Abstract 4207: Androgen receptor expression and ER+ breast cancer prognosis in the BIG 1-98 trial
Authors: Kensler Kevin H. , Regan Meredith M. , Heng Yujing J. , Pyle Michael E. , Schnitt Stuart J. , Thürlimann Beat , Viale Giuseppe , Colleoni Marco , Brown Myles , Tamimi Rulla M. 
Published: August 2018

Background The androgen receptor (AR) is emerging as a potential biomarker of breast cancer prognosis and therapeutic target. AR is expressed in 60-80% of breast cancers, with higher prevalence among estrogen receptor (ER) positive tumors. Treatment with dihydrotestosterone has been found to inhibit ER signaling in ER+/AR+ breast cancer cell lines, and epidemiologic studies have shown AR expression to be associated with improved survival among women with ER+ breast cancer. However, it is unknown if AR expression modifies the efficacy of selective ER modulators or aromatase inhibitors in patients with ER+ cancers.

Methods We evaluated AR expression among 3,103 postmenopausal patients with ER+ breast cancer in the Breast International Group (BIG) 1-98 trial (NCT00004205). The BIG 1-98 study was a four-armed randomized double-blind phase III clinical trial that compared 5 years of tamoxifen or letrozole monotherapy, or sequences of 2 years and 3 years treatment with one drug and then the other. Tissue microarrays were constructed from tumor tissue from trial participants. AR expression was measured by immunohistochemistry and the percentage of AR positive nuclei was digitally quantified. The association between AR expression and prognosis was evaluated through use of Cox proportional hazards models, adjusting for patient, tumor, and treatment factors. Continuous AR-by-treatment interactions were assessed by use of Subpopulation Treatment Effect Pattern Plots (STEPP).

Results In the univariate Kaplan-Meier analysis, AR expression (≥1% vs. &lt;1%) was associated with longer breast cancer-free interval (247 events) over a median 8.2 years (IQR: 7.3-9.1) of follow-up (p=0.029 from log-rank test). Patients with AR+ cancers were more likely to have smaller, lower-grade tumors, as well as tumors with greater ER and PR expression and lower Ki67 expression. However, upon adjustment for patient, tumor, and treatment factors, AR expression (≥1% vs. &lt;1%) was not associated with breast cancer-free interval (HR=1.06, 95% CI 0.82-1.36). A 10% increase in AR expression similarly did not predict breast cancer-free interval (HR=1.02, 95% CI 0.96-1.07). The letrozole vs. tamoxifen treatment effect was non-significantly stronger among AR- tumors (HR=0.42, 95% CI 0.24-0.74) than among AR+ tumors (HR=0.65, 95% CI 0.48-0.87). STEPP analysis also suggested no heterogeneity of treatment effect across the continuum of AR expression (p=0.280). Findings were likewise null when evaluating the secondary endpoints of distant recurrence free interval, disease free survival, and overall survival.

Conclusions After adjustment for tumor characteristics, AR expression did not predict prognosis among postmenopausal patients with ER+ breast cancer, nor did it modify the effect of tamoxifen or letrozole treatment. These findings suggest that AR expression may not be an informative biomarker for the treatment of postmenopausal ER+ breast cancers.

Citation Format: Kevin H. Kensler, Meredith M. Regan, Yujing J. Heng, Michael E. Pyle, Stuart J. Schnitt, Beat Thürlimann, Giuseppe Viale, Marco Colleoni, Myles Brown, Rulla M. Tamimi. Androgen receptor expression and ER+ breast cancer prognosis in the BIG 1-98 trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4207.