ER and PI3K Pathway Activity in Primary ER Positive Breast Cancer Is Associated with Progression-Free Survival of Metastatic Patients under First-Line Tamoxifen

Abstract

Estrogen receptor positive (ER+) breast cancer patients are eligible for hormonal treatment, but only around half respond. A test with higher specificity for prediction of endocrine therapy response is needed to avoid hormonal overtreatment and to enable selection of alternative treatments. A novel testing method was reported before that enables measurement of functional signal transduction pathway activity in individual cancer tissue samples, using mRNA levels of target genes of the respective pathway-specific transcription factor. Using this method, 130 primary breast cancer samples were analyzed from non-metastatic ER+ patients, treated with surgery without adjuvant hormonal therapy, who subsequently developed metastatic disease that was treated with first-line tamoxifen. Quantitative activity levels were measured of androgen and estrogen receptor (AR and ER), PI3K-FOXO, Hedgehog (HH), NFκB, TGFβ, and Wnt pathways. Based on samples with known pathway activity, thresholds were set to distinguish low from high activity. Subsequently, pathway activity levels were correlated with the tamoxifen treatment response and progression-free survival. High ER pathway activity was measured in 41% of the primary tumors and was associated with longer time to progression (PFS) of metastases during first-line tamoxifen treatment. In contrast, high PI3K, HH, and androgen receptor pathway activity was associated with shorter PFS, and high PI3K and TGFβ pathway activity with worse treatment response. Potential clinical utility of assessment of ER pathway activity lies in predicting response to hormonal therapy, while activity of PI3K, HH, TGFβ, and AR pathways may indicate failure to respond, but also opens new avenues for alternative or complementary targeted treatments.

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

“…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.…”

“…Pathway analysis in three independent clinical studies (performed using both Affymetrix microarrayand qPCR-based pathway analysis) showed that in primary ER positive breast cancer patients, the ER pathway activity score predicted response to neoadjuvant treatment with an aromatase inhibitor (Inda et al, 2020). 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).…”

“…Some pathways, such as the TGFβ pathway, can exert tumor promoting and suppressive effects depending on the cancer type. A drug can either target the signal transduction pathway at the receptor, for example trastuzumab to target the HER2 receptor, or at downstream nodes, for example a PI3K inhibitor to target the PIK3CA signaling molecule or everolimus targeting the mTOR protein (Baudino, 2015;Sieuwerts et al, 2020). Many targeted drugs, such as those which target the ER, PI3K and MAPK signaling pathways, have been clinically approved based on evidence of clinical benefit and are being used to treat various cancer types (Massard et al, 2017;Dugger et al, 2018;Marquart et al, 2018;National Cancer Institute, 2021).…”

Measurement of Cellular Immune Response to Viral Infection and Vaccination

“…The approach used to develop tests to measure activity of signal transduction pathways is based on measuring the mRNA levels of target genes of the pathway-specific transcription factor and has been described before (6)(7)(8)(16)(17)(18)(19)(20). Target genes that were identified and used to develop the JAK-STAT1/2 models and the JAK-STAT3 models are listed in Supplementary Table S1.…”

Quantitative measurement of activity of JAK-STAT signaling pathways in blood samples and immune cells to predict innate and adaptive cellular immune response to viral infection and accelerate vaccine development

“…We describe development, as well as evaluation in preclinical and clinical studies, of an mRNAbased test to quantify the immune response to a viral infection, based on measuring activity of the JAK-STAT1/2 and JAK-STAT3 signal transduction pathways in a whole blood or Peripheral Blood Mononuclear Cell (PBMC) sample, or in separate immune cell types. The technology used to develop tests to measure activity of signal transduction pathways is based on measuring the mRNA levels of target genes of the pathway-specific transcription factor and has been described before (6), (7),(8),(9),(10),(11), (12) , (13).…”