bluuebunny/crossref_metadata_2025_split huggingface dataset:
Bioequivalence study of BH009 and Winthrop (docetaxel) injection (an authorized generic drug of Taxotere) in patients with advanced solid tumor: An open-label, randomized, single-dose, two-way crossover evaluation.
Authors: Sun Qun 
Published: June 2023

e13002 Background: Taxotere (docetaxel injection) clinically used to treat solid tumors (e.g., breast, prostate, gastric, lung, and head and neck cancer) is associated with hypersensitivity reactions attributed to its excipient, polysorbate 80. BH009 is a novel polysorbate 80-free formulation of docetaxel injection that could reduce hypersensitivity reactions associated with polysorbate 80 and preclude the need for dexamethasone premedication. Methods: This multicenter, randomized, open-label, two-way crossover study compared the pharmacokinetics and safety of BH009 and Taxotere (Winthrop (docetaxel) injection). Patients received single-dose of 75 mg/m2 BH009 or Taxotere IV over 60 min, with ≥21-day washout between doses. Primary endpoints were to evaluate pharmacokinetics and establish the bioequivalence of BH009 relative to Taxotere. Blood samples were evaluated for pharmacokinetics and bioequivalence, and safety evaluation included treatment-emergent adverse events (TEAEs) and serious adverse events. A total of 46 subjects were randomized, and 41 subjects have completed the study. Results: The ratio of geometric means for AUC0-t, AUC0-∞ and Cmax following administration of BH009 (Test product (T)) and Taxotere (Winthrop (docetaxel) injection) (Reference product (R)), were 0.99 (90% CI, 91.89% - 107.18%) , 0.98 (90% CI, 91.10% - 106.04%) and 1.00 (90% CI, 92.18% - 108.00%), respectively. Statistical analyses reveal that 90% confidence interval for geometric least square mean ratio of (T/R) is within the acceptance range of 80.00% to 125.00% for primary pharmacokinetic parameters Cmax, AUC0-t and AUC0-∞ required for concluding bioequivalence between the test and reference product. The test and reference product were well tolerated by the patients, and the safety profile of the test product complies with the known safety profile of the reference product. A total of 198 TEAEs were reported during the course of the study. 94 TEAEs were reported after administration of Test product (T). 104 TEAEs were reported after administration of reference product (R). No serious adverse events or deaths occurred during the course of the study. Conclusions: This study established the bioequivalence of BH009 to Taxotere. BH009 is the first polysorbate 80-free formulation of docetaxel injection which is bioequivalent to Taxotere and may provide a safer alternative to Taxotere. Clinical trial information: NCT04889599 .
Risk factors of early liver metastasis in patients with breast cancer.
Authors: Zhu Minxue , Yang Sujin 
Published: June 2023

e13011 Background: Breast Cancer Liver Metastasis is very common in the clinical treatment of breast cancer. Although great progress has been made in the early diagnosis and treatment of breast cancer, 20% to 30% of patients with early breast cancer will develop tumor metastasis. Relevant studies have found that liver metastasis is an independent predictor of poor overall survival in breast cancer patients compared with bone metastasis and other factors. There is a lack of large-scale clinical research on the risk factors of early liver metastasis of breast cancer across the world. This study aims to explore the possible risk factors of early liver metastasis of breast cancer patients by analyzing the clinical data of 70 breast cancer patients with first liver metastasis. Methods: A retrospective study was conducted on 70 female breast cancer patients with liver metastasis who were diagnosed and treated in the First Affiliated Hospital of Nanjing Medical University from January 2011 to December 2021 and had complete medical records. The main clinical and pathological data of the patients were obtained by reading the medical records, such as age, menstrual status, surgical method, history of non-alcoholic fatty liver disease, T stage of the primary tumor, molecular type, vascular tumor thrombus and pathological type. SPSS 25.0 statistical software was used to analyze the data. Kaplan-Meier Survival curve and log-rank test were used to compare the disease-free survival (DFS) of breast cancer patients with and without non-alcoholic fatty liver Disease, different ER expression, Ki67 expression and histological grade. DFS is the interval between breast cancer surgery and the occurrence of metastases. COX regression model was used to analyze the risk factors of early metastasis of breast cancer. P < 0.05 was considered statistically significant. Results: The median liver metastasis-free time of the 70 breast cancer patients was 34 months (range 4-121 months). High histological grade, non-alcoholic fatty liver disease, negative expression of ER and Ki-67>15% were risk factors for early liver metastasis in patients with breast cancer after operation (χ2 =8.367, P=0.015; χ2 =6.883, P=0.009; χ2 =7.507, P=0.006; χ2 =10.488, P=0.001). Conclusions: In this study, the independent risk factors of early liver metastasis in breast cancer patients are high histological grade, high expression of Ki-67, and combined with alcoholic fatty liver, which is consistent with most studies at home and abroad, and proves that Chinese breast cancer patients have the same risk factors as foreign patients. However, the role of ER, PR and HER-2 expression is unclear, which may be related to the fact that some patients do not receive systemic endocrine and targeted therapy. More samples and multi-center prospective clinical studies are needed to confirm, but it still has certain clinical significance for the prognosis and intervention of breast cancer patients.
HER2-low expression as a prognostic factor in patients treated with CDK4/6 inhibitors: A retrospective analysis.
Authors: Cejuela Solís Mónica , Castilla Maria Angeles , Gil Ana , Falcon Alejandro , Benavent Marta , Miras Rodríguez Isabel , Ruiz-Borrego Manuel , Molina-Pinelo Sonia , Salvador Bofill Javier 
Published: June 2023

e13015 Background: Novel HER2 antibody-drug conjugates have demonstrated clinical benefit in breast cancer with HER2 IHC scores 1+ or 2+/ISH negative. As a result, a new concept of HER2 low breast cancer has been proposed. The prognostic implications of this expression remain unclear. To determine whether HER2 low expression affects disease evolution in patients with endocrine receptor positive, HER2 negative breast cancer, we performed a retrospective analysis of patients treated with first line CDK4/6 inhibitors in our center. Methods: We conducted a search for patients who received first line CDK4/6 inhibitors plus endocrine therapy at Virgen del Rocio Hospital between June 2016 and September 2021. 175 subjects were selected and followed for 42 months. Patients were grouped according to HER2 expression: HER2 0+ and HER2 low (IHC 1+ or 2+/ISH negative). Clinical characteristics and PFS were then compared. Clinical characteristics were evaluated by descriptive analysis. Kaplan Meier curves were used to estimate PFS, and Breslow test to estimate p-value. Statistical analyses were performed with SPSS 28.0. Results: All patients were female and median age at treatment initiation was 61 years. 49 patients received abemaciclib, 83 palbociclib and 43 ribociclib. 49 patients were HER2 0+, 57 HER2 1+ and 69 HER2 2+. Key clinical and treatment characteristics are shown. Overall PFS was 35.61 months (95% CI 25.46 - 45.76). PFS was 21.52 months (95% CI: 14.30 - 28.73), 31.15 months (95% CI: 15.59 - 46.70) and 39.49 months (95% CI: not estimable) in the HER2 0+, 1+ and 2+ population, respectively. There was no difference between the three arms: HER2 0+ vs HER2 1+ p=0.881; HER2 0+ vs HER2 2+ p=0.155; HER2 1+ vs HER2 2+ p=0.238. No significant differences were observed when comparing the HER2 0+ cohort to the overall HER2 low population: p=0.347. Conclusions: In our cohort of patients with luminal phenotype breast cancer treated with CDK4/6 inhibitors, HER2 low expression was associated with a trend toward longer PFS, although no statistically significant differences were found. [Table: see text]
Androgen receptor expression in female patients with triple-negative breast cancer: Relation to clinical, pathological, and ethnical data and comparison with non–triple-negative breast cancer.
Authors: Zidan Jamal 
Published: June 2023

e13022 Background: Breast cancer is the most common tumor among women. It constitutes 33% of all tumors in women in Israel. In addition to stage of the disease, other detective factors such as estrogen and progesterone receptors (ER) (PR), Human epidermal growth factor receptor 2 (HER2) and proliferation index (KI67) are examined to determine the treatment for metastatic disease and for the adjuvant therapy. Despite a good prognosis of breast cancer about 10-15% of breast tumors do not contain ER, PR, HER2. This group of is more, aggressive, called Triple negative (TN) tumor. In TN tumors the treatment is mainly chemical therapy, and the survival is lower than other types (Non triple negative: NTN) of breast cancers. Androgen receptor (AR) receptor is very important in prostate cancer and forms the basis of hormonal treatments for prostate cancer. AR can also be present in some breast cancer patients. This study examined AR levels in patients with TN breast cancer in order to evaluate whether AR could be used as a prognostic or therapeutic factor in patients with TN breast cancer. Methods: Demographic, clinical and pathological data were collected from the files of breast cancer patients treated at the Oncology Institute at Ziv Medical Center, Israel, between 2013 and 2020. Tissue samples were taken from the tumors at the Ziv Pathological Institute which were stored in paraffin. The evaluation of AR in breast cancer tissues was done by immunohistochemistry test. 55 TN cases were examined along in addition 90 cases with NTN were examined for comparison. Results: The mean age of the patients in the TN group was 56.9 ± 16.2 compared with 59.8 ± 13.5 years in the NTN group. 83.6% were Jewish and 16.4% Arab. 36.4% of TN patients were of childbearing age. 61.8% of the tumors in TN were Grade 3 compared to 32.2% in the NTN group (P = 0.001). Ki67) was 57.4 ± 27.8 in TN tumors and 24.9 ± 25.4 in NTN (0.001 <P =). In 69.1% of TN patients AR was found to be negative compared to 26.7% in NTN (P = <0.001). AR was found to be high in 9% of TN patients and in 72.8% in NTN who survived 5 years without disease (P = <0.001). Negative AR was found in 75% of the patients who died from the disease in both groups. Positive AR was found in 30.9% of TN tumors compared to 73.3% in NTN (P = <0.001). Conclusions: The AR receptor has a prognostic importance in breast cancer. We found that positive AR is more common in NTN patients than in TN. Survival of patients with low expression of AR is lower. The test is also relatively inexpensive, and it could be possible to be checked in all patients with TN breast cancer all over the hospitals. On the basis of the recent results, we suggest performing a new multicenter study for the treatment of AR-positive TN patients who failed conventional therapies with AR based hormone therapy.
Radiotherapy combined with pyrotinib plus capecitabine in patients with human epidermal growth factor receptor 2 (HER2)-positive breast cancer and brain metastases: A single-arm, exploratory trial.
Authors: Wang Jing , Wang Ping , You Jinqiang , Hou Hailing , Zhang Baozhong , Chai Yanlan , Cao Yuanjie , Zhang Bin , Wang Xu 
Published: June 2023

e13024 Background: Previous researches indicated the enhanced radiosensitivity in HER2-positive cancer cells by pyrotinib. For patients with treatment-naive brain metastases and central nervous system (CNS) symptoms, whether radiotherapy (current mainstay treatment) combined with pyrotinib-based systemic regimen is more beneficial remains unclear. This study explored radiotherapy combined with pyrotinib plus capecitabine in this population. Methods: In this exploratory trial (NCT04767828), patients aged 18-75 years who had HER2-positive metastatic breast cancer and untreated symptomatic brain metastases with an Eastern Cooperative Oncology Group performance status of 0-2 were included. Patients with meningeal metastases or without measurable CNS lesions were excluded. Eligible patients received whole-brain radiotherapy (WBRT) or stereotactic radiotherapy (SRT). The irradiation sites, total radiation dose, and fractions were decided by investigator based on the number of CNS lesions and size. Pyrotinib (400 mg, once a day) and capecitabine (1000 mg/m2, twice a day, on days 1-14 of each 21-day cycle) were given since the start of radiotherapy until disease progression or intolerable toxicity. The primary endpoint was CNS progression-free survival (PFS), assessed by Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM). Extracranial lesions were assessed by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Results: Between May 5, 2020 and November 25, 2022, a total of 19 patients were enrolled. Thirteen (68%) patients had other visceral metastases, and 18 (95%) had prior trastuzumab treatment (5 for early breast cancer, 12 for advanced breast cancer, and 1 for both). Fifteen (79%) patients received WBRT and 4 (21%) received SRT. By the data cutoff date on January 16, 2023, the median follow-up duration was 15.0 months (range, 1.7-24.8). Median CNS PFS was 10.0 months (95% CI, 5.3-14.7). CNS objective response rate was 100%, including two (11%) patients with CNS complete response. Median overall PFS was 8.5 months (95% CI, 4.8-12.2). Median overall survival was 19.0 months (95% CI, 13.1-24.9). The most common grade 3 or 4 adverse events were vomiting (16%) and nausea (11%). For 11 patients with available results of Mini-Mental State Examination (MMSE), 10 (91%) had normal cognitive function during study period or recovered to normal level within 6 months after radiotherapy. Conclusions: Radiotherapy combined with pyrotinib plus capecitabine shows favorable CNS response and promising survival outcomes in patients with HER2-positive metastatic breast cancer and untreated symptomatic brain metastases, with an acceptable safety profile. This combination strategy warrants further validation in large samples. Clinical trial information: NCT04767828 .
Effect of suppressing the p38 pathway through upregulation of Wip1 on Her2 early dissemination of breast cancer.
Authors: Wang Nan , Sun Peiqing , Liu Hong 
Published: June 2023

e13029 Background: Metastasis is the leading cause of cancer-related deaths. While mechanisms for metastasis were extensively studied in cancer cells from patients with detectable tumors, pathways underlying metastatic dissemination from early lesions are poorly understood. Her2 promotes breast cancer early dissemination by suppressing p38, but how it downregulates p38 is unclear. In this study, we investigated the mechanism underlying suppression of p38 by Her2 in breast cancer early dissemination using cell models of early lesions of breast cancer. Methods: We studied the role of Wip1 in disseminating phenotypes in cell line models of breast cancer early lesions. These disseminating phenotypes include cell motility measured in transwell assays, cell invasion measured by percentage of organoids with outwards in organoid-forming medium, and epithelial-to-mesenchymal transition (EMT) measured by E-cadherin and Vimentin levels in Western blotting analysis, percentage of organoids with High E-cadherin junctions and nuclear translocation and activation of β-catenin in immunofluorescence (IF) staining assays. Results: We demonstrate that high levels of Wip1, a p38 phosphatase, correlated with Her2+ status, and reduced phosphorylation of p38 and its downstream effectors MK2 and Hsp27 in tissue samples and cell models of breast cancer early lesions. We found that Wip1 promoted migration, invasion and EMT, while Wip1 knockdown abrogated the ability of Her2 to induce these disseminating phenotypes, in cell line models of early lesion of breast cancer. In contrast to the wild type Wip1, the catalytically inactive mutants of Wip1 failed to induce the disseminating phenotypes. Thus, Wip1 induction is both sufficient, and necessary for Her2, to promote migration, invasion and EMT in breast cancer early lesion cells. In an attempt to identify the Wip1 downstream effectors involved in disseminating phenotypes, we found that ectopic expression of the constitutively active mutants of p38γ and δ, but not that of p38α and β, reversed the ability of Wip1 to suppress MK2 and Hsp27 phosphorylation and to induce migration, invasion and EMT. It suggests that Wip1 promotes the early dissemination by suppressing p38γ and δ. We investigate the mechanism by which Her2 induces Wip1 expression. Ectopic expression of Her2 did not alter the level of Wip1 mRNA or the Wip1 protein stability, suggesting that Her2 may promote Wip1 expression by regulating its translation. Moreover, inhibitors of Her2, Wip1 and Skp2 can each reduce the disseminating phenotypes in cells models of breast cancer early lesions ectopically expressing Her2, Wip1 or Skp2. Conclusions: Our findings identify the Her2-Wip1-p38-Mk2-Hsp27 cascade as a novel mechanism mediating breast cancer early dissemination and provide a basis for new therapies targeting early metastatic dissemination in Her2+ breast cancer using inhibitors for Her2, Wip1 or Skp2.
Construction of a prognostic hierarchical model for patients with HER2 positive breast cancer with brain metastases.
Authors: Chen Jiaxin , Yuan Sh , Zhang Huiqiang , Zhou Jinmei , Jiang Zefei , Wang Tao 
Published: June 2023

e13030 Background: Brain metastasis occurs in about 50% of advanced HER2-positive breast cancer patients. In clinical practice, we need accurate model to predict the patients’ survival time. According to survival time, we can arrange reasonable treatment strategy for HER2 positive breast cancer with brain metastases. Methods: The study recruited HER2-positive breast cancer brain metastasis (BCBM) patients who attended the Fifth Medical Center of PLA General Hospital from June 2003 to June 2022.All statistics were performed using SPSS version 22.0 and R version 3.4.3 software. Results: This study included 300 patients with HER2-positive BCBM. The median age at Brain Metastases diagnosis was 48.5 years, and the median Brain Metastases Overall Survival time (BMOS) was 18.0 months (95% CI: 14.6-21.4). A single-factor analysis of BMOS revealed that age, number of brain metastasis lesions, number of extracranial lesions during BCBM, radiotherapy after BCBM, anti-HER2 therapy after BCBM, and survival prognosis after BCBM were associated with survival prognosis after diagnosis of BCBM. According to a multi-factor analysis, the age, the number of brain metastases, radiotherapy after BCBM, and anti-HER2 therapy after BCBM were all independent factors influencing survival after diagnosis of BCBM. Different independent prognostic factors comprised the patient hierarchical evaluation model. Patients' warning scores range from 0 to 7. We divided the patients into three groups with obvious differences in prognosis： Low- intermediate-risk (score≥1), stroke group (score≥3) and high-risk group (score≥6). The patient prognosis was worse when the warning score was high. The results of Kaplan-Meier survival curve analysis showed significant prognosis differences between the three groups of patients (P < 0.0001). The mean Area Under Curve of the receiver operating characteristic curve for 1-yeasr, 2-year, and 3-year prognosis prediction was 0.69,0.71, and 0.67, respectively. For low-risk patients, the prognosis was significantly improved by using any anti-HER2 medications (P<0.05). Trastuzumab + Pertuzumab can significantly improve the prognosis of patients at intermediate risk (P<0.001, HR=0.24,95%CI: 0.13-0.43). Patients in the intermediate-risk group received both anti-HER2 medication and combined radiotherapy significantly prolonged BMOS in patients who received only drug therapy or radiotherapy (P=0.0132). Conclusions: A survival and prognostic stratification model was constructed based on the clinicopathological characteristics and treatment pattern of a large cohort of HER2-positive breast cancer patients with brain metastases, and the patients were divided into the low-risk group, intermediate-risk group and high-risk group. The optimal individualized treatment strategy was recommended according to different groups.
ADC vs HP dual-antibody for HER2-positive advanced breast cancer after failed to TKI.
Authors: Bian Li , Li Feng , Ji Chenchen , Li Jianbin , Yuan Yang , Zhang Huiqiang , Zhang Shaohua , Wang Tao , Jiang Zefei 
Published: June 2023

e13036 Background: The application of tyrosine kinase inhibitor (TKI) is higher than that of antibody-drug conjugate (ADC) in the second-line anti-HER2 targeted therapy of patients with advanced breast cancer in China. The purpose of this study is to explore the efficacy and safety of the new generation anti-HER2 ADC, the previous generation ADC(T-DM1) and HP dual-antibody (trastuzumab + pertuzumab) in patients with HER2 positive advanced breast cancer who failed TKI therapy. Methods: This is a retrospective, nonrandomized, controlled study to compare the regimen of the new generation ADC, HP dual-antibody and T-DM1 for patients who failed TKI treatment. The primary end point was progression-free survival (PFS). The secondary end points included the overall response rate (ORR), the clinical benefit rate (CBR) and the safety. Results: A total of 213 patients were enrolled from January 2013 to June 2022. All patients were from the department of oncology, the fifth medical center of Chinese PLA General Hospital. The median age of all patients was 47y. Among these patients,73 cases were in the new generation ADC group (including DS8201 30 cases, MRG002 24 cases, ARX788 10 cases and RC48 9 cases), 71 cases were in T-DM1 group and 69 cases were in HP group (combination chemotherapy including taxane, vinorelbine, gemcitabine and capecitabine). The median PFS of the patients in the new generation ADC group , HP group and T-DM1 group was 7.0m, 6.6m, 4.0m respectively. The difference between the new generation ADC group and T-DM1 group was significant (HR=0.44,95%CI 0.30-0.66, P<0.0001), which between HP group and T-DM1 group was also significant (HR=0.50,95%CI 0.34-0.74, P<0.0001), meanwhile, which between the new generation ADC group and HP group was not significantly (HR=0.88, 95%CI 0.58-1.32, P=0.527)(Figure 1). The ORR in three groups was 54.8%, 27.5%, 22.5% respectively, and the new generation ADC group was significantly higher than the other two groups (P<0.0001). The CBR in three groups was 65.8%, 62.3%, 47.9% respectively. The difference between the new generation ADC group and HP group was not significantly (P=0.67), and both were significantly higher than T-DM1 group (P=0.03). The most common grade 3 or 4 adverse event in the new generation ADC group was neutropenia (20.5%) and which in T-DM1 group was thrombocytopenia (28.1%). The incidence of interstitial lung disease in the two groups was 5.4% and 1.4% respectively. No grade 5 adverse event occurred. Conclusions: In our study, the new generation ADC significantly improved PFS and ORR compared with that for T-DM1 with manageable toxicity, so it can be considered an optimized subsequent treatment for HER2 positive advanced breast cancer after TKI failure. In addition, there was no significant difference in PFS and CBR between HP and the new generation ADC, thus HP dual-antibody regimen is also an optional treatment for patients who never used pertuzumab.