Oestrogen receptor pathway activity is associated with outcome in endometrial cancer

Abstract

Background Oestrogen receptor (ER) expression is a prognostic biomarker in endometrial cancer (EC). However, expression does not provide information about the functional activity of the ER pathway. We evaluated a model to quantify ER pathway activity in EC, and determined the prognostic relevance of ER pathway activity. Methods ER pathway activity was measured in two publicly available datasets with endometrial and EC tissue, and one clinical cohort with 107 samples from proliferative and hyperplastic endometrium and endometrioid-type EC (EEC) and uterine serous cancer (USC). ER pathway activity scores were inferred from ER target gene mRNA levels from Affymetrix microarray data (public datasets), or measured by qPCR on formalin-fixed paraffin-embedded samples (clinical cohort) and related to ER expression and outcome. Results ER pathway activity scores differed significantly throughout the menstrual cycle supporting the validity of the pathway test. The highest ER pathway scores were found in proliferative and hyperplastic endometrium and stage I EEC, whereas stage II–IV EEC and USCs had significantly lower levels. Low ER pathway activity was associated with recurrent disease, and added prognostic value in patients with low ER expression. Conclusion The ER pathway test reflects activity of the ER pathway, and may improve prediction of outcome in EC patients.

Signal Transduction Pathway Activity in High-Grade, Serous Ovarian Carcinoma Reveals a More Favorable Prognosis in Tumors with Low PI3K and High NF-κB Pathway Activity: A Novel Approach to a Long-Standing Enigma

“…Furthermore, STA analysis was able to identify a subgroup of patients with a more favorable prognosis among women diagnosed with ER-positive breast cancer treated with tamoxifen, based on actual ER pathway activity [7]. Similar findings are reported in endometrial cancer [15]. These results indicate that STA analysis may be a superior approach to assess STP activity and select patients for individualized therapies.…”

RNA Based Approaches to Profile Oncogenic Pathways From Low Quantity Samples to Drive Precision Oncology Strategies

“…RNA sequencing on single cells has recently developed into a feasible technology (Hedlund and Deng, 2018;Hwang et al, 2018;Chen et al, 2019). Using the STP analysis technology, measurement of activity of the Wnt pathway on a single (circulating tumor) cell using RNA sequencing data has already been reported, underscoring the highly sensitive nature of the pathway analysis approach (van Strijp et al, 2017). Initial results using the qPCR-based STP analysis similarly indicated the feasibility of measuring pathway activity on only a few cells, using an adaptation of the protocol to include a pre-amplification method (Figure 4).…”

“…cancer pathophysiology and to predict prognosis and response to therapy van Boxtel et al, 2019;Inda et al, 2020;Sieuwerts et al, 2020;van Weelden et al, 2020). A few key results are summarized below, centered around the role of the different signaling pathways in the various cancer types.…”

“…In ER positive breast cancer patients who developed metastatic disease and were subsequently treated with first line tamoxifen, an active ER pathway was associated with a better prognosis (Sieuwerts et al, 2020). In both ovarian cancer and endometrial cancer, loss of ER pathway activity was associated with higher grade cancer type and worse prognosis (van Lieshout et al, 2020;van Weelden et al, 2020). Results suggest that for all three cancer types, ER pathway activity reflects a more differentiated cancer type associated with a better prognosis, and measuring ER pathway activity may predict response to hormonal therapy in ER positive breast cancer.…”

Predictive and Prognostic Biomarker Identification in a Large Cohort of Androgen Receptor-Positive Salivary Duct Carcinoma Patients Scheduled for Combined Androgen Blockade

“…For instance, for AR-signaling, samples of the AR-positive human prostate cancer cell line LNCaP, treated with and without dihydrotestosterone, were used as ground truth values for active and inactive pathway activity state, respectively [ 15 ]. This Bayesian approach of expressing the odds of a pathway being active or inactive based on quantitative measurements of target gene sets has previously been published and validated in several tissue types for different pathways [ 15 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 ]. Target gene expression was quantified with one-step RT-qPCR, using SuperScript ® III Platinum ® One-Step qRT-PCR Kit (Invitrogen, Waltham, MA, USA) on FFPE-extracted RNA.…”