Purpose: Androgen receptor (AR) is commonly expressed in breast cancers. However, the association between tumor AR status and breast cancer survival is uncertain. Hence, we examined the association between AR status and breast cancer survival in the Nurses' Health Study (NHS).Experimental Design: It was a prospective study of postmenopausal women enrolled in the Nurses' Health Study with stage I to III breast cancer diagnosed between 1976 and 1997 and followed from the date of diagnosis until January 1, 2008 or death. Analyses were conducted using Kaplan-Meier methods and Cox proportional hazard models, to determine the association of AR status with survival outcomes adjusting for covariates.Results: Among 1467 breast cancers, 78.7% were AR-positive (ARþ). Among 1,164 estrogen receptor (ER)-positive cases, 88.0% were ARþ. AR positivity was associated with a significant reduction in breast cancer mortality (HR, 0.68; 95% CI, 0.47-0.99) and overall mortality (HR, 0.70; 95% CI, 0.53-0.91) after adjustment for covariates. In contrast, among women with ER-negative tumors (303 cases), 42.9% were ARþ. There was a nonsignificant association between AR status and breast cancer death (HR, 1.59; 95% CI, 0.94-2.68).Conclusions: The association of AR status and breast cancer survival is dependent on ER status. In particular, AR expression was associated with a more favorable prognosis among women with ER-positive tumors. Thus, determination of AR status may provide additional information on prognosis for postmenopausal women with breast cancer, and provide novel opportunities for targeted therapy.

Prior studies have demonstrated that androgen receptor is expressed in many breast cancers, but its expression in relation to the various breast cancer subtypes as defined by molecular profiling has not been studied in detail. We constructed tissue microarrays from 3,093 breast cancers that developed in women enrolled in the Nurses’ Health Study. Tissue microarray sections were immunostained for estrogen receptor, progesterone receptor, human epidermal growth factor receptor2, cytokeratin 5/6, epidermal growth factor receptor and androgen receptor. Immunostain results were used to categorize each cancer as luminal A or B, HER2 and basal-like. The relationships between androgen receptor expression and molecular subtype were analyzed. Overall, 77% of the invasive breast carcinomas were androgen receptor positive. Among 2,171 invasive cancers, 64% were luminal A, 15% luminal B, 6% HER2 and 11% basal-like. The frequency of androgen receptor expression varied significantly across the molecular phenotypes (p<0.0001). In particular, androgen receptor expression was commonly observed in luminal A (91%) and B (68%) cancers, but was less frequently seen in HER2 cancers (59%). Despite being defined by the absence of estrogen and progesterone receptor expression and being considered hormonally unresponsive, 32% of basal-like cancers expressed androgen receptor. Among 246 cases of ductal carcinoma in situ, 86% were androgen receptor-positive, but the frequency of androgen receptor expression differed significantly across the molecular phenotypes (p=0.001) and high nuclear grade lesions were less likely to be androgen receptor-positive compared with lower grade lesions. Androgen receptor expression is most commonly seen in luminal A and B invasive breast cancers. However, expression of androgen receptor is also seen in approximately one-third of basal-like cancers, providing further evidence that basal-like cancers represent a heterogeneous group. Our findings raise the possibility that targeting the androgen receptor pathway may represent a novel therapeutic approach to the management of patients with basal-like cancers.

Introduction At least four major categories of invasive breast cancer that are associated with different clinical outcomes have been identified by gene expression profiling: luminal A, luminal B, human epidermal growth factor receptor 2 (HER2) and basallike. However, the prevalence of these phenotypes among cases of ductal carcinoma in situ (DCIS) has not been previously evaluated in detail. The purpose of this study was to compare the prevalence of these distinct molecular subtypes among cases of DCIS and invasive breast cancer.