Objective:To explore the impact of the stimulator of interferon genes(STING)-interferon regulatory factor 3(IRF3)pathway on the senescence of rapid pacing HL-1 myocytes.Methods:HL-1 cells were divided into five groups: the control group(HL-1 cells without any treatment), pacing group(HL-1 cells paced for 48 hours), STING siRNA group(HL-1 cells paced for 48 hours and transfected with STING siRNA), NC siRNA group(HL-1 cells paced for 48 hours and transfected with NC siRNA), and H151 inhibitor group(HL-1 cells paced for 48 hours with the addition of 1 μmol/L STING inhibitor H151). Mitochondrial membrane potential was assessed in control and pacing group cells, and mitochondrial MitoTracker and TFAM co-localization staining was performed on these cells.Cellular senescence was evaluated using β-galactosidase staining in each group, and the positive rate of cellular senescence was observed and calculated.Western blotting was employed to detect the expression levels of STING, IRF3, P-IRF3, P16, P21, and P53 proteins in all groups.Immunofluorescence was utilized to examine the expression distribution of STING and P21 across the various groups.ELISA was performed to measure the concentrations of interleukin(IL)-1β, IL-6, and IL-8 in the cell supernatants from each group as part of the senescence-associated secretory phenotype(SASP).Results:Compared with the control group, the ratio of mitochondrial JC-1 multimer to monomer was significantly decreased in the pacing group( t=16.42, P<0.05), the co-localization of mitochondrial MitoTracker and TFAM in the cells was significantly weakened, the proportion of cells with positive cellular senescence-associated β-galactosidase staining significantly increased in the pacing group, the expression levels of STING, P-IRF3/IRF3, P16, P21, and P53 proteins were significantly elevated in the pacing group, and the concentrations of IL-1β, IL-6, and IL-8 in the cell supernatants were markedly increased.Compared with the pacing group, the proportion of cells with positive cellular senescence-associated β-galactosidase staining decreased in the STING siRNA group and H151 inhibitor group ( F= 18.13, P<0.05), the expression levels of STING, P-IRF3/IRF3, P16, P21, and P53 were reduced in the STING siRNA group and H151 inhibitor group ( F=16.84, 26.56, 74.70, 31.80, 31.23, all P<0.05), and the concentrations of IL-1β, IL-6, and IL-8 in the cell supernatants decreased( F=197.80、1 339.00、1 308.00, all P<0.001). Conclusions:Rapid pacing of HL-1 cells can promote mtDNA release into the cytoplasm, activate the STING-IRF3 pathway, accelerate cellular senescence, and enhance the secretion of SASP.Inhibiting the expression of STING can delay the senescence induced by the rapid pacing of HL-1 cells and reduce SASP secretion.

Objective:To explore the impact of the stimulator of interferon genes(STING)-interferon regulatory factor 3(IRF3)pathway on the senescence of rapid pacing HL-1 myocytes.Methods:HL-1 cells were divided into five groups: the control group(HL-1 cells without any treatment), pacing group(HL-1 cells paced for 48 hours), STING siRNA group(HL-1 cells paced for 48 hours and transfected with STING siRNA), NC siRNA group(HL-1 cells paced for 48 hours and transfected with NC siRNA), and H151 inhibitor group(HL-1 cells paced for 48 hours with the addition of 1 μmol/L STING inhibitor H151). Mitochondrial membrane potential was assessed in control and pacing group cells, and mitochondrial MitoTracker and TFAM co-localization staining was performed on these cells.Cellular senescence was evaluated using β-galactosidase staining in each group, and the positive rate of cellular senescence was observed and calculated.Western blotting was employed to detect the expression levels of STING, IRF3, P-IRF3, P16, P21, and P53 proteins in all groups.Immunofluorescence was utilized to examine the expression distribution of STING and P21 across the various groups.ELISA was performed to measure the concentrations of interleukin(IL)-1β, IL-6, and IL-8 in the cell supernatants from each group as part of the senescence-associated secretory phenotype(SASP).Results:Compared with the control group, the ratio of mitochondrial JC-1 multimer to monomer was significantly decreased in the pacing group( t=16.42, P<0.05), the co-localization of mitochondrial MitoTracker and TFAM in the cells was significantly weakened, the proportion of cells with positive cellular senescence-associated β-galactosidase staining significantly increased in the pacing group, the expression levels of STING, P-IRF3/IRF3, P16, P21, and P53 proteins were significantly elevated in the pacing group, and the concentrations of IL-1β, IL-6, and IL-8 in the cell supernatants were markedly increased.Compared with the pacing group, the proportion of cells with positive cellular senescence-associated β-galactosidase staining decreased in the STING siRNA group and H151 inhibitor group ( F= 18.13, P<0.05), the expression levels of STING, P-IRF3/IRF3, P16, P21, and P53 were reduced in the STING siRNA group and H151 inhibitor group ( F=16.84, 26.56, 74.70, 31.80, 31.23, all P<0.05), and the concentrations of IL-1β, IL-6, and IL-8 in the cell supernatants decreased( F=197.80、1 339.00、1 308.00, all P<0.001). Conclusions:Rapid pacing of HL-1 cells can promote mtDNA release into the cytoplasm, activate the STING-IRF3 pathway, accelerate cellular senescence, and enhance the secretion of SASP.Inhibiting the expression of STING can delay the senescence induced by the rapid pacing of HL-1 cells and reduce SASP secretion.

BACKGROUND: Pertuzumab has been approved for application in China by the National Medical Products Administration, and both national and international guidelines make recommendations for the use of neoadjuvant treatment with trastuzumab or trastuzumab + pertuzumab plus chemotherapy regimens for patients with indications. The goal of this study was to investigate the short-term clinical efficacy of the neoadjuvant therapies trastuzumab and trastuzumab+pertuzumab for patients with early human epidermal growth factor receptor 2 (HER2)-positive breast cancer in China. METHODS: A real-world study was conducted using the clinicopathological data of patients with early HER2-positive breast cancer who were admitted to the member hospitals of the Chinese Society of Breast Surgery, Chinese Surgical Society of Chinese Medical Association between March 2019 and December 2020. This study analyzed the efficacy and tolerance of trastuzumab+chemotherapy and trastuzumab+pertuzumab+chemotherapy in patients with early HER2-positive breast cancer. The Response Evaluation Criteria in Solid Tumors 1.1 was adopted to evaluate clinical efficacy. The pathological efficacy was evaluated using the MillerPayne grade. The Common Terminology Criteria for Adverse Events (version 5.0) was adopted to evaluate adverse events (AEs). The propensity scores were subjected to propensity score matching using the R language (1:1 matching with a maximum allowable difference of 0.05 between the two groups). Efficacy was compared using the chi-square test, and correlation analysis was performed using linear regression. RESULTS: A total of 1032 patients with early HER2-positive breast cancer met the enrollment criteria and were included in this study. Among these patients, 472 received neoadjuvant trastuzumab+chemotherapy (the trastuzumab group), and 560 received neoadjuvant trastuzumab+pertuzumab+chemotherapy (the trastuzumab+pertuzumab group). The overall pathologic complete response (pCR) rate was 47.2% (487/1032), while the pCR rates of the trastuzumab and trastuzumab+pertuzumab groups were 34.5% (163/472) and 57.9% (324/560), respectively, and the difference was significant (P < 0.001). The incidence of grade 4 AEs was 24/321 (7.5%) in the trastuzumab+pertuzumab group, and there were no cases in which the left ventricular ejection fraction decreased by more than 10%. CONCLUSIONS Patients in the trastuzumab+pertuzumab group had a higher pCR rate than those in the trastuzumab group, and the toxic side effects were tolerable.
Humans ; Female ; Breast Neoplasms/metabolism* ; Neoadjuvant Therapy ; Stroke Volume ; Ventricular Function, Left ; Receptor, ErbB-2/metabolism* ; Trastuzumab/therapeutic use* ; Antineoplastic Combined Chemotherapy Protocols/therapeutic use*

Objective:To explore the feasibility of predicting axillary lymph node metastasis of breast cancer using radiomics analysis based on dynamic contrast-enhanced (DCE) MRI.Methods:The retrospective study enrolled 163 patients (163 lesions) with breast cancer diagnosed by core needle biopsy from January 2013 to December 2013 in Peking University First Hospital. The status of axillary lymph nodes in all patients was pathologically confirmed, and they had complete preoperative breast MRI images. Among the 163 patients, 94 patients were confirmed with axillary lymph node metastasis, and 69 patients without axillary lymph node metastasis. They were randomly divided into the training dataset ( n=115) and testing dataset ( n=48) in a 7∶3 ratio. The radiomics analysis was performed in the training dataset, including image preprocessing and labeling, radiomics feature extraction, radiomics model establishment and model predictive performance inspection. Model performance was tested in the testing dataset. Receiver operating characteristic curve and area under curve (AUC) was used to analyze the model prediction performance. Results:Of the 1 075 features extracted from the training dataset, principal component analyses (PCA) features 8, 41 and 67 were selected by random forest classifier. The radiomics model including 3 PCA features reached an AUC of 0.956 (95%CI 0.907-0.988), with sensitivity of 91.2%, specificity of 100% and accuracy of 94.8%. In the testing dataset, the radiomics model including 3 PCA features reached an AUC of 0.767 (95%CI 0.652-0.890), with sensitivity of 80.8%, specificity of 72.7% and accuracy of 77.1%.Conclusion:It is feasible to predict axillary lymph node metastasis using radiomics features based on DCE-MRI of breast cancer.

Objective:To explore the feasibility of classification between carcinoma in situ and invasive carcinoma of breast using intratumoral and peritumoral radiomics based on breast dynamic contrast-enhanced (DCE) MRI.Methods:The retrospective study included consecutive invasive breast carcinoma pathological diagnosed by core needle biopsy or surgery from January 2013 to December 2013 and carcinoma in situ of breast diagnosed by surgery from January 2013 to December 2015 in Peking University First Hospital. All patients had pretreatment breast MRI images. A total of 251 cases (251 lesions) were included, with 208 invasive breast carcinoma and 43 carcinoma in situ of breast. They were all females and median age was 53 (23-82) years old. Patients were randomly divided into the training ( n=176) and testing dataset ( n=75) in a 7∶3 ratio. In the training dataset, combined with DCE mask and early enhancement images, intratumoral and peritumoral area were semi-automatic segmentation, and radiomics features were extracted and dimension reduction, finally a prediction model was established. Model performance was tested in the testing dataset. Receiver operating characteristic (ROC) curve and area under curve (AUC) were used to analyze the model prediction performance. Results:The prediction models established by intratumoral, peritumoral and intratumoral combined with peritumoral radiomics had good performance. The AUC of intratumoral, peritumoral and intratumoral combined with peritumoral radiomics prediction models in differentiating breast carcinoma in situ and invasive carcinoma were 0.865, 0.896 and 0.922 in the testing dataset, there was no significant difference in pairwise comparisons ( P>0.05). The sensitivity of intratumoral, peritumoral and intratumoral combined with peritumoral radiomics prediction models were 77.4%, 87.1%, 83.9%, the specificity were 92.3%, 84.6%, 100%, and the accuracy were 80.0%, 85.3%, 86.7%. Conclusion:It is potential feasible for classification between carcinoma in situ and invasive carcinoma of breast using intratumoral and peritumoral radiomics based on breast DCE MRI.

Objective:To examine the efficacy of docetaxel, carboplatin plus trastuzumab regimen (TCH) as neoadjuvant setting in early-stage human epidermal growth factor receptor 2 (HER2) positive breast cancer.Methods:Totally 522 patients diagnosed with early-stage HER2 positive breast cancer at Breast Disease Center, Peking University First Hospital between January 2013 to December 2018 were enrolled, which constituted 21.8% (522/2 394) of early-stage invasive breast cancer. Clinical pathological factors were retrospectively analyzed. There were 113 female patients underwent TCH neoadjuvant chemotherapy, aging 52(13) years (range: 23 to 69 years). Pathologic complete pathological response(pCR) was defined as ypT0N0M0, and the rate of pCR was calculated. Kaplan-Meier method and Log-rank test were used for survival comparison.Results:Patients who received trastuzumab-based therapy( n=294) had higher disease-free survival (DFS) compared with those who omitted trastuzumab( n=177) (84.4% vs. 72.4%, χ2=4.095, P=0.046). Eighteen of 113 patients (15.9%) experienced grade 3 to 4 chemotherapy-realted toxicity. Grade 3 to 4 neutropenia occurred in 12 patients, while grade 3 to 4 diarrhea occurred in 6 patients. Thirty-one of 113 (27.4%) patients achieved pCR. DFS and overall survival (OS) were similar between patients who achieved pCR and non-pCR (DFS: 91.8% vs. 85.0%, OS: 92.5% vs. 90.5%, all P>0.05). According to Miller-Payne system, patients who achieved G4 to G5 had improved DFS compared with G1 to G3 (89.6% vs. 81.5%, χ2=5.340, P=0.021), but they had similar OS (91.4% vs. 89.1%, χ2=1.008, P=0.315). Conclusions:TCH is an effective regimen in neoadjuvant setting for patients with HER2 positive breast cancer. Patients who achieved G4 to G5 had improved DFS.

Objective:To examine the efficacy of docetaxel, carboplatin plus trastuzumab regimen (TCH) as neoadjuvant setting in early-stage human epidermal growth factor receptor 2 (HER2) positive breast cancer.Methods:Totally 522 patients diagnosed with early-stage HER2 positive breast cancer at Breast Disease Center, Peking University First Hospital between January 2013 to December 2018 were enrolled, which constituted 21.8% (522/2 394) of early-stage invasive breast cancer. Clinical pathological factors were retrospectively analyzed. There were 113 female patients underwent TCH neoadjuvant chemotherapy, aging 52(13) years (range: 23 to 69 years). Pathologic complete pathological response(pCR) was defined as ypT0N0M0, and the rate of pCR was calculated. Kaplan-Meier method and Log-rank test were used for survival comparison.Results:Patients who received trastuzumab-based therapy( n=294) had higher disease-free survival (DFS) compared with those who omitted trastuzumab( n=177) (84.4% vs. 72.4%, χ2=4.095, P=0.046). Eighteen of 113 patients (15.9%) experienced grade 3 to 4 chemotherapy-realted toxicity. Grade 3 to 4 neutropenia occurred in 12 patients, while grade 3 to 4 diarrhea occurred in 6 patients. Thirty-one of 113 (27.4%) patients achieved pCR. DFS and overall survival (OS) were similar between patients who achieved pCR and non-pCR (DFS: 91.8% vs. 85.0%, OS: 92.5% vs. 90.5%, all P>0.05). According to Miller-Payne system, patients who achieved G4 to G5 had improved DFS compared with G1 to G3 (89.6% vs. 81.5%, χ2=5.340, P=0.021), but they had similar OS (91.4% vs. 89.1%, χ2=1.008, P=0.315). Conclusions:TCH is an effective regimen in neoadjuvant setting for patients with HER2 positive breast cancer. Patients who achieved G4 to G5 had improved DFS.

Objective:The incidence of breast cancer in Chinese women continues to rise. The large breast cancer cohort studies in China are relatively scarce. There are many bottlenecks in the construction of large clinical cohort for breast cancer diagnosis, treatment, and prognoses, such as inconsistent standards, high rates of lost follow-up, repeated construction, and inability to share. To better solving the difficulties and problems faced by large-scale clinical cohort research in China, this project will cooperate with several tertiary A hospitals to establish a breast cancer cohort in Chinese women. It also provides a data platform and technical support for breast cancer multi-center clinical cohort research.Methods:Based on the evidence-based medicine and expert opinion and consensus, we established a breast cancer cohort standardized indicator set-recording baseline information, diagnosis and treatment-related information of the enrolled patients, and collecting biological specimens. According to the technical specification of long-term follow-up for the endpoint, data management, and data security and in the large population-based cohort study, a standardized follow-up system for the diagnosis, treatment, and prognosis of breast cancer prospective cohorts is formed.Results:Based on standardized data sets and the computer discipline’s advantage from the University of Science and Technology Beijing, we integrate the new information technology methods, including dynamic information collection terminals and social networks. Thus, the quality of control programs on compliance and intelligence data was improved, and a Chinese women breast cancer cohort database was developed. By February 2020, 12 147 patients were included in the clinical cohort database. Biological specimens’resources in cohort construction were collected and cooperated with Shandong University to research the multi-center quality control system and shared evaluation system of biobanks. Building an open and shared biobank network and forming a full chain of breast cancer research platform.Conclusion:With the implementation of the "13 th Five-Year Plan" precision medicine research, this study provides a research foundation for precision diagnosis and treatment of breast cancer and provides data support for the country to formulate relevant medical policies.

Objective: To investigate the clinical relevance of prognostic staging according to the AJCC Breast Cancer Staging System, Eighth Edition for evaluation of the prognosis of triple-negative breast cancer. Methods: The clinical data of 293 patients with triple-negative breast cancer who were treated at the Breast Disease Center, Peking University First Hospital, between January 2008 and December 2014, were retrospectively analyzed. All patients were female, with age of 53(16) years (M(Q_R)). The patients were staged according to the AJCC Breast Cancer Staging System, Eighth Edition. Survival analysis was performed by Kaplan-Meier method and Log-rank test. The role of clinical staging and prognostic staging in prognostic evaluation was investigated. Results: In all, 293 patients with triple-negative invasive breast cancer with complete clinical data and follow-up data were treated over a 7-year period. The follow-up time was 64.5(32.8) months, the 5-year overall survival (OS) rate was 83.9%, and the 5-year disease-free survival (DFS) rate was 84.1%. The results showed that clinical staging and prognostic staging were correlated with the DFS rate and OS rate of patients with triple-negative breast cancer (χ² were 15.395 to 50.084,P=0.00). However, these two staging systems yielded different results. The prognostic stage of 91.8%(269/293) patients was higher than that of the original anatomical stage. There were significant differences in disease-free survival rate (χ²=22.357,P=0.00) and overall survival rate (χ²=50.084, P=0.00) among patients with different clinical stages. There were significant differences in disease-free survival rate (χ²=15.395,P=0.00) and overall survival rate (χ²=29.187,P=0.00)among patients with different prognostic stages. Conclusions The prognostic stage according to the AJCC Breast Cancer Staging System, Eighth Edition complements the clinical stage. It has a good predictive value for the prognosis of triple-negative breast cancer.

Objective: To discuss the androgen receptor (AR) expresion and its association with clinicopathological features and prognosis in early stage triple-negative breast cancer patients (TNBC). Methods: The present study retrospectively analyzed the clinic data of 1 018 patients with early-stage invasive breast cancer treated at the Breast Disease Center at Peking University First Hospital between January 2014 and December 2016, including 1 011 females and 7 males; the age range was 21 to 92 years, and the median age was 57 years. Patients with TNBC were enrolled, and divided into AR positive group and AR negative group according to the expression of AR.The clinicopathological features were analysed, including menopause status, pathological type, T staging, lymph node involvement, anatomic staging, prognostic staging, Ki-67 index, histological grade, vascular tumor thrombus and neuroinvation, and the correlation between the expression of AR and clinicopathological features, curative effect of neoadjuvant chemotherapy and prognosis were calculated. The Student’s t test was used to compare continuous data, the Pearson χ² test or Fisher exact test was used to compare categorical variables, and the Mann-Whitney U test was used for quantitative data. The Kaplan-Meier method was used to analyze survival status, and comparisons between groups were calculated by the log-rank test. Results: This study included 148 TNBC, accounting for 14.5% of all patients, in which all patients were females, and the median age was 55 years, ranging from 27 years to 75 years. The number of AR-positive TNBC was 59, accounted for 39.9% of all TNBC patients, and the numbers of AR-negative were 89, accounted for 60.1%. Ki-67 index, histological grade and prognostic stage were significantly different in AR-positive and AR-negative TNBC(P<0.05). There was no statistically significant difference between AR-positive TNBC and AR-negative TNBC in OS (98.3% vs 95.4%, P=0.830) or in DFS (91.4% vs 91.0%, P=0.812). Among TNBC who received neoadjuvant chemotherapy, AR-positive patients showed a lower pCR rate than AR-negative patients(χ²=4.381, P=0.046). Conclusions AR expression is associated with lower respond to neoadjuvant chemotherapy in TNBC. However, the association between AR expression and prognosis in TNBCs was still not clear.