• What is AR?
  • AR in Breast Cancer
  • AR Expression
  • Clinical Trials

AR

The androgen receptor (AR) plays a role in the pathogenesis of prostate cancer and can be expressed in invasive breast cancer (Itkonen and Mills 2012; Gonzalez et al 2008). AR is the product of the AR gene, which is located on the X chromosome. AR is in the nuclear receptor superfamily and is part of the steroid receptor family, and it has a six-region structure with a defined functional domain (Itkonen and Mills 2012).

Amplification of the AR gene and AR mutations occur in 30% and 1-30% of castration-resistant prostate cancer, respectively (Waltering et al. 2012). AR expression is measured using immunohistochemistry (IHC), and is detectable in the majority of castration-resistant prostate cancer (Linja et al. 2001; Waltering et al. 2012) and 75% of invasive breast cancers (Collins et al. 2011; Gonzalez et al 2008).

Related Pathways

Contributors: Justin M. Balko, Pharm. D., Ph.D., Ingrid A. Mayer, M.D., M.S.C.I., Mia Levy, M.D., Ph.D., Carlos L. Arteaga, M.D.

Suggested Citation: Balko, J., I. Mayer, M. Levy, C. Arteaga. 2016. AR. My Cancer Genome https://www.padiracinnovation.org/content/disease/breast-cancer/ar/?tab=0 (Updated September 12).

Last Updated: September 12, 2016

AR in Breast Cancer

Androgen receptor (AR) expression is detectable in 75% of breast cancers (Collins et al. 2011; Gonzalez et al 2008). AR mutations are not known to be important in breast cancer.

Gene or Protein Invasive Breast Cancer Hormone Receptor Positive (ER+ and/or PR+) Invasive Breast Cancer HER2-positive Invasive Breast Cancer Triple-negative Invasive Breast Cancer
AR expression 75% (Collins et al. 2011; Gonzalez et al 2008) 90% (References in Secreto et al. 2012) 44% (Arslan et al. 2012) ≤ 50% (McNamara et al. 2013; Mrklić et al. 2012)
NOTE: AR = androgen receptor; ER = estrogen receptor; PR = progesterone receptor

Testing for AR Expression in Breast Cancer

In contrast with ER and PR expression in breast cancer, standard practice guidelines have not been established for measuring AR expression and defining AR status. Even so, retrospective studies demonstrate that AR status may have prognostic implications in some types of breast cancer (Hu et al. 2011). There are preliminary data that AR status may be predictive of benefit with an androgen receptor antagonist (Ayca Gucalp et al. 2013).

Several different immunohistochemistry (IHC) cutoff levels have been used to define AR status in breast tumors (Table 2). Another approach is to calculate IHC scores ranging from 0 to 3 to define AR status as positive or negative (Gonzalez et al. 2008; Ren et al. 2013). Other studies follow the protocol established for prostate cancer, which involves an immune-reactivity scoring system combining several measures for AR protein levels (Loibl et al. 2011).


Table 2. AR Immunohistochemistry Test Interpretations Across Studies.
Percentage Of Cells That Are Immunoreactive AR Status (Reference)
>60 Highly positive (Secreto et al. 2012)
>30–60 Moderately positive (Secreto et al. 2012)
>50 High (Ogawa et al. 2008)
>10 Positive (Ayca Gucalp et al. 2013; Collins et al. 2011; Hu et al. 2011)
≥10 Positive (Moinfar et al. 2003; Park et al. 2010; Niemeier et al. 2010; Micello et al. 2010)
10–50 Intermediate (Ogawa et al. 2008)
≥1–30 Poorly positive (Secreto et al. 2012)
≥1 Positive (Mrklić et al. 2012; Sutton et al. 2012)
1–10 Low positive (Collins et al. 2011; Hu et al. 2011)
<10 Low (Ogawa et al. 2008)
<10 Negative (Moinfar et al. 2003; Park et al. 2010; Niemeier et al. 2010; Micello et al. 2010; Ayca Gucalp et al. 2012)
0 Negative (Collins et al. 2011; Hu et al. 2011)
0 None (Ogawa et al. 2008)
0 Absent (Secreto et al. 2012)
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Contributors: Justin M. Balko, Pharm. D., Ph.D., Ingrid A. Mayer, M.D., M.S.C.I., Mia Levy, M.D., Ph.D., Carlos L. Arteaga, M.D.

Suggested Citation: Balko, J., I. Mayer, M. Levy, C. Arteaga. 2014. AR in Breast Cancer. My Cancer Genome https://www.padiracinnovation.org/content/disease/breast-cancer/ar/ (Updated March 31).

Last Updated: March 31, 2014

AR Expression in Breast Cancer

Properties
Location of mutation Not applicable
Frequency of AR expression in breast cancer 75% (Collins et al. 2011; Gonzalez et al. 2008)
Implications for Targeted Therapeutics
Response to androgen receptor modulators and antagonists Confers increased sensitivitya
Response to PI3K inhibitors Unknown at this timeb

Androgen receptor (AR) expression may have prognostic implications in breast cancer. In a retrospective study of primary invasive ductal carcinoma of the breast tumor samples, AR-positive status correlated with longer overall survival (Gonzalez et al. 2008).

AR expression appears to play a different prognostic role in ER-positive and ER-negative metastatic breast cancer subsets in retrospective studies. In ER-positive breast cancer, AR expression occurs in 67-88% of cases (Loibl et al. 2011; Hu et al. 2011), and is associated with a reduction in mortality (Hu et al. 2011). In ER-negative metastatic breast cancer, AR expression is detectable in 12-50% of cases, a subset that has been termed ‘molecular apocrine’ tumors (Ayca Gucalp et al. 2013; Hu et al. 2011; Farmer et al. 2005), and is associated with lower survival rates (Farmer et al. 2005; Park et al. 2011). Preliminary evidence indicates that AR expression may also be predictive of response with AR antagonists in this subset.a

In a review of 19 published studies, the prevalence of AR expression in triple negative breast cancer (TNBC) ranged from 0 to 53% of cases, with the variation likely due to methodological differences (McNamara et al. 2013). The clinical prognostic and predictive relevance of AR expression in TNBC remains a topic of investigation (Chen et al. 2010; Hu et al. 2011; McNamara et al. 2013; Mrklić et al. 2012, Sutton et al. 2012). This subtype of TNBC has been defined as the luminal androgen receptor (LAR) subtype.

a In preclinical studies, the AR antagonist bicalutamide was effective against LAR cell lines (Lehman et al. 2011). In a recently reported phase II trial, patients with ER-/PR-/AR+ (by IHC) metastatic breast cancer experienced a 19% clinical benefit rate (percent of patients with complete response, partial response, or stable disease for greater than six months) with the AR antagonist bicalutamide (Ayca Gucalp et al. 2013). Investigational clinical trials where AR antagonists are combined with other drugs in patients with this subtype of breast cancer are currently ongoing.

b AR-positive breast cancer tumors have been associated with a high rate of PIK3CA mutations, but the clinical significance of this correlation remains unknown (Gonzalez-Angulo et al. 2009). In preclinical studies, LAR cell lines were noted to have activating PIK3CA mutations and responded to the PI3K inhibitor NVP-BEZ235 (Lehman et al. 2011).

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Contributors: Justin M. Balko, Pharm. D., Ph.D., Ingrid A. Mayer, M.D., M.S.C.I., Mia Levy, M.D., Ph.D., Carlos L. Arteaga, M.D.

Suggested Citation: Balko, J., I. Mayer, M. Levy, C. Arteaga. 2014. AR Expression in Breast Cancer. My Cancer Genome https://www.padiracinnovation.org/content/disease/breast-cancer/ar/311/ (Updated March 31).

Last Updated: March 31, 2014

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