Abstract LB-258: Upregulation of androgen receptor in breast cancer is associated with more aggressive disease when PI3K signaling is active

Abstract

Abstract Endocrine treatment has been the therapeutic mainstay for hormone receptor positive breast cancer; however, as with all drugs, the development of resistance in some cases will be inevitable. In response to these challenges there has been a great deal of interest in the clinical potential of combined endocrine therapy and PI3K inhibition as a treatment for advanced breast cancers. As PI3K signalling has previously been associated with androgen receptor (AR) protein expression in a luminal A subtype, we wished to explore this further in the context of elevated AR protein expression. The role of the AR, in both triple-negative and hormone receptor positive breast cancer, has recently been reappraised with evidence suggesting that it may facilitate tumorigenesis. This current study explores the relationship between these two signalling pathways in endocrine receptor positive disease. A tissue microarray (n = 488) of breast tumor specimens was stained for AR (Novocastra) and p-AKT (Cell Signalling). All patients provided written consent and are currently enrolled on a clinical trial (ICORG - 09-07). The median follow-up period for the cohort was 60 months. In vitro cell line models used in the study included endocrine sensitive, MCF7 (AR low, p-AKT low), ZR75.1 (AR high, p-AKT moderate) and endocrine resistant, LetR (AR high, p-AKT high). Cell line evaluation of sensitivity to PI3K treatment (BEZ235) showed MCF7 cells to be most sensitive (IC50: 0.01M); whereas the AR high cell lines, ZR75.1 and the endocrine resistant, LetR, had reduced responsiveness to the drug (IC50: 0.0011M and 0.0018M respectively). In line with the findings of other studies we found elevated levels of AR protein to be associated with good disease free survival in the total population, however, the positive influence was diminished in AI treated patients. Furthermore when this dataset is stratified (as per Cochrane et al., 2014) to determine survival based on an elevated AR: ER ratio there is a significant association with poor outcome (p = 0.03). Analysis of clinical associations between p-AKT protein levels and elevated AR protein was performed (Stata10). Kaplan Meier analysis show that AR is indeed associated with good outcome in p-AKT negative patients but that this is lost when evaluated in the context of elevated p-AKT. In order to ascertain whether AR and PI3K mutational status may have an impact on clinical attributes, the breast invasive carcinoma TCGA dataset (n = 963) was investigated. Patients with upregulated AR mRNA and wildtype PI3K exhibited more invasive disease compared with those harboring a PI3K mutation (p = 0.02). In summary, breast cancers in which AR is upregulated associate with more aggressive disease when co-occurring with active PI3K signalling. Anti-AR therapies are currently undergoing clinical evaluation as treatment for advanced breast cancer and elucidation of the associated tumor subtypes warrants further investigation. Citation Format: Azlena Ali, Laura Creevey, Arnold Hill, Leonie Young, Marie McIlroy. Upregulation of androgen receptor in breast cancer is associated with more aggressive disease when PI3K signaling is active. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-258.