and ERa expression in predicting OS. ApoD expression (>1% ApoD positivity) was found in 72% (154/214) of tissues. High ApoD positivity (≥20.7%, fourth quartile) was an independent predictor of MFS and OS, and conferred a 2.2fold increased risk of developing metastatic disease and a 2.1-fold increased risk of breast cancer-related death. ApoD positivity was not associated with AR or ERa nuclear positivity. However, patients with (≥1%) ERa-positive cancers with low (<20.7%) ApoD positivity, or those showing high (≥78%) AR positivity and low (<20.7%) ApoD positivity had better OS than other patient groups. Conclusions: ApoD expression could be used to predict breast cancer prognosis independently of ERa and AR expression.

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

Cited by 63 publications

References 98 publications

Influence of Androgen Receptor on the Prognosis of Breast Cancer

Influence of Androgen Receptor on the Prognosis of Breast Cancer

The Divergent Function of Androgen Receptor in Breast Cancer; Analysis of Steroid Mediators and Tumor Intracrinology

Elevated levels of tumour apolipoprotein D independently predict poor outcome in breast cancer patients

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