Abstract 6221: Support for targeted therapy selection in triple negative breast cancer patients using aberrant signal transduction pathway activity profiles
Authors: Keizer Diederick M. , Wesseling Yvonne J. , van Strijp Dianne A. , Vermeer Saskia M. , den Biezen Eveline C. 
Published: April 2023

Abstract
Introduction: Success of therapeutic interventions largely rely on the pathological and biological characteristics of the tumor and varies due to the heterogeneous nature of breast cancers. Triple negative breast cancers (TNBC) stain IHC negative for both hormone receptors (ER, PR) and HER-2. TNBC is usually treated with chemotherapy because of absence of any molecular target. This study is initiated to characterize TNBC based on a new methodology that measures and quantifies signal transduction pathways (STPs) activities to reveal potential tumor-driving STPs in TNBC and create new options for targeted therapy.
Method: Using the mRNA-based OncoSIGNal pathway activity profiling PCR test (InnoSIGN) STP activities of 7 pathways (AR, ER, PI3K, MAPK, HH, TGFβ and Notch) in 39 samples from normal breast tissue and 12 TNBC patients were quantified and expressed on a scale from 0-100. Normal healthy breast tissue was obtained from breast reduction surgery and areas where epithelial cells content was at least 50% were annotated and harvested for mRNA isolation and STP analyses. The normal STP activity is representing the normal physiological activity and is used as reference value. Aberrant high pathway activity in a patient tumor sample was concluded when this score was higher than twice the standard deviation above the mean of normal breast tissue STP activity.
Results: STP thresholds for interpretation of high aberrant activity were determined from 39 normal breast samples. Using these thresholds, STP activities in 12 TNBC samples were analyzed. In these TNBC samples, MAPK was in 75%, HH in 67%, PI3K in 58%, and AR, Notch and TGFβ were in 17% of the cases above the thresholds. In 50% of the cases a combination of MAPK and HH or a combination of PI3K and HH were found above thresholds. In 42% of the cases MAPK in combination with PI3K were above thresholds. Increased activity of AR was never observed in combination with increased HH activity.
Conclusion: By using the OncoSIGNal test high aberrant STP activities could be determined in TNBC patient samples. Results show that different pathways are aberrantly active, depending on the patient sample, which opens the opportunity for personalized targeted treatment of individual TNBC patients.
Next steps: The TNBC data set will be extended to further profile the STP activity in relation to different clinical outcomes and to investigate new opportunities for targeted therapies.
Citation Format: Diederick M. Keizer, Yvonne J. Wesseling, Dianne A. van Strijp, Saskia M. Vermeer, Eveline C. den Biezen. Support for targeted therapy selection in triple negative breast cancer patients using aberrant signal transduction pathway activity profiles [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6221.