Breast cancer is the most common cancer in the world, and 5-year survival rate of metastatic breast cancer is about 20%. The treatment of metastatic breast cancer is mainly chemotherapy, endocrine therapy and targeted therapy. However, after multiline treatment, patients with MBC especially the triple negative breast cancer face the problem of drug resistance. Tumor angiogenesis theory suggests that blocking angiogenesis can inhibit tumor growth and migration. Based on this, angiogenesis treatment strategy is proposed. Antiangiogenic drugs mainly include biological macromolecular drugs targeting vascular endothelial growth factor (VEGF) or vascular endothelial growth factor receptor (VEGFR) and small molecule VEGFR inhibitors. Angiogenesis is known to play a key role in the growth and metastasis of breast cancer. Therefore, anti-angiogenetic therapy has potential in metastatic breast cancer patients. Since the approval of tumor drug indications by NPMA in China is often later than the release of the latest research data, the National Health Commission issued "the guiding principles for the clinical application of new antitumor drugs" in 2020. The principle pointed out that under special circumstances such as the absence of better treatment, medical institutions should manage the usage of drugs that are not clearly defined in the instructions but have evidence-based data. Based on the latest research progress in breast cancer, the consensus writing expert group collated published reports, international academic conferences, conducted analysis, discussion and summary, collected data on the use of small molecule anti-vascular targeting drugs for advanced breast cancer, and formulated "expert consensus on the application of small molecule anti-angiogenic drugs in the treatment of advanced breast cancer" . For clinicians' reference only.
Angiogenesis Inhibitors/therapeutic use* ; Breast Neoplasms/pathology* ; Consensus ; Female ; Humans ; Neovascularization, Pathologic/pathology* ; Off-Label Use ; Vascular Endothelial Growth Factor A/metabolism*

Breast cancer,one of the common malignant tumors in women,has shown rising incidence in recent years,posing a serious threat to women's health.The advancement of molecular biology facilitates the revealing of the relationships between signaling pathways and breast cancer.Fibroblast growth factor receptor (FGFR) signaling pathway plays an important role in the proliferation,survival,differentiation,migration,and apoptosis of breast cancer cells.Strategies targeting the FGFR signaling pathway thus exhibit a promising prospect in breast cancer treatment.
Apoptosis ; Breast Neoplasms/metabolism* ; Female ; Humans ; Receptors, Fibroblast Growth Factor/metabolism* ; Signal Transduction

breast lesions and in predicting the biological characteristics of invasive breast cancer.MATERIALS AND METHODS: Between January 2016 and February 2019, this study included 368 women with 368 pathologically proven breast lesions, which appeared as poor-quality regions in the QM of SWE. To measure shear-wave velocity (SWV), seven regions of interest were placed in each lesion with and without QM guidance. Under QM guidance, poor-quality areas were avoided. Diagnostic performance was calculated for mean SWV (SWV(mean)), max SWV (SWV(max)), and standard deviation (SD) with QM guidance (SWV(mean) + QM, SWV(max) + QM, and SD + QM, respectively) and without QM guidance (SWV(mean) − QM, SWV(max) − QM, and SD − QM, respectively). For invasive cancers, the relationship between SWV findings and biological characteristics was investigated with and without QM guidance.RESULTS: Of the 368 women (mean age, 47 years; SD, 10.8 years) enrolled, 159 had benign breast lesions and 209 had malignant breast lesions. SWV(mean) + QM (3.6 ± 1.39 m/s) and SD + QM (1.02 ± 0.84) were significantly different from SWV(mean) − QM (3.29 ± 1.22 m/s) and SD − QM (1.46 ± 1.06), respectively (all p < 0.001). For differential diagnosis of breast lesions, the sensitivity and areas under the receiver operating characteristic curve (AUC) of SWV(mean) + QM (sensitivity: 89%; AUC: 0.932) were better than those of SWV(mean) − QM (sensitivity, 84.2%; AUC, 0.912) (all p < 0.05). There was no significant difference in sensitivity and specificity between SD + QM and SD − QM (all p = 1.000). Among the biological characteristics of invasive cancers, lymphovascular involvement, axillary lymph node metastasis, negative estrogen receptor status, negative progesterone receptor status, positive human epidermal growth factor receptor status, and aggressive molecular subtypes showed higher SWV(mean) + QM (all p < 0.05), while only lymphovascular involvement showed higher SWV(mean) − QM (p = 0.036).CONCLUSION: The use of QM in SWE might improve the diagnostic performance for breast lesions and facilitate prediction of the biological characteristics of invasive breast cancers.]]>
Area Under Curve ; Breast Neoplasms ; Breast ; Diagnosis ; Diagnosis, Differential ; Elasticity Imaging Techniques ; Estrogens ; Female ; Humans ; Lymph Nodes ; Neoplasm Metastasis ; Population Characteristics ; Receptor, Epidermal Growth Factor ; Receptors, Progesterone ; ROC Curve ; Sensitivity and Specificity ; Ultrasonography

OBJECTIVE: To examine the expressions of JMJD3, matrix metalloproteinase-2 (MMP-2) and vascular endothelial growth factor (VEGF) in invasive ductal breast carcinoma, their association with the clinicopathological features of the patients and the effect of JMJD3 overexpression on proliferation and MMP-2 and VEGF expressions in breast cancer cells. METHODS: The protein and mRNA expressions of JMJD3, MMP-2, and VEGF in invasive ductal breast carcinoma and paired adjacent tissues were detected by immunohistochemistry and RT-PCR, respectively, and their correlation with the clinicopathological characteristics of the patients was analyzed. Kaplan-Meier survival analysis was used to evaluate the correlation of JMJD3, MMP-2 and VEGF expression levels with the survival of the patients. In breast cancer MDA-MB-231 cells transfected with a JMJD3-expression plasmid, the expression of Ki67 was examined immunohistochemically, the cell proliferation was assessed with CCK8 assay, and the mRNA expressions of MMP-2 and VEGF were detected with RT-PCR. RESULTS: Breast cancer tissues had significantly lower JMJD3 expression and higher MMP-2 and VEGF expressions at both the mRNA and protein levels than the adjacent tissue ( CONCLUSIONS The expressions of JMJD3, MMP-2 and VEGF in invasive ductal breast carcinoma are closely correlated to tumor proliferation, invasion, metastasis and prognosis and can be used for prognostic evaluation of breast cancer.
Breast Neoplasms/genetics* ; Carcinoma, Ductal, Breast/genetics* ; Humans ; Jumonji Domain-Containing Histone Demethylases ; Lymphatic Metastasis ; Matrix Metalloproteinase 2 ; Prognosis ; Vascular Endothelial Growth Factor A

p90 ribosomal S6 kinase (p90RSK), one of the downstream effectors in ERK1/2 pathways, shows high expression in human breast cancer tissues. However, its role in breast cancer development and drug resistance is not fully understood. Here, we demonstrate that Cis-DDP treatment failed to increase cytotoxicity in MDA-MB-231 cells compared to MCF-7 cells and p90RSK activation was involved in Cis-DDP-resistance to MDA-MB-231 cells. In the study, we found that inhibition of p90RSK expression or activation using a small interfering RNA (siRNA) or dominant-negative kinase mutant (DN-p90RSK) plasmid overexpression increased Cis-DDP-induced cytotoxicity of MDA-MB-231 cells, respectively. Mechanistically, we found that Cis-DDP resistance was associated with up-regulation of epithelial growth factor (EGF) expression and EGF treatment induced cancer survival signaling pathway including activation of ERK1/2, p90RSK, and Akt. We also examined the expression of epithelial-mesenchymal transition (EMT)-associated proteins using a reverse transition-quantitative PCR analysis. Cis-DDP treatment induced EMT by increasing the expression levels of N-cadherin, Snail, and Twist, while decreasing the expression levels of E-cadherin. Furthermore, we examined the epithelial marker, Zonula occludens-1 (ZO-1) using immunofluorescence analysis and found that Cis-DDP-inhibited ZO-1 expression was recovered by p90RSK deactivated condition. Therefore, we conclude that Cis-DDP resistance is involved in EMT via regulating the EGF-mediated p90RSK signaling pathway in MDA-MB-231 cells.
Breast Neoplasms ; Cadherins ; Cisplatin ; Drug Resistance ; Epidermal Growth Factor ; Epithelial-Mesenchymal Transition ; Fluorescent Antibody Technique ; Humans ; MCF-7 Cells ; Phosphotransferases ; Plasmids ; Polymerase Chain Reaction ; Ribosomal Protein S6 Kinases, 90-kDa ; RNA, Small Interfering ; Snails ; Triple Negative Breast Neoplasms ; Up-Regulation

OBJECTIVES: Hypoxia—a characteristic of almost all types of solid tumors—has been associated with poor outcomes in several human malignancies. Genipin—an active constituent of Gardenia fruit— has been reported to exert an anti-tumor effect in several cancers. In this study, we investigated inhibition of angiogenesis using Genipin-mediated hypoxia-induced hypoxia inducible factor (HIF-1) and VEGF expression in human cervical cancer cells.METHODS: Under normoxic and hypoxic conditions, the expression of HIF-1α and VEGF in cervical cancer HeLa cells was detected by quantitative reverse transcription polymerase chain reaction and western blotting. Luciferase reporter assays were used to investigate the molecular mechanisms underlying the hypoxia-induced survivin activation.RESULTS: Surprisingly, we found that Genipin suppressed the HIF-1α accumulation during hypoxia in human liver cancer cell line (HepG2), human prostate cancer cell line (LNCaP), colon cancer cell line (HCT116), and breast cancer cell line (MDA231). Genipin treatment also significantly reduced hypoxia-induced secretion of VEGF.CONCLUSIONS: Suppression of HIF-1α accumulation following treatment with Genipin under hypoxia was associated with PI3K and MAPK pathways. Taken together, these results suggested that Genipin inhibits HIF-1α expression through inhibition of PI3K and MAPK signaling pathways. These results provide new insights into a potential mechanism of the anticancer properties of Genipin.
Anoxia ; Blotting, Western ; Breast Neoplasms ; Cell Line ; Colonic Neoplasms ; Gardenia ; HeLa Cells ; Humans ; Liver Neoplasms ; Luciferases ; Polymerase Chain Reaction ; Prostatic Neoplasms ; Reverse Transcription ; Uterine Cervical Neoplasms ; Vascular Endothelial Growth Factor A

OBJECTIVE: To compare digital breast tomosynthesis (DBT) and conventional full-field digital mammography (FFDM) in the detectability of breast cancers in patients with dense breast tissue, and to determine the influencing factors in the detection of breast cancers using the two techniques. MATERIALS AND METHODS: Three blinded radiologists independently graded cancer detectability of 300 breast cancers (288 women with dense breasts) on DBT and conventional FFDM images, retrospectively. Hormone status, histologic grade, T stage, and breast cancer subtype were recorded to identify factors affecting cancer detectability. The Wilcoxon signed-rank test was used to compare cancer detectability by DBT and conventional FFDM. Fisher's exact tests were used to determine differences in cancer characteristics between detectability groups. Kruskal-Wallis tests were used to determine whether the detectability score differed according to cancer characteristics. RESULTS: Forty breast cancers (13.3%) were detectable only with DBT; 191 (63.7%) breast cancers were detected with both FFDM and DBT, and 69 (23%) were not detected with either. Cancer detectability scores were significantly higher for DBT than for conventional FFDM (median score, 6; range, 0–6; p < 0.001). The DBT-only cancer group had more invasive lobular-type breast cancers (22.5%) than the other two groups (i.e., cancer detected on both types of image [both-detected group], 5.2%; cancer not detected on either type of image [both-non-detected group], 7.3%), and less detectability of ductal carcinoma in situ (5% vs. 16.8% [both-detected group] vs. 27.5% [both-non-detected group]). Low-grade cancers were more often detected in the DBT-only group than in the both-detected group (22.5% vs. 10%, p = 0.026). Human epidermal growth factor receptor-2 (HER-2)-negative cancers were more often detected in the DBT-only group than in the both-detected group (92.3% vs. 70.5%, p = 0.004). Cancers surrounded by mostly glandular tissue were detected less often in the DBT only group than in the both-non-detected group (10% vs. 31.9%, p = 0.016). DBT cancer detectability scores were significantly associated with cancer type (p = 0.012), histologic grade (p = 0.013), T and N stage (p = 0.001, p = 0.024), proportion of glandular tissue surrounding lesions (p = 0.013), and lesion type (p < 0.001). CONCLUSION: Invasive lobular, low-grade, or HER-2-negative cancer is more detectable with DBT than with conventional FFDM in patients with dense breasts, but cancers surrounded by mostly glandular tissue might be missed with both techniques.
Breast Neoplasms* ; Breast* ; Carcinoma, Intraductal, Noninfiltrating ; Epidermal Growth Factor ; Female ; Humans ; Mammography* ; Retrospective Studies

PURPOSE: The prevalence of PIK3CA in Chinese breast cancer patients may be underestimated. Therefore, we investigated the distribution of somatic PIK3CA/AKT1 mutations in Chinese breast cancer patients and explored their roles in tumor phenotypes and disease prognosis. MATERIALS AND METHODS: Tumors from 507 breast cancer patients were prospectively collected from the West China Hospital between 2008 and 2013. Whole exons of AKT1 and PIK3CA were detected in fresh-frozen tumors using next-generation sequencing, and correlations between PIK3CA/AKT1 mutations and clinicopathological features were analyzed. RESULTS: The AKT1 mutation was found in 3.6% (18/507) of patients. Tumors from patients that carried the AKT1 mutation were estrogen receptor (ER)+/progesterone receptor (PR)+/human epidermal growth factor receptor 2 (HER2)‒ and were more likely to have high expression levels of Ki67. The prevalence of the PIK3CA mutation was 46.5% (236/507), and 35 patients carried two or three variants of the PIK3CA gene. PIK3CA mutations were associated with ER+/PR+/HER2‒ status. The prognosis of patients with one mutation in PIK3CA (or PIK3CA/AKT1) was not significantly different than that of patients with wild-type PIK3CA (or PIK3CA/AKT1), while patients with two or three variants in PIK3CA (or PIK3CA/AKT1) exhibited poorer outcomes in the entire group and in all three subgroups (ER+, HER2‒, Ki67 high), particularly with respect to overall survival. CONCLUSION: A high frequency of somatic PIK3CA mutations was detected in Chinese breast cancer patients. In addition to the mutation frequency, the tumor mutational burden of the PIK3CA and AKT1 genes should also be of concern, as they may be associated with poor prognosis.
Asian Continental Ancestry Group* ; Breast Neoplasms* ; Breast* ; China ; Estrogens ; Exons ; Humans ; Mutation Rate ; Phenotype ; Prevalence* ; Prognosis ; Prospective Studies ; Receptor, Epidermal Growth Factor

PURPOSE: We investigated whether irinotecan plus capecitabine improved progression-free survival (PFS) compared with capecitabine alone in patients with human epidermal growth factor 2 (HER2) negative and anthracycline and taxane pretreated metastatic breast cancer (MBC). MATERIALS AND METHODS: A total of 221 patients were randomly assigned to irinotecan (80 mg/m2, days 1 and 8) and capecitabine (1,000 mg/m2 twice a day, days 1-14) or capecitabine alone (1,250 mg/m2 twice a day, days 1-14) every 3 weeks. The primary endpoint was PFS. RESULTS: There was no significant difference in PFS between the combination and monotherapy arm (median, 6.4 months vs. 4.7 months; hazard ratio [HR], 0.84; 95% confidence interval [CI], 0.63 to 1.11; p=0.84). In patients with triple-negative breast cancer (TNBC, n=90), the combination significantly improved PFS (median, 4.7 months vs. 2.5 months; HR, 0.58; 95% CI, 0.37 to 0.91; p=0.02). Objective response rate was numerically higher in the combination arm, though it failed to reach statistical significance (44.4% vs. 33.3%, p=0.30). Overall survival did not differ between arms (median, 20.4 months vs. 24.0 months; p=0.63). While grade 3 or 4 neutropenia was more common in the combination arm (39.6% vs. 9.0%), hand-foot syndrome was more often observed in capecitabine arm. Quality of life measurements in global health status was similar. However, patients in the combination arm showed significantly worse symptom scales especially in nausea/vomiting and diarrhea. CONCLUSION: Irinotecan plus capecitabine did not prove clinically superior to single-agent capecitabine in anthracycline- and taxane-pretreated HER2 negative MBC patients. Toxicity profiles of the two groups differed but were manageable. The role of added irinotecan in patients with TNBC remains to be elucidated.
Arm ; Breast Neoplasms* ; Breast* ; Capecitabine* ; Diarrhea ; Disease-Free Survival ; Epidermal Growth Factor ; Global Health ; Hand-Foot Syndrome ; Humans ; Neutropenia ; Quality of Life ; Triple Negative Breast Neoplasms ; Weights and Measures

PURPOSE: The purpose of this study was to evaluate the risk of central nervous system (CNS) failure in Korean patients with human epidermal growth factor receptor 2 (HER2)-enriched breast cancer treated with surgery followed by postoperative radiotherapy (RT). METHODS: A total of 749 patients from eight institutions were enrolled in this study. All of them underwent surgery followed by postoperative RT from 2003 to 2011; 246 (32.8%) received neoadjuvant chemotherapy and 649 (81.7%) received adjuvant chemotherapy. Adjuvant trastuzumab was administered to 386 patients (48.6%). RESULTS: The median follow-up duration was 84 (range, 8–171) months. The 7-year disease-free and overall survival rates were 79.0% and 84.2%, respectively. On multivariate analysis, mastectomy, nodal involvement, and presence of lymphatic invasion were correlated with poor overall survival (p = 0.004, 0.022, and 0.011, respectively), whereas T stage and lymphatic invasion were associated with disease-free survival (p = 0.018 and 0.005, respectively). Regarding CNS failures, 30 brain metastases, 2 leptomeningeal metastases, and 8 brain and leptomeningeal metastases were noted. The 7-year CNS relapse-free survival rates in patients receiving and not receiving trastuzumab were 91.2% and 96.9%, respectively (p = 0.005). On multivariate analysis, the administration of adjuvant trastuzumab was the only prognostic factor in predicting a higher CNS failure rate (hazard ratio, 2.260; 95% confidence interval, 1.076–4.746; p = 0.031). CONCLUSION: Adjuvant trastuzumab was associated with higher CNS failure rate in Korean patients with HER2-enriched breast cancer. Close monitoring and reasonable approaches such as CNS penetrating HER2 blockades combined with the current standard therapy could contribute to improving intracranial tumor control and quality of life in patients with CNS metastasis from HER2-enriched breast cancer.
Brain ; Breast Neoplasms ; Breast ; Central Nervous System Neoplasms ; Central Nervous System ; Chemotherapy, Adjuvant ; Disease-Free Survival ; Drug Therapy ; Follow-Up Studies ; Humans ; Mastectomy ; Multivariate Analysis ; Neoplasm Metastasis ; Quality of Life ; Radiation Oncology ; Radiotherapy ; Receptor, Epidermal Growth Factor ; Retrospective Studies ; Survival Rate ; Trastuzumab