Search

Background: Clinical research competence determines the quality of clinical research and the reliability of research findings. We aimed to explore the clinical research implementation capabilities of breast cancer treatment departments in China., Methods: This was a department-based cross-sectional study conducted in the form of electronic questionnaires on the Wenjuanxing platform from 7th August to 31 st August 2023 among hospitals from the first batch of breast cancer standardized diagnosis and treatment quality control pilot centers in China., Results: A total of 127 questionnaires from 122 hospitals were ultimately included in the analysis. Medical personnel involved in the clinical research of 118 (92.9 %) departments received good clinical practice (GCP) training. The steps of the approval process from research initiation to completion lasted 2-4 weeks or longer. The majority of departments initiated or participated in 2 or fewer clinical research projects over the past year. Among the differences between different departments, the Department of Medical Oncology had a better qualification profile and process and greater number of initiated and participated clinical studies than did the Department of Surgical Oncology. For needs and problems, most of the departments were strongly willing to undertake clinical research and receive professional training; the most common problem in the process of conducting studies was patient recruitment., Conclusions: Most departments generally exhibited complete capabilities for implementing clinical research. Improvements in implementation efficiency, quality of research and patient recruitment are still needed. Professional training and communication, as well as the recommendation of clinical research, are required in future development., Competing Interests: Declaration of competing interest None., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Purpose: To analyze the safety and efficacy of orally administered metronomic capecitabine plus pyrotinib in HER2 positive metastatic breast cancer (MBC) patients, we conducted a prospective phase II study with a single-arm design., Methods: HER2 positive patients received oral metronomic capecitabine 500 mg three times a day and pyrotinib 400 mg per day. The primary endpoint was progression-free survival (PFS). Other endpoints included objective response rate (ORR), overall survival (OS), clinical benefit rate (CBR) and safety., Results: The study included 50 patients with MBC that was HER2-positive, while 1 patient was excluded due to nonstandard medication. The median PFS and OS was 11.9 months (95%CI 8.8-14.6) and 29.3 months (95%CI 24.4-34.8) respectively. ORR was 34.7%, and CBR was 81.6% with 2 CR (4.1%), 15 PR (30.6%) and 23 SD (46.9%). The mPFS in first- or second-line treatment was 12.2 months. The most frequent treatment-related adverse events included hand-foot syndrome, diarrhea, vomiting and nausea. Grade 3 adverse events occurred in 15(30.6%) patients, including hand-foot syndrome (12.2%), diarrhea (12.2%), vomiting (4.1%), and nausea (2.0%). 1 grade 4 adverse event of diarrhea (2.0%) was observed., Conclusion: The combination of metronomic capecitabine and pyrotinib is a promising regimen with competitive efficacy and improved tolerability in HER2 positive metastatic breast cancer patients., Competing Interests: Declaration of Competing interest The authors declare that there are no conflict of interests, we do not have any possible conflicts of interest., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: This study sought to compare the benefits and safety of agents including Cyclin-dependent kinase 4/6 (CDK4/6) inhibitors, phosphoinositide 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) inhibitors, and histone deacetylase (HDAC) inhibitors as second-line treatments for these patients by conducting a comprehensive systematic review and network meta-analysis., Methods: The Medline, Embase and Cochrane Library databases were searched for randomized trials comparing CDK4/6 inhibitors, PI3K/mTOR inhibitors, or HDAC inhibitors vs. placebo with the addition of exemestane or fulvestrant as second-line treatments in patients with HR + advanced breast cancer up to December 16, 2021. Outcomes of interest were progression-free survival (PFS), overall response rate (ORR), overall survival (OS), clinical benefit rate (CBR), and grade 3-4 adverse drug events (ADEs). The present study was conducted according to the Cochrane Collaboration and PRISMA statements. The overall effect was pooled using the random effects model., Results: Seventeen studies with a total of 9,100 participants were included in the current study. Compared with placebo plus fulvestrant, PFS was significantly improved by CDK4/6 inhibitor plus fulvestrant, mTOR inhibitor plus fulvestrant, mTOR inhibitor plus exemestane, and PI3K inhibitor plus fulvestrant, but not HDAC inhibitor plus exemestane. While mTOR inhibitor plus exemestane was the best regimen (SUCRA value 89.5%), the mTOR inhibitor plus exemestane regimen induced more severe adverse events (SAEs) than the HDAC inhibitor plus exemestane regimen [OR, 95% CI: 2.40 (1.40-4.10)]., Conclusion: mTOR inhibitor and CDK4/6 inhibitor-based regimens demonstrated superior clinical efficacy and comparable safety profiles as second-line treatment in patients with HR-positive, HER2-negative advanced breast cancer., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Purpose: Patients with breast cancer are more likely to experience psychological distress than the general population. This study aimed to explore the relationship between depression and anxiety status measured before chemotherapy and adverse events during adjuvant chemotherapy in Chinese breast cancer patients., Methods: This prospective study was conducted on 290 postoperative early-stage breast cancer patients (response rate 96.7%) in China. Depression and anxiety status before adjuvant chemotherapy were assessed by the Hospital Anxiety and Depression Scale (HADS). Adverse events that occurred throughout the course of chemotherapy were graded and recorded according to Common Terminology Criteria for Adverse Events (CTCAE) 4.02., Results: The rates of depression and anxiety were 20.0% and 31.4%, respectively, at baseline. The incidence of grade two or higher myelosuppression induced by chemotherapy was correlated with depression before chemotherapy (p = 0.037). Multivariate analysis showed that the incidence of myelosuppression was significantly related to depression before chemotherapy (p = 0.032). There was no association between depression and anxiety status and other adverse events (p > 0.05)., Conclusions: We observed an association between depression status in breast cancer patients receiving adjuvant chemotherapy and chemotherapy-induced myelosuppression. Monitoring the depression status of breast cancer patients before chemotherapy may help to optimize the management of adverse events., (© 2022 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Objective: To explore the dynamic changes of Distress Thermometer scores and the relationship between psychological distress and quality of life in Chinese early breast cancer patients during chemotherapy. Methods: This prospective study enrolled 110 Chinese postoperative early breast cancer patients between March 2019 and December 2019. The psychological distress and quality of life (QOL) of patients were assessed by using the psychological distress management screening tool and the patient quality of life scale. Logistic regression model was used to analyze the influencing factors of psychological distress degree. The correlation between distress thermometer (DT) score changes and quality of life was analyzed by Pearson correlation analysis. Results: In total, 96 valid cases were analyzed. Before chemotherapy, 47 cases (49.0%) had DT score ≥4 points. After 2 cycles of chemotherapy, 40 cases (41.7%) had DT score ≥4 points. Thirty-four patients (35.4%) had DT score ≥4 points after chemotherapy. The DT score after chemotherapy was lower than that before chemotherapy and after 2 cycles of chemotherapy. Univariate analysis showed that income level and pathological stage were still significant related to the detection of DT score ≥4 points after chemotherapy ( P <0.05). The changes of DT scores before and after chemotherapy were negatively correlated with the changes of quality of life ( r =-0.298, P =0.003). Conclusions: The detection rate of psychological distress in patients with early breast cancer during chemotherapy showed a decreasing trend. Income level and tumor stage are significant factors affecting the psychological distress of patients. There is a significant correlation between the psychological distress and the quality of life during chemotherapy. We should pay attention to the evaluation and monitoring state of psychological distress of patients during chemotherapy.

Background: A large number of breast cancer survivors suffer from psychological distress. The purpose of this study was to investigate the association between genetic variations in Chinese breast cancer patients and anxiety or depression, and to screen patients who are susceptible to psychological problems., Methods: A total of 300 early-stage breast cancer patients were recruited in this prospective observational single-center cohort study. With reference to the previous literature and the mechanism concerning anxiety and depression, 9 candidate genes and 29 single-nucleotide polymorphisms (SNPs) loci were selected. The association between SNP variations and anxiety/depression were analyzed., Results: After we incorporated meaningful clinicopathological and demographic factors, multivariate analysis showed that the A/G and G/G genotypes of IFNGR1 (rs2234711) and the T/C and T/T genotypes of BDNF (rs6265) were significantly associated with depression (HR 3.10, P = .008; HR 2.04, P = .03). The G/A and G/G genotypes of IL-10 (rs1554286) remained independent predictors of anxiety (HR 1.85, P = .019)., Conclusions: These findings suggested that variations in IL-10, IFNGR1 and BDNF were associated with anxious/depressive symptoms in early-stage breast cancer patients in China, which could help identify patients at high risk for psychological problems., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Introduction: Drug-induced pulmonary toxicity (DIPT) associated with breast cancer (BC) therapy has been a major concern in recent times. DIPT may not be attributed to a single type of therapy because of the concomitant use of other anticancer drugs or along with radiotherapy, which is an independent risk factor for pulmonary toxicity., Areas Covered: In this systematic literature review, we evaluated the probable cause and prevalence of DIPT in various systemic therapies used in BC treatment. A literature search was conducted in PubMed, Embase and Cochrane database, up to October 2020. Clinical studies reporting DIPT and related clinical manifestations due to systemic therapy in BC treatment were included. A total of 1749 articles were retrieved, and 193 articles were included., Expert Opinion: : The leading cause of DIPT among patients with BC was targeted therapy followed by chemotherapy containing regimens. A total of 17 studies reported 35 deaths (15 deaths in chemotherapy) due to DIPT. Physicians must take extra precaution while prescribing systemic therapy known to be associated with DIPT and need to be familiar with early diagnosis of DIPT in order to avoid respiratory-related complications during treatment in BC patients.

Evidence of an oligometastatic state in metastatic breast cancer (MBC) is relatively limited. The aim of our study was to investigate the clinical features and prognostic factors for extracranial oligometastatic breast cancer and to identify the best treatment approaches in this select population. Fifty postoperative inpatients diagnosed with extracranial oligometastatic breast cancer at the National Cancer Center in China between 2009 and 2014 were consecutively enrolled. Oligometastatic breast cancer was defined as MBC with three or fewer metastatic lesions confined to one organ; de novo Stage IV disease and local-regional recurrence were excluded. The median progression-free survival (PFS) and overall survival (OS) times were 15.2 and 78.9 months, respectively, and the 2-year PFS and 5-year OS rates were 40% and 58%, respectively. First-line treatment approach with standard systemic treatment + surgical resection for all metastatic lesions was an independent prognostic factor for prolonged PFS (hazard ratio = 0.32; 95% confidence interval [CI], 0.14-0.73; P = .006) and OS (hazard ratio = 0.35; 95% CI, 0.14-0.86; P = .022). Subgroup analysis showed that patients with a disease-free interval (DFI) ≥24 months, one metastatic lesion or the hormone receptor (HR) + subtype were more likely to get benefit from resection. Patients with oligometastatic breast cancer have a relatively good prognosis. Surgical resection for metastatic lesions could significantly improve PFS and OS. Further prospective research is warranted to confirm the results and to develop biomarkers for better patient selection., (© 2020 UICC.)

Background: It has been reported that younger breast cancer patients are at greater risk of having psychological problems than their older counterparts. This study is conducted to evaluate the psychological status of Chinese postoperative breast cancer patients aged 35 years or younger and understand the associated factors in this patient group., Methods: This cross-sectional study prospectively enrolled 114 Chinese postoperative breast cancer patients aged 35 years or younger. They completed standard instruments evaluating depression (Patient Health Questionnaire [PHQ]-9) and anxiety (General Anxiety Disorder-7). Logistic regression was used to identify the associated factors., Results: The mean scores were 5.21 and 4.19 for the PHQ-9 and General Anxiety Disorder-7, respectively. There were 76.3%, 20.2%, and 3.5% patients categorized into the none and/or mild (score 1-7), moderate (score 8-14), and moderate to severe depression (score 15-19) groups, respectively. For anxiety, there were 91.2%, 5.3% and, 3.5% of patients in the none and/or mild anxiety (score 0-9), moderate anxiety (score 10-14), and severe anxiety (score 15-21) groups, respectively. With univariate analysis, cohabitation status (P = 0.002) and adjuvant endocrine therapy (P = 0.048) tended to be associated with the level of depression (PHQ-9 ≥ 8). In the multivariate analysis, living alone (odds ratio = 5.08, 95% confidence interval = 1.81-14.26, P = 0.002) and the administration of ovarian function suppression (odds ratio = 2.76, 95% confidence interval = 1.04-7.37, P = 0.042) were still independently correlated with a higher level of depression. No significant predictors were found for anxiety., Conclusions: Our study evaluated the depression and anxiety of young Chinese breast cancer patients; addressing the psychosocial assessment of these patients should be integrated into cancer treatments and follow-ups, especially for those receiving ovarian function suppression and living alone., (Copyright © 2020. Published by Elsevier Inc.)

Objective: To explore whether the addition of ovarian function suppression in endocrine therapy of Chinese breast cancer patients under 35 years old will affect the psychological state. Methods: This cross-sectional study enrolled 91 Chinese postoperative breast cancer patients aged 35 years or younger. The depression and anxiety state of patients were assessed by Patient Health Questionnaire-9 (PHQ-9) and General Anxiety Disorder-7 (GAD-7), and their sociodemographic characteristics were collected. Results: Among the 91 patients, 61 were receiving ovarian function suppression (OFS) treatment, 30 were not. Among the 30 patients with out OFS treatment, 2 had PHQ-9 score ≥8, 28 had PHQ-9 score < 8, 1 had GAD-7 score ≥10, and 29 had GAD-7 score < 10. Among the 61 patients with OFS, 19 had PHQ-9 score ≥8, 42 had PHQ-9 score < 8, 8 had GAD-7 score ≥10, and 53 had GAD-7 score <10. The incidence of depression was 6.7% and 31.1% in the non-OFS group and OFS group, respectively ( P =0.018). The incidence of anxiety in the two groups was 3.3% and 13.1%, respectively ( P =0.174). Univariate analysis showed that the incidence of depression was significantly higher in patients with OFS ( P =0.018). After taking into account the sociodemographic factors, pathological stage and treatment of the patients, multivariate analysis showed that the administration of OFS was still significantly related to the incidence of depression ( OR =9.14, 95% CI =1.52~55.16, P =0.016). There was no significant difference in the incidence of anxiety ( P =0.174). Conclusions: For Chinese young breast cancer patients under 35 years old, the use of OFS in the adjuvant endocrine therapy may lead to a significant increase in the incidence of depression. We should pay attention to the evaluation and monitoring of the psychological state of this population.

Each cell comprising an intact, healthy, confluent epithelial layer ordinarily remains sedentary, firmly adherent to and caged by its neighbors, and thus defines an elemental constituent of a solid-like cellular collective [1,2]. After malignant transformation, however, the cellular collective can become fluid-like and migratory, as evidenced by collective motions that arise in characteristic swirls, strands, ducts, sheets, or clusters [3,4]. To transition from a solid-like to a fluid-like phase and thereafter to migrate collectively, it has been recently argued that cells comprising the disordered but confluent epithelial collective can undergo changes of cell shape so as to overcome geometric constraints attributable to the newly discovered phenomenon of cell jamming and the associated unjamming transition (UJT) [1,2,5-9]. Relevance of the jamming concept to carcinoma cells lines of graded degrees of invasive potential has never been investigated, however. Using classical in vitro cultures of six breast cancer model systems, here we investigate structural and dynamical signatures of cell jamming, and the relationship between them [1,2,10,11]. In order of roughly increasing invasive potential as previously reported, model systems examined included MCF10A, MCF10A.Vector; MCF10A.14-3-3ζ; MCF10.ErbB2, MCF10AT; and MCF10CA1a [12-15]. Migratory speed depended on the particular cell line. Unsurprisingly, for example, the MCF10CA1a cell line exhibited much faster migratory speed relative to the others. But unexpectedly, across different cell lines higher speeds were associated with enhanced size of cooperative cell packs in a manner reminiscent of a peloton [9]. Nevertheless, within each of the cell lines evaluated, cell shape and shape variability from cell-to-cell conformed with predicted structural signatures of cell layer unjamming [1]. Moreover, both structure and migratory dynamics were compatible with previous theoretical descriptions of the cell jamming mechanism [2,10,11,16,17]. As such, these findings demonstrate the richness of the cell jamming mechanism, which is now seen to apply across these cancer cell lines but remains poorly understood., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Purpose: This phase I study assessed the safety, tolerability, MTD, pharmacokinetics, antitumor activity, and predictive biomarkers of pyrotinib, an irreversible pan-ErbB inhibitor, in combination with capecitabine in patients with HER2-positive metastatic breast cancer (MBC)., Patients and Methods: Patients received oral pyrotinib 160 mg, 240 mg, 320 mg, or 400 mg once daily continually plus capecitabine 1,000 mg/m 2 twice daily on days 1 to 14 of a 21-day cycle. Pharmacokinetic blood samples were collected on days 1 and 14. Next-generation sequencing was performed on circulating tumor DNA to probe for predictive biomarkers., Results: A total of 28 patients were enrolled, 22 patients were treated at the two top-level doses. Among 17 (60.7%) trastuzumab-pretreated patients, 11 received trastuzumab for metastatic disease and 6 received adjuvant trastuzumab. No dose-limited toxicity was observed. Grade 3 treatment-related adverse events (AE) occurred in 12 (42.9%) patients; anemia (14.3%) and diarrhea (10.7%) were the most common grade 3 AEs. The overall response rate (ORR) was 78.6% [95% confidence interval (CI): 59.0%-91.7%], and the clinical benefit rate was 85.7% (95% CI: 67.3%-96.0%). The median progression-free survival (PFS) was 22.1 months (95% CI: 9.0-26.2 months). ORR was 70.6% (12/17) in trastuzumab-pretreated patients and 90.9% (10/11) in trastuzumab-naïve patients. Analysis of all genetic alterations in HER2-related signaling network in baseline blood samples suggested that multiple genetic alterations were significantly associated with poorer PFS compared with none or one genetic alteration (median, 16.8 vs. 29.9 months, P = 0.006)., Conclusions: In a population largely naïve to HER2-targeted therapy, pyrotinib in combination with capecitabine was well-tolerated and demonstrates promising antitumor activity in patients with HER2-positive MBC., (©2019 American Association for Cancer Research.)

Introduction: UGT1A4 is a major enzyme responsible for the glucuronidation of tamoxifen (TAM) and its metabolites. Genetic variations in the UGT1A4 gene could have a significant impact on the clinical efficacy of TAM. This study was performed to validate the association between UGT1A4 polymorphisms and the clinical outcomes for patients with breast cancer who received adjuvant TAM., Patients and Methods: A total of 773 patients with breast cancer who received adjuvant TAM (n = 321) or aromatase inhibitors (n = 452) at the National Cancer Center in China were analyzed. Through a series of screenings, the single nucleotide polymorphism rs869283 (c.-1180G>A) in the promoter region of the UGT1A4 gene was selected. The associations of rs869283 genotype with disease-free survival (DFS) and clinicopathologic characteristics were analyzed., Results: A total of 608 (78.7%) patients were wild-type G/G genotype, 154 (19.9%) patients were G/A genotype, and 11 (1.4%) patients were A/A genotype. In the TAM treatment group, patients with A/A or G/A genotype had a lower 5-year DFS rate than those with the wild-type G/G genotype (69.3% vs. 83.7%; P = .031). The rs869283 genotype remained an independent prognostic marker for DFS in multivariate analysis (hazard ratio, 1.74; P = .014). No association between the rs869283 genotype and DFS was found in patients who received AIs (P = .772)., Conclusions: Our findings showed that patients with the UGT1A4 rs869283 G/A or A/A genotype received less benefit from adjuvant TAM treatment than those with the G/G genotype. Further studies are warranted to confirm our findings., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Toremifene (TOR) is a valid and safe alternative to tamoxifen (TAM) for adjuvant endocrine therapy in breast cancer patients with a metabolic pathway that differs from that of TAM. TOR might have a therapeutic advantage in certain subgroups of patients, such as Chinese women with the CYP2D6 *10 (c.100C > T) T/T genotype, who would get less benefit when receiving adjuvant TAM treatment. A total of 230 breast cancer patients who received adjuvant TAM (n = 115) or TOR (n = 115) at the National Cancer Center were analyzed. The CYP2D6 *10 genotype was not significantly associated with DFS in patients who received TOR (p = 0.737). Patients treated with TOR had a higher 5-year disease-free survival (DFS) rate than those treated with TAM (89.6% vs. 80.9%, p = 0.009). TOR treatment remained an independent prognostic marker of DFS in multivariate analysis compared with TAM (hazard ratio = 0.51; p = 0.014). For all of the 50 CYP2D6 *10 T/T genotype patients, TOR treatment group had a significantly higher 5-year DFS rate than TAM group (90.9% vs. 67.9%, p = 0.031). For the remaining 170 CYP2D6 *10 C/C or C/T genotype patients, there was no significant difference between the 5-year DFS rates of the TOR and TAM groups (89.2% vs. 85.1%, p = 0.188). The advantage of adjuvant TOR over TAM in Chinese breast cancer patients might be caused by the significant benefit obtained by the CYP2D6 *10 T/T patients, who accounted for one-fifth of the overall population. TOR might be a good option for adjuvant endocrine therapy in this subgroup of patients in China., (© 2018 UICC.)

Variants of the CYP2D6 gene may lead to a poor prognosis of tamoxifen (TAM)-treated patients. Our study validated the association between the CYP2D6 genotype and outcomes of patients receiving TAM in adjuvant endocrine therapy. A total of 778 breast cancer patients who received adjuvant TAM (n = 325) or aromatase inhibitors (AIs) (n = 453) at the National Cancer Center were analyzed. Nine single nucleotide polymorphisms (SNPs) in the CYP2D6 gene were selected from online databases. The associations of each SNP genotype with disease-free survival (DFS) and clinicopathological characteristics were analyzed. A total of 167 (21.5%) patients carried the CYP2D6*10 (c.100C>T) T/T genotype. Among the 325 patients who received TAM, the 5-year DFS rate was considerably lower in CYP2D6*10 T/T genotype patients than C/C or C/T patients (54.9% vs. 70.9%, p = 0.007). The T/T genotype for CYP2D6*10 was a significant prognostic marker for DFS in multivariate analysis (hazard ratio = 1.87; p = 0.006). The CYP2D6*10 genotype in women who received AIs was not significantly associated with DFS (p = 0.332). Other SNPs were not related to the survival of patients who received TAM. Our finding showed patients with CYP2D6*10 T/T received less benefit from TAM adjuvant treatment. This conclusion may optimize the individualized treatments for this subgroup of patients., (© 2018 UICC.)

Purpose This phase I study assessed the safety, tolerability, pharmacokinetics, antitumor activity, and predictive biomarkers of pyrotinib, an irreversible pan-ErbB inhibitor, in patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer. Patients and Methods Pyrotinib was administered continuously, orally, once per day to patients who did not have prior exposure to tyrosine kinase inhibitors of HER2. Planned dose escalation was 80, 160, 240, 320, 400, and 480 mg. For pharmacokinetic analysis, timed blood samples were collected on day 1 and day 28. Next-generation sequencing was performed on circulating tumor DNA and genomic DNA from tumor samples. Results Thirty-eight patients were enrolled. The dose-limiting toxicity was grade 3 diarrhea, which occurred in two patients administered 480 mg of pyrotinib; thus, the maximum tolerated dose was 400 mg. Common pyrotinib-related adverse events included diarrhea (44.7% [17 of 38]), nausea (13.2% [five of 38]), oral ulceration (13.2% [five of 38]), asthenia (10.5% [four of 38]), and leukopenia (10.5% [four of 38]). The only grade 3 adverse event was diarrhea. Pharmacokinetic analyses indicated that pyrotinib exposure was dose dependent. The overall response rate was 50.0% (18 of 36), and the clinical benefit rate (complete response + partial response + stable disease ≥ 24 weeks) was 61.1% (22 of 36). The median progression-free survival was 35.4 weeks (95% CI, 23.3 to 40.0 weeks). The overall response rate was 83.3% (10 of 12) in trastuzumab-naive patients and 33.3% (eight of 24) in trastuzumab-pretreated patients. Preliminary results suggest that PIK3CA and TP53 mutations in circulating tumor DNA ( P = .013) rather than in archival tumor tissues ( P = .474) may predict the efficacy of pyrotinib. Conclusion Continuous once-per-day pyrotinib was well tolerated and demonstrated promising antitumor activity in HER2-positive patients with metastatic breast cancer. The maximum tolerated dose was established as 400 mg. Diarrhea was the dose-limiting toxicity. The promising antitumor activity and acceptable tolerability of pyrotinib warrant its further evaluation in a phase II study.

Vav1, a guanine nucleotide exchange factor (GEF) for Rho family GTPases, is a hematopoietic protein involved in a variety of cellular events. In recent years, aberrant expression of Vav1 has been reported in non-hematopoietic cancers including human breast cancer. It remains to be answered how Vav1 is expressed and what Vav1 does in its non-resident tissues. In this study, we aimed to explore the mechanism for Vav1 expression in breast cancer cells in correlation with estrogen-ER pathway. We not only verified the ectopic expression of Vav1 in human breast cancer cell lines, but also observed that Vav1 expression was induced by 17β-estradiol (E2), a typical estrogen receptor (ER) ligand, in ER-positive cell lines. On the other hand, Tamoxifen, a selective estrogen receptor modulator (SERM), and ICI 182,780, an ER antagonist, suppressed the expression of Vav1. The estrogen receptor modulating Vav1 expression was identified to be α form, not β. Furthermore, treatment of E2 increased the transcription of vav1 gene by enhancing the promoter activity, though there was no recognizable estrogen response element (ERE). Nevertheless, two regions at the vav1 gene promoter were defined to be responsible for E2-induced activation of vav1 promoter. Chromatin immunoprecipitation (ChIP) and co-immunoprecipitation (Co-IP) analyses suggested that ERα might access to the vav1 promoter via interacting with transcription factors, c-Myb and ELF-1. Consequently, the enhanced expression of Vav1 led to the elevation of Cyclin D1 and the progression of cell cycle. The present study implies that estrogen-ER modulates the transcription and expression of Vav1, which may contribute to the proliferation of cancerous cells.

Background: Asparaginyl endopeptidase (AEP) has been implicated in human cancer development. However, the molecular mechanisms underlying AEP regulation, including the role of pro-AEP activation, remain elusive., Methods: We investigated the regulation of AEP by TRAF6 and its effects on tumor progression and metastasis in cancer cell lines, murine models, and specimens from patients using biochemical analyses, confocal microscopy, immunoelectron microscopy, and migration-invasion assays. The sera of healthy donors and breast cancer patients were examined by enzyme-linked immunosorbent assay, and a tissue array of 314 breast cancer specimens was assessed for AEP and TRAF6 by immunohistochemistry. Furthermore, the effects of AEP inhibitors or monoclonal antibodies on pulmonary metastasis were evaluated in murine models. The statistical significance between groups was determined using two-tailed Student t tests., Results: We demonstrate that TRAF6 ubiquitinates the proform of AEP through K63-linked polyubiquitin, reversible by USP17, and forms a complex with HSP90α to subsequently promote pro-AEP intracellular stability as well as secretion. Disrupting the interaction between pro-AEP and TRAF6 or inhibiting HSP90α reduced pro-AEP secretion and consequently reduced tumor metastasis. Higher circulating AEP levels were detected in the sera of breast cancer patients, and AEP inhibitors or neutralizing antibodies remarkably decreased tumor metastasis in murine models. Notably, TRAF6 and AEP were overexpressed in human breast neoplasms and correlated with poor prognosis. Patients with low AEP/TRAF6 expression survived for a mean of 111 months (95% confidence interval [CI] = 108 to 115 months), whereas those with high AEP/TRAF6 expression survived for a mean of only 61 months (95% CI = 42 to 79 months; P < .001)., Conclusions: Our study elucidates a novel mechanism of AEP regulation and an alternative oncogenic pathway for TRAF6 in breast cancer, which suggests that AEP and TRAF6 protein levels may have prognostic implications in breast cancer patients. Thus, AEP may serve as a biomarker as well as new therapeutic target.