P4-09-02: G Protein-Coupled Estrogen Receptor 1 Positively Correlates with Estrogen Receptor a Expression and Increased Distant Disease-Free Survival of Breast Cancer Patients.
Authors: Leeb-Lundberg FLM , Sjöström M , Broselid S , Jirström K , Belting M , Olde B , Lövgren K , Malmström P , Bendahl P-O , Hartman L , Fernö M 
Published: June 2012

Background: Endocrine therapy is an important therapeutic choice for patients with estrogen receptor (ER)a-positive breast carcinoma and functions by blocking proliferative estrogen signalling through the classical nuclear ERa. G protein-coupled estrogen receptor 1 (GPER1) is a novel membrane estrogen receptor responsible for unique estrogen responses in vitro and in vivo and that is activated by tamoxifen. The aim of this study was to determine the correlation of GPER1 with clinicopathological variables and distant disease-free survival (DDFS) in breast cancer patients treated with and without adjuvant tamoxifen, and whether the prognostic impact is dependent on ERa-status.

Material and Methods: GPER1 was investigated by immunohistochemistry in tissue microarrays of breast tumors from 208 premenopausal node-negative patients (median age 47 years; range 30–57), mainly (87%) not subjected to any adjuvant systemic treatment, and from 273 stage II patients (median age 63 years; range 26–81), all treated with adjuvant tamoxifen for 2 years. Because almost 90% of the samples had a high percentage (&gt;50%) GPER1-stained cells, we decided to evaluate only the staining intensity (negative, very weak, weak, moderate, and strong) for this variable. Pearson's χ2 test for trend was used for analyzing association between GPER1 and categorical clinicopathological variables, a test for trend based on ranks for association with age and tumor size, and a log-rank test for trend for evaluating the impact of GPER1 on DDFS after 5 years of follow-up.

Results: GPER1 positively correlated with ERa (P=0.0005 and P=0.01, respectively) and progesterone receptor expression (P=0.004 and P=0.01, respectively) in both the premenopausal and tamoxifentreated groups, but not with HER2 expression (P=0.45 and P=0.42, respectively). In the premenopausal group, GPER1 negatively correlated with tumor size (P=0.02) and positively with age (P=0.003), whereas in the tamoxifen group GPER1 did not correlate with either tumor size or age. During 5 years of follow up, 64 patients were diagnosed with distant recurrences in the tamoxifen group and 34 patients in the premenopausal group. In univariate analysis, GPER1 positively correlated with DDFS in the tamoxifen group (P=0.04), but non-significantly in the premenopausal group (P=0.08). When stratifying for ERa-status, GPER1 was a prognostic factor in the ERa-positive subgroup (P=0.02 in tamoxifen group and P=0.08 in premenopausal group), but not in the ERa-negative subgroup (P=0.57 and P=0.95, respectively).

Conclusion: We propose that GPER1 is a prognostic marker for increased DDFS in ERa-positive breast cancer. While our results suggest that GPER1 is also a tamoxifen-predictive factor, this needs to be further studied, ideally in a randomized trial comparing clinical outcome for patients treated with and without adjuvant tamoxifen.

Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P4-09-02.