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Published OnlineFirst November 9, 2016; DOI: 10.1158/1078-0432.CCR-16-0979 Cancer Therapy: Clinical Clinical Cancer Research The Prognostic Role of Androgen Receptor in Patients with Early-Stage Breast Cancer: A Meta- analysis of Clinical and Gene Expression Data Ivana Bozovic-Spasojevic1,2, Dimitrios Zardavas3, Sylvain Brohee 4, Lieveke Ameye5, Debora Fumagalli3, Felipe Ades1,6, Evandro de Azambuja1, Yacine Bareche4, Martine Piccart7, Marianne Paesmans5, and Christos Sotiriou4 Abstract Purpose: Androgen receptor (AR) expression has been as evaluable for the current study after the qualitative assess- observed in about 70% of patients with breast cancer, but its ment. AR positivity defined by IHC was associated with prognostic role remains uncertain. improved DFS in all patients with breast cancer [multivariate Experimental Design: To assess the prognostic role of AR (M) analysis, HR 0.46; 95% confidence interval (CI) 0.37– expression in early-stage breast cancer, we performed a meta- 0.58, P < 0.001] and better OS [M-HR 0.53; 95% CI, 0.38– analysis of studies that evaluated the impact of AR at the protein 0.73, P < 0.001]. Thirty-five datasets including 7,220 patients and gene expression level on disease-free survival (DFS) and/or were eligible for the pooled gene expression analysis. High AR overall survival (OS). Eligible studies were identified by system- mRNA levels were found to confer positive prognosis overall atic review of electronic databases using the MeSH-terms "breast in terms of DFS (HR 0.82; 95% CI 0.72–0.92;P ¼ 0.0007) and neoplasm" and "androgen receptor" and were selected after a OS (HR 0.84; 95% CI, 0.75–0.94; P ¼ 0.02) only in univariate qualitative assessment based on the REMARK criteria. A pooled analysis. gene expression analysis of 35 publicly available microarray data Conclusion: Our analysis, conducted among more than sets was also performed from patients with early-stage breast 17,000 women with early-stage breast cancer included in clinical cancer with available gene expression and clinical outcome data. and gene expression analysis, demonstrates that AR positivity is Results: Twenty-two of 33 eligible studies for the clinical associated with favorable clinical outcome. Clin Cancer Res; 1–11. meta-analysis, including 10,004 patients, were considered Ó2016 AACR. Introduction with metastatic breast cancer, ranging from 14% to 53% (1). However, due to their adverse effects associated with virilization, The androgen receptor (AR) is a steroid hormone nuclear lack of solid understanding of their biological mode of action receptor, which is frequently expressed in breast cancer. Still, the and the development of aromatase inhibitors, androgens were contribution of AR signaling in breast cancer carcinogenesis and not further pursued as therapeutic modality for patients with its clinical relevance as potential prognostic factor and therapeutic breast cancer. target remain largely unknown. The AR expression in primary In vitro evidence indicated that AR has both inhibitory and breast cancer was discovered long ago, and androgens such as stimulatory effects on different breast cancer cell lines' growth, fuoxymesterone showed promising response rates in patients which is considered to be modulated by the presence or absence of estrogen receptor (ER) expression (2). fl 1Breast Data Centre, Medical Oncology Department, Institut Jules Bordet, Epidemiologic studies also provided con icting results, report- Universite Libre de Bruxelles, Brusells, Belgium. 2Institute for Oncology and ing significant association between androgen serum level and risk Radiology of Serbia, National Cancer Research Centre, Belgrade, Republic of for developing breast cancer or no association at all. Those results Serbia. 3Breast International Group, Brussels, Belgium. 4Breast Cancer Transla- were dependent on age and more importantly on menopausal tional Research Laboratory, Institut Jules Bordet, Universite Libre de Bruxelles, status and estrogen milieu suggesting that androgen could act as 5 Brusells, Belgium. Data Centre, Institut Jules Bordet, UniversiteLibrede anti-estrogen in premenopausal women, whereas it acts as an Bruxelles, Brussels, Belgium. 6Hospital Albert Einstein, Sao~ Paulo, Brazil. 7Med- estrogen agonist in postmenopausal women (3). Indeed, some ical Oncology Department, Institut Jules Bordet, Universite Libre de Bruxelles, Brussels, Belgium. epidemiologic studies demonstrate that high circulating andro- gen level in postmenopausal women was linked with higher risk Note: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/). for developing breast cancer, but it is not known if these effects are mediated through AR signaling (4). I. Bozovic-Spasojevic and D. Zardavas contributed equally to this article. More recent results originated by gene expression profiling Corresponding Author: Christos Sotiriou, Jules Bordet Institute, 121 Blvd. de studies renewed the interest in AR receptor signaling and its Waterloo, 1000, Brussels 1000, Belgium. Phone: 322-541-3428; Fax: 322-538- potential clinical relevance for breast cancer. One of these studies 0858; E-mail: [email protected] identified ER-negative, AR-positive breast cancer as a subtype doi: 10.1158/1078-0432.CCR-16-0979 showing a distinct transcriptome profile, called the molecular Ó2016 American Association for Cancer Research. apocrine subtype (2, 5). Of note, these studies indicated possible www.aacrjournals.org OF1 Downloaded from clincancerres.aacrjournals.org on September 23, 2021. © 2016 American Association for Cancer Research. Published OnlineFirst November 9, 2016; DOI: 10.1158/1078-0432.CCR-16-0979 Bozovic-Spasojevic et al. together and, whenever possible, within different breast cancer Translational Relevance subtypes, defined as follows: (i) ER-positive (ERþ); (ii) ER-neg- Androgen receptor (AR) recently regained interest as a ative (ERÀ); (iii) HER2þ and (iv) TN (ERÀHER2À). Patients were possible therapeutic option in breast cancer treatment; considered to have AR-positive tumors according to the cut-off however, little is known about the clinical significance of points defined by the authors in each of the eligible studies. AR in breast carcinogenesis. To our knowledge, we report the largest combined clinical and gene expression meta-analy- Identification and selection of studies fi sis, assessing the prognostic signi cance of AR expression in The eligible studies were identified by an electronic search on early-stage breast cancer indicating that AR expression at PubMed/Medline, Cochrane Review, and Google Scholar using both protein and mRNA level serves as a positive prognos- the MeSH terms "breast neoplasm" and "androgen receptor." The ticator for women with early-stage breast cancer. In addi- literature search was conducted independently by two investiga- tion, we explore connection among AR and pathologic tors (I. Bozovic-Spasojevic and D. Zardavas) up to June 2015. complete response after neoadjuvant chemotherapy in the Identified studies were eligible for this meta-analysis if they met gene expression publicly available datasets, and also corre- the following inclusion criteria: studies conducted in patients with lation of AR and genes and gene signatures of interest. early-stage breast cancer that assessed AR expression in primary Additional information about distinct prognostic relevance breast cancer, studies that compared clinical outcomes (DFS of AR expression in different breast cancer subtypes was and/or OS) in association with AR status, studies published in fi provided; however, further studies are warranted to con rm extenso and reported in the English language. fi these ndings. It is apparent that AR has many effects on the Of note, no minimum threshold for either number of patients biology of breast cancer and deserves more clinical and or duration of follow-up period was mandated. Cross-referencing translational research attention. from relevant studies was performed to confirm retrieval of all potentially eligible studies. To avoid duplication of data, when the same patient population was reported in several publications, only study with the highest number of events was included in the fi antagonism between AR and ER mediated by competition for the current analysis. In terms of study eligibility, nal decisions were DNA-binding sites in the cells and a possible adoption of AR in taken upon consensus between two investigators (I. Bozovic- ER-like oncogenic role in the absence of ER (2, 5). Spasojevic and D. Zardavas). AR expression by IHC has been observed in up to 90% of primary breast cancer, and in up to 75% of breast cancer metas- Data extraction tases, depending on the method, patient's population and cutoffs Data, such as authors, publication date, number of patients, used. These studies indicate that the frequency of AR positivity subgroup analysis, method of AR assessment, and AR threshold differs between different breast cancer subtypes; the highest were extracted by two investigators (I. Bozovic-Spasojevic and positivity observed in ER-positive tumors in up to 80%–90% D. Zardavas) using a predesigned abstraction form. Survival data (6–10) and the lowest in triple-negative (TN) tumours, in up to within all patients and whenever possible within different breast 30% (6, 7, 11). Of note, a phase II trial assessing enzalutamide in cancer subtypes [including HR and P value] were extracted inde- metastatic TNBC, reported AR positivity (defined as 1%) in 79% pendently
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