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.

Unmet Clinical Need: Developing Prognostic Biomarkers and Precision Medicine to Forecast Early Tumor Relapse, Detect Chemo-Resistance and Improve Overall Survival in High-Risk Breast Cancer.

Chemo-resistant breast cancer is a major barrier to curative treatment for a significant number of women with breast cancer. Neoadjuvant chemotherapy (NACT) is standard first- line treatment for most women diagnosed with high-risk TNBC, HER2+, and locally advanced ER+ breast cancer. Current clinical prognostic tools evaluate four clinicopathological factors: Tumor size, LN status, pathological stage, and tumor molecular subtype. However, many similarly treated patients with identical residual cancer burden (RCB) following NACT experience distinctly different tumor relapse rates, clinical outcomes and survival. This problem is particularly apparent for incomplete responders with a high-risk RCB classification following NACT. Therefore, there is a pressing need to identify new prognostic and predictive biomarkers, and develop novel curative therapies to augment current standard of care (SOC) treatment regimens to save more lives. Here, we will discuss these unmet needs and clinical challenges that stand in the way of precision medicine and personalized cancer therapy.

Lung cancer metastasis to the breast mimicking inflammatory breast carcinoma on imaging.

While metastatic disease to the breast has been documented from many primary neoplasms with incidence ranging from 0.2% to approximately 2.7% among reported clinical cases, breast cancer metastases resulting from a primary lung neoplasm is significantly less commonly reported in the literature. Routes of metastatic spread of lung neoplasms include both hematologic and lymphatic routes. We present a case of biopsy proven lymphangitic spread of primary lung neoplasm to the ipsilateral breast and axillary nodes mimicking inflammatory breast cancer. It remains crucial to differentiate between extramammary diseases with metastatic deposits in the breast from a primary breast neoplasm as treatment remains very different between these entities. As in this case, the pathologic, histologic, and immunohistochemistry analyses are critical in determining the origin of the malignant cells and formulating a treatment plan.

Adult metastatic pancreaticoblastoma detected with Tc-99m MDP bone scan.

Osteotropic radiopharmaceutical uptake has been reported in a wide variety of benign and malignant soft tissue tumors. We present an unusual case of pancreaticoblastoma with mesenteric and omental metastases detected by bone scan in a 69-year-old man who presented with fever, weight loss, and renal insufficiency. Pancreaticoblastoma is a rare childhood tumor that may occur in adults, although only two cases of adults with metastatic disease have been described.

Evaluation of serum creatine kinase in ectopic pregnancy with reference to tubal status and histopathology.

OBJECTIVE: To study the value of creatine kinase in ectopic pregnancy with reference to tubal histopathology. DESIGN: Prospective controlled study. SETTING: Academic tertiary-care institution. POPULATION: Thirty-two women with ectopic pregnancy and 20 controls with intrauterine pregnancies. METHODS: Creatine kinase and beta-hCG levels were measured on admission. Ectopic pregnancies were removed at surgery and examined histologically. MAIN OUTCOME MEASURES: Tubal localisation and integrity of ectopic pregnancies as judged at surgery and later histologically, and placental growth patterns in unruptured ectopic pregnancies classified as intraluminal, extraluminal or mixed as determined histologically. RESULTS: Creatine kinase levels were higher in isthmic than ampullary ectopic pregnancies (P = 0.011), and higher in ruptured than in unruptured cases (P = 0.003) and normal pregnancies (P < 0.0001). A creatine kinase value >120iu/L was 65% sensitive and 87% specific in discriminating ruptured from unruptured ectopic pregnancies. Creatine kinase levels were above this cutoff in two of five unruptured ampullary ectopic pregnancies with invasive trophoblastic growth, yet in none of nine cases with intraluminally confined placentation (P = 0.04). Creatine kinase was positively correlated with gestational age in ruptured (P = 0.007), but not in unruptured ectopic pregnancies or normal pregnancies. CONCLUSIONS: Serum creatine kinase may help in discriminating ruptured from unruptured ectopic pregnancies, while it is not useful for the primary diagnosis of ectopic pregnancy. An increase in creatine kinase levels accompanying muscular damage in ectopic pregnancy probably antedates tubal rupture, and may be related to trophoblastic growth patterns.