Abstract P4-11-23: Membranous ERα-36 expression is an independent predictor of poor prognosis in operable breast cancer

Abstract

Abstract Background ERα-36 is a splice variant of ER-α with molecular weight of 36-kDa that lacks transactivation domains, and is expressed in the cytoplasm and cell membrane of ER (ERα66) negative as well as ERα66 positive breast cancer cells. It is also thought to predict resistance to tamoxifen therapy. Here we investigate its prognostic significance, its association with other clinico-pathologic factors and correlation with other biomarkers of the PI3K/AKT/mTOR pathway. Methods We studied ERα-36 expression on TMA blocks prepared from samples of 160 consecutive operable breast cancer patients who presented at CLB between 1998 and 2001. The intensity of the staining and the percentage of tumor cells stained for each biomarker (ERα-36, PI3K, pAKT, p4EBP1, pS6RP and LKB1) were integrated into a single score and a cutoff was defined for high versus low expression. Correlations were done between ERα-36 expression and the clinico-pathological parameters and other biomarkers using Pearson’s chi-square test. Kaplan-Meier method was used to estimate distant metastasis free survival (DMFS), disease free survival (DFS) and overall survival (OS) and the difference between the groups was evaluated with log-rank test. Cox regression model was used to adjust for other prognostic parameters in the multivariate analysis. Results Median age at diagnosis was 56.9 years (range: 30 to 87 years). The maximum tumor size was larger than 2 cm in 57.5% of cases and axillary lymph nodes (LN) were positive (N1a to N3) in 52.5% of cases. 16.3% of the patients had SBR grade I, 44.4% had grade II and 39.4% had grade III tumors. ERα66 was positive in 91.2%, PgR in 74.7% and HER2 was over-expressed in 15% of the cases. High ER-α36 expression in the cell membrane was observed in 65 patients (40.6%). ERα-36 expression was independent of the ERα66, PgR or HER2 expression and was not associated with age, tumor size, SBR grade or axillary LN invasion. There was no correlation between ERα-36 expression and PI3K, pAKT, p4EBP1, pS6RP or LKB1 expression. ERα-36 expression in tumor cells was a predictor of poor prognosis regarding DMFS (HR=2.02; 95% CI: 1.2 to 3.4; p=0.008), DFS (HR=1.7; 95% CI: 1.05 to 2.7; p=0.031) and OS (HR=1.8; 95% CI: 1.02 to 3.2; p=0.043). In the multivariate analysis and after adjustment for age, tumor size, SBR grade and LN invasion, ERα-36 remained an independent predictor of shorter DMFS (p=0.016) and DFS (p=0.052) in addition to SBR grade and axillary LN metastasis. The ERα-36 expression predicted shorter DMFS for patients who received tamoxifen as the only adjuvant systemic treatment (p=0.022) and also for those who received other hormonal therapy and adjuvant chemotherapy (p=0.039). Conclusion Immunohistochemically detected membranous ERα-36 expression can be a poor prognostic factor for patients with operable breast cancer that is independent from the traditional clinico-pathologic parameters and from PI3K/AKT/mTOR pathway activation status. Citation Format: Loay Kassem, Soleilmane Omarjee, Sylvie Chabaud, Emilie Lavergne, Christelle Faure, Frédéric Beurrier, Olivier Tredan, Laura Corbo, Isabelle Treilleux, Muriel Le Romancer. Membranous ERα-36 expression is an independent predictor of poor prognosis in operable breast cancer [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 P4-11-23.