The development of novel anti-HER2 drugs opens new treatment options for women with breast cancers, including lower expression of HER2. The epidemiology and clinical outcome of metastatic HER2-low breast cancer remain not well described. We designed a retrospective cohort study of the 2010–2017 National Cancer Database (NCDB) was designed to compare the overall survival of HER2-low and HER2-zero de novo metastatic breast cancer with systemic therapy. Multivariable Cox regression models were performed to estimate hazard ratios (HR), adjusting for sociodemographic and clinical factors. A total of 20,636 of 30,929 (66.7%) patients were HER2-low and 10,293 (33.3%) were HER2-zero. When stratified by hormonal receptor status, HER2-low tumors account for 18,066 (69.7%) cases in HR+/HER2− population and 2570 (51.4%) cases in HR−/HER2− population. The prevalence of HER2-low tumors was similar across racial groups with a slightly lower prevalence among the Hispanic population. Women with HER2-low tumors had longer overall survival (OS) than women with Her2-zero tumors in both HR-positive (median OS 39.0 months vs. 37.1 months; adjusted HR: 0.95, 95%CI (0.91–0.98)) and HR-negative groups (median OS 15.8 months vs. 14.1 months; adjusted HR: 0.92 95%CI (0.86–0.98)). The survival advantage was primarily observed in patients who received chemotherapy as their first line of treatment (HR 0.92 95%CI (0.88–0.96) vs. 0.99 95%CI (0.94–1.04), p-interaction = 0.04). In summary, HER2-low tumors, irrespective of hormone receptor status, have better survival than HER2-zero tumors in the de-novo metastatic setting. The survival advantage was primarily observed in patients who received chemotherapy in the first line.
Astragalus membranaceus Bunge is widely used in Traditional Chinese Medicine to treat various cancers. Astragaloside-IV (AS-IV) is one of the major compounds isolated from A. membranaceus Bunge and has been demonstrated to have antitumor effects by inhibiting cell proliferation, invasion and metastasis in various cancer types. Numerous studies have used in vitro cell culture and in vivo animal models of cancer to explore the antitumor activities of AS-IV.In the present study, the antitumor effects and mechanisms of AS-IV reported in studies recorded in the PubMed database were reviewed. First, the antitumor effects of AS-IV on proliferation, cell cycle, apoptosis, autophagy, invasion, migration, metastasis and epithelial-mesenchymal transition processes in cancer cells and the tumor microenvironment, including angiogenesis, tumor immunity and macrophage-related immune responses to cancer cells, were comprehensively discussed. Subsequently, the molecular mechanisms and related signaling pathways associated with antitumor effects of AS-IV as indicated by in vitro and in vivo studies were summarized, including the Wnt/AKT/GSK-3β (glycogen synthase kinase-3β)/β-catenin, TGF-β/PI3K/AKT/mTOR, PI3K/MAPK/mTOR, PI3K/AKT/NF-κB, Rac family small GTPase 1/RAS/MAPK/ERK, TNF-α/protein kinase C/ERK1/2-NF-κB and Tregs (T-regulatory cells)/IL-11/STAT3 signaling pathways. Of note, several novel mechanisms of Toll-like receptor 4 (TLR4)/NF-κB/STAT3, pSmad3C/3L, nuclear factor erythroid 2-related factor (NrF2)/heme oxygenase 1, circDLST/microRNA-489-3p/eukaryotic translation initiation factor 4A1 and macrophage-related high-mobility group box 1-TLR4 signaling pathways associated with the anticancer activity of AS-IV were also included. Finally, the limitations of current studies that must be addressed in future studies were pointed out to facilitate the establishment of AS-IV as a potent therapeutic drug in cancer treatment. Contents1. Introduction 2. Inhibitory effects of AS-IV on growth and proliferation of cancer cells 3. Inhibiting tumor growth by improving the TME, tumor immunity and immunotherapy and decreasing tumor angiogenesis 4. Antitumor mechanisms and related signaling pathways 5. Other novel anticancer mechanisms and related pathways 6. Conclusion and future perspectives
558 Background: The development of novel anti-HER2 drugs opens new treatment options, including women with lower expression of HER2. This study aimed to compare local/regional HER2-low and HER2-0 breast cancer outcomes in the real world. Methods: Women diagnosed between 2010 and 2017 with clinical stage I-III breast cancers with low HER2 expression or HER2-zero (0) expression were identified in the National Cancer Database (NCDB), a nationwide oncology outcomes database in the United States. HER2-Low was defined as IHC1+ or 2+/ISH negative, whereas HER2-zero was IHC-0. The primary outcome was overall survival (OS). We performed a multivariable Cox regression model to estimate hazard ratios and adjusted for the following factors: age, race/ethnicity, education, insurance, comorbidities, grade, stage, lymph nodes, type of surgery, the type of cancer center, and if any chemotherapy, any hormonal therapy, and any adjuvant radiation in the first treatment course. Stratification factors were hormone receptor status. Subgroup analyses for those who received neoadjuvant (NAC), adjuvant (AC), and no chemotherapy were performed, and the pathologic complete response (pCR) rates in NAC groups were estimated. Results: 376,199 (68%) women with HER2-low tumors and 177,298 (32%) with HER2-0 tumors were analyzed. 336,147 (89%) of the HER2-low tumors and 141,528 (79%) of the HER2-0 tumors were HR-positive. Low HER2 expression was associated with longer OS in both HR-positive (adjusted Hazard Ratio (aHR): 0.94, 95%CI 0.93-0.96, p<0.001) and HR-negative diseases (aHR: 0.88, 95%CI 0.85-0.91, p<0.001). HR-positive, HER2-low tumors had statistically significantly better survival than HR-positive, HER2-0 tumors in NAC (aHR 0.84, 95%CI 0.79-0.90, p<0.001) and AC (aHR 0.90, 95%CI 0.85-0.94, p<0.001) groups, but not in the no-chemo group (aHR 1.02, 95%CI 1.00-1.05, p=0.09, p interaction<0.001). In contrast, HR negative, HER2-low tumors had better OS than HR negative, HER2-0 tumors in all subgroups, regardless of receipt or timing of chemotherapy (NAC aHR 0.88, 95%CI 0.83-0.94, p<0.001, AC aHR 0.86, 95%CI 0.81-0.92, p<0.001, No chemo aHR 0.93, 95%CI 0.87-0.99, p=0.03, p interaction=0.06). In NAC groups, HER2-low expression was linked to lower pCR rates in both HR-positive (8.9% vs. 11.2%, p<0.001) and HR-negative (31.2% vs. 34.1%, p<0.001). Conclusions: Local/regional HER2-low breast cancer has better survival than HER2-0 breast cancer, irrespective of its hormone receptor status. The survival advantage was observed in HR-negative disease and only with receipt of chemotherapy in HR-positive breast cancer. Specific therapies, such as trastuzumab deruxtecan, have activity in HER2-low breast cancers, and other therapeutics for HER-2 low diseases should be sought.
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