Abstract 464: Gene expression signatures for the prediction of endocrine treatment outcome in early-stage luminal breast cancer patients

Abstract

Estrogen (ER) and/or progesterone (PR) receptor-positive, early breast cancer benefits from targeted therapy via long-term estrogen deprivation. Valid treatment options include the selective ER modulator tamoxifen (TAM) that interferes with estrogen-binding at the ER, and aromatase inhibitors (AI) that block the enzyme aromatase to prevent the conversion of androgens to estrogen. Both treatment principles are in clinical use however fail in about one third of the patients. The choice of endocrine treatment is currently not well supported by predictive tumor markers. Gene expression signatures covering critical breast cancer pathways were tested to predict TAM and AI associated outcomes in a prospectively collected postmenopausal, hormone-receptor positive, early breast cancer cohort (IKP211; 1200 patients, median follow up 5.5 years; DRKS00000605). RNA was extracted from formalin-fixed paraffin-embedded tumor sections of 631 patients and subjected to gene expression profiling with 770 genes across 23 key breast cancer pathways/processes (NanoString®BC360 panel) including the prognostic PAM50 signature for intrinsic subtype classification. Signatures were measured with the nCounter Digital Analyzer system (Nanostring) and revealed 60% Luminal A, 31% Luminal B, 6% HER2 enriched and 3% Basal-like tumor subtypes. Predefined signature scores (Nanostring) or single gene expression scores were analyzed in relation to breast cancer recurrence-free survival (EFS). PAM50 subtype designation and its derived Genomic Risk Score (ROR) were strongly associated with EFS of patients treated with AI (Log Rank P<0.05 all comparisons) but not in patients treated with mono-TAM. Preliminary data show that higher levels of FOXA1 and androgen receptor (AR) gene expression are both associated with longer EFS in patients with AI therapy. Likewise, increased (mutant-like) p53 signaling was prognostic for shorter EFS (Log Rank P<0.05). These relations were not observed in patients treated with TAM or with a switch treatment regimen. A trend for longer EFS linked to an increased anti-tumor immune activity, as deduced by cytotoxic cell abundance and activity, was observed in a subgroup of mainly TAM treated patients. Our preliminary data suggest that gene expression signatures pertaining to FOXA1 and AR signaling, p53 and anti-tumor immune activity may define subgroups of patients with different outcomes and may aid in future personalized treatment concepts for hormone-sensitive postmenopausal early breast cancer. Citation Format: Werner Schroth, Reiner Hoppe, Florian Büttner, Stefan Winter, Siarhei Kandabarau, Jörg Kumbrink, Heather A. Brauer, Peter Fritz, Matthias Schwab, Thomas Mürdter, Hiltrud Brauch. Gene expression signatures for the prediction of endocrine treatment outcome in early-stage luminal breast cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 464.

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“…From each sample, 100 ng of RNA was hybridized to the human nCounter Breast Cancer 360 (BC360) gene expression panel (NanoString Technologies), and processed on the nCounter SPRINT Profiler (NanoString Technologies) according to manufacturer's protocols. The BC360 panel includes 776 individual genes, including 18 housekeeping genes for normalization, and 40 gene signatures associated with breast cancer signaling pathways and biological processes (15)(16)(17)(18). Our analyses of BC360 data focus primarily on the 758 unique, nonhousekeeping genes, and the 40 gene signatures.…”

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“…This efficiency of NanoString BC360 ® (Seattle, USA) was evident in Phase I clinical trial evaluating Eribulin and Everolimus in TNBC candidates whereby the panel was capable of disclosing the diversity of breast cancer and its microenvironment [ 124 ]. In another study, the NanoString ® BC360 panel aided in distinguishing the intrinsic breast carcinoma subtypes and subsequently evaluated endocrine therapy effectiveness for stage I luminal breast cancer [ 125 ]. In addition, the validity of NanoString BC360 ® in determining breast cancer subtype (ESR1, PGR, MK167, and ERBB2 genes) was recently proven to draw a parallel with the traditional immunohistochemistry method [ 126 ].…”