Strategy and Status of Neoadjuvant Therapy for HER2-positive Breast Cancer / 肿瘤防治研究

Neoadjuvant therapy is a preoperative systemic treatment for patients with breast cancer. This therapy has greatly improved the clinical outcomes of human epidermal growth factor receptor 2 (HER2)-positive breast cancer, which is associated with poor prognosis. Currently, dual anti-HER2 antibodies, including trastuzumab and pertuzumab, combined with non-anthracycline chemotherapy is one of the standard regimens to achieve high pathologic complete response rate and satisfactory efficacy. The combination of trastuzumab with tyrosine kinase inhibitors, antibody-drug conjugate drugs, or immunotherapy combined with target therapy, under the indications of reasonable biomarkers, is effective for HER2-positive breast cancer. In this article, we briefly reviewed neoadjuvant therapy in the dual-targeting therapy era and discussed its future perspectives.

Efficacy and safety of tyrosine kinase inhibitors in the treatment of HER2-positive breast cancer：a meta-analysis / 中国药房

OBJECTIVE To evaluate the efficacy and safety of tyrosine kinase inhibitors （TKI） in the treatment of HER2- positive breast cancer in order to provide evidence-based evidence for clinical medication. METHODS Retrieved from CNKI， Wanfang database， VIP， PubMed， Cochrane Library， Embase and Web of Science， randomized controlled trial （RCT） about TKI （trial group） versus drugs excluding TKI （control group） in the treatment of HER2-positive breast cancer were collected from the establishment of the database to April 2023. Meta-analysis and sensitivity analysis were performed by using RevMan 5.4.1 and Stata 17 software. RESULTS Total of 24 RCT studies were included， involving 15 538 HER2-positive breast cancer patients. The meta- analysis results showed that compared with the control group， the progression-free survival （PFS） [HR＝0.91， 95%CI （0.80， 1.02）， P＝0.12]， overall survival （OS） [HR＝0.95， 95%CI （0.89， 1.01）， P＝0.11]， objective response rate （ORR） [OR＝1.21， 95%CI （0.86， 1.69）， P＝0.27]， and pathological complete response rate （pCR） [OR＝1.44， 95%CI （0.91， 2.27）， P＝0.12] had no statistically significant difference in the trial group； among the 3/4 grade ADRs， the trial group had a higher incidence of anemia [OR＝1.77， 95%CI （1.16，2.70）， P＝0.008]， rash [OR＝11.26， 95%CI （7.32，17.31）， P＜0.000 01]， paronychia [OR＝8.67， 95%CI（1.62，46.53）， P＝0.01]， diarrhea [OR＝10.17， 95%CI（5.03，20.58）， P＜0.000 01]， oral mucositis inflammation [OR＝ 9.34， 95%CI （3.13， 27.83）， P＜0.000 1]， elevated aspartate aminotransferase [OR＝2.09， 95%CI （1.13，3.84）， P＝0.02]， and hypokalemia [OR＝2.37， 95%CI （1.31，4.30）， P＝0.005] than that of the control group. Subgroup analysis results showed that compared with the placebo group， TKI could improve OS and ORR （P＜0.05）， while compared with trastuzumab， TKI had no advantage in PFS， OS， ORR， and pCR， and TKI combined with trastuzumab could significantly improve PFS， OS， ORR， and pCR compared with the trastuzumab group （P＜ 0.05）. Sensitivity analysis suggested that the results were relatively robust and the risk of publication bias was low. CONCLUSIONS Compared with trastuzumab， TKI has no advantages in PFS， OS， ORR and pCR in the treatment of HER2- positive breast cancer， but TKI combined with trastuzumab can significantly improve PFS， OS， ORR and pCR； TKI can increase the risk of grade 3/4 anemia， rash， paronychia， diarrhea， oral mucositis， elevated aspartate aminotransferase， and hypokalemia.

Cost-utility analysis of trastuzumab deruxtecan versus trastuzumab emtansine in the second-line treatment for HER2-positive metastatic breast cancer / 中国药房

OBJECTIVE To evaluate the cost-effectiveness of trastuzumab deruxtecan（T-DXd） versus trastuzumab emtansine （T-DM1） in the second-line treatment of HER2-positive metastatic breast cancer， and to provide a basis for the selection of clinical medication regimen and medical and health decisions. METHODS Based on the clinical trial DESTINY-Breast03， a partitioned survival model was constructed， with a cycle of 3 weeks as the simulation of patients’ lifetime. The incremental cost-effectiveness ratio （ICER） was calculated by using quality-adjusted life years （QALY） as output indicators， and sensitivity analysis was used to verify the robustness of the basic analysis results； the cost-effectiveness of the second-line treatment for HER2-positive metastatic breast cancer was compared between T-DXd and T-DM1. RESULTS Under the premise of taking 3 times China’s per capita gross domestic product （GDP） in 2022 as the willingness-to-pay threshold （257 094 yuan/QALY）， the T-DXd group also needed to pay more cost compared with T-DM1 group while obtaining incremental utility （0.69 QALYs）， and the ICER value was 1 850 478.40 yuan/QALY. The results of univariate sensitivity analysis showed that progression-free survival state utility value， T-DXd price， cost discount rate were factors that had a great influence on ICER value， but these parameters could not flip the basic analysis results within a reasonable range. In the probability sensitivity analysis， when the threshold of willingness-to-pay rose to 1 500 400 yuan/QALY， the probability of economic activity was 50% in the T-DXd regimen. The results of the scenario analysis also verified the robustness of the original research results. CONCLUSIONS Under the premise of 3 times China’s per capita GDP as the WTP threshold， compared with T-DM1， T-DXd is not cost-effective in the second-line treatment of HER2-positive metastatic breast cancer.

Construction of a column-line graph for predicting the probability of survival in early-stage elderly HER2-positive breast cancer based on the SEER database / 中国临床药理学与治疗学

AIM: To construct column-line plots to predict survival in elderly patients with early-stage HER2-positive breast cancer using the Surveillance, Epidemiology and End Results (SEER) database. METHODS: 5 220 (based on the era of single-targeted therapy) and 1 176 (based on the era of dual-targeted therapy) patients screened in the SEER database were randomized into a training group and an internal validation group. COX proportional risk regression was used to screen survival-related predictors and build a column-line graphical model, and the accuracy and utility of the model were tested using the consistency index (C-index), calibration curves, and time-dependent ROC curves. Patients receiving chemotherapy and non-chemotherapy were statistically paired using two-group propensity score matching, and subgroup analyses were performed on the screened variables. RESULTS: The single-targeted therapy era line graph was constructed from seven variables: age, marital status, T-stage, N-stage, surgery, chemotherapy, and radiotherapy. The dual-targeted therapy era line graph was constructed from five variables: age, AJCC staging, surgery, chemotherapy, and radiotherapy. The results of the subgroup analysis showed that older HER2-positive breast cancer patients who received chemotherapy had better OS. CONCLUSION: Based on the SEER database, an accurate column-line graph predicting survival in elderly patients with early-stage HER2-positive breast cancer was established and validated. This study suggests that chemotherapy increases survival benefit in elderly patients.

Advances in targeted therapy for HER2-positive breast cancer / 中国临床药理学与治疗学

Since the beginning of the 21st century, with the continuous development of anti-HER2-targeted drugs, more treatment options have been provided for patients with HER2-positive breast cancer and the survival prognosis has been significantly improved. At present, anti-HER2 targeted drugs mainly include monoclonal antibody drugs such as trastuzumab and pertuzumab, small molecule tyrosine kinase inhibitors such as lapatinib and neratinib, and antibody-drug conjugates such as TDM1 and T-DXd, which play an extremely important role in different disease processes. The treatment of HER2-positive breast cancer is based on targeted therapy with trastuzumab. Early-stage patients with high risk factors can be treated with intensive targeted therapy to further improve the prognosis, while advanced patients need a reasonable arrangement of targeted therapy to overcome drug resistance and prolong survival. This article will review the current status, the latest research progress and the future prospects of anti-HER2 targeted therapy in different stages of the disease.

Research progress of biomarkers related to the efficacy of HER2 positive breast cancer / 中国临床药理学与治疗学

Breast cancer is the most commonly diagnosed cancer and the main cause of cancer deaths among women worldwide. HER2 positive breast cancer accounts for 15% of all breast cancer. This subtype of breast cancer is highly invasive and has a very poor prognosis. With the development of anti - HER2 targeted therapy, the prognosis of these patients has been improved. However, some patients have poor response to the anti-HER2 therapy. Therefore, it is necessary to select biomarkers that can predict the therapeutic effect for improving the efficacy of these patients. This article describes the research progress of HER2 positive biomarkers for breast cancer, focusing on biomarkers related to the efficacy of targeted therapy, in order to provide some reference for future clinical optimization of targeted therapy.

Real-world Efficacy and Safety Comparison of Neoadjuvant Treatment of HER2-positive Breast Cancer with TCbHP Versus AC-THP / 肿瘤防治研究

Objective To compare the efficacy, safety, and survivability of TCbHP versus AC-THP in the neoadjuvant therapy of HER2-positive breast cancer in real-world. Methods Clinical data of patients with HER2 positive breast cancer, who have received TCbHP or AC-THP as neoadjuvant therapy and completed surgery in 11 third-class hospitals in various cities of Hebei Province, were retrospectively collected.The total pathological complete remission (tpCR) rate, the incidence of grade 3 or higher adverse reactions and the completion rate of the given approaches were compared. Results A total of 110 cases were collected, including 78 cases in the TCbHP group and 32 cases in the AC-THP group.The tpCR rate of the TCbHP group was higher than that of the AC-THP group, but the difference was not statistically significant (64.10% vs. 56.25%, P=0.441).No significant difference was found in the breast pathologic complete response (bpCR) and axillary pathologic complete response (apCR) rates between the TCbHP group and the AC-THP group (70.51% vs. 56.25%, P=0.150;78.21% vs. 84.38%, P=0.462).Exploratory analysis revealed that the tpCR rate of the TCbHP group was significantly higher than that of the AC-THP group in patients with HR-positive breast cancer (51.11% vs. 22.22%, P=0.036).As for the patients with HR-negative breast cancer, the tpCR rate of the AC-THP group tended to be higher than that of the TCbHP group (100% vs. 81.82%, P=0.088).The incidence of grade 3 or higher adverse reactions in the TCbHP group was slightly higher than that in the AC-THP group (12.82% vs. 9.38%, P=0.753).No deaths occurred in the whole group.Moreover, no significant difference was observed in the completion rate of the given approaches between the TCbHP group and the AC-THP group (92.31% vs. 90.63%, P=0.718). Conclusion In real-world clinical practice, the neoadjuvant therapy of TCbHP and AC-THP are effective, safe, and well tolerated among patients with HER2-positive breast cancer.The tpCR rate between the two approaches was not significantly different.The AC-THP regimen could also be considered as one of the optimal regimens for HER2-positive breast cancer in neoadjuvant therapy.

Characteristics and Research Progress of Traditional Chinese Medicine in Treatment of HER-2-Positive Breast Cancer： A Review / 中国实验方剂学杂志

Human epidermal growth factor receptor-2 （HER-2）-positive breast cancer has higher predilection to metastasize and invade other organs， leading to poor prognosis. The anti-HER-2 drugs， such as trastuzumab， pertuzumab， and trastuzumab emtansinehas， can remarkably prolong the disease free survival （DFS） of patients. However， frequent multidrug resistance， tumor recurrence and metastasis， and adverse reactions such as cardiotoxicity and gastrointestinal discomfort caused by adjuvant therapy are still challenges for the treatment of HER-2-positive breast cancer. The understanding of breast cancer in traditional Chinese medicine （TCM） has a long history. In thousands of years of inheritance and innovation， a standardized treatment system with TCM characteristics has been gradually formed， which shows unique advantages and significant curative effects in breast cancer treatment. The treatment principles of ''treatment based on syndrome differentiation''， ''treatment based on stages and types''， ''treatment according to individual conditions''， and ''treatment of different viscera and viscera based on the toxin and pathogen'' are closely related to the precise treatment concept. In view of the challenges in the treatment of HER-2-positive breast cancer， such as multidrug resistance， tumor recurrence and metastasis， cardiotoxicity， and gastrointestinal discomfort， this paper summarizes the characteristics of TCM in reversing the multidrug resistance， inhibiting tumor recurrence and metastasis， prolonging DFS， improving prognosis， reducing adverse reactions caused by adjuvant therapy， and improving the quality of life after breast cancer surgery according to the principles of reinforcing healthy Qi and eliminating pathogen， and treatment based on syndrome differentiation. This article is expected to serve as a reference for TCM treatment of HER-2 positive breast cancer.

Reform and Prospect of Systemic Therapy on HER2-positive Early-stage Breast Cancer / 肿瘤防治研究

In the past two decades, the survival of HER2-positive early-stage breast cancer patients has significantly improved with the development of HER2-targeted therapies. The focus has been placed on maximizing the clinical benefit of HER2-positive early-stage breast cancer by optimizing the treatment frameworks and therapeutic strategies in this field. In this paper, several important clinical studies of HER2-positive early-stage breast cancer in the neoadjuvant or adjuvant settings will be summarized and analyzed to provide clues for the development of personalized treatment strategies in the future.

Comparison of adverse effects of trastuzumab with other drug combinations for the treatment of breast cancer: A review

OBJECTIVES: This study compares the adverse effects (AEs) associated with trastuzumab in the treatment of human epidermal growth factor receptor 2-positive breast cancer (HER-2 + BC) when used alone or in combination with chemotherapy or with tyrosine kinase inhibitors, so as to aid in rational treatment choices. MATERIALS AND METHODS: An electronic search was conducted on PubMed using the Mesh terms ‘BC’, ‘HER-2 positive’, ‘metastasis BC, ‘trastuzumab’, and ‘safety’. Data from 32 studies regarding AEs were extracted and categorised as trastuzumab + chemotherapy (T+C), trastuzumab biosimilar (Tb), trastuzumab + tyrosine kinase inhibitors+ chemotherapy (T+TKi+C), and trastuzumab + tyrosine kinase inhibitors (T+TKi). The data are presented as the mean percentage of AEs. The statistical comparison was represented by a box and whisker plot of the interquartile range value of AEs. RESULTS: AEs related to the gastrointestinal tract, skin, nervous, blood, and lymph were reported to be the most common in T+C, T+TKi+C, and T+TKi. Nausea, vomiting, diarrhoea, constipation, neuropathy peripheral, alopecia, rash, anaemia, leucopenia, raised aspartate transaminase and alanine transaminase were the most common complaints. AEs such as myalgia, nasopharyngitis, hypertension, and ejection fraction decrease was reported to be the most common in Tb. CONCLUSION: This study concluded that biosimilar of trastuzumab is safest for the treatment of HER-2-positive BC. Cardiovascular disorder is often reported in the biosimilar group, but this group has fewer AEs reported as compared with chemotherapy, and tyrosine kinase inhibitors groups related to other systems such as digestive, nervous, and respiratory. The choice of combination is depending on the type of BC and the condition of the patients. The patients must monitor for cardiotoxicity when the biosimilar of trastuzumab is used.

Advances in immunotherapy for human epidermal growth factor receptor 2-positive breast cancer / 中华微生物学和免疫学杂志

Human epidermal growth factor receptor 2 (HER2)-targeted therapy has greatly improved the prognosis of HER2-positive breast cancer. HER2-targeted therapy combined with chemotherapy dominated by trastuzumab+ pertuzumab is important in the neoadjuvant therapy, postoperative adjuvant therapy and late-stage standard treatment for HER2-positive breast cancer. Antibody-drug conjugates (ADCs) and tyrosine kinase inhibitors (TKIs) have further improved the efficacy of therapy. However, advanced breast cancer will eventually get a recurrence or drug resistance. HER2-positive breast cancer is characterized by moderate immunogenicity with the presence of large tumor-infiltrating lymphocytes (TILs), which provides a theoretical basis for immunotherapy. The application of HER2-targeted cancer vaccines and immune checkpoint inhibitors is promising and would offer more treatment options for the patients.

Metformin inhibits proliferation and promotes apoptosis of HER-2 positive breast cancer cells possibly through the Hippo-YAP pathway / 南方医科大学学报

OBJECTIVE@#To investigate the effect of metformin on the proliferation and apoptosis of HER-2-positive breast cancer cell line SKBR3 and explore the possible mechanism of its action.@*METHODS@#SKBR3 cells were treated with different concentrations (20-120 μmol/L) of metformin, and the changes in cell proliferation and colony formation ability were assessed using CCK-8 assay and crystal violet staining, respectively. Flow cytometry was performed to analyze cell apoptosis and cell cycle changes. Real-time fluorescent quantitative PCR (qRT-PCR) was used to detect mRNA expressions of YAP, TAZ, EGFR, CTGF, CYR61, E-cadherin, N-cadherin, vimentin and fibronectin in the treated cells, and the protein expressions of YAP and TAZ were detected using Western blotting; immunofluorescence assay was used to observe YAP/TAZ nuclear translocation in the cells.@*RESULTS@#Metformin treatment significantly inhibited the proliferation of SKBR3 cells (P < 0.05) in a concentration- and time-dependent manner. The results of flow cytometry showed that metformin significantly promoted apoptosis and caused cell cycle arrest at G1 phase in SKBR3 cells. Metformin treatment significantly down-regulated the mRNA expressions of YAP, TAZ, EGFR, CTGF and CYR61, N-cadherin, vimentin and fibronectin (P < 0.05) and up-regulated the expression of E-cadherin (P < 0.05); Western blotting results showed that YAP and TAZ protein expressions were significantly down-regulated in the cells after metformin treatment (P < 0.05). Immunofluorescence assay revealed that metformin treatment caused the concentration of YAP and TAZ in the cytoplasm, and significantly reduced their amount in the cell nucleus.@*CONCLUSION@#Metformin can inhibit proliferation and promote apoptosis and epithelal-mesenchymal transition of HER-2 positive breast cancer cells possibly by that inhibing YAP and TAZ expression and their nuclear localization.

Cost-effectiveness analysis of Ado-trastuzumab emtansine for the treatment of residual invasive HER2-positive breast cancer

ABSTRACT Objective Human epidermal growth factor receptor 2 (HER2) overexpression occurs in up to 30% of breast cancer cases. Ado-trastuzumab emtansine (T-DM1) is approved to treat residual HER2-positive breast cancer after neoadjuvant therapy. The aim of this study was to determine the quality-adjusted time with symptoms or toxicity and without symptoms or toxicity (Q-TWiST) of T-DM1 compared to trastuzumab for residual invasive HER2-positive breast cancer. Methods The authors developed an analytical model extracting individual patient data and estimated invasive disease-free survival and overall survival over a 30-year time horizon. Only direct costs from adjuvant treatment were considered as well as relapse treatment from Brazilian and American payer perspectives. Heart events were considered for utility and cost analysis. Results The 30-year projection utilizing the Weibull method estimated a mean invasive disease-free survival of 16.4 years for T-DM1 and 10.4 for Trastuzumab, in addition to a mean overall survival of 18.1 and 15.4 years, respectively. We determined a Q-TWiST gain of 3,812 years for the T-DM1 arm when compared to trastuzumab and an Incremental cost-effectiveness ratio per Q-TWiST of US$ 11,467.65 in the United States and US$ 3,332.73 in Brazil. Conclusion Ado-trastuzumab emtansine is cost-effective from both Brazilian and American perspectives.

Expression and clinical significance of KIF20A in HER2-positive breast cancer / 国际生物医学工程杂志

Objective:To explore the expression and clinical significance of KIF20A in HER2-positive breast cancer.Methods:The clinicopathological characteristics of 82 cases of HER2-positive breast cancer were retrospectively analyzed. The expression of KIF20A in tissues was detected by immunohistochemical method, and the expression of KIF20A in HER2 overexpression breast cancer and its relationship with clinicopathological characteristics were analyzed. The mRNA level of KIF20A in HER2-positive breast cancer tissues and normal tissues adjacent to cancer were analyzed by bioinformatics methods.Results:The positive expression of KIF20A was in the nucleus, forming brown-yellow particles. In HER2-positive breast cancer tissues, the positive high expression rate of KIF20A is 57.3%, while it is mainly low or no expression in the adjacent tissues. The high expression of KIF20A is significantly correlated with tumor size and pTNM stage, while the correlation with age and tumor grade is not statistically significant. The results of bioinformatics analysis suggest that the high expression of KIF20A in invasive breast cancer is significantly related to poor disease-free survival.Conclusions:KIF20A is abnormally expressed in HER2-positive breast cancer, which is related to the tumor grade and pTNM stage of HER2 overexpression breast cancer, and the high expression of KIF20A indicates a poor prognosis.

Anti-HER2 Antibodies In Combination With Chemotherapy Or Chemotherapy-Free Regimens Targeting Her2-Positive Breast Cancer: A Systematic Review

@#Breast cancer is the leading cause of cancer-related death in female worldwide. Human epidermal growth factor receptor 2 (HER2) amplification is observed in approximately 20% of breast cancer cases and is associated with poor clinical outcomes. Dual HER2 blockade without chemotherapy represents an attractive therapeutic approach, and it remains unresolved if anti-HER2 therapeutic antibodies are sufficient to replace chemotherapy regimens. In this review, we discuss the approved therapeutic monoclonal antibodies (pertuzumab and trastuzumab) and antibody-drug conjugate (trastuzumab emtansine or T-DM1) for the treatment of HER2-positive breast cancer patients. In summary, phase II and III clinical trials have demonstrated that dual HER2 blockade (pertuzumab and trastuzumab) plus chemotherapy regimens confer better efficacy compared with dual HER2 blockade alone, or anti-HER2 antibody monotherapy, in HER2-positive breast cancer patients. Dual HER2 blockade (pertuzumab and trastuzumab) combined with chemotherapies (5-fluorouracil, epirubicin, cyclophosphamide and docetaxel) yield superior response. Moreover, dual HER2 blockade (T-DM1 and pertuzumab) in combination with docetaxel represents a promising treatment regimen containing T-DM1. Ongoing clinical trials are assessing the optimal chemotherapy of choice with anti-HER2 antibodies combinations. In conclusion, improved outcomes are attributable to selection for the optimal chemotherapy regimen in combination with anti-HER2 antibodies instead of replacing chemotherapy altogether with the current line of anti-HER2 therapeutic antibodies.

Research progress of targeted therapy for HER2 positive breast cancer with brain metastases / 医学研究生学报

Breast Cancer, nowadays, is the malignant tumor with the highest incidencein females.HER2 Positive Breast Canceraccounts for 20%-25% of the total, among which about 34% of patients with this type will occur brain metastasis.HER2 Positive Breast Cancer patients with brain metastasis, which seriously affects the quality of life, has a poor prognosis. Currently, surgery or radiotherapy is still the main treatment for brain metastasis. However, surgery is only applicable in localized brain metastasis, and it is obviously that terminaladverse reaction such as cognitive impairment can be causedby radiotherapy. Therefore, it is particularly important to discovery effective targeted drugs or new drug delivery methods for brain metastasis.This articlewill review the research progress of targeted therapy for brain metastases in HER2positive breast cancer.

Evaluation value of the MRI parameter and immunohistochemistry in the neoadj uvant chemotherapy for HER-2 positive breast cancer / 实用放射学杂志

Objective To explore the evaluation value of MRI parameters and immunohistochemistry in the neoadjuvant chemotherapy (NAC)for the HER-2 positive breast cancer.Methods 7 6 patients with locally advanced HER-2 positive breast cancer were analyzed retrospectively.According to the postoperative pathology,patients were divided into pathological complete response (PCR)group and non-PCR (Non-PCR)group.First,univariate and multivariate Logistic regression analysis were used to analyze the predictors of PCR,and then we assessed the evaluation value of the assessment model which was built on multivariate logistic regression.Results Univariate regression analysis showed that menstrual status,ER expression,K-i 67 expression,ADC value,tumor diameter, ΔADC%(NAC2－NAC0),ΔD%(NAC0－NAC2) had predictive value for PCR;the parameters ΔADC% and ΔD%,the expression of ER and K-i 67 were independent predictors of PCR based on multivariate Logistic regression analysis.The AUC of the assessment model model was 0.873.Conclusion Based on the heterogeneity of breast cancer,combine MRI with immunohistochemistry parameters could improve the prediction in the middle of NAC,and provide imaging basis for the adj ustment of follow-up chemotherapy regimen.

Growth differentiation factor 15 plays a role in predicting and monitoring the cardiotoxicity of epirubicin/cyclophosphamide-docetaxel-trastuzumab in the treatment of patients with HER-2 positive breast cancer / 实用肿瘤学杂志

Objective The aim of current study was to evaluate the effect of growth differentiation factor 15( GDF-15) on predicting and monitoring the cardiotoxicity of epirubicin/cyclophosphamide-docetaxel-trastuzumab(EC-D-T)in the treatment of HER-2 positive breast cancer patients. Methods Seventy-three patients with HER-2 positive breast cancer who received EC-D-T adjuvant therapy were enrolled. Serum levels of GDF-15,cardiac troponin I(cTnl)and amino terminal brain natriuretic peptide precursor(NT-proBNP)were measured before adjuvant therapy(M0)and after adjuvant therapy at 3 months(M3 ),6 months(M6 ),9 months(M9 ),12 months(M12 )and 15 months(M15 ). At the same time,patients underwent echocardiography at various time points to assess the left ventricular ejection fraction(LVEF). The cardiotoxicity of this study was defined as:(1)LVEF level decreased by ≥10% after treatment and the absolute value of LVEF was below 53% (normal);(2) heart failure,acute coronary syndrome or severe life-threatening heart rate abnormal. Results After initiation of EC-D-T treatment,the level of LVEF gradually decreased. Dur-ing the whole study,a total of 21(28. 8% )patients developed cardiotoxicity. At the same time,patients with cardiotoxicity had signifi-cantly higher levels of GDF-15 at M0 and cTn1 at various time points than those without cardiotoxicity. The level of ProBNP was comparable to those without cardiotoxicity. In addition,Univariate logistic regression analysis showed that baseline GDF-15 might af-fect the risk of cardiotoxicity. Multivariate logistic regression analysis showed that only cTnl level was an independent predictor for the risk of cardiotoxicity, while NT-proBNP level did not predict the risk of cardiotoxicity. Conclusion The incidence of cardiotoxicity in patients with HER-2 positive breast cancer after receiving EC-D-T is high,and GDF-15 can predict and monitor the risk of cardiotoxicity.

Analysis and validation of PI3K/AKT signaling pathway associated with overall survival time of patients with HER2-positive breast cancer / 解放军医学杂志

Objective To analyze and validate the key molecular targets correlated with the overall survival of patients with HER2-positive breast cancer.Methods First,the survival time and transcriptome data of patients with HER2-positive breast cancer in stage Ⅰ / Ⅱ and Ⅲ/Ⅳ were downloaded from the TCGA database.The significantly differential genes between overall survival ＜2 years and ＞8.5 years in stage Ⅰ / Ⅱ were picked out by edgeR package,and the pathways were enriched by KEGG.Similarly,the differential genes between overall survival ＜2 years and ＞7 years in stage Ⅲ/Ⅳ were analyzed.Furthermore,KEGG pathway analysis was performed using the differential genes overlapped by stage Ⅰ /Ⅱ and Ⅲ/Ⅳ.Second,the relationships between the expression levels of key node genes and other genes in enriched pathway and the overall survival of patients with HER2-positive breast cancer were validated by KMplot database.Last,the correlation between the activity of pathway enriched in KEGG and the resistance to anti-HER2 treatment was validated in HER2-positive breast cancer cell line BT474.Results In patients with stage Ⅰ / Ⅱ HER2-positive breast cancer whose overall survival was ＜2 years,PI3K/AKT was the 9th signaling pathway enriched by up-regulated differential genes.In patients with stage Ⅲ/Ⅳ whose overall survival was ＜2 years,PI3K/AKT was the 2nd signaling pathway enriched by up-regulated differential genes.Furthermore,PI3K/AKT was the first signal pathway enriched by the overlapping upregulated genes of patients in stage Ⅰ / Ⅱ and Ⅲ / Ⅳ whose overall survival was ＜2 years.Patients with high expression of PI3K and AKT (key node genes) or CFAP221 and COL4A6 (other genes) of PI3K/AKT pathway had shorter overall survival than those with low expression.PI3K inhibitors could enhance the growth inhibitory effect of HER2 small molecule inhibitor on HER2-positive breast cancer cell line BT474.Conclusions The overexpression of PI3K/AKT pathway is associated with the shorter overall survival in HER2-positive breast cancer patients,and associated with anti-HER2 resistance in HER2-positive breast cancer cell line.

The inhibitory effect and molecular mechanism of delphindin on HER-2 positive breast cancer / 天津医药

@#Objective To investigate the inhibitory effect and molecular mechanism of delphinidin (Dp) on HER-2 positive breast cancer. Methods The HER-2 positive breast cancer cells (MDA-MB-453 and BT-474) were treated with different concentrations of delphinidin (10，20，40，80 and 160 μmol/L) for 48 hours. The same concentration of DMSO was used as the solvent control. CCK-8 method was used to measure the effect of Dp on cell activity, and half maximal inhibitory concentration (IC50) was calculated to determine the concentration of subsequent experiments. The cells were treated with different concentrations of Dp (20, 40 and 80 μmol/L) for 48 hours. HE staining was used to observe the cell morphological changes. Flow cytometry was used to analyze the cell cycle. Cell apoptosis rate was detected by TUNEL assay. The phosphorylation levels of NF - κB signaling pathway related proteins were determined by Western blot assay. Results Delphinidin inhibited the proliferation of MDA-MB-453 and BT-474 in the concentration ranges of 10，20，40，80 and 160 μmol/L (IC50: 41.02 and 60.97 μmol/L). In the concentrations of 20，40 and 80 μmol/L, compared with the control group, it was found that some cells were detached, floated and lysed, and the cell volume was decreased, the proportion of cells in G2/ M phase and the apoptosis rate were increased in DP treatment groups. Compared with the control group, the expression levels of p-NF-κB/p65, p-IκBα, p-IKKα/β and p-PKCα were significantly decreased in the 40 and 80 μmol/L Dp treatment groups, while the expression levels of IκBα, IKKα, IKKβ and PKCα were increased in the Dp treatment groups (P＜0.05). Conclusion Delphinine can inhibit the proliferation of breast cancer cells by blocking the NF-κB signaling pathway and inducing the G2/M cycle arrest and apoptosis of MDA-MB-453 and BT-474 cells. Key words：receptor, epidermal growth factor; antineoplastic agents, phytogenic; breast neoplasms; cell cycle; delphinidin;HER-2 positive breast cancer; NF-κB signaling pathway