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.

Background: Non-functional well-differentiated pancreatic neuroendocrine tumors (WD-PanNETs) are complex, heterogeneous malignancies with variable prognosis. Despite guideline recommendations, disparities in access to specialized care may impact survival. This study examines whether treatment facility type, geographic travel distance, and treatment modalities are associated with survival outcomes in patients diagnosed with WD-PanNETs. Results: Among 20,174 patients with WD-PanNETs, the median age was 62 years (IQR: 52–70), and 54% were men. The majority were treated at non-academic hospitals (76%), with 2.9% traveling >250 miles for care. Patients treated at non-academic hospitals (24%) had 50% lower 15-year survival rates compared to those treated at academic hospitals (58%) and integrated hospitals (56%) (p < 0.001). Patients traveling >250 miles had a 72% 15-year survival rate, compared to 43% for those traveling <12.5 miles (p < 0.001). In the context of facility-type and geographic distance, treatment at non-academic hospitals <250 miles was associated with a 21% higher mortality risk (HR 1.21, 95% CI 1.12–1.31, p < 0.001), and treatment at low-volume hospitals increased mortality risk by 25% (HR 1.25, 95% CI 1.14–1.37, p < 0.001). In contrast, primary tumor resection was associated with a 64% reduction in mortality risk (HR 0.36, 95% CI 0.33–0.38, p < 0.001), which remained significant at all disease stages. Conclusion: Treatment at academic or high-volume centers and longer travel distances were associated with improved OS in patients with WD-PanNETs. Primary tumor resection remains critical, while systemic therapies were primarily used in later-stage disease. These findings support policies that improve access to centralized, multidisciplinary care.