Abstract P1-08-12: G protein-coupled estrogen receptor in the plasma membrane is prognostic in early breast cancer
Authors: Sjöström M , Hartman L , Fornander T , Grabau D , Malmström P , Nordenskjöld B , Skoog L , Stål O , Leeb-Lundberg F , Fernö M 
Published: August 2014

Abstract
Background: G protein-coupled estrogen receptor (GPER), also known as GPR30, is a novel putative estrogen receptor. Although contradictory results have been presented e.g. regarding the subcellular localization and function of the receptor, previous studies have shown a prognostic value in breast cancer and proposed treatment predictive information for tamoxifen (Tam). This study aimed at clarifying the prognostic and treatment predictive value for Tam of GPER, in different subcellular localizations, by using samples from a randomized clinical trial - the ideal population for assessing treatment prediction.
Material and Methods: GPER levels were assessed semi-quantitatively by immunohistochemistry in tissue microarrays from 742 postmenopausal breast cancer patients with no lymph node metastasis and tumor size ≤ 30mm. Patients were originally included in the STO-3 trial 1976-1990. After surgery, they were randomized to Tam treatment (40mg for 2 years or no systemic treatment), regardless of classical estrogen receptor α (ER) status. GPER staining was evaluated in carcinoma both as intensity in 5 levels regardless of subcellular localization, and in the plasma membrane in 3 levels. Due to statistical considerations regarding group size, the final analysis was made with intensity in 3 levels and plasma membrane as positive or negative. The Kaplan-Meier method and logrank test (for trend when applicable) were used for survival analysis and Cox regression analysis for obtaining hazard ratios (HR), interaction testing and multivariate modeling. Distant disease-free survival (DDFS) was used as endpoint.
Results: Analyzing all patients, we found no association between DDFS and GPER intensity. However, positive plasma membrane staining showed a strong correlation with poor prognosis (HR 1.8 p = 0.002). This was only observed in the ER+ subgroup (ER+ patients HR 2.1, p&lt;0.001, ER- patients HR 1.1 p = 0.79). The prognostic value, in untreated patients only, was analyzed with similar results (plasma membrane staining positive vs. negative: all untreated patients HR 1.8 p = 0.008, ER+ patients HR 2.1 p = 0.003, ER- patients HR 1.1 p = 0.83).
No obvious difference in tamoxifen response was observed across plasma membrane or intensity groups, and tests for interaction were not significant.
A multivariate model including GPER in plasma membrane, ER, histological grade, HER2, tamoxifen and tumor size showed that GPER was an independent prognostic factor (HR 1.6 p = 0.01). Finally we created a group with ER+, progesterone receptor (PR) + patients treated with Tam, as this group today is treated with Tam and thought to have a good response. GPER in the plasma membrane significantly separated this group into an excellent prognosis group and a poor prognosis group (HR 3.3, p = 0.01). The excellent prognosis group, which constitutes more than half of ER+ patients, had a 20 year DDFS of 91% (95% CI 84-95).
Conclusion: We found no treatment predictive value of GPER for Tam. However, GPER expressed in the plasma membrane was a strong independent prognostic factor for a poor prognosis in ER+ breast cancer. Used in ER+, PR+, tamoxifen treated patients, it can distinguish patients with an excellent prognosis from patients with a poor outcome that may benefit from additional treatment.
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P1-08-12.