Abstract P6-08-19: Activated form of the estrogen receptor α (ER) in breast cancer (BC) and its correlation with prognosis
Authors: Gilles Erard , Bosq Jacques , Alleaume Charline , Zukiwski Alexander , Hutt Emile , Bonneterre Jacques 
Published: May 2015

Abstract
Background: About 50% of ER positive (ERpos) BCs are resistant to hormone treatment. In absence of ligand, ERs are evenly distributed in nuclei in normal tissue. Upon ligand binding, ERs dimerizes and form a discrete focal subnuclear distribution pattern (FDP), which is associated with transcriptional activation of ER and can be visualized with high powered microscopy. We have developed an IHC method to characterize the FDP in archival BC specimens (ASCO 2013 abst#592). We hypothesized that, in BC, the presence/absence of FDP of ER could predict anti-estrogen (anti-E) activity. We could determine two tumor phenotypes for ERpos tumors: a diffuse nuclear ER staining or "D-ER" corresponding to the expression of non-functional ER, which is the pattern observed in vitro or in vivo when no ligand are bound to steroid receptors (SR); D-ER thus is thought to predict lack of treatment effect of anti-E. And an aggregated nuclear pattern which corresponds to a similar pattern observed in vitro or in vivo when ligand is bound to ER; A-ER would suggest that ER is activated and a potential target to anti-Es.
Methods: A previously reported study (ASCO 2013 abst #592) was expanded from 254 evaluable cases to 755 with paraffin embedded formalin fixed (PEFF) BC specimens with clinical and pathology data. Specimens were analyzed for standard HES, ER, progesterone receptor (PR) and Ki67. The A-ER and D-ER nuclear patterns were analyzed at 1000x magnification.
Results: Mean age; 57 (17 -89). Histology: ductal 85% lobular 13%, other 2%; 82% ERpos and 78% either PRApos or PRBpos, 10% ERpos and 6% PRpos only. 92% of ERpos cases had received anti-Es; Adj. Chemotherapy 36%, Stage: I 47%, II 45%, III 8 %. Grade: I 25%, II 52%, III 23%. Median follow up 42 months. ER status was D-ER in 71% and A-ER in 29% of the specimens. With DFS defined as time to PD or death (5 year cut off), 125/755 events were observed. ERpos was better that ERneg (HR= 0.36, p = 0.00001). Within ERpos tumors group, in univariate analysis, a time-dependent Cox model showed that A-ER pattern was associated with better DFS vs D-ER pattern (HR = 0.03, p=0.02, time interaction = 0.01). A-ER was not correlated with SBR Grade, and was associated with its anisonucleosis (Aniso) index (0.02), with histology (ductal, 0.005) but not age, stage or HER2 status. Ki67 testing is ongoing. In monovariate analysis stage (0.00004), grade (p &lt; 10-6), PR (p &lt; 10-6) were prognostic on DFS, but not histology and HER2. In a time-dependent multivariate Cox model, A-ER remained an independent predictor (p = 0.013), with grade (p =0.001 with Mitotic Index 0.002, Differentiation 0.023, Aniso NS), stage 0.001, time interaction 0.009), PR and HER2 NS.
Conclusions: This study supports the hypothesis that anti-Es are mainly active in BC with A-ER pattern, which is targetable by anti-Es. Independent statistical significance was reached after adjusting for well-established prognostic factors. Given the 10-year hormonal treatment adjuvant recommendation guidelines, a better assay than the simple ER status determination would have important implications in BC management.
Citation Format: Erard Gilles, Jacques Bosq, Charline Alleaume, Alexander Zukiwski, Emile Hutt, Jacques Bonneterre. Activated form of the estrogen receptor α (ER) in breast cancer (BC) and its correlation with prognosis [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P6-08-19.