VERESCA PRECISION ONCOLOGY
US | Onconostic Technologies, Inc.
EU | 3N Diagnostics Ltd.
®
FOXC1 in ER+ Breast Cancer
Through breast cancer awareness and screening programs, the majority (ASCO 2020: 79%-84%) of patients present with early-stage ER+ breast cancer. Most patients with ER+ cancers are offered adjuvant endocrine therapy. Although these patients may initially respond well, up to 41% will have a recurrence [3], often with more aggressive, endocrine therapy-resistant, and metastatic tumors. [4] More than 20% of ER+ patients ultimately die from their disease after developing distant relapse [102, 103] and approximately 62% of breast cancer deaths occur five to 20-years after initial diagnosis.
ER+ tumors rapidly respond to growth factor/cytokine signaling, reprogramming cancer cells to proliferate and survive without estrogen (ER-) resulting in acquired therapeutic resistance. While most (87%) ER+ patients present with tumors containing fewer than 20% ER- cells, the remaining ER+ patients (13%), may present with up to 89% ER- cells in the tumor landscape requiring aggressive therapeutic management.
More importantly, ER+ tumors and derived cell lines can proliferate in low‑estrogen settings, demonstrating that ER positivity does not always imply estrogen dependence. Multiple breast‑cancer studies show ER+ cells can sustain hyperproliferation without circulating estrogen, thus resulting in endocrine therapy resistance through the following mechanisms: 1) Receptor Tyrosine Kinase (RTK) ligand activation and signaling cascade; 2) signaling cascade mutations; 3) ER expression driving tumor suppression pathways (i.e., TGF beta and NFkB) into aggressive tumorigenic phenotypes; and 4) Overexpression of c‑Myc, cyclin D1/E1 and CDK activation bypass estrogen control of G1→S. All of the above result in the activation of FOXC1 and the transformation to FOXC1 Pro-metastatic cancer cells, when left untreated, may eventually dominate the tumor landscape.
A new dimension in defining heterogeneity
VERESCA FOXC1 IHC is a breakthrough in precision medicine identifying the heterogeneous (proportion and intensity) nature of previously undetectable aggressive FOXC1 pro-metastatic subpopulations in tumors. FOXC1+ tumor cells, historically eluding detection, often co-existed in tumors identified via standard-of-care IHC (i.e., ER, PR, HER2) classification. FOXC1+ cells are resistant to ER targeted therapy. Thus, residual untreated FOXC1+ cells are often responsible for recurrence, disease progression, IHC receptor switching, and distant organ metastasis.
Estrogen independent HER2+ overexpressing cells, identified in 1998, are the most recognized estrogen independent tumor subpopulation co-existing in ER+ heterogeneous breast cancer. Specific ligands from cells in the tumor microenvironment (TME) bind to HER2, a membrane Receptor Tyrosine Kinase (RTK) of the Epidermal Growth Factor Receptor (EGFR) family activating downstream signal transduction pathways. The complex dimerization of HER2 with nearby HER2 receptors (HER2:HER2) and other EGFR family members (HER1:HER2 and HER2:HER3) significantly affect estrogen independent proliferation and survival. Moreover, other RTKs, cytokines, and growth factors, along with mutations and crossover in the downstream signal transduction pathways lead to endocrine therapy resistant subpopulations hidden in ER+ disease elevating risk of recurrence.
A complex network of signal transduction pathways (STP) leads to the activation of estrogen independent proliferation and endocrine therapy resistance
FOXC1 - THE METASTATIC HUB
All estrogen independent signal transduction pathways converge upon the activation of FOXC1
All of the above signal transduction pathways converge upon the activation of FOXC1. Thus, the presence of FOXC1+ pro-metastatic cells identify the landscape of endocrine therapy resistant subpopulations co-existing in ER+ disease. VERESCA Precision Oncology, in multi-center clinical trials in the US, found that 21.6% of patients diagnosed with ER+ disease had some degree of FOXC1+ pro-metastatic subpopulations co-existing in the tumor landscape. Previously unrecognized endocrine therapy resistant FOXC1+ cells are primarily responsible for the high recurrence rate (up to 41%) seen in ER+ disease.
