Adjuvant abemaciclib combined with endocrine therapy for high-risk early breast cancer: updated efficacy and Ki-67 analysis from the monarchE study.

BACKGROUND: Adjuvant abemaciclib combined with endocrine therapy (ET) previously demonstrated clinically meaningful improvement in invasive disease-free survival (IDFS) and distant relapse-free survival (DRFS) in hormone receptor-positive, human epidermal growth factor receptor 2-negative, node-positive, high-risk early breast cancer at the second interim analysis, however follow-up was limited. Here, we present results of the prespecified primary outcome analysis and an additional follow-up analysis. PATIENTS AND METHODS: This global, phase III, open-label trial randomized (1 : 1) 5637 patients to adjuvant ET for ≥5 years ± abemaciclib for 2 years. Cohort 1 enrolled patients with ≥4 positive axillary lymph nodes (ALNs), or 1-3 positive ALNs and either grade 3 disease or tumor ≥5 cm. Cohort 2 enrolled patients with 1-3 positive ALNs and centrally determined high Ki-67 index (≥20%). The primary endpoint was IDFS in the intent-to-treat population (cohorts 1 and 2). Secondary endpoints were IDFS in patients with high Ki-67, DRFS, overall survival, and safety. RESULTS: At the primary outcome analysis, with 19 months median follow-up time, abemaciclib + ET resulted in a 29% reduction in the risk of developing an IDFS event [hazard ratio (HR) = 0.71, 95% confidence interval (CI) 0.58-0.87; nominal P = 0.0009]. At the additional follow-up analysis, with 27 months median follow-up and 90% of patients off treatment, IDFS (HR = 0.70, 95% CI 0.59-0.82; nominal P < 0.0001) and DRFS (HR = 0.69, 95% CI 0.57-0.83; nominal P < 0.0001) benefit was maintained. The absolute improvements in 3-year IDFS and DRFS rates were 5.4% and 4.2%, respectively. Whereas Ki-67 index was prognostic, abemaciclib benefit was consistent regardless of Ki-67 index. Safety data were consistent with the known abemaciclib risk profile. CONCLUSION: Abemaciclib + ET significantly improved IDFS in patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative, node-positive, high-risk early breast cancer, with an acceptable safety profile. Ki-67 index was prognostic, but abemaciclib benefit was observed regardless of Ki-67 index. Overall, the robust treatment benefit of abemaciclib extended beyond the 2-year treatment period.

[The effect of adjuvant radiotherapy on postoperative complications of immediate deep inferior epigastric artery perforator flap breast reconstruction].

Objective: To examine the effect of adjuvant radiotherapy on postoperative complications of immediate deep inferior epigastric artery perforator (DIEP) flap breast reconstruction. Methods: Data was collected from 185 patients underwent immediate DIEP reconstruction during November 2006 to March 2020 Department of Breast surgery, Fudan University shanghai Cancer Center. All the patients were female, aging (43.0±7.8) years (range: 29 to 61 years). The series included with a total of 187 flaps (2 bilateral, 183 unilateral). Included patients were divided into 2 groups: immediate DIEP reconstruction requring or not requring post-mastectomy radiation therapy (71 cases (71 flaps) in PMRT group, 114 cases (116 flaps) in control group). The aesthetic outcome were measured by Kroll score system and compared between the groups by t test. The complications included partial flap loss, minor necrosis were analyzed between the groups by χ2 test, while the influence of the other correlation factors on complication occurrence was analyzed by Logistic analysis. Results: The controll groups showed higher aesthetic results (2.21±0.55 vs. 2.47±0.82, t=-2.593, P=0.010). Complication rate in PMRT group was higher than that in control group (19.7% (15/71) vs. 4.2% (4/116), χ²=15.079,P<0.01). The complication rate was not correlated with age, body mass index, perforator number, neoadjuvant chemotherapy and adjuvant chemotherapy. Conclusions: Correlation was observed between adiuvant radiotherapy and post-operative complication of the DIEP flap. However, the complication occurrence and aesthetic results remain in the acceptable range. The other factors such as age, body mass index, perforator number, neoadjuvant chemotherapy and adjuvant chemotherapy should not be considered as prognosis factor of post-operative complication of the DIEP flap.

[Neoadjuvant chemotherapy in breast cancer of consensuses and controversial perspectives].

Neoadjuvant chemotherapy (NACT) is a vital part of the systemic treatment to breast cancer. With the formation of consensuses on NACT, controversial perspectives on NACT have been widely discussed, especially in the fields of indication and therapeutic strategy. To define the indication of NACT, blind obedience to the results of clinical trials is not recommended. Instead, indications of NACT should be strictly controlled based on the targets of the clinical practice. Oriented by the early effectiveness of NACT, various chemotherapy or local therapeutics for different molecular subtypes of breast cancer should be conducted to the patients with unsatisfied effect. What's more, the evolvement of precision medicine accelerates the research of drugs and helps to form an individualized NACT plan. After clarifying the controversial opinions towards NACT in breast cancer, controlling the indication and optimizing the therapeutic strategy will improve the survival of breast cancer patients.

[Current trend of breast cancer neoadjuvant treatment in China: a cross-sectional study].

Objective: To investigate the current trend of breast cancer neoadjuvant therapy and provide reference for the improvement of breast cancer clinical guideline in the future. Methods: Questionnaires of cross-sectional survey were sent to 110 hospitals (breast cancer surgery quantity surpassing 200) between July 2018 and September 2018. The stages and subtypes, therapeutic regimen, treatment assession, operation choice and preforming of patients underwent neoadjuvant therapy were recorded. Results: Neoadjuvant treatment has been performed in all of the 110 hospitals. The total number of breast patients underwent neoadjuvant therapy was about 14 550 (17.0% in surgical patients) in 2017. For all of the neoadjuvant patients, the proportion of stageⅡ patients was less than 30% in 81 hospitals, and the proportion of stage Ⅲ was more than 50% in 84 hospitals. The numbers of estrogen receptor (ER) (+ )/human epidermal growth factor receptor-2 (HER-2) (-), ER (-)/HER-2 (+ ) and triple negative subtype breast cancer patients were 3 550 (24.4%), 6 024 (41.4%) and 4 991 (34.3%), respectively. Patient's scruples of relatively delayed operation and weak will of breast conservation after neoadjuvant therapy were the majority reasons for neoadjuvant therapy restriction. Anthracycline followed by taxane was the most usual neoadjuvant therapeutic regimens in 53.6% hospitals, and anthracycline plus taxane was the first choice in 42.7% hospitals. Chemotherapy with targeting therapy was recommended to HER-2 positive neoadjuvant patients in 80.9% hospitals. To assess treatment outcome of neoadjuvant treatment, 42.7% hospitals used MRI in more than 50% patients while the usage rate of MRI was less than 20% in 37.3% hospitals. The proportions of hospital using repeat-marking, tattoo and metal clip as the first method to identify the primary tumor region and lymph nodes were 60.0%, 29.1% and 10.9%, respectively. Breast-conservation rate after neoadjuvant therapy was less than 20% in 87.3% hospitals. Conclusions: Neoadjuvant therapy for breast cancer is widely performed in most hospitals in China, while the proportion of neoadjuvant treatment in patients with operable breast cancer is still low. Meanwhile, the idea of achieving de-escalation operation through neoadjuvant treatment is not promoted and the therapeutic evaluation method of neoadjuvant treatment needs further studies to improve.

[Challenges and countermeasures in the treatment of luminal breast cancer].

Luminal breast cancer is the most common subtype of breast cancer, representing more than 60% of all breast cancers. Endocrine resistance and late recurrence are two challenges in the treatment of luminal breast cancer. To overcome endocrine resistance in multiple levels, high-dose-fulvestrant can inhibit estrogen-receptor (ER)-dependent pathways, while targeted drugs can block ER-independent pathways.To reduce the risk of late recurrence in luminal breast cancer, recurrence prediction model should be formed. For patients with high risk of late recurrence, extended endocrine therapy, combination of ovarian function suppression (OFS) or vascular endothelial growth factor (VEGF) inhibitor could be utilized. Based on the challenges of the treatment, scientific research achievements can be used in clinical practice, and finally optimize the clinical treatment strategy.

[A single-center retrospective study on axillary evaluation in 1 557 breast ductal carcinoma in situ patients between 2006 and 2016].

Objectives: To examine the influence factors on axillary evaluation in ductal carcinoma in situ (DCIS) patients, and the prognosis of different choices of axillary evaluation in a single-center retrospective study. Methods: Totally 1 557 DCIS patients admitted in Department of Breast Surgery, Fudan University Shanghai Cancer Center from January 2006 to November 2016 were retrospectively enrolled. All patients were female. The median age was 49 years (range: 21 to 85 years). Surgical methods included modified radical mastectomy, simple mastectomy (with or without axillary evaluation) and breast conservation surgery (with or without axillary evaluation). Axillary evaluation included axillary lymph node dissection (ALND) and sentinel lymph node biopsy (SLNB). T tests, χ(2) test and Logistic regression analysis was used to analyze influence factors on axillary evaluation, respectively. Kaplan-Meier curve and Log-rank analysis were used to evaluate recurrence-free survival (RFS) and loco-regional recurrence-free survival (LRRFS) in patients with different surgical methods. Results: Among the 1 557 DCIS patients, there were 1 226 cases received axillary evaluation, while 331 cases not received axillary evaluation. Patients were separated into 3 groups by different axillary evaluation choices: SLNB group (957 cases, 61.46%), ALND group (197 cases, 12.65%) and no evaluation group (403 cases, 25.88%). The patients in SLNB group increased significantly (P=0.000), from 3.85% (60/1 557) in 2006 to 75.19% (1 170/1 557) in 2016. The independent influence factors of receiving axillary evaluation were high nuclear grade (OR=3.191, 95%CI: 1.722 to 5.912, P=0.001) and tumor size>15 mm (OR=1.698, 95%CI: 1.120 to 2.573, P=0.012). Also, patients received breast conservation surgery were more likely to refuse axillary evaluation (OR=0.155, 95%CI: 0.103 to 0.233, P=0.000). There were no significant differences in RFS and LRRFS in patients with different axillary evaluation choices. Conclusions: The investigation in trends and influence factors of different axillary evaluation choices provided basis on surgical precision medicine in DCIS patients. Patients received SLNB increased significantly. The independent influence factors of axillary evaluation were nuclear grade, tumor size and surgical methods. There was no significant differences in prognosis among the groups receiving different axillary evaluations.

[Current practice of implant-based breast reconstruction: results from China national practice questionnaire survey].

Objective: To explore the current clinical practice of implant-based breast reconstruction (IBBR) in China. Methods: The current survey was sponsored by Chinese Anti-Cancer Association, Committee of Breast Cancer Society and Chinese Society of Breast Surgeons. A survey was mailed to 110 hospitals in China, which have more than 200 breast cancer operations performed in 2017. The survey mainly included questions on the clinical practice of IBBR, sociodemographic and geographical factors associated with IBBR practice, reasons and concerns for selecting IBBR, type and timing of breast reconstruction, and the complications of IBBR. Data were analyzed using χ(2) test, Fisher's exact test or Kruskal-Wallis rank sum test. Results: IBBR was available in 86.4% (95/110) included hospitals. It was predominantly performed breast reconstruction surgery, the proportion of IBBR in all the breast reconstruction was 65.75% (4 296/6 534). However, the rate of IBBR in all the patients received mastectomy was only 7.06% (4 296/60 877). Among all the included hospitals, the number of implant reconstructions performed in 2017 was 24 (57.5) cases (M(Q(R)), range: 2-565 cases). Factors associated with the performance of IBBR including regional per capita gross domestic product (H=10.47, P=0.005) and annual surgery volume (H=8.30, P=0.016). The main reasons for choosing IBBR were relatively simple surgical procedure, short learning curve and short operation time. The effects of adjuvant radiotherapy on prosthesis, postoperative complications and patient satisfaction were the main concerns for implant reconstruction. Compared with delay reconstruction, a higher proportion of IBBR was observed in immediate reconstruction (83.1% vs. 62.0%, χ(2)=12.522, P=0.000). In all, 10.5% (10/95) hospitals reported more than 10% grade Ⅲ to Ⅳ capsular contracture. The incidence of infections need surgical intervention was reported between 10% and 20% by 4.2% (4/95) hospitals. Hospitals with 6% to 10% implant rupture and 6% to 15% implant removal were 1.1% (1/95) and 4.2% (4/95) respectively. Conclusions: IBBR was the most common used surgery in breast reconstruction after mastectomy. However, the proportion of IBBR in patients after mastectomy was still low. Reginal economy, surgery volume of hospitals, lack of specialty training program and the concern about complications and patient's satisfaction were the factors affecting the development of IBBR.

[Current trends of breast reconstruction after mastectomy in China: a cross-sectional study].

Objective: To investigate the current trends of breast reconstruction(BR) after mastectomy in China. Methods: A list of hospitals with more than 200 cases of breast cancer surgery per year nationwide was obtained, and 110 institutions were selected according to the geographical distribution. The research was conducted in the form of a questionnaire survey, and 92.3% (169/183) of the questions were single-choice questions. Information such as demographics of surgeons and hospitals, number of mastectomy and BR, type and timing of BR was included in the survey. Survey formal notification letter was issued by the China Anti-Cancer Association Breast Cancer Committee and Chinese College of Surgeons, Committee of Mammary Surgeons. Questionnaires were sent to the respondents of each center by email. The survey time range was from January 1, 2017 to December 31, 2017. All data were completely collected before September 7, 2018. Results: A total of 110 units participated in the survey. In total, 87.3% (96/110) of the hospitals have conducted BR surgery. The BR after mastectomy was 10.7% (6 534/61 099), among this, implant BR accounted for 65.7%(4 296/6 534), autologous BR accounted for 20.1% (1 312/6 534), and autologous combined implant BR accounted for 14.2% (927/6 534). Immediate reconstruction accounted for 67.6% (4 417/6 534) of BR, while delayed BR accounted for 32.4% (2 097/6 534). In 2017, 77.8% (35/45) of the plastic surgery departments cooperated with general surgery departments. General BR could be conducted after mastectomy accounted for 83.6% (92/110). The proportion of reconstruction was positively correlated with the gross domestic product (GDP) per capita (r=0.311, P=0.002). The one-step implant-based BR(IBBR) was the most preferred type in immediate BR. Two-step IBBR was the most preferred method in delayed BR. Hospitals that routinely evaluated aesthetics after BR accounted for 64.6% (62/96), while only 16.7% (16/96) of hospitals used patient-reported outcome measure (PROM). The most commonly used PROM tool was BREAST-Q. Conclusions: The overall BR in China is on upward trend, but gap between China and the developed countries still exists. Breast surgery departments should strengthen further cooperation with plastic surgery departments. Simultaneously, the aesthetics evaluation and PROM after BR should be put a high premium.

[Comprehensive management guideline for breast cancer follow-up and concomitant diseases].

In recent years, with the emphasis on breast cancer screening and the improvement of breast cancer diagnosis and treatment, five-year survival rate and the overall survival time of breast cancer patients have been significantly improved in China. The adverse events caused by patients' age, changes in hormone levels or anti-cancer treatment during follow-up have become new challenges in the management of patients with breast cancer, not only affecting the quality of life, but also impacting disease recurrence and death. The management of patients should not be restricted to the diagnosis and treatment of breast cancer, but to a most comprehensive management. This could improve the therapeutic efficacy of anti-cancer treatment and the quality of life of patients. Based on the current landscape of treatment and follow-up of breast cancer patients in China, the experts committee drafted the "Comprehensive Management Guideline for Breast Cancer Follow-up and Concomitant Diseases" according to the literature and relevant guidelines. This guideline is composed of four parts: path diagram, follow-up management, concomitant diseases and adverse events management. It aims to standardize the long-term follow-up of breast cancer patients, guide clinicians to deal with the concomitant diseases and adverse events, and further improve the prognosis and quality of life of breast cancer patients in China.

Biomarker assessment of the CBCSG006 trial: a randomized phase III trial of cisplatin plus gemcitabine compared with paclitaxel plus gemcitabine as first-line therapy for patients with metastatic triple-negative breast cancer.

Background: CBCSG006 trial reported the superior efficacy of cisplatin plus gemcitabine (GP) regimen than paclitaxel plus gemcitabine (GT) regimen as first-line treatment of metastatic triple-negative breast cancer (mTNBC). This study focused on the updated survival data and the explorations of potential biomarkers for efficacy. Patients and methods: Germ-line mutations of homologous recombination (HR) panel, BRCA1/2 included, were evaluated in 55.9% (132/236) patients. PD-L1 expression was evaluated in 48.3% (114/236) patients. A nonparametric sliding-window subpopulation treatment effect pattern plot (STEPP) methodology was used to analyze the absolute survival benefits. All statistical tests were two-sided. Results: Median progression-free survival (PFS) was 7.73 [95% confidence interval (CI) 6.46-9.00] months for GP arm and 6.07 (95% CI 5.32-6.83) months for GT arm (P = 0.005). No significant difference in overall survival (OS) was observed. There was significant interaction between HR status and treatment for PFS and status of HR deficient significantly correlated with higher objective response rate (ORR) and longer PFS in GP arm than in GT arm (71.9% versus 38.7%, P = 0.008; 10.37 versus 4.30 months, P = 0.011). There was no significant interaction between germ-line BRCA1/2 (gBRCA1/2) status and treatment for PFS. Patients with gBRCA1/2 mutation had numerically higher ORR and prolonged PFS in GP arm than in GT arm (83.3% versus 37.5%, P = 0.086; 8.90 versus 3.20 months, P = 0.459). There was no significant interaction between PD-L1 status and treatment for PFS, and no significant differences in ORR, PFS or OS between two arms regardless of PD-L1 status. In STEPP analysis, patients with lower composite risks had more absolute benefits in PFS than those with higher composite risks. Conclusions: GP regimen has superior efficacy than GT regimen as first-line chemotherapy for mTNBC patients. Germ-line mutations of BRCA1/2 and HR panel are possible biomarkers for better performance of cisplatin-based regimens. A composite risk model was developed to guide patient selection for GP treatment in TNBC patients. Trial registration: ClinicalTrials.gov, NCT01287624.

[Cost-effectiveness of multiple screening modalities on breast cancer in Chinese women from Shanghai].

Objective: To determine the most cost-effective modality for breast cancer screening in women living in Shanghai. Methods: A Markov model for breast cancer was redeveloped based on true effect which was derived from a project for detection of women at high risk of breast cancer and an organized breast cancer screening program conducted simultaneously in Minhang district, Shanghai, during 2008 to 2012. Parameters of the model were derived from literatures. General principles related to cost-effectiveness analysis were used to compare the costs and effects of 12 different screening modalities in a simulated cohort involving 100 000 women aged 45 years. Incremental cost-effectiveness ratio (ICER) was used to determine the most cost-effective modality. Sensitivity analysis was conducted to evaluate how these factors affected the estimated cost-effectiveness. Results: The modality of biennial CBE followed by ultrasonic and mammography among those with positive CBE was observed as the most cost-effective one. The costs appeared as 182 526 Yuan RMB per life year gained and 144 386 Yuan RMB per quality adjusted life-year (QALY) saved, which were within the threshold of 2-3 times of local per capita Gross Domestic Product. Results from sensitivity analysis showed that, due to higher incidence rate of breast cancer in Shanghai, the cost per QALY would be 64 836 Yuan RMB lower in Shanghai than the average level in China. Conclusion: Our research findings showed that the biennial CBE program followed by ultrasonic and mammography for those with positive CBE results might serve as the optimal breast cancer screening modality for Chinese women living in Shanghai, and thus be widely promoted in this population elsewhere.

[Chinese expert consensus on the diagnosis and treatment of breast carcinoma in situ].

In situ carcinomas of the breast constitute 15% to 30% of all newly diagnosed breast cancer cases. Although the concept of carcinoma in situ has been proposed for a long time, there is still a great controversy regarding the screening, diagnosis and treatment. This article attempts to reach some consensus on the management of ductal carcinoma in situ and lobular carcinoma in situ and provide references for clinicians in the following aspects: definition and classification, natural history and prognosis, diagnosis, local and systemic treatment for primary carcinoma in situ, recurrence risk and treatment approaches for recurrent cancers.

[Incidental internal mammary lymph node biopsy in 113 cases of breast cancer undergoingfree abdominal flap breast reconstruction and its influencing factors].

Objective: The aim of the current study is to determine the clinical value of incidental internal mammary lymph node biopsy in free abdominal flap breast reconstruction using internal mammary vessels as recipient vessels and to investigate the risk factors of internal mammary lymph nodes metastasis. Methods: The clinical data of all patients who underwent free abdominal flap breast reconstruction using internal mammary vessels as recipient vessels from November 2006 to December 2015 in the Department of Breast Surgery, Fudan University Shanghai Cancer Center were reviewed in the study. The incidence of internal mammary lymph node biopsy and the rate of metastasis were analyzed. Statistical analysis was conducted to evaluate the risk factors of internal mammary lymph node metastasis. Results: A total of 113 patients met the inclusion criteria, 53 (46.9%) of whom had internal mammary lymph nodes harvested. Four of these were positive for metastatic disease, all in immediate breast reconstructions. The incidence of metastasis was 7.5% in patients who had successful internal mammary lymph node biopsies.The multi-variate Logistic regression analysis showed that invasive tumor size, tumor location and axillary lymph node metastasis were not risk factors for internal mammary lymph node metastasis (P>0.05). Conclusions: Internal mammary lymph nodes found incidentally during recipient vessel exposure may provide important information about internal mammary lymph node metastasis in free flap breast reconstruction. This approach for internal mammary lymph node biopsy reveals an appreciable success rate and is convenient in clinical practice. The size of invasive tumor and the axillary lymph node metastasis are probably associated with internal mammary lymph node positivity.

Better predictive value of axillary lymph node (ALN) status after systemic therapy for operable HER2-overexpressing breast cancer: A single-institution retrospective study.

BACKGROUND: Thresholds for using Preoperative Systemic Therapy (PreST) have decreased to include early breast cancer. This study investigates the predictive value of axillary lymph node (ALN) status before and after systemic therapy and discusses whether it is better to receive PreST first in operable HER2-overexpressing breast cancer patients. METHODS: From January 2008 to June 2013 at Fudan University Shanghai Cancer Center, we identified 406 eligible female patients with stage II-IIIa, operable and pathologically confirmed HER2-overexpressing invasive ductal carcinoma. Of these patients, 269 underwent surgery first followed by chemotherapy plus trastuzumab (chemo-trastuzumab) (SurgFirst group), whereas 137 received systemic chemo-trastuzumab therapy first followed by surgery (STFirst group). Disease-free survival (DFS) and overall survival (OS) were evaluated according to different ALN statuses using the Kaplan-Meier method. Multivariate COX model analyses were also conducted. RESULTS: The median follow-up time was 47 months (IQR: 37-60). Both ALN status and overall pathological complete remission (pCR) status were shown to be significant for the prediction of DFS (p = 0.001 and p = 0.005, respectively) and OS (p = 0.009 and p = 0.027, respectively) in the STFirst group. However, patients with positive ALN(s) did not experience significantly poorer survival compared with those with negative ALN in the SurgFirst group. The adjusted hazard ratios (HRs) for positive ALN status in the STFirst and SurgFirst groups were 6.66 (p = 0.001, 95%CI: 2.18-20.38) and 2.40 (p = 0.126, 95%CI: 0.78-7.34), respectively. CONCLUSION: The ALN status after systemic chemo-trastuzumab therapy better predicts the survival outcome. We recommend the application of PreST followed by surgery in patients with operable HER2-overexpressing breast cancer.

[Breast cancer research in the era of precision medicine].

Precision medicine is an emerging medical strategy that takes into account individual molecular variations of disease to guide accurate prevention and treatment.Tumor molecular markers closely related to aggressive behavior and treatment response will be identified by integrating clinical information and multiple-omics, and will be verified in well-designed clinical trials. Breast cancer is a highly heterogeneous disease. Its treatment based on molecular subtyping has achieved initial success. However, drug resistance and tumor heterogeneity are still major challenges. This review will focus on the recent progress and future prospects of clinical research on breast cancer in the era of precision medicine.

MiRNA-621 sensitizes breast cancer to chemotherapy by suppressing FBXO11 and enhancing p53 activity.

MicroRNAs (miRNAs) have been demonstrated to have critical roles in regulating cancer cell proliferation, survival and sensitivity to chemotherapy. The potential application of using miRNAs to predict therapeutic response to cancer treatment holds high promise, but miRNAs with predictive value remain to be identified and underlying mechanisms have not been completely understood. Here, we show a strong correlation between miR-621 expression and chemosensitivity to paclitaxel plus carboplatin (PTX/CBP) regimen, an effective neoadjuvant chemotherapy for breast cancer patients. High level of miR-621 predicts better response to PTX/CBP regimen neoadjuvant chemotherapy in breast cancer patients, who also tend to achieve pathological complete response. Ectopic overexpression of miR-621 promoted apoptosis and increased chemosensitivity to PTX and CBP both in cultured breast cancer cells and in xenograft tumor model. We further show that FBXO11 is a direct functional target of miR-621 and miR-621 level is negatively correlated with FBXO11 expression in breast cancer patients. Ectopic expression of FBXO11 attenuated increased apoptosis in breast cancer cells overexpressing miR-621 upon PTX or CBP treatment. Consistently, high FBXO11 expression significantly correlated with poor survival in breast cancer patients. Mechanistically, we found in breast cancer cells FBXO11 interacts with p53 and promotes its neddylation, which suppressed the p53 transactivity. Accordingly, miR-621-dependent FBXO11 suppression enhanced p53 activity and increased apoptosis in breast cancer cells exposed to chemotherapeutics. Taken together, our data suggest that miR-621 enhances chemosensitivity of breast cancer cells to PTX/CBP chemotherapy by suppressing FBXO11-dependent inhibition of p53. miR-621 may serve as a predictive biomarker and a potential therapeutic target in breast cancer treatment.

Hsa-miR-206 represses the proliferation and invasion of breast cancer cells by targeting Cx43.

OBJECTIVE: Hsa-miR-206, a microRNA, was found to be able to switch subtypes by targeting ER-α in breast cancer. However, there are few studies addressing the role of miR-206 in triple-negative breast cancer (TNBC). The purpose of this study was to evaluate the metastatic-regulatory ability of miR-206 in TNBC. MATERIALS AND METHODS: We treated two TNBC lines (MDA-MB-231 and MDA-MB-436) with miR-206 mimics, inhibitors and paired controls and examined the in vitro and in vivo functions of miR-206 via the degradation of Connexin43 (Cx43). A luciferase reporter assay was used to identify the binding site of GJA1 (gap junctional intercellular communication) (Cx43) and miR-206. Furthermore, quantitative RT-PCR was used to evaluate miR-206 expression in 77 breast cancer samples to determine the association with lymph node status and Cx43 expression. RESULTS: Up-regulation of miR-206 in TNBC contributed to a decreasing metastatic potential, as demonstrated by a reduction of cell viability and proliferation, decreased cell migration and invasion, lower expression levels of matrix metalloproteinase (MMP)-2, MMP-9 and a higher expression level of breast cancer metastatic suppressor (BRMS)-1. In vitro dual luciferase assays showed GJA1 (Cx43) is a target of miR-206. Quantitative RT-PCR was conducted to evaluate miR-206 expression in 77 breast cancer samples to determine the associations between miR-206 levels and both lymph node status and Cx43 expression. Restoring Cx43 expression positively regulated cell adhesion and GJA1, which may facilitate metastasis. MiR-206 significantly attenuated the proliferation and metastatic potential of cancer cells but did not inhibit tumor onset in a mouse xenograft model because of the dual function of Cx43. CONCLUSIONS: Our results suggest hsa-miR-206 may repress the tumor proliferation and invasion in breast cancer by targeting Cx43.

Norepinephrine attenuates CXCR4 expression and the corresponding invasion of MDA-MB-231 breast cancer cells via ß2-adrenergic receptors.

OBJECTIVE: The growing evidence from laboratory and clinical studies has shown that the stress hormone, norepinephrine, and chronic stress promote tumor progression in a variety of tumor types. Chemokines and chemokine receptors have been shown to play a pivotal role in tumor progression. Recently, norepinephrine was reported to have a significant effect on macrophage migration by altering the expression of the chemokine receptor CCR2. MATERIALS AND METHODS: We investigated whether chemokines and their receptors are involved in the effects of norepinephrine on breast cancer. First, we used microarray analyses to detect the alteration of 128 chemotactically relevant genes after MDA-MB-231 cells were treated for 12 h with 100 µM norepinephrine. The CXCR4 gene demonstrated the greatest response to norepinephrine treatment, with a reduction of transcription of 95.7%, and was the focus of subsequent investigations. Real-time reverse transcription-PCR was used to determine the level of CXCR4 transcription after treatment with norepinephrine at various concentrations and for different durations. RESULTS: The results revealed that norepinephrine reduced CXCR4 transcription in a dose-dependent manner. Norepinephrine was also found to exert a negative effect on CXCR4 translational expression, as evidenced by a 44 ± 1.7% reduction in expression after a 12-h treatment with 10 µM norepinephrine. A Matrigel assay demonstrated a 51.3 ± 9.1% reduction in the number of MDA-MB-231 cells driven to migrate by CXCR4. Finally, we found the specific ß2-adrenergic antagonist, ICI 118,551, eliminated the impact of norepinephrine on CXCR4 expression. CONCLUSIONS: Norepinephrine attenuates CXCR4 expression and the corresponding invasion of MDA-MB-231 tumor cells via the ß2-adrenergic receptor. The complexity of the ß2-adrenergic receptor signaling pathway might contribute to these unexpected observations in our research, and this justifies further investigation into the intricate mechanisms involved.

Nodal ratio of positive to excised nodes, but not number of positive lymph nodes is better to predict group to avoid chemotherapy among postmenopausal ER-positive, lymph node-positive T1-T2 breast cancer patients.

AIM OF STUDY: To identify whether nodal ratio (NR) of positive to excised nodes is superior to number of positive lymph nodes to predict group to avoid chemotherapy among postmenopausal ER-positive, lymph node-positive, T1-T2 breast cancer patients. MATERIALS AND METHODS: Postmenopausal estrogen receptor (ER)-positive, lymph node-positive patients who received endocrine therapy (n = 173) with complete baseline data in our hospital between 2000 and 2006 were included. The disease-free survival (DFS) was compared. Survival analysis was performed using Kaplan-Meier method. Cox proportional hazard models were used to evaluate the prognostic value of chemotherapy with different NR for DFS. P--values less than 0.05 were regarded as significant. RESULTS: The median follow-up was 72 months. Three of 13 variables analyzed remained significantly prognostic for survival in the Cox proportional hazards model. These included age (hazard ratio (HR) =1.642, 95% confidence interval (CI) =1.154-2.337, P = 0.006); histological grade (HR = 2.463,95% CI = 1.389-4.367, P = 0.002); and NR (HR = 2.280, 95% CI = 1.113-4.671, P = 0.024). Subgroup analysis by NR status showed that in patients with NR ≥ 0.20, chemotherapy significantly improves DFS (HR = 0.360, 95% CI = 0.195-0.663, P = 0.001); while in patients with NR < 0.20, chemotherapy did not significantly affect DFS (HR = 0.677, 95% CI = 0.227-2.107, P = 0.493). Radiotherapy is an important factor that improves DFS in lymph node-positive patients, so it is considered in all analysis. CONCLUSION: This retrospective analysis demonstrates that NR of positive to excised nodes, but not number of positive lymph nodes is better to predict group to avoid chemotherapy among postmenopausal ER-positive, lymph node-positive T1-T2 breast cancer patients.

Effects of rehabilitation management on gastric emptying function in older adults with diabetes.

The relationship between gastric emptying dysfunction and blood glucose concentration in elderly with type 2 diabetes mellitus was investigated, and the effect of rehabilitation exercise prescription training on gastric emptying in the geriatric diabetic patients was evaluated. A total of 160 older type 2 diabetic adults and 30 cases of non-diabetic patients were studied with regard to the gastric half emptying time (GET1/2) of solid meals radiolabelled with 99mTc. Eighty delayed gastric emptying diabetic patients were randomly divided into 4 four groups: rehabilitation exercise + mosapride group (N = 20), rehabilitation exercise group (N = 20), mosapride group (N = 20), and control group (N = 20). The level of blood glucose was measured every six months in a two-year follow-up. The solid GET1/2 of regulated blood glycemic control patients showed no statistically significant differences from non-diabetic patients (P > 0.05). However, the value for poor blood glycemic control patients exhibited significant statistical differences compared with both non-diabetic (P < 0.01) and regulated blood glycemic control group patients (P < 0.01). It showed that the gastric emptying time improved in the rehabilitation exercise group, mosapride group and rehabilitation exercise group + mosapride group after two years of treatment (P < 0.05). Fasting blood glucose in both rehabilitation exercise group and rehabilitation exercise + mosapride group was significantly decreased. Postprandial blood glucose in the rehabilitation exercise group, mosapride group, rehabilitation exercise group + mosapride group was significantly decreased. High blood glucose level can delay gastric emptying in older type 2 diabetic patients. Gastric emptying and blood glucose control affect each other. It was shown that appropriate rehabilitation exercise combined with prokinetic agent may improve gastric emptying in some geriatric type 2 diabetic patients and help control their blood glucose.