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

Anieta M Sieuwerts,Márcia A Inda,John W M Martens,Henk Van Ooijen,Anja Van De Stolpe,Wim F J Verhaegh,Marcel Smid

doi:10.3390/cancers12040802

Anieta M Sieuwerts, Márcia A Inda + Show 5 more

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https://doi.org/10.3390/cancers12040802

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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.

Highlights

IntroductionChoice of endocrine treatment assumes that the Estrogen receptor (ER) signal transduction pathway is in the active state and represents the tumor-driving pathway, but this assumption may be questioned in these patients
All patients in the cohort were assessed as Estrogen receptor (ER) positive luminal breast cancer patients based on conventional pathology diagnostics, but we have shown before that this does not mean that they all had a high ER pathway activity, and that in tumors with low ER activity another signal transduction pathway may be more likely to drive tumor growth [2]
We performed, in addition to assessment of ER pathway activity, a broad analysis of signaling pathway activity in the primary tumor samples and related this to metastasis treatment outcome of the patients included in this study

Summary

Introduction

Choice of endocrine treatment assumes that the ER signal transduction pathway is in the active state and represents the tumor-driving pathway, but this assumption may be questioned in these patients. Bayesian network-based computational models have been developed and validated biologically to assess the functional activity of signal transduction pathways in a cancer tissue sample in a quantitative manner, based on gene expression levels of pathway-specific target genes [2]. Initial results of the ER pathway model provide evidence that the ER pathway is not always active in breast cancer tissue from patients in which routine ER evaluation indicates ER positivity, and that ER pathway activity as identified by the model is associated with improved clinical outcome after adjuvant hormonal treatment [2]. The pathway model series has recently been extended to include, besides

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