Abstract 2145: Detect early tumor relapse in high-risk breast cancer
Authors: Amy H. Tang, Lauren L. Siewertsz van Reesema, Vasilena P. Zheleva, Janet S. Winston, Rick J. Jansen, Emanuel F. Petricoin, Matthew P. Goetz, Matthew P. Goetz, Harry D. Bear, Richard A. Hoefer
Journal: Cancer Research (2019)

Abstract Chemotherapy resistant breast cancer is a major health challenge, resulting in high relapse rates and poor survival. Neoadjuvant chemotherapy (NACT) is a standard treatment for women with high-risk TNBC, HER2+, and locally advanced ER+ breast cancer. A completed course of NACT results in two possible outcomes: pathologic complete response (pCR) or residual disease. While pCR is a reliable clinical prognostic biomarker associated with excellent outcomes and prolonged survival, especially for TNBC and HER2+ cancers, patients with residual disease have a higher risk of recurrence. Patients with residual disease can be further stratified clinically using the Residual Cancer Burden (RCB) classification; however, patients with similar RCB classes may experience dramatically different clinical outcomes. Thus, additional precision biomarkers to stratify patients with residual disease after NACT are needed to identify patients at highest risk of recurrence, and to develop new therapeutic strategies to eradicate multidrug-resistant tumors. Supported by strong evidence in developmental, evolutionary and cancer biology, we found that K-RAS-SIAH pathway activation is a major tumor driver, and SIAH represents a key tumor vulnerability in breast cancer. Normal K-RAS/SIAH signaling pathway activation is indispensable for proper cell-cell communication, cell proliferation and tissue homeostasis in multicellular organisms. However, abnormal K-RAS/SIAH pathway activation is highly prevalent in high-risk and locally advanced breast cancer, and may confer chemo-resistance to these high-risk mammary tumors. Based on its evolutionary conservation and significance as the most downstream signaling module indispensable for K-RAS signal transduction, SIAHON/OFF expression is a reliable readout of K-RAS/EGFR/HER2 pathway activation/inactivation. We showed that SIAHON/OFF expression is a binary code in residual mammary tumors that can be used to stratify patients, augment RCB classification, forecast tumor relapse, and predict patient survival after 1st line NACT in a pilot retrospective study. Multidrug-resistant high-grade breast cancer is a genetically diverse, highly heterogeneous disease that challenges our ability to individualize and optimize precision therapy. Persistent K-RAS-SIAH-EGFR pathway activation endows TNBC with therapy resistance, and increases the risk of metastasis and early relapse. As such, we developed a K-RAS/SIAH-centered biomarker discovery program and a new anti-SIAH research initiative with the intended goal of designing novel and potentially life-saving anti-K-RAS targeted strategies to control and eradicate multidrug-resistant and intractable mammary tumors. Citation Format: Amy H. Tang, Lauren L. Siewertsz van Reesema, Vasilena P. Zheleva, Janet S. Winston, Rick J. Jansen, Emanuel F. Petricoin, Matthew P. Goetz, Matthew P. Goetz, Harry D. Bear, Richard A. Hoefer. Detect early tumor relapse in high-risk breast cancer [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 2145.