Abstract P2-07-04: A novel diagnostic androgen receptor gene signature links clinical outcomes and preclinical response to enzalutamide, paclitaxel or the combination in triple-negative breast cancer
Authors: Phan VT , Protter AA , Peterson AC , Parker JS , Yoon K , Tudor IC , Paton V , Noonberg S , Uppal H 
Published: May 2016

Background: The androgen receptor (AR) is expressed in ≈70% of all breast cancers (BCs) and may be necessary for proliferation and survival advantage in AR+ tumors. A novel gene signature associated with AR-signaling biology (PREDICT AR) was developed by sequencing triple-negative BC (TNBC) tumors collected in a phase 2 study evaluating enzalutamide (ENZA) monotherapy1; clinical outcomes were superior in patients (pts) with PREDICT AR+ vs PREDICT AR- tumors.1,2 ENZA blocks nuclear localization and suppresses its activity.3 Paclitaxel (PTX) stabilizes microtubules and may also block AR nuclear localization. Thus we hypothesize that response to PTX-based therapy may be additive in PREDICT AR+ vs PREDICT AR- disease. This study sought to identify independent clinical datasets with PREDICT AR+ gene signature to assess outcomes following PTX-based therapy. Preclinically, we investigated the antitumor activity of ENZA, PTX, or ENZA+PTX in AR-driven TNBC models.

Methods: We probed publicly available TNBC clinical databases from Gene Expression Omnibus datasets to assess PREDICT AR status and clinical outcomes. Similarly, we assessed 21 TNBC lines for PREDICT AR status. BT549, MDA-MB-436, and MDA-MB-453 were treated with ENZA, PTX, or ENZA+PTX to determine activity. Cell signaling and pathway activation were assessed by western blot. ENZA and PTX activity was assessed in PREDICT AR+ xenograft models. Tumor RNA sequencing and immunohistochemistry were used to identify gene signatures, potentially predictive biomarkers, and potential synergistic effects of ENZA+PTX.

Results: The prevalence of PREDICT AR+ tumors in one cohort of 182 pts with primary TNBC4 was 51%. Distant relapse-free survival following PTX-based adjuvant/neoadjuvant therapy was not statistically different between pts with PREDICT AR+ vs PREDICT AR- TNBC (p=0.605). Pathologic complete response rates were 12.5% for PREDICT AR+ vs 21.0% for PREDICT AR- TNBC. Additional sets of pts with primary TNBC are being evaluated. Preclinically, we observed a dose-dependent inhibition of cell viability with either ENZA or PTX in AR+ TNBC cell lines and additive effects from ENZA+PTX. In PREDICT AR+ xenograft models, ENZA or PTX treatment resulted in a dose-dependent antitumor response. Combination studies are underway. Tumor RNA sequencing are being evaluated for gene signature of synergistic antitumor response to ENZA+PTX.

Conclusion: Analyzing publicly available clinical datasets, we found that PREDICT AR+ status was not associated with differential outcomes following PTX-based therapy in primary TNBC, suggesting there is potential to provide additive benefits in PTX-based therapy with ENZA. In preclinical studies, we observed additive effects when combining ENZA+PTX in PREDICT AR+ TNBC lines compared with single agent treatments. Taken together, these data suggest ENZA combined with PTX might provide additive benefits in a clinical setting for pts with PREDICT AR+ TNBC.

References

1. Traina TA et al. J Clin Oncol 2015:33(suppl):abstr 1003.

2. Parker J et al. J Clin Oncol 2015;33(suppl):abstr 1083.

3. Tran C et al. Science 2009;324:787-90.

4. Hatzis C et al. JAMA 2011;305:1873-81.

Citation Format: Phan VT, Protter AA, Peterson AC, Parker JS, Yoon K, Tudor IC, Paton V, Noonberg S, Uppal H. A novel diagnostic androgen receptor gene signature links clinical outcomes and preclinical response to enzalutamide, paclitaxel or the combination in triple-negative breast cancer. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P2-07-04.