Abstract P4-05-01: G protein-coupled estrogen receptor expression in lymph node metastasis and contralateral breast cancer during endocrine treatment
Authors: Sjöström M , Fernö M , Rydén L , Leeb-Lundberg FLM , Alkner S 
Published: February 2018

Background: G protein-coupled estrogen receptor (GPER) is a putative estrogen receptor (ER) with potential clinical implications in breast cancer. Depending on subcellular location, cut-off and treatment, GPER has been proposed as both a marker of aggressive disease and of good prognosis. The correlation with known prognostic factors appears to be biphasic. Furthermore, plasma membrane GPER-overexpression (GPERPM) is associated to a worse prognosis, suggesting potential receptor mutation or amplification. In vitro studies also show that tamoxifen upregulates GPER in breast cancer cells, suggesting GPER as a mediator of endocrine resistance. To further clarify the role of GPER in breast cancer and endocrine treatment we studied GPER during evolution from primary tumor to lymph node metastasis (lgl-met), and from first tumor (BC1) to a second contralateral tumor (CBC), with/without endocrine treatment (mainly tamoxifen) in between. As a CBC developed despite adjuvant treatment given for BC1 is presumably resistant to this treatment, it may be used to study endocrine treatment escape mechanisms in vivo.

Patients and methods: From a well-defined population-based cohort of CBC-patients we constructed a unique tissue-microarray including 688 patients with metachronous CBC. Overall GPER staining intensity (0-5) (GPERoverall) and GPERPM (present/absent) was evaluated by two investigators in BC1 (n=559), CBC (n=595) and corresponding lgl-met (nBC1=151 and nCBC=158). Impact on survival was analyzed using the Kaplan-Meier method and Cox regression, and p-values calculated with the log rank test. Association was tested with a chi-square test (for trend when appropriate), and differences between paired samples with Wilcoxon signed rank test.

Results: GPR30overall showed the expected biphasic association with ER-α and the progesterone receptor (PgR) in BC1 and CBC, where high and low GPER expression associated with ER/PgR negativity (p&lt;0.001). High GPER expression was also associated with increased Ki67 expression (p=0.04 and p=0.08). Similar results were seen for GPERPM (ER/PgR-negativity p&lt;0.001, high Ki67 p&lt;0.001). There was no association between GPER in BC1 and CBC, and prior endocrine treatment did not seem to affect GPER expression in CBC. However, a significant association between primary tumor and corresponding lgl-met was seen in both BC1 and CBC. Further, a comparison between BC1/CBC and corresponding lgl-met showed a decrease in GPERoverall (p&lt;0.001), but an increase in GPERPM (p=0.01). A high CBC GPER expression was associated with a worse OS, both when considering GPERoverall (p=0.02, HR=1.18, 95%CI: 1.05-1.32) and GPERPM (p=0.007, HR=1.61 95%CI: 1.14-2.29). Similar results were seen when analyzing survival in relation to CBC lgl-met GPER expression.

Conclusion: A high GPER expression in CBC and matched lgl-met is associated with worse OS. The overall expression of GPER decreases from primary tumor to lgl-met, but plasma membrane staining increases, supporting a mutation or amplification of the receptor. In addition, GPER expression correlates with other markers of aggressive disease, highlighting the potential as a novel treatment target. However, prior tamoxifen treatment did not alter tumor GPER expression.

Citation Format: Sjöström M, Fernö M, Rydén L, Leeb-Lundberg FLM, Alkner S. G protein-coupled estrogen receptor expression in lymph node metastasis and contralateral breast cancer during endocrine treatment [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P4-05-01.