HR-positive/HER2-negative breast cancer arising in patients with or without BRCA2 mutation: different biological phenotype and similar prognosis.

Background: BRCA2 plays a key role in homologous recombination. However, information regarding its mutations in Chinese patients with breast cancer remains limited. Objectives: This study aimed to assess the clinicopathological characteristics of BRCA2 mutation breast cancer and explore the mutation's effect on hormone receptor (HR)-positive/human epidermal growth factor receptor 2 (HER2)-negative breast cancer survival in China. Design: This hospital-based cohort study prospectively included 629 women with breast cancer diagnosed from 2008 to 2023 at Zhejiang Cancer Hospital in China. Methods: We compared the clinicopathological characteristics and metastatic patterns and analysed the invasive disease-free survival (iDFS), distant relapse-free survival (DRFS) and first-line progression-free survival (PFS1) of patients with HR-positive/HER2-negative breast cancer according to BRCA2 mutations. Results: Among the 629 patients, 78 had BRCA2 mutations (12.4%) and 551 did not (87.6%). The mean age at diagnosis was lower in the BRCA2 mutation breast cancer group than in the non-mutation breast cancer group (38.91 versus 41.94 years, p = 0.016). BRCA2 mutation breast cancers were more likely to be lymph node-positive than non-mutation breast cancers (73.0% versus 56.6%, p = 0.037). The pathological grade was higher in 47.1% of BRCA2 mutation breast cancers than in 29.6% of non-mutation breast cancers (p = 0.014). The proportions of patients with BRCA2 mutations who developed contralateral breast cancer (19.2% versus 8.8%, p = 0.004), breast cancer in the family (53.8% versus 38.3%, p = 0.009) and ovarian cancer in the family (7.6% versus 2.4%, p = 0.022) were higher than those of patients without the mutation. The median follow-up time was 92.78 months. Multivariate analysis showed that BRCA2 mutation was not associated with poorer iDFS [hazard ratio = 0.9, 95% confidence interval (CI) = 0.64-1.27, p = 0.56] and poorer distant relapse-free survival (DRFS) (hazard ratio = 1.09, 95% CI = 0.61-1.93, p = 0.76). There was no significant difference between the two groups with regard to metastatic patterns in the advanced disease setting. In the first-line metastatic breast cancer setting, PFS1 expression was broadly similar between the two groups irrespective of chemotherapy or endocrine therapy. Conclusion: HR-positive/HER2-negative breast cancer with BRCA2 mutations differs from those without mutations in clinical behaviour and reflects more aggressive tumour behaviour. Our results indicate that BRCA2 mutations have no significant effect on the survival of Chinese women with HR-positive/HER2-negative breast cancer.

LncRNA TDRKH-AS1 promotes breast cancer progression via the miR-134-5p/CREB1 axis.

BACKGROUND: Breast cancer (BC) is a prevalent malignancy with complex etiology and varied clinical behavior. Long non-coding RNAs (lncRNAs) have emerged as key regulators in cancer progression, including BC. Among these, lncRNA TDRKH-AS1 has been implicated in several cancers, but its role in BC remains unclear. METHODS: We conducted a comprehensive investigation to elucidate the role of TDRKH-AS1 in BC. Clinical samples were collected from BC patients, and BC cell lines were cultured. Bioinformatics analysis using the starBase database was carried out to assess TDRKH-AS1 expression levels in BC tissue samples. Functional experiments, including knockdown, colony formation, CCK-8, Transwell, and wound-healing assays, were conducted to determine the role of TDRKH-AS1 in BC cell proliferation and invasion. Luciferase reporter and RIP assays were used to examine the interactions between TDRKH-AS1 and miR-134-5p. In addition, the downstream target gene of miR-134-5p, cAMP response element-binding protein 1 (CREB1), was identified and studied using various methods, including RT-qPCR, immunoprecipitation, and rescue experiments. In vivo experiments using mouse tumor xenograft models were conducted to examine the role of TDRKH-AS1 in BC tumorigenesis. RESULTS: TDRKH-AS1 was found to be significantly upregulated in BC tissues and cell lines. High TDRKH-AS1 expression correlated with advanced BC stages and worse patient outcomes. Knockdown of TDRKH-AS1 led to decreased BC cell proliferation and invasion. Mechanistically, TDRKH-AS1 acted as a sponge for miR-134-5p, thereby reducing the inhibitory effects of miR-134-5p on CREB1 expression. Overexpression of CREB1 partially rescued the effects of TDRKH-AS1 knockdown in BC cells. In vivo studies further confirmed the tumor-promoting role of TDRKH-AS1 in BC. CONCLUSIONS: Our study unveiled a novel regulatory axis involving TDRKH-AS1, miR-134-5p, and CREB1 in BC progression. TDRKH-AS1 functioned as an oncogenic lncRNA by promoting BC cell proliferation and invasion through modulation of the miR-134-5p/CREB1 axis. These findings highlighted TDRKH-AS1 as a potential diagnostic biomarker and therapeutic target for BC treatment.

The Value of Neoadjuvant Anthracycline-Based Regimens for HER2-Positive Breast Cancer: A Systematic Review and Meta-analysis Including 1366 Patients.

Background: The standard recommendation for neoadjuvant therapy for human epidermal growth factor receptor-2 (HER2)-positive breast cancer patients is trastuzumab in combination with chemotherapy, but there is no current standard recommendation for appropriate chemotherapy regimens. This meta-analysis evaluated the efficacy and cardiac safety of the concurrent use of anti-HER2 targeted drugs and anthracycline-based neoadjuvant chemotherapy (NAC) for HER2-positive breast cancers. Methods: The pooled odds ratio (OR) rate for pathologic complete response (pCR), the pooled hazard ratio (HR) of overall survival (OS), and the left ventricular ejection fraction (LVEF) decline events were all calculated. Differences in efficacy, prognosis, and cardiac safety were compared between patients receiving an anthracycline-containing regimen (AB) and those treated with non-anthracycline-based (nAB) NAC. Results: A total of 1366 patients in 4 prospective and 3 retrospective studies were included in the meta-analysis. The pooled OR for pCR rate was 0.73 with a 95% confidence interval (CI) of 0.43 to 1.24 (P = .246). Subgroup analysis of low tumor burden cases showed no improvement in pCR rate for patients in the AB group compared with nAB, with the pooled OR rate being 0.73 with a 95% CI of 0.37 to 1.44 (P= .357). The 3-year OS rate was 95.63% and 95.54% in the AB and nAB groups, respectively, with no statistical difference (P= .157). There was a significant increase in the rate of LVEF decline of 19.07% in the AB group compared with 13.33% for the nAB group, with an HR of 1.62 and a 95% CI of 1.11 to 2.36 (P = .013). Conclusions: The addition of anthracyclines did not improve pCR rates and survival after neoadjuvant and the increased cardiotoxicity of anthracyclines further limited their application. This study showed that it was feasible to use anti-HER2 drugs without anthracyclines in neoadjuvant therapy for HER2-positive breast cancer patients.

A comprehensive analysis of Fanconi anemia genes in Chinese patients with high-risk hereditary breast cancer.

BACKGROUND: Four Fanconi anemia (FA) genes (BRCA1, BRCA2, PALB2 and RAD51C) are defined as breast cancer (BC) susceptibility genes. Other FA genes have been inconsistently associated with BC. Thus, the role of other FA genes in BC should be explored in specific populations. METHODS: Mutations in 16 FA genes were screened with a 98-gene panel sequencing assay in a cohort of 1481 Chinese patients with high-risk hereditary BC. The association between mutations and clinicopathological characteristics as well as prognosis was analyzed. The risk of BC in carriers of FA gene mutations was assessed in the Genome Aggregation Database and the Westlake Biobank for Chinese cohort. RESULTS: A total of 2.57% (38/1481) BC patients were identified who had 12 other FA gene germline mutations. Among them, the most frequently mutated gene was FANCA (8/1481, 0.54%). These 38 patients carried 35 distinct pathogenic/likely pathogenic variants, of which 21 were novel. We found one rare FANCB deleterious variant (c.1327-3dupT) in our cohort. There was a statistically significant difference in lymph node status between FA gene mutation carriers and non-carriers (p = 0.041). We observed a trend that mutation carriers had larger tumor sizes, lower estrogen receptor (ER) and progesterone receptor (PR) positivity rates, and lower 3.5-year invasive disease-free survival (iDFS) and distant recurrence-free survival (DRFS) rates than non-carriers (tumor size > 2 cm: 51.43% vs. 45.63%; ER positivity rates: 51.43% vs. 60.81%; PR positivity rates: 48.57% vs. 55.16%; 3.5-year iDFS rates: 58.8% vs. 66.7%; 3.5-year DRFS rates: 58.8% vs. 68.8%). The frequency of the mutations in FANCD2, FANCM and BRIP1 trended to be higher among BC cases than that in controls (p = 0.055, 0.08 and 0.08, respectively). CONCLUSION: This study comprehensively estimated the prevalence, clinicopathological characteristics, prognosis and risk of BC associated with deleterious variants in FA genes in Chinese high-risk hereditary BC patients. It enriches our understanding of the role of FA genes with BC.

Neoadjuvant Pyrotinib plus Trastuzumab, Docetaxel, and Carboplatin in Early or Locally Advanced Human Epidermal Receptor 2-Positive Breast Cancer in China: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Phase 2 Trial.

INTRODUCTION: This multicenter, randomized, double-blind, placebo-controlled phase 2 trial compared the efficacy, and safety of adding pyrotinib to trastuzumab, docetaxel, and carboplatin versus placebo, trastuzumab, docetaxel, and carboplatin in Chinese patients with human epidermal receptor 2 (HER2)-positive early or locally advanced breast cancer (ClinicalTrials.gov identifier: NCT03756064). METHODS: Sixty-nine women with HER2-positive early (T1-3, N0-1, M0) or locally advanced breast cancer (T2-3, N2 or N3, M0; T4, any N, M0) were recruited from October 1, 2019, to June 1, 2021. Before surgery, patients received 6 cycles of orally pyrotinib (400 mg once per day), trastuzumab (8-mg/kg loading dose and 6-mg/kg maintenance doses), docetaxel (75 mg/m2), and carboplatin (AUC = 6 mg/mL·min) or orally placebo, trastuzumab, and docetaxel, and carboplatin every 3 weeks. The primary end point was independent review committee-assessed total pathologic complete response rate. The 2-sided Cochran-Mantel-Haenszel test, stratified by age, hormone receptor status, tumor stage, nodal status, cTNM stage, and Ki-67 level was used to compare rates between treatment groups. RESULTS: In total, 69 female patients were randomized (pyrotinib, 36; and placebo, 33; median age, 53 [31-69] years). In the intention-to-treat population, total pathologic complete response rates were 65.5% (19/29) in the pyrotinib group and 33.3% (10/30) in the placebo group (difference, 32.2%, p = 0.013). Diarrhea was been reported in 86.1% of patients (31/36) in the pyrotinib group as the most common adverse events (AEs) and 15.2% of patients (5/33) in the placebo group. But no grade 4 or 5 AEs were reported. CONCLUSION: Treatment with pyrotinib, trastuzumab, docetaxel, and carboplatin resulted in a statistically significant improvement in the total pathologic complete response rate versus placebo, trastuzumab, docetaxel, and carboplatin for the neoadjuvant treatment of HER2-positive early or locally advanced breast cancer in Chinese patients. Safety data were in line with the known pyrotinib safety profile and generally comparable between treatment groups.

Long non-coding RNAs in breast cancer stem cells.

Breast cancer, one of the most commonly diagnosed cancers worldwide, is a heterogeneous disease with high rates of recurrence and metastasis that contribute to its high mortality rate. Breast cancer stem cells (BCSCs) are a small but significant subset of heterogeneous breast cancer cells that possess stem cell characteristics such as self-renewal and differentiation abilities that may drive metastasis and recurrence. Long non-coding RNAs (lncRNAs) are a class of RNAs that are longer than 200 nucleotides in length and do not possess protein-coding properties. An increasing number of studies have shown that some lncRNAs are abnormally expressed in BCSCs, and have great biological significance in the occurrence, progression, invasion, and metastasis of various cancers. However, the importance of lncRNAs, as well as the molecular mechanisms that regulate and promote the stemness of BCSCs, are still poorly understood. In the current review, we aim to summarize recent studies that highlight the role of lncRNAs in tumor occurrence and progression through BCSCs. In addition, the utility of lncRNAs as biomarkers of breast cancer progression, and their potential use as therapeutic targets for treatment of breast cancer, will be discussed.

Physical activity (PA) influences the risk of depression associated with long working hours.

BACKGROUND: Growing evidences showed that long working hours is associated with depression epidemic, but few studies investigate whether physical activity (PA) could modify the risk of depression associated with long working hours, which was the purpose of the present study. METHODS: A cross-sectional data obtained from the National Health and Nutrition Examination Survey 2015-2018. According to the criteria of International Labour Organization, long working hours was defined as >40 h/wk. The Nine-item Patient Health Questionnaire (PHQ-9) was used to identify depression. Binary logistic regression and restricted cubic spline (RCS) models were used to estimate the associations between long working hours and depression, furthermore to estimate the association of PA. RESULTS: 5958 participants were included in the study. The results indicated that 3074 (51.6 %) of participants worked >40 h/wk. The prevalence of depression was 7.7 %. Logistic regression analysis indicated a positive association between long working hours and depression [OR = 1.738, 95 CI (1.427, 2.117)], and the results were still robust after controlling other confounding factors. RCS models indicated that the high intensity PA group had the lowest risk of depression, followed by low intensity PA group and no PA group. CONCLUSION: Long working hours probably be associated with depression, while PA can modify the risk to some degree.

α-Cyperone ameliorates depression in mammary gland hyperplasia and chronic unpredictable mild stress rat by regulating hormone, inflammation, and oxidative stress.

BACKGROUND: Hyperplasia of mammary gland (HMG) is caused by endocrine disorders, and patients are prone to anxiety and depression. α-Cyperone has a variety of pharmacological activities including antidepressant. The purpose of this study was to explore the effect and its possible mechanism of α-Cyperone on HMG-associated depression rats. METHODS: The depression model was constructed using chronic unpredictable mild stress (CUMS), while the HMG model was induced by estrogen, with or without α-Cyperone intervention. The effect of α-Cyperone on the depression-like phenotype of model rats was measured by sucrose preference test (SPT), forced swim test (FST), and open field test (OFT). Dendritic spines density in ventral medial prefrontal cortex (vmPFC) neurons was evaluated by Golgi staining. The second pair of nipple height, diameter, organ index, and oxidative stress-related factors were analyzed. Serum sex hormone concentration, histopathological changes, inflammatory factor expression, and p65 were evaluated by enzyme-linked immunosorbent assay (ELISA), hematoxylin and eosin (HE) staining, real-time quantitative PCR and western blot, respectively. RESULTS: The sucrose preference rate, dendritic spine density decreased, and immobility time increased in CUMS rats; α-Cyperone reversed the effect of CUMS on depression-like behavior and dendritic spine density in rats. α-Cyperone reduced nipple height and diameter, uterine index, estradiol concentration, increased ovary, thymus, spleen index, progesterone, and testosterone concentration, relieved pathological damage, oxidative stress, depression-like behavior, and inflammatory reaction in HMG combine CUMS rats. In addition, α-Cyperone inhibited the phosphorylation of p65 in HMG and CUMS rats. CONCLUSIONS: α-Cyperone has an effective therapeutic effect on HMG combined with CUMS rats.

Associations Between Serum Reproductive Hormone Concentrations and Hormonal Receptor Status Among Postmenopausal Chinese Women With Breast Cancer: An Observational Study.

Background and Objectives: Reproductive hormones and receptors play crucial roles in breast cancer development and progression. The association between preoperative serum reproductive hormone levels and receptor status in postmenopausal women with breast cancer remains unclear. Therefore, this study investigated the relationship between serum reproductive hormone concentrations and patient characteristics and hormone receptor status among postmenopausal Chinese women with breast cancer. Materials and Methods: The medical records of 352 postmenopausal breast cancer patients who underwent an operation between October 2007 and October 2010 at the Department of Breast Tumor Surgery of Zhejiang Cancer Hospital were retrospectively evaluated. Serum levels of reproductive hormones were measured before surgery by liquid-chromatography tandem mass spectrometry. Hormone receptor levels were measured by an immunohistochemical assay using a mouse monoclonal antibody. The associations between serum hormone concentrations and hormone receptors were investigated by analysis of covariance. Results: In this patient cohort, the serum level of luteinizing hormone (LH) declined with PMP duration. The median LH concentration was significantly higher in patients within 5 years of PMP than that in patients with PMP duration exceeding 5 years (23 vs. 18.32 mIU/ml, P <.0001). Significantly more patients with strong estrogen receptor (ER) or progesterone receptor (PR) expression had postmenopausal durations of less than 5 years compared to those with postmenopausal durations greater than 5 years (103 vs. 61 cases, P = .019; 93 vs. 46 cases, P = .0005). While most patients either lacked (97.1%) or co-expressed (84.3%) ER and PR, some patients expressed either ER or PR alone. ER and PR expression were negatively associated with receptor-tyrosine kinase erbB-2 (HER2) expression in postmenopausal patients with breast cancer. Meanwhile, increased ER and PR expression were associated with decreased serum levels of LH or follicle-stimulating hormone (FSH). Conclusion: Decreased serum LH and FSH levels were associated with increased ER and PR expressions and decreased HER2 expression in postmenopausal patients with breast cancer.

Effects of Genistein and Exercise Training on Brain Damage Induced by a High-Fat High-Sucrose Diet in Female C57BL/6 Mice.

In recent decades, a shift in the nutritional landscape to the Western-style diet has led to an unprecedented rise in the prevalence of obesity and neurodegenerative diseases. Consumption of a healthy diet and engaging in regular physical activity represents safe and affordable approaches known to mitigate the adverse consequences of the Western diet. We examined whether genistein treatment, exercise training, and a combination treatment (genistein and exercise training) mitigated the effects of a Western diet-induced by high-fat, high-sugar (HFHS) in brain of female mice. HFHS increased the amyloid-beta (Aß) load and phosphorylation of tau, apoptosis, and decreased brain-derived neurotrophic factor (BDNF) levels. Exercise training and genistein each afforded modest protection on Aß accumulation and apoptosis, and both increased BDNF. The greatest neuroprotective effect occurred with combination treatment. BDNF and all markers of Aß accumulation, phosphorylation of tau, and apoptosis were improved with combined treatment. In a separate series of experiments, PC12 cells were exposed to high glucose (HG) and palmitate (PA) to determine cell viability with genistein as well as in the presence of tamoxifen, an estrogen receptor antagonist, to assess a mechanism of action of genistein on cell apoptosis. Genistein prevented the neurotoxic effects of HG and PA in PC12 cells and tamoxifen blocked the beneficial effects of genistein on apoptosis. Our results indicate the beneficial effects of genistein and exercise training on HFHS-induced brain damage. The benefits of genistein may occur via estrogen receptor-mediated pathways.

Effects of Gonadotropin-Releasing Hormone Analogs on Ovarian Function Against Chemotherapy-Induced Gonadotoxic Effects in Premenopausal Women With Breast Cancer in China: A Randomized Clinical Trial.

IMPORTANCE: Studies of the use of gonadotropin-releasing hormone analogs (GnRHa) to protect ovarian function have shown mixed results. OBJECTIVE: To determine whether administering GnRHa during chemotherapy in premenopausal women with breast cancer can reduce ovarian impairment. DESIGN, SETTING, AND PARTICIPANTS: This randomized clinical trial, conducted at the Shanghai Jiao Tong University Affiliated Shanghai Sixth People's Hospital and Zhejiang Cancer Hospital in China, was an open-label trial involving premenopausal women aged 18 to 49 years with operable stage I to III breast cancer for which treatment with adjuvant or neoadjuvant cyclophosphamide-containing chemotherapy was planned in 2 parallel groups: treatment with chemotherapy with or without GnRHa. Enrollment occurred from September 2015 to August 2017, and follow-up ended December 2020. The data were analyzed in March 2021. A total of 405 patients were enrolled in the study, among whom 27 patients (6.7%) quit participation voluntarily, 33 (8.1%) did not meet the inclusion criteria and were excluded, and 15 (3.7%) were lost to follow-up. Ultimately 330 patients were included in the primary analysis, including 29 patients with baseline anti-Müllerian hormone levels less than 0.5ng/ mL. INTERVENTIONS: Eligible patients were randomly assigned (1:1) to receive chemotherapy with (n = 165) or without (n = 165) GnRHa. In patients randomized to receive GnRHa, 3.6 mg of goserelin or 3.75 mg of leuprorelin was injected subcutaneously once every 28 days from 1 to 2 weeks before the first cycle of chemotherapy to 4 weeks after the last cycle of chemotherapy. MAIN OUTCOMES AND MEASURES: The primary end point was the rate of premature ovarian insufficiency (POI) at 12 months after chemotherapy. Premature ovarian insufficiency was defined as anti-Müllerian hormone levels of less than 0.5 ng/mL in this study. The secondary end point was overall survival (OS) and tumor-free survival (TFS). RESULTS: A total of 330 eligible patients could be evaluated with complete data, among whom 301 patients (91.2%; GnRHA group: mean [SD] age, 40.6 [6.7] years; control group: mean [SD] age, 40.2 [5.9] years) were eligible for primary end point analysis. At 12 months after the completion of chemotherapy, the POI rate was 10.3% (15 of 146) in the GnRHa group and 44.5% (69 of 155) in the control group (odds ratio, 0.23; 95% CI, 0.14-0.39; P < .001). Anti-Müllerian hormone resumption in the GnRHa group was significantly better than that in the control group (15 of 25 vs 6 of 44; odds ratio, 4.40; 95% CI, 1.96-9.89; P < .001). After a median follow-up of 49 months (range, 25-60 months), the differences in 4-year OS and TFS between the 2 groups were not significant. A post hoc analysis showed that in patients younger than 35 years, the TFS was higher in the GnRHa group than in the control group (93% vs 62%; P = .004; hazard ratio, 0.15; 95% CI, 0.03-0.82; P = .03). CONCLUSIONS AND RELEVANCE: This randomized clinical trial found that administering GnRHa in treatment with chemotherapy for premenopausal patients with breast cancer reduces the risk of POI, which promotes the recovery of ovarian function. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02518191.

Study of lncRNA TPA in Promoting Invasion and Metastasis of Breast Cancer Mediated by TGF-ß Signaling Pathway.

PURPOSE: This study was to investigate the effects of lncRNA TPA overexpression and knockdown in stable transfected cell lines on the EMT, migration and invasion capabilities of breast cancer cells. METHODS: WB and qRT-PCR were used to detect the expression of E-cadherin, Vimentin, fibronectin and N-cadherin, the key molecules of EMT, to determine whether lncRNA regulates EMT; scratch, migration and invasion assay were used to detected the effect of lncRNA TPA on the migration and invasion of breast cancer cells. The effect of lncRNA TPA on breast cancer metastasis was observed in nude mice model. Pierce Magnetic RNA-Protein Pull-Down Kit was used to bind the 3'-terminal desulfurized biotin-labeled lncRNA TPA with Magnetic beads, and then incubated with the proteins extracted from cell line C and D, respectively. After elution of the binding proteins, the interacting proteins were further identified by mass spectrometry to screen out the interacting proteins. The candidate proteins were expressed and purified in vitro, and the interaction between lncRNA-candidate proteins were verified by RNA-EMSA. RESULTS: Overexpression of lncRNA TPA decreased the expression of E-cadherin, and significantly increased the expression of Vimentin, fibronectin and TGF-ß1 (p < 0.01), and increased the migration rate, migration ability and invasion ability of cell group (P < 0.01). Multiple lung metastases were observed in the lung tissue of nude mice with overexpression of lncRNA TPA. CONCLUSION: LncRNA TPA affects the occurrence of breast cancer EMT through TGF-ß signaling pathway, and then promotes the invasion and metastasis of breast cancer. LncRNA TPA may affect the corresponding signaling pathways through one or more interacting proteins, and ultimately promote the invasion and metastasis of breast cancer.

Identification of a 6-gene signature for the survival prediction of breast cancer patients based on integrated multi-omics data analysis.

PURPOSE: To identify a gene signature for the prognosis of breast cancer using high-throughput analysis. METHODS: RNASeq, single nucleotide polymorphism (SNP), copy number variation (CNV) data and clinical follow-up information were downloaded from The Cancer Genome Atlas (TCGA), and randomly divided into training set or verification set. Genes related to breast cancer prognosis and differentially expressed genes (DEGs) with CNV or SNP were screened from training set, then integrated together for feature selection of identify robust biomarkers using RandomForest. Finally, a gene-related prognostic model was established and its performance was verified in TCGA test set, Gene Expression Omnibus (GEO) validation set and breast cancer subtypes. RESULTS: A total of 2287 prognosis-related genes, 131 genes with amplified copy numbers, 724 gens with copy number deletions, and 280 genes with significant mutations screened from Genomic Variants were closely correlated with the development of breast cancer. A total of 120 candidate genes were obtained by integrating genes from Genomic Variants and those related to prognosis, then 6 characteristic genes (CD24, PRRG1, IQSEC3, MRGPRX, RCC2, and CASP8) were top-ranked by RandomForest for feature selection, noticeably, several of these have been previously reported to be associated with the progression of breast cancer. Cox regression analysis was performed to establish a 6-gene signature, which can stratify the risk of samples from training set, test set and external validation set, moreover, the five-year survival AUC of the model in the training set and validation set was both higher than 0.65. Thus, the 6-gene signature developed in the current study could serve as an independent prognostic factor for breast cancer patients. CONCLUSION: This study constructed a 6-gene signature as a novel prognostic marker for predicting the survival of breast cancer patients, providing new diagnostic/prognostic biomarkers and therapeutic targets for breast cancer patients.

Nerve growth factor in metabolic complications and Alzheimer's disease: Physiology and therapeutic potential.

As the population ages, obesity and metabolic complications as well as neurological disorders are becoming more prevalent, with huge economic burdens on both societies and families. New therapeutics are urgently needed. Nerve growth factor (NGF), first discovered in 1950s, is a neurotrophic factor involved in regulating cell proliferation, growth, survival, and apoptosis in both central and peripheral nervous systems. NGF and its precursor, proNGF, bind to TrkA and p75 receptors and initiate protein phosphorylation cascades, resulting in changes of cellular functions, and are associated with obesity, diabetes and its complications, and Alzheimer's disease. In this article, we summarize changes in NGF levels in metabolic and neuronal disorders, the signal transduction initiated by NGF and proNGF, the physiological and pathophysiological relevance, and therapeutic potential in treating chronic metabolic diseases and cognitive decline.

Does dose-dense neoadjuvant chemotherapy have clinically significant prognostic value in breast cancer?: A meta-analysis of 3,724 patients.

PURPOSE: Neoadjuvant chemotherapy (NCT) is typically the initial treatment for non-early breast cancer patients. We thereby conducted a meta-analysis to explore whether dose-dense neoadjuvant chemotherapy (ddNCT) improved the long-term prognosis of patients compared to the standard NCT regimen. METHODS: We compared the differences in efficacy and prognosis between patients receiving standard NCT and ddNCT. We also calculated the pooled odds ratio (OR) of pathological complete response (pCR) and the pooled hazard ratio (HR) of overall survival (OS) and disease-free survival (DFS). RESULTS: Nine randomized controlled trials involving 3,724 patients from 10 published studies were included in the meta-analysis. The pooled OR for ddNCT was 1.18 (95% confidence interval (CI): 0.83-1.67, P = 0.356). A subgroup analysis in the cases with low hormone receptor expression levels showed the pCR in patients undergoing ddNCT was significantly higher than the pCR in patients undergoing standard NCT (OR = 1.36, 95% CI: 1.09‒1.69, P = 0.007). There was no significant difference in DFS and OS between ddNCT and standard NCT (DFS: HR = 0.90, 95% CI: 0.79‒1.02, P = 0.095; OS; HR = 0.91, 95% CI: 0.81‒1.04, P = 0.160), regardless of hormone receptor expression levels. These data suggested the higher pCR rate in patients receiving ddNCT did not result in a survival benefit. CONCLUSIONS: The meta-analysis demonstrated that ddNCT can significantly improve the pCR rate in patients with low hormone receptor expression levels, although patient survival was not significantly improved. The ddNCT can increase the breast-conserving rate and reduced pre-operative waiting time without increasing adverse reactions. This regimen can be considered when developing an NCT plan.

The treatment option of progressive disease in breast cancer during neoadjuvant chemotherapy: a single-center experience.

Patients' responses to breast cancer neoadjuvant chemotherapy (NACT) differ because of heterogeneous tumor characteristics. Reports about NACT progression are sporadic. Here we enrolled 1187 patients who received NACT in our cancer center between January 1, 2007, and December 31, 2016. We analyzed the characteristics and treatments of patients with progressive disease (PD) or non-PD or pathological complete response (pCR). In total, 45 (3.8%) patients had PD. PD patients were associated with a significantly worse disease-free survival (DFS) (hazard ratio (HR) = 3.77; 95% CI, 1.77 to 8.00; P =.001) and overall survival (OS) (HR = 3.85; 95% CI, 1.77 to 8.35; P =.001). For the PD patients, 28 (62.2%) patients received mastectomy immediately after PD, and 17 (37.8%) changed to chemotherapy. DFS and OS exhibited no significant differences between these two salvage therapies. After a change to second chemotherapy, 58.8% (10/17) patients had PD or SD. With the exception of tumor size, pretreatment T stage, and histology type, no other significant differences were noted between PD and pCR patients. Our results demonstrated that PD patients were associated with a significantly worse prognosis. Based on these results, we suggest to give the addition of trastuzumab to HER-2 positive patients instead of changing the chemotherapy regimen and proceeding to surgery instead of further chemotherapy once patients have PD during NACT. Given that some similar characteristics exist between PD and pCR patients, more studies to identify novel molecular markers to predict disease response to NACT should be performed.

Impact on survival of estrogen receptor, progesterone receptor and Ki-67 expression discordance pre- and post-neoadjuvant chemotherapy in breast cancer.

PURPOSE: To investigate whether estrogen receptor (ER), progesterone receptor (PR) and Ki-67 expression discordance before and after neoadjuvant chemotherapy (NAC) correlates with prognosis and treatment of breast cancer patients. METHODS: The study cohort included 482 breast cancer patients at the Zhejiang Cancer Hospital from January 1, 2008, to December 31, 2018. Core needle biopsies and excised tissue biopsies pre- and post-NAC were obtained. Immunohistochemistry was used to determine ER, PR and Ki-67 status. The relationship between biomarker discordance before and after NAC and clinicopathological features was compared retrospectively. RESULTS: ER (n = 482), PR (n = 482) and Ki-67 (n = 448) expression was assessed in the same lesion pre- and post-NAC. Discordance in the three markers pre- and post-NAC was observed in 50 (10.4%), 82 (17.0%) and 373 (77.4%) cases, respectively. Positive-to-negative PR expression changes were the most common type of discordance observed. The risk of death in patients with a PR positive-to-negative conversion was 6.58 times greater than for patients with stable PR expression. The risk of death in patients with increased Ki-67 expression following NAC treatment was 2.05 times greater than for patients with stable Ki-67 expression. CONCLUSION: Breast cancer patients showed changes in ER, PR and/or Ki-67 status throughout NAC, and these changes possibly influenced disease-free survival and overall survival. A switch to negative hormone receptor expression with increased Ki-67 expression following NAC could be indicators of a worse prognosis. Biomarker expression investigations following NAC may potentially improve patient management and survival.

An experimental study on the prosthesis produced by inactivated autologous subcutaneous adipose tissue and skin dermal tissue in a mini-pig model.

BACKGROUND: Autologous adipose tissue grafting is a valuable strategy for breast reconstruction in breast cancer patients. However, adipose tissue is absorbed and liquefies easily, and the cosmetic effects do not last. The purpose of this study is to evaluate the cosmetic effects and histopathologic changes of the prostheses produced by inactivated autologous subcutaneous adipose tissue and dermal outer capsule in the mini-pig model. METHODS: This prospective study was conducted in 6 Bama adult female mini-pigs weighing 15.5-20 kg. Autologous subcutaneous adipose tissue and dermis were harvested and made into the different prostheses. Then, the prostheses were implanted into abdominal subcutaneous tissue of the mini-pigs. At the 14th and 30th day after implantation, the skin appearances were observed, and the prostheses were harvested. The histopathologic changes of adipocytes and dermis in the different prostheses were evaluated. RESULTS: In vitro experiments showed that there were no significant changes in the size and histomorphology of autologous adipose tissue and/or dermis in the different prostheses. However, the results of the in vivo experiment found that the prosthesis produced by the inactivated adipose tissue with a dermal outer capsule produced the best cosmetic effect and the least fibrous connective tissue proliferation around the prosthesis. Moreover, the fewest proliferative fibrous connective tissues and infiltrated inflammatory cells were found in the adipocytes wrapped by dermis. The adipocyte morphology was normal. CONCLUSIONS: Results in this animal model indicated that the prosthesis produced by inactivated autologous subcutaneous adipose tissue with a dermal outer capsule may be a promising prosthesis for breast reconstruction. Validation of this new prosthesis requires more experiments to assess the long-term cosmetic effects and histopathologic changes.

Associations between folate metabolism enzyme polymorphisms and breast cancer: A meta-analysis.

We performed this meta-analysis to explore associations between folate metabolism enzyme polymorphisms and breast cancer (BC) in a larger pooled population. Systematic literature research was performed to identify eligible studies for pooled analyses. Totally 92 genetic association studies were included for analyses. The pooled analyses revealed significant findings for MTRR rs1801394 polymorphism in South Asians, for MTR rs1805087 polymorphism in Caucasians and East Asians, and for MTHFR rs1801133 polymorphism in East Asians. In conclusion, the present meta-analysis indicated that MTRR rs1801394, MTR rs1805087, and MTHFR rs1801133 polymorphisms could be used to identify individuals at high risk of developing BC.

Prognosis and endocrine therapy selection for patients with low hormone receptor-positive breast cancer following neoadjuvant chemotherapy: A retrospective study of 570 patients in China.

The 2010 American Society of Clinical Oncology guidelines have reduced the immunohistochemistry cut-off value for determining estrogen receptor b positivity from 10 to 1% of stained cells in breast cancer. In clinical practice, low-hormone receptor positive (low HR+) tumors are classified in the luminal subtype, although they exhibit aggressive features and poor prognosis. Information regarding the prognosis of patients with breast cancer following treatment with optimal endocrine therapy and neoadjuvant chemotherapy (NAC) is currently lacking. In the present study, the differences in clinical characteristics and survival of patients with breast cancer were compared among those with low and high HR+ breast cancer who received NAC. Furthermore, the effects of different types of endocrine therapies on the prognosis of patients with breast cancer were compared. The study population comprised patients with primary breast cancer who were treated at the Zhejiang Cancer Hospital between January, 2007 and December, 2017. Patients were divided into three groups based on the results of immunohistochemistry: HR+ (positive staining >10%), HR- (positive staining <1%) and low HR+ (positive staining 1-10%). The low HR+ group was further divided into three subgroups according to the different endocrine therapies administered: Tamoxifen, aromatase inhibitor or no treatment. Among the 570 patients included in the present study, 60 (10.53%) patients had low HR+ tumors. With a median follow-up of 48.98 months, patients with low HR+ tumors had reduced survival rates compared with those with HR+ tumors. Furthermore, the pathologic complete response rate (pCR) of patients with low HR+ was comprised between pCR from patients with HR+ and pCR from patients with HR- following NAC treatment. In addition, no significant difference in the overall prognosis was observed among patients with low HR+ following treatment with different endocrine therapies. Subsequently, patients in the low HR+ group were more likely to benefit from NAC compared with patients in the HR+ group. Intensive endocrine therapy may therefore improve the prognosis of patients with breast cancer and low HR+; however, further investigation is required.