Pre-Menopausal Women With Breast Cancers Having High AR/ER Ratios in the Context of Higher Circulating Testosterone Tend to Have Poorer Outcomes.

Savitha Rajarajan,Aruna Korlimarla,B S Srinath,C E Anupama,Jyothi S Prabhu,Annie Alexander,T S Sridhar,Rakesh Ramesh

doi:10.3389/fendo.2021.679756

Abstract

PurposeWomen with breast tumors with higher expression of AR are in general known to have better survival outcomes while a high AR/ER ratio is associated with poor outcomes in hormone receptor positive breast cancers mostly in post menopausal women. We have evaluated the AR/ER ratio in the context of circulating androgens specifically in patients younger than 50 years most of whom are pre-menopausal and hence have a high estrogenic hormonal milieu.MethodsTumor samples from patients 50 years or younger at first diagnosis were chosen from a larger cohort of 270 patients with median follow-up of 72 months. Expression levels of ER and AR proteins were detected by immunohistochemistry (IHC) and the transcript levels by quantitative PCR. Ciculating levels of total testosterone were estimated from serum samples. A ratio of AR/ER was derived using the transcript levels, and tumors were dichotomized into high and low ratio groups based on the third quartile value. Survival and the prognostic significance of the ratio was compared between the low and high ratio groups in all tumors and also within ER positive tumors. Results were further validated in external datasets (TCGA and METABRIC).ResultsEighty-eight (32%) patients were ≤50 years, with 22 having high AR/ER ratio calculated using the transcript levels. Circulating levels of total testosterone were higher in women whose tumors had a high AR/ER ratio (p = 0.02). Tumors with high AR/ER ratio had significantly poorer disease-free survival than those with low AR/ER ratio [HR-2.6 (95% CI-1.02–6.59) p = 0.04]. Evaluation of tumors with high AR/ER ratio within ER positive tumors alone reconfirmed the prognostic relevance of the high AR/ER ratio with a significant hazard ratio of 4.6 (95% CI-1.35–15.37, p = 0.01). Similar trends were observed in the TCGA and METABRIC dataset.ConclusionOur data in pre-menopausal women with breast cancer suggest that it is not merely the presence or absence of AR expression but the relative activity of ER, as well as the hormonal milieu of the patient that determine clinical outcomes, indicating that both context and interactions ultimately influence tumor behavior.

Highlights

Breast cancer in the young is more commonly associated with aggressive features and poorer clinical outcomes when compared to that of an older age group [1]
We have investigated the role of androgen receptor (AR) by evaluating the AR/estrogen receptor (ER) ratio in patients younger than 50 years of age and who are likely to have a dominant estrogenic environment and the role of this particular hormonal environment on tumor progression
Endocrine therapy was recorded as tamoxifen or aromatase inhibitor, and chemotherapy regimens were noted for intake of anthracyclines or taxanes

Summary

Introduction

Breast cancer in the young is more commonly associated with aggressive features and poorer clinical outcomes when compared to that of an older age group [1]. Hormonal risk factors are different in this age group, and younger women tend to have more hormone receptor negative breast cancers with adverse prognostic features [4]. Recent studies which have characterized genomic and transcriptomic profile of the breast cancers in the young and pre-menopausal women have shown them as a unique etiologic and biological entity [5]. Circulating androgens are detected during all ages in adult women and thought to have biological roles [6] Multiple studies both in pre- and post-menopausal women have reported a significant positive association between higher levels of circulating androgens and the risk of developing breast cancer [7,8,9,10]. Women with estrogen receptor (ER) positive, AR positive (ER+AR+) tumors are known to have better survival and more favorable clinicopathological features, like negative lymph node metastasis and lower tumor grade than women whose tumors are negative for AR [11]

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