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

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 (ERß), 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.

Time to Adjuvant Radiotherapy in Breast Cancer Affects Survival: Implications for the American College of Surgeons Commission on Cancer Quality Metrics.

BACKGROUND: To optimize breast cancer care, the American College of Surgeons Commission on Cancer developed quality measures regarding receipt and timing of adjuvant radiotherapy (RT). Nationwide compliance with these measures and its impact on overall survival (OS) are evaluated herein. PATIENTS AND METHODS: Patients (n = 285,291) diagnosed with invasive breast cancer from 2004 to 2012 were identified from the National Cancer Database. Compliance with RT administration within 365 days from diagnosis was determined for patients with stage III disease with ≥ 4 positive lymph nodes post mastectomy and stage I-III disease post breast-conserving surgery (BCS). Univariate and multivariate logistic regression and Cox proportional hazard models were used to assess factors associated with compliance and OS, respectively. RESULTS: In the mastectomy cohort, 66.9% received timely RT, showing improved OS versus no RT patients (HR 0.70, 95% CI 0.67-0.73). Delayed RT patients (≥ 365 days) achieved equivalent OS to those receiving timely RT (HR 1.07, 95% CI 0.93-1.23) and superior OS to no RT patients (HR 0.74, 95% CI 0.65-0.85). In the BCS cohort, 89.4% received timely RT, showing improved OS versus no RT patients (HR 0.47, 95% CI 0.45-0.49). Delayed RT was associated with improved OS versus no RT (HR 0.64, 95% CI 0.56-0.74) and decreased OS versus timely RT (HR 1.37, 95% CI 1.19-1.58). Factors associated with noncompliance included insurance type and distance to hospital. CONCLUSIONS: Quality measure compliance with adjuvant RT improves OS, regardless of timing after mastectomy. However, timeliness does impact OS after BCS. Focus on modifiable factors to improve compliance such as access to care may lead to improved compliance and OS.

Multivisceral robotic liver surgery: feasible and safe.

The application of robotic technology allows for the performance of multi-organ liver resections by multidisciplinary teams in a minimally invasive manner. Their technique and outcomes are not established. Herein we describe our technique with robotic liver surgery combined with colon, pancreas and urologic resections. Our patients are an 84-year-old (yo) female (Body Mass Index, BMI: 25) with a recently diagnosed right colon adenocarcinoma and two synchronous liver metastases at segments 5 and 6, a 75-year-old female (BMI: 50.4) with a history of right renal cell cancer status post (s/p) right robotic radical nephrectomy now with tumor recurrence with multiple intra-abdominal masses including a segment 7 liver lesion and a 71-year-old female (BMI: 24) with history of pancreatic ductal adenocarcinoma of the tail and a segment 3 liver lesion s/p neoadjuvant chemotherapy. The Xi robotic system (Intuitive Surgical, Sunnyvale, CA, USA) was utilized in all cases. Port placement in all cases was decided within the multidisciplinary teams to accommodate both the hepatic and the extra-hepatic portion of the operation. Parenchymal transections were performed with the use of the Vessel Sealer and the robotic stapler as appropriate. Indocyanine green (ICG) was used to assess the anastomotic perfusion in the first patient. Blood loss was 50 ml for the first two cases and 300 ml for the third. Surgical margins were negative in all cases. Patients were discharged at POD 8, 3 and 5 with one patient experiencing postoperative ileus. Robotic multivisceral liver resections are feasible and safe within multidisciplinary surgical teams with expertise in robotic surgery. The robotic platform can offer a minimally invasive approach in liver surgery synchronous with colonic, pancreatic and urologic surgery.

A New Strategy to Control and Eradicate "Undruggable" Oncogenic K-RAS-Driven Pancreatic Cancer: Molecular Insights and Core Principles Learned from Developmental and Evolutionary Biology.

Oncogenic K-RAS mutations are found in virtually all pancreatic cancers, making K-RAS one of the most targeted oncoproteins for drug development in cancer therapies. Despite intense research efforts over the past three decades, oncogenic K-RAS has remained largely "undruggable". Rather than targeting an upstream component of the RAS signaling pathway (i.e., EGFR/HER2) and/or the midstream effector kinases (i.e., RAF/MEK/ERK/PI3K/mTOR), we propose an alternative strategy to control oncogenic K-RAS signal by targeting its most downstream signaling module, Seven-In-Absentia Homolog (SIAH). SIAH E3 ligase controls the signal output of oncogenic K-RAS hyperactivation that drives unchecked cell proliferation, uncontrolled tumor growth, and rapid cancer cell dissemination in human pancreatic cancer. Therefore, SIAH is an ideal therapeutic target as it is an extraordinarily conserved downstream signaling gatekeeper indispensable for proper RAS signaling. Guided by molecular insights and core principles obtained from developmental and evolutionary biology, we propose an anti-SIAH-centered anti-K-RAS strategy as a logical and alternative anticancer strategy to dampen uncontrolled K-RAS hyperactivation and halt tumor growth and metastasis in pancreatic cancer. The clinical utility of developing SIAH as both a tumor-specific and therapy-responsive biomarker, as well as a viable anti-K-RAS drug target, is logically simple and conceptually innovative. SIAH clearly constitutes a major tumor vulnerability and K-RAS signaling bottleneck in pancreatic ductal adenocarcinoma (PDAC). Given the high degree of evolutionary conservation in the K-RAS/SIAH signaling pathway, an anti-SIAH-based anti-PDAC therapy will synergize with covalent K-RAS inhibitors and direct K-RAS targeted initiatives to control and eradicate pancreatic cancer in the future.

SIAH and EGFR, Two RAS Pathway Biomarkers, are Highly Prognostic in Locally Advanced and Metastatic Breast Cancer.

BACKGROUND: Metastatic breast cancer exhibits diverse and rapidly evolving intra- and inter-tumor heterogeneity. Patients with similar clinical presentations often display distinct tumor responses to standard of care (SOC) therapies. Genome landscape studies indicate that EGFR/HER2/RAS "pathway" activation is highly prevalent in malignant breast cancers. The identification of therapy-responsive and prognostic biomarkers is paramount important to stratify patients and guide therapies in clinical oncology and personalized medicine. METHODS: In this study, we analyzed matched pairs of tumor specimens collected from 182 patients who received neoadjuvant systemic therapies (NST). Statistical analyses were conducted to determine whether EGFR/HER2/RAS pathway biomarkers and clinicopathological predictors, alone and in combination, are prognostic in breast cancer. FINDINGS: SIAH and EGFR outperform ER, PR, HER2 and Ki67 as two logical, sensitive and prognostic biomarkers in metastatic breast cancer. We found that increased SIAH and EGFR expression correlated with advanced pathological stage and aggressive molecular subtypes. Both SIAH expression post-NST and NST-induced changes in EGFR expression in invasive mammary tumors are associated with tumor regression and increased survival, whereas ER, PR, and HER2 were not. These results suggest that SIAH and EGFR are two prognostic biomarkers in breast cancer with lymph node metastases. INTERPRETATION: The discovery of incorporating tumor heterogeneity-independent and growth-sensitive RAS pathway biomarkers, SIAH and EGFR, whose altered expression can be used to estimate therapeutic efficacy, detect emergence of resistant clones, forecast tumor regression, differentiate among partial responders, and predict patient survival in the neoadjuvant setting, has a clear clinical implication in personalizing breast cancer therapy. FUNDING: This work was supported by the Dorothy G. Hoefer Foundation for Breast Cancer Research (A.H. Tang); Center for Innovative Technology (CIT)-Commonwealth Research Commercialization Fund (CRCF) (MF14S-009-LS to A.H. Tang), and National Cancer Institute (CA140550 to A.H. Tang).

RAS pathway biomarkers for breast cancer prognosis.

Metastatic breast cancer is a highly heterogeneous, rapidly evolving and devastating disease that challenges our ability to find curative therapies. RAS pathway activation is an understudied research area in breast cancer. EGFR/RAS pathway activation is prevalent in breast cancer with poor prognosis. The prognostic RAS pathway biomarkers can be used to identify resistant tumour clones, stratify patients and guide therapies.