Abstract P6-15-02: Phenotypically distinct HRG positive cancer cells impact standard of care therapies in metastatic breast cancer models
Authors: GJ Finn, H Zhang, A Blois, SE Mathews, AJ Kudla, JS Baum, NA Demars, MJ Cieslewicz, A Czibere
Journal: Cancer Research (2017)

Abstract ErbB3 is a member of the human epidermal growth factor receptor (ErbB or HER) family which is comprised of four receptors (ErbB1-4). A defining feature of the ErbB network is that two members of the family, ErbB2 and ErbB3, are non-autonomous. ErbB2 lacks the capacity to interact with a growth-factor ligand, whereas the kinase activity of ErbB3 is defective. Heregulin (HRG), the ErbB3 ligand, has been identified as a potent driver of proliferation and enhanced survival. HRG expression leads to a distinct tumor cell phenotype characterized by an inability to respond to the effects of numerous Standard of Care (SOC) therapies, including chemotherapies, anti-hormonal agents and other targeted therapeutics. In surveys of HRG expression, we have shown the presence of HRG+ cells in approximately 50% of the cases of most solid tumor types. We hypothesize that these HRG+ cells are protected from the effects of SOC therapy and continue to proliferate even in the presence of SOC, resulting in limited clinical benefit. In this model, if HRG activity is blocked, HRG+ cells become susceptible to SOC, resulting in enhanced clinical benefit. Seribantumab is a fully human anti-ErbB3 monoclonal antibody designed to block HRG activity by inhibiting the binding of HRG to ErbB3. In the presence of seribantumab, HRG+ tumor cells are predicted to be able to respond to co-administered SOC therapy. For hormone receptor positive (HR+) breast cancer, hormone deprivation strategies have proven clinical benefit in the adjuvant and metastatic settings. Unfortunately, clinical benefit from these therapies can be short-lived in some patients. Optimal clinical management of these patients requires a comprehensive molecular understanding of the drivers of rapid clinical progression. We and others have found that HRG mRNA expression measured in tumor samples defines a subgroup of patients who derive only limited clinical benefit from SOC when compared to patients whose tumors do not express HRG. This was observed in a previously published Phase 2 clinical study with exemestane, and preclinically with multiple classes of anti-hormonal agents, including letrozole and fulvestrant -- treatments that currently represent the mainstay of treatment options for HR+, HER2 negative (HER2-) advanced breast cancer. Here we will present data supporting the hypothesis that phenotypically distinct HRG+ cells in breast cancer models persist despite treatment with SOC and various novel classes of therapy. We will also show that the addition of the anti-ErbB3 antibody seribantumab to these other therapies promotes sustained treatment responses. Continued expansion of HRG+ cells could be the key to rapid clinical progression in breast cancer patients treated with SOC therapy. These findings support the development of seribantumab in combination with anti-hormonal agents in a planned Phase 3 clinical trial in HR+, HER2- advanced breast cancer. Citation Format: Finn GJ, Zhang H, Blois A, Mathews SE, Kudla AJ, Baum JS, Demars NA, Cieslewicz MJ, Czibere A. Phenotypically distinct HRG positive cancer cells impact standard of care therapies in metastatic breast cancer models [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P6-15-02.