Perspectives on Triple-Negative Breast Cancer: Current Treatment Strategies, Unmet Needs, and Potential Targets for Future Therapies

Abstract

Triple-negative breast cancer (TNBC), characterized by the absence or low expression of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor (HER2), is the most aggressive subtype of breast cancer. TNBC accounts for about 15% of breast cancer cases in the U.S., and is known for high relapse rates and poor overall survival (OS). Chemo-resistant TNBC is a genetically diverse, highly heterogeneous, and rapidly evolving disease that challenges our ability to individualize treatment for incomplete responders and relapsed patients. Currently, the frontline standard chemotherapy, composed of anthracyclines, alkylating agents, and taxanes, is commonly used to treat high-risk and locally advanced TNBC. Several FDA-approved drugs that target programmed cell death protein-1 (Keytruda) and programmed death ligand-1 (Tecentriq), poly ADP-ribose polymerase (PARP), and/or antibody drug conjugates (Trodelvy) have shown promise in improving clinical outcomes for a subset of TNBC. These inhibitors that target key genetic mutations and specific molecular signaling pathways that drive malignant tumor growth have been used as single agents and/or in combination with standard chemotherapy regimens. Here, we review the current TNBC treatment options, unmet clinical needs, and actionable drug targets, including epidermal growth factor (EGFR), vascular endothelial growth factor (VEGF), androgen receptor (AR), estrogen receptor beta (ERβ), phosphoinositide-3 kinase (PI3K), mammalian target of rapamycin (mTOR), and protein kinase B (PKB or AKT) activation in TNBC. Supported by strong evidence in developmental, evolutionary, and cancer biology, we propose that the K-RAS/SIAH pathway activation is a major tumor driver, and SIAH is a new drug target, a therapy-responsive prognostic biomarker, and a major tumor vulnerability in TNBC. Since persistent K-RAS/SIAH/EGFR pathway activation endows TNBC tumor cells with chemo-resistance, aggressive dissemination, and early relapse, we hope to design an anti-SIAH-centered anti-K-RAS/EGFR targeted therapy as a novel therapeutic strategy to control and eradicate incurable TNBC in the future.

Keywords: Cytoxan; EGFR/K-RAS/SIAH signaling pathway; and Taxotere); chemo-resistance; clinical diagnostics; concurrent ACT regimen (Adriamycin; improved patient survival; neoadjuvant chemotherapy (NACT); pathologic incomplete responders (pIR); prognostics; residual cancer burden (RCB); sequential ACT regimen (AC-T); triple-negative breast cancer (TNBC); tumor recurrence; tumor-driving signaling pathways in TNBC.

Figure 1

SIAH^ON/OFF binary expression in residual tumors post-neoadjuvant systemic therapy (NST) can be used to risk-stratify pIR patients and predict patient survival in high-risk TNBC at 5 years. (A) Schematic illustration of the K-RAS–SIAH–EGFR pathway activation in TNBC. SIAH is the most downstream “gatekeeper” signaling module in the canonical K-RAS/EGFR signal transduction pathway in TNBC. (B,C) Loss of SIAH expression is correlated with K-RAS pathway inactivation and tumor regression, whereas persistent SIAH expression is correlated with K-RAS activation and tumor relapse in breast cancer of mixed molecular subtypes. The box-and-whisker plots were used to graphically illustrate the population distribution of median SIAH expression levels in both node-positive (as marked by purple color bar graphs) and node-negative (as marked by teal color bar graphs) in breast cancer of the four molecular subtypes: Luminal A (LumA), Luminal B (LumB), HER2, and TNBC. (B) The median SIAH expression levels in the untreated node-negative and node-positive primary tumors of the 4 molecular subtypes pre-NST are shown: Luminal A (LN-negative LumA at 20% and LN-positive LumA at 20%), Luminal B (LN-negative LumB at 20% and LN-positive LumB at 30%), HER2-positive breast cancer (LN-negative HER2-positive breast cancer at 30% and LN-negative HER2-positive breast cancer at 50%), and TNBC (LN-negative TNBC at 70% and LN-positive TNBC at 70%). The data showed that TNBC has the highest proliferative index in a peerwise comparison. (C) The median SIAH expression levels in the treated node-negative and node-positive residual tumors of the 4 molecular subtypes post-NST are shown: Luminal A (LN-negative LumA at 2% and LN-positive LumA at 3%), Luminal B (LN-negative LumB at 0.5% and LN-positive LumB at 1%), HER2-positive breast cancer (LN-negative HER2-positive breast cancer at 3% and LN-negative HER2-positive breast cancer at 0.5%), and TNBC (LN-negative TNBC at 8% and LN-positive TNBC at 15%). The data showed that TNBC is a high-risk cohort with intrinsic chemo-resistance, independent of the LN status, in a group comparison. The error bars or whiskers in the histogram and bar charts represent the 95% CI, and in the box plots, they represent the upper (top) and lower quartiles (bottom) data distribution—with points beyond 95% CI representing the outliers. Importantly, SIAH^ON expression can be used to accurately identify the individual pIR outliers with high SIAH expression and poor survival in breast cancer. (D,E) Representative IHC images of SIAH, EGFR, phospho-ERK, and Ki67 staining in TNBC pIR residual tumors are shown. (D) The pIR patients with no or low SIAH expression in residual tumors post-NACT stayed in remission. SIAH^OFF marked chemo-sensitive TNBC tumor cells that have stopped growing post-NACT, predicting increased patient survival (Alive). (E) The partial responders with high SIAH expression in residual tumors (despite 90% tumor shrinkage) post-NACT developed tumor relapse and succumbed to their metastatic diseases. SIAH^ON identified chemo-resistant TNBC tumor cells that are still growing post-NACT, thus predicting poor survival (Dead). Conclusion: For TNBC pIR patients with 70–90% tumor reduction post-NACT, it is evident that persistent high SIAH expression in residual tumors will predict early tumor relapse, poor prognosis, and reduced survival, whereas no or low SIAH expression in residual tumors will predict tumor remission, good prognosis, and increased survival in both the node-negative and node-positive TNBC post-NACT.