Pyrotinib plus capecitabine for patients with human epidermal growth factor receptor 2-positive breast cancer and brain metastases (PERMEATE): a multicentre, single-arm, two-cohort, phase 2 trial.

BACKGROUND: Patients with HER2-positive metastatic breast cancer have a high risk of developing brain metastases. Efficacious treatment options are scarce. We investigated the activity and safety of pyrotinib plus capecitabine in patients with HER2-positive metastatic breast cancer and brain metastases. METHODS: We did a multicentre, single-arm, two-cohort, phase 2 trial in eight tertiary hospitals in China. Patients aged 18 years or older who had radiotherapy-naive HER2-positive brain metastases (cohort A) or progressive disease after radiotherapy (cohort B), with an Eastern Cooperative Oncology Group performance status of 0-2, received pyrotinib 400 mg orally once daily, and capecitabine 1000 mg/m2 orally twice daily for 14 days, followed by 7 days off every 3 weeks until disease progression or unacceptable toxicity. The primary endpoint was confirmed intracranial objective response rate by investigator assessment according to the Response Evaluation Criteria In Solid Tumours (version 1.1). Activity and safety were analysed in patients with at least one dose of study drug. The study is ongoing, but recruitment is complete. The study is registered with ClinicalTrials.gov, NCT03691051. FINDINGS: Between Jan 29, 2019, and July 10, 2020, we enrolled 78 women: 51 (86%) of 59 patients in cohort A and 18 (95%) of 19 patients in cohort B had previous exposure to trastuzumab. Median follow-up duration was 15·7 months (IQR 9·7-19·0). The intracranial objective response rate was 74·6% (95% CI 61·6-85·0; 44 of 59 patients) in cohort A and 42·1% (20·3-66·5; eight of 19 patients) in cohort B. The most common grade 3 or worse treatment-emergent adverse event was diarrhoea (14 [24%] in cohort A and four [21%] in cohort B). Two (3%) patients in cohort A and three (16%) in cohort B had treatment-related serious adverse events. No treatment-related deaths occurred. INTERPRETATION: To our knowledge, this is the first prospective study showing the activity and safety of pyrotinib plus capecitabine in patients with HER2-positive breast cancer and brain metastases, especially in radiotherapy-naive population. This combination deserves further validation in a randomised, controlled trial. FUNDING: National Cancer Centre Climbing Foundation Key Project of China, Jiangsu Hengrui Pharmaceuticals. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.

Serum HER2 Level Predicts Therapeutic Efficacy and Prognosis in Advanced Breast Cancer Patients.

Background: The purpose of this study was to investigate the therapeutic efficacy and prognosis of serum HER2 (sHER2) in patients with advanced breast cancer. Methods: We analyzed the sHER2 levels of 200 patients with advanced breast cancer receiving first or second line treatment, the tissue HER2 (tHER2) level was also analyzed. Indicators of therapeutic efficacy and prognosis were objective response rate (ORR), disease control rate (DCR), and time to progression (TTP). Results: The baseline sHER2 level was high in 132 patients and low in 68 patients. The high level of sHER2 is correlated with molecular subtype (p=0.016), visceral metastasis (p<0.001), liver metastasis (p<0.001), tissue HER-2 (tHER2) (p=0.001), and, among tHER2-low tumors (59 patients), the baseline sHER2 high level was associated with a higher proportion of brain metastasis. The ORR of patients with baseline sHER2 high level is higher than those with baseline sHER2 low level (p=0.026). The TTP of patients with baseline sHER2 low level is longer than the patients with baseline sHER2 high level (p=0.024). For patients with baseline sHER2 high level, a significant decrease in sHER2 after two cycles of treatment indicates higher ORR, DCR, and an extension of TTP. After multiple cycles of treatment, for patients with tHER-2 positive and baseline sHER2 high level, the DCR in the sHER2 decrease in the negative group was higher than that in the continuous positive group (p=0.037). Patients with a rapid decline type of sHER2 dynamic change curve had higher ORR and prolonged TTP compared with patients with other types of sHER2 dynamic change curve. There is no correlation between OS and sHER2 levels. Conclusion: Our study showed that patients with advanced breast cancer had a high level of sHER2 at recurrence, regardless of whether they are tHER2 positive or negative. Dynamic detection of sHER2 can help predict therapeutic efficacy and prognosis, regardless of whether tHER-2 is positive or negative.

Expert consensus on the clinical application of immunotherapy in breast cancer: 2024.

Background: Significant progress has been made in immunotherapy of breast cancer (BC) with the approval of multiple immune checkpoint inhibitors (ICIs), particularly in early and metastatic triple-negative breast cancer (TNBC) settings. Most guidelines have recommended immune therapy as the important approach in BC, yet several critical aspects still require further clarification, including proper patient selection, treatment duration, optimized chemotherapy partner, predictive biomarkers, and specific considerations for Chinese patients. Methods: (I) Establishment of expert group: the expert group consists of 32 experts from departments such as medical oncology, breast surgery, and pathology; (II) literature search: mainly conducted in English databases (such as PubMed, Embase, and Cochrane Library) and Chinese databases (such as China National Knowledge Infrastructure, China Biology Medicine disc, and Wanfang Database), with a search cutoff date of April 23, 2024; (III) assessment of evidence quality and recommendation strength: evidence quality and recommendation opinions are graded based on the evidence category and recommendation level of the Chinese Society of Clinical Oncology (CSCO) guidelines; (IV) consensus formulation: on the March 2, 2024, through online consensus meeting, the consensus content is thoroughly discussed, and opinions from all experts are solicited. Results: The consensus meeting has resulted in 15 detailed recommendations, providing clearer guidance on the clinical application of immunotherapy in BC management. The core suggestions are as follows: for early-stage II-III TNBC and metastatic TNBC (mTNBC) in the first-line setting, programmed cell death protein 1 (PD-1) inhibitors can be considered. However, for hormone receptor-positive/human epidermal growth factor receptor 2-negative BC (HR+/HER2- BC), HER2+ BC, and mTNBC in later lines of therapy, evidence is lacking to support the use of immunotherapy. Conclusions: This consensus provides a comprehensive overview of BC immunotherapy, including immunotherapy for early-stage BC and late-stage BC, immune related adverse event (irAE) management, biomarkers of immunotherapy, and future directions. The consensus consolidates these deliberations into 15 evidence-based recommendations, serving as a practical guide for clinicians to more scientifically and systematically manage the clinical application of immunotherapy.

Real-world data for the renal safety of abemaciclib combined with bisphosphonate in HR+/HER2- advanced breast cancer.

OBJECTIVE: Our study evaluated the renal safety of abemaciclib plus endocrine therapy (ET) with bisphosphonate as a treatment option for hormone receptor positive, human epidermal growth factor receptor 2 (HER-2) negative (HR+/HER2-) advanced breast cancer (ABC), especially with bone metastasis. METHODS: Data were collected from HR+/HER2- ABC patients who received abemaciclib with ET between March 2021 and May 2022 in a single medical center in China. We performed an analysis of the change in serum creatine (Cr) and creatine clearance (CrCl), time to first abnormal Cr value, and Common Terminology Criteria for Adverse Events grade of increased creatinine. RESULTS: A total of 210 patients were included in the final analysis, with a median age of 56 years and a median weight of 65 kg. Any grade laboratory-assessing increased Cr occurred in 87.1% of patients, while CrCl rarely went down to 30 ml/min. Associations between start dose with grade of increased Cr and menopausal status with alert value, which is defined as creatinine clearance <30 ml/min, were indicated. CONCLUSION: This study shows that abemaciclib combined with bisphosphonate would be safe for renal function in HR+/HER2- ABC patients with bone metastases.

The changes of subtype markers between first and second primary breast cancers.

BACKGROUND: Previous studies investigated the changes of subtype markers [estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2)] in several clinical settings, but not for second primary breast cancer (SPBC) after first primary breast cancer (FPBC). METHODS: A total of 15,390 patients with SPBC were preliminarily selected from the Surveillance, Epidemiology, and End Results Program, and 3777 patients with complete information on three subtype markers in both FPBC and SPBC were included in the final analyses. The changes of subtype markers and their prognostic implications and potential influential factors were well investigated. RESULTS: The overall change rates of ER, PR, and HER2 between FPBC and SPBC were 23.0% (867/3777), 35.0% (1322/3777), and 18.3% (691/3777), respectively. Gains of ER, PR, and HER2 after negative index markers were 48.7% (364/748), 37.9% (418/1103), and 11.5% (370/3211), while losses of markers after positive index markers were 16.6% (503/3029), 33.8%(904/2674), and 56.7%(321/566). Loss of ER was significantly associated with increased mortality (18.1% vs. 7.9%, p < 0.001), while gain of ER was significantly associated with decreased mortality (11.5% vs. 23.2%, p < 0.001). Similar results were observed for changes of PR status. However, loss of HER2 was significantly associated with decreased mortality (8.7% vs. 16.3%, p = 0.014), and no significant association was observed between the gain of HER2 and the prognosis of SPBC. Multivariate competing risk analyses showed similar results. HER2 status in FPBC, chemotherapy, and radiotherapy was significantly associated with changes of ER/PR (all p < 0.05), and no available therapies associated with HER2 change. CONCLUSION: The changes of subtype markers are observed in a considerable proportion of patients and has statistically significant prognostic implications. Biopsies should be taken as a routine procedure for better therapy management.

Clinicopathological Features and Prognosis of Gastrointestinal Metastases From Breast Carcinoma: A Clinicopathological Study of 22 Patients.

Background. Breast carcinoma is the most common malignancy in women. Gastrointestinal metastasis is rarely found or diagnosed in patients with breast cancer. Methods. Clinicopathological features, treatment options, and prognosis were evaluated retrospectively for 22 patients with gastrointestinal metastases of breast carcinoma in Chinese women. Results. Presenting symptoms were non-specific: anorexia (21/22), epigastric pain (10/22), and vomiting (8/22), and 2 patients (2/22) presented with nonfatal hemorrhage. The first sites of metastases were skeleton (9/22), stomach (7/22), colorectal (7/22), lung (3/22), peritoneal (3/22), and liver (1/22). ER, PR, GATA binding protein 3 (GATA3), gross cystic disease fluid protein-15 (GCDFP-15), and keratin 7 can effectively confirm the diagnosis, especially in the case of keratin 20 negativity. Histology showed mainly ductal breast carcinoma (n = 11) was the predominant source of gastrointestinal metastases in this study, and lobular breast cancer (n = 9) accounted for a considerable proportion. The disease control rate to systemic therapy was 81% (17 of 21 treated patients), and the objective response rate was 10% (2 of 21 treated patients). Median overall survival was 71.5 months (range, 22-226 months), median survival for distant metastases was 23.5 months (range, 2-119 months) and the median survival for the time of gastrointestinal metastases diagnosis was 6 months (range, 2-73 months). Conclusions. Performing the endoscopy with biopsy was crucial for patients with any subtle gastrointestinal symptoms and a history of breast cancer. It is important to distinguish primary gastrointestinal carcinoma from breast metastatic carcinoma in order to select the optimal initial treatment and avoid unnecessary surgery.

Comparisons of clinical characteristics, prognosis, epidemiological factors, and genetic susceptibility between HER2-low and HER2-zero breast cancer among Chinese females.

BACKGROUND: Traditional human epidermal growth factor receptor 2 (HER2)-negative breast cancer (BC) is recommended to be divided into HER2-low and HER2-zero subtypes due to different prognosis. However, few studies investigated their differences in clinical characteristics and prognosis among Chinese HER2-negative BC and their stratified differences by hormone receptor (HR), while fewer studies investigated their differences in epidemiological factors and genetic susceptibility. METHODS: A total of 11,911 HER2-negative BC were included to compare the clinical characteristics and prognosis between HER2-zero and HER2-low BC, and 4227 of the 11,911 HER2-negative BC were further compared to 5653 controls to investigate subtype-specific epidemiological factors and single nucleotide polymorphisms(SNPs). RESULTS: Overall, 64.2% of HER2-negative BC were HER2-low BC, and the stratified proportions of HER2-low BC were 61.9% and 75.2% for HR-positive and HR-negative BC, respectively. Compared to HER2-zero BC, HER2-low BC among HR-positive BC showed younger age at diagnosis, later stage, poorer differentiation, and higher Ki-67, while elder age at diagnosis and lower mortality were observed for HER2-low BC among HR-negative BC (all p values <0.05). Compared to healthy controls, both HER2-low and HER2-zero BC are associated with similar epidemiological factors and SNPs. However, stronger interaction between epidemiological factors and polygenic risk scores were observed for HER2-zero BC than HER2-low BC among either HR-positive [odds ratios: 10.71 (7.55-15.17) and 8.84 (6.19-12.62) for the highest risk group compared to the lowest risk group] or HR-negative BC [7.00 (3.14-15.63) and 5.70 (3.26-9.98)]. CONCLUSIONS: HER2-low BC should deserve more attention than HER2-zero BC, especially in HR-negative BC, due to larger proportion, less clinical heterogeneity, better prognosis, and less susceptibility to risk factors.

Establishing extended pluripotent stem cells from human urine cells.

BACKGROUND: Extended pluripotent stem cells (EPSCs) can contribute to both embryonic and trophectoderm-derived extraembryonic tissues. Therefore, EPSCs have great application significance for both research and industry. However, generating EPSCs from human somatic cells remains inefficient and cumbersome. RESULTS: In this study, we established a novel and robust EPSCs culture medium OCM175 with defined and optimized ingredients. Our OCM175 medium contains optimized concentration of L-selenium-methylcysteine as a source of selenium and ROCK inhibitors to maintain the single cell passaging ability of pluripotent stem cells. We also used Matrigel or the combination of laminin 511 and laminin 521(1:1) to bypass the requirement of feeder cells. With OCM175 medium, we successfully converted integration-free iPSCs from easily available human Urine-Derived Cells (hUC-iPSCs) into EPSCs (O-IPSCs). We showed that our O-IPSCs have the ability to form both intra- and extra- embryonic chimerism, and could contribute to the trophoblast ectoderm lineage and three germ layer cell lineages. CONCLUSIONS: In conclusion, our novel OCM175 culture medium has defined, optimized ingredients, which enables efficient generation of EPSCs in a feeder free manner. With the robust chimeric and differentiation potential, we believe that this system provides a solid basis to improve the application of EPSCs in regenerative medicine.

Effectiveness and Safety of Palbociclib Plus Endocrine Therapy in Patients with Advanced Breast Cancer: A Multi-Center Study in China.

BACKGROUND: Palbociclib has been approved for marketing in China. However, its effectiveness, safety, and latent variables in the Chinese population require further investigation. METHODS: Information was retrieved from 397 patients with metastatic breast cancer (mBC) who received at least two cycles of palbociclib plus endocrine therapy (PAL plus ET) at eight clinical sites in China. The patients' demographic characteristics, treatment patterns, and adverse events (AEs) were analyzed. RESULTS: The objective response rate (ORR) and clinical benefit rate (CBR) for PAL plus ET were 28.97% and 66.25%, respectively. The median PFS was 14.2 months in the whole population. In addition to protein Ki-67 status and sensitivity to ETs, no liver metastases, fewer metastatic sites, an earlier line of therapy, and treatment combined with AI instead of FUL were also considered as independent prognostic factors for PAL treatment. Administration of PAL was generally well tolerated in patients with hormone-receptor-positive and human-epidermal-growth-factor-receptor-2-negative (HR+/HER2-) advanced breast cancer (ABC). The therapy was safe in the elderly population, which is consistent with the outcomes of the whole population and previous reports. CONCLUSIONS: In this most widely distributed study in China to date, palbociclib combined with ET proved its effectiveness for HR+/HER2- ABC treatment, and adverse events were manageable. Here, we identified some independent prognosis factors, but the mechanism by which these factors influence effectiveness requires further verification.

The effects of RKIP gene expression on the biological characteristics of human triple-negative breast cancer cells in vitro.

The purpose of this study was to investigate the effect of Raf kinase inhibitor protein (RKIP) on the growth, proliferation, invasion and metastasis of triple-negative breast cancer (TNBC) cells to provide experimental evidence for developing future therapies against human TNBC. The pcDNA3.1-RKIP eukaryotic expression vector was constructed and transfected into the TNBC cell line MDA-MB-231. The alterations of the biological characteristics of RKIP-transfected MDA-MB-231 cells were analyzed using the following approaches: a growth curve, a 3-(4,5-dimethylthiazol-2-Yl)-2,5-diphenyltetrazolium bromide (MTT) assay, bromodeoxyuridine (BrdU) staining and a cell migration assay. The effects of the RKIP gene on MMP-1 and MMP-2 expression were also examined. The pcDNA3.1 empty vector-transfected and mock-transfected MDA-MB-231 cells were used as control groups. Compared with the empty vector-transfected and mock-transfected cells, the cell growth of RKIP-transfected MDA-MB-231 cells was significantly reduced. The empty vector-transfected group was not significantly different compared with the mock-transfected MDA-MB-231 cells. The results of the MTT and BrdU assays demonstrated that the proliferation of pcDNA3.1-RKIP-transfected cells was significantly reduced compared to the control cells (P < 0.05). The result of the cell migration assay suggested that the cross-membrane migration rate of the pcDNA3.1-RKIP-transfected cells was significantly lower than that of the control MDA-MB-231 cells (P < 0.05). We also demonstrated that RKIP may inhibit MMP-1 and MMP-2 expression in MDA-MB-231 cells. The RKIP gene may play a role in inhibiting cellular proliferation. The RKIP gene may also have some inhibitory effects on the invasiveness and metastatic capability of human TNBC cells.

Effects of BTG2 on proliferation inhibition and anti-invasion in human lung cancer cells.

The objective of the study was to investigate the impact of the B cell translocation gene 2 (BTG2) on lung cancer cell growth, proliferation, metastasis, and other biological characteristics and to provide experimental evidence for the biological treatment of human lung cancer. A pcDNA3.1-BTG2 eukaryotic expression vector was constructed and transfected into the human lung cancer cell line A549. The biological changes in the BTG2-expressing cells were analyzed using growth curves, the MTT (tetrazolium) assay, propidium iodide (PI) staining, and the Transwell invasion chamber. Additionally, Western blotting was used to determine the impact of BTG2 on the protein expression of cyclin D1, MMP-1, and MMP-2. Compared to the empty vector-transfected A549 cells or the mock-transfected A549 cells, the pcDNA3.1-BTG2-transfected A549 cells grew significantly slower. No significant differences were detected between the empty vector-transfected group and the mock-transfected A549 cells. The growth curve analysis and the PI staining showed that the pcDNA3.1-BTG2-transfected cells grew significantly slower than the empty vector-transfected A549 cells (P < 0.05). The cell invasion assay results suggested that the invasion rate of the pcDNA3.1-BTG2-transfected A549 cells was significantly slower than the invasion rate of the empty vector-transfected group and the mock-transfected group (P < 0.05). The overexpression of BTG2 may inhibit the protein expression of cyclin D1, MMP-1, and MMP-2 in A549 cells. The overexpression of BTG2 may inhibit the growth, proliferation, and invasiveness of the A549 human lung cancer cell line.

The therapeutic function of the chemokine RANTES on the H22 hepatoma ascites model.

This study aimed at analyzing the therapeutic function of the chemokine RANTES on the H22 hepatoma ascites model and preliminarily explore the mechanism of RANTES in malignant ascites to provide an important reference for applying chemokines in anti-tumor therapy. The murine H22 hepatoma ascites model was used. Three treatment groups were analyzed: a RANTES treatment group, an IL-2 control group, and an NS control group. Two regimens of early treatment and late treatment were designed, and the therapeutic effect of RANTES on malignant ascites was studied by measuring changes in mouse body weight and abdominal circumference and observing the survival time. The expression of TNF-α, IFN-γ, TGF-ß1, and MCP-1 in mouse ascites was detected by ELISA, and the chemotactic function of RANTES on B lymphocytes and T lymphocytes was analyzed by flow cytometry. In the early and late treatment regimens, RANTES could effectively inhibit the increase in mouse body weight and abdominal circumference in the murine H22 hepatoma ascites model. The secretion of TNF-α and IFN-γ, which had anti-tumor effects, was higher in the RANTES treatment group than in the control groups (P < 0.05), whereas the secretion of TGF-ß1 and MCP-1, which promoted tumor growth, invasion, and metastasis, was lower than in the control groups (P < 0.05). RANTES had chemotactic effects on CD4(+) and CD8(+) T lymphocytes; therefore, the percentage of CD3, CD4, and CD8 in the mouse ascites in the RANTES treatment group was significantly higher than in the NS control and IL-2 treatment groups, and the CD4/CD8 ratio was also significantly higher. RANTES can effectively inhibit the increase in body weight and abdominal circumference and significantly extend survival time in mice in the H22 hepatoma ascites model.

Gene Mutations Associated With Clinical Characteristics in the Tumors of Patients With Breast Cancer.

Background: Clinical characteristics including estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor 2 (HER2) are important biomarkers in the treatment of breast cancer, but how genomic mutations affect their status is rarely studied. This study aimed at finding genomic mutations associated with these clinical characteristics. Methods: There were 160 patients with breast cancer enrolled in this study. Samples from those patients were used for next-generation sequencing, targeting a panel of 624 pan-cancer genes. Short nucleotide mutations, copy number variations, and gene fusions were identified for each sample. Fisher's exact test compared each pair of genes. A similarity score was constructed with the resulting P-values. Genes were clustered with the similarity scores. The identified gene clusters were compared to the status of clinical characteristics including ER, PR, HER2, and a family history of cancer (FH) in terms of the mutations in patients. Results: Gene-by-gene analysis found that CCND1 mutations were positively correlated with ER status while ERBB2 and CDK12 mutations were positively correlated with HER2 status. Mutation-based clustering identified four gene clusters. Gene cluster 1 (ADGRA2, ZNF703, FGFR1, KAT6A, and POLB) was significantly associated with PR status; gene cluster 2 (COL1A1, AXIN2, ZNF217, GNAS, and BRIP1) and gene cluster 3 (FGF3, FGF4, FGF19, and CCND1) were significantly associated with ER status; gene cluster 2 was also negatively associated with a family history of cancer; and gene cluster 4 was significantly negatively associated with age. Patients were classified into four corresponding groups. Patient groups 1, 2, 3, and 4 had 24.1%, 36.5%, 38.7%, and 41.3% of patients with an FDA-recognized biomarker predictive of response to an FDA-approved drug, respectively. Conclusion: This study identified genomic mutations positively associated with ER and PR status. These findings not only revealed candidate genes in ER and PR status maintenance but also provided potential treatment targets for patients with endocrine therapy resistance.

CSCO expert consensus on the diagnosis and treatment of breast cancer brain metastasis.

Breast cancer is one of the most common malignancies among women worldwide. According to the International Agency for Research on Cancer, breast cancer affected more Chinese women than any other cancer in 2020. The brain is an increasingly common metastatic sites of breast cancer. Although the risk of developing brain metastases (BMs) is lower in breast cancer than in lung cancer and melanoma, due to its high prevalence, it is the second most common cause of BM among solid tumors, being second only to lung cancer. The incidence of breast cancer brain metastasis (BCBM) differs by molecular subtype. Half of patients with advanced human epidermal growth factor receptor-2 (HER2)-positive and one-third of patients with triple-negative breast cancer (TNBC) develop BM. The clinical manifestations of leptomeningeal metastasis (LM) are often non-specific and may manifest as a variety of signs and symptoms, mainly including brain parenchyma involvement and meningeal irritation syndromes cranial nerve involvement, increased intracranial pressure, and progressive brain dysfunction. Therefore, the Chinese Society of Clinical Oncology (CSCO) Breast Cancer Committee has developed this expert consensus on BM, in an effort to improve the overall prognosis of BCBM and promote the standardized diagnosis and treatment of this disease. During the development of this expert consensus, we carried out a comprehensive literature review and referred to some of the most authoritative guidelines in China and abroad. In this consensus, we will discuss clinical manifestations, imaging examinations, pathological diagnosis, treatments, prognosis, follow-up and monitoring. We hope this consensus will be of help to all the clinicians majored in breast cancer and other similar professions.

Chinese Society of Clinical Oncology (CSCO) Breast Cancer Guidelines 2022.

Developing guidelines for the diagnosis and treatment of common cancers in China based on the evidence-based practice, the availability of diagnosis and treatment products, and the up-to-date advances in precision medicine is one of the basic tasks of the Chinese Society of Clinical Oncology (CSCO). In recent years, the availability of medical resources has become a major concern in clinical guidelines, which is particularly important for developing countries or socioeconomically diverse countries and territories. China is the world's largest developing country, with a large territory and uneven economic and academic developments. The CSCO guidelines must take into account the differences in regional development, the availability of medicines and diagnostic methods, and the social value of cancer treatment. Therefore, for each clinical problem and intervention in the CSCO guidelines, the levels of evidence should be graded according to the currently available evidences and expert consensuses, and the grades of recommendations should be based on the availability and cost-effectiveness of the products. Protocols with high evidence level and good availability are used as the Level I recommendations; protocols with relatively high evidence level but slightly lower expert consensus or with poor availability are used as the Level II recommendations; and protocols that are clinically applicable but with low evidence level are regarded as the Level III recommendations. Based on the findings of clinical research at home and abroad and the opinions of CSCO experts, the CSCO guidelines determine the levels of recommendations for clinical application. The CSCO Guidance Working Group firmly believes that evidence-based, availability-concerned, and consensus-based guidelines will be more feasible for clinical practice. Again, any comments from our readers are greatly appreciated and will be considered in updates of these guidelines, so as to maintain the accuracy, fairness, and timeliness of the CSCO guidelines.

MicroRNA-449 targets histone deacetylase 1 to regulate the proliferation, invasion, and apoptosis of synovial fibroblasts in rheumatoid arthritis.

BACKGROUND: Rheumatoid arthritis (RA) is a chronic joint disease. The study aimed to explore the effects of microRNA (miR)-449 and histone deacetylase 1 (HDAC1) on the proliferation, invasion, and apoptosis of synovial fibroblasts in rheumatoid arthritis. METHODS: Synovial tissue was collected from 20 patients with RA and 20 patients with osteoarthritis (OA) who underwent joint replacement surgery. RA synovial fibroblasts (RASFs) and OA synovial fibroblasts (OASFs) were isolated and cultured. Real-time quantitative PCR was used to detect the expression levels of miR-449 and HDAC1 in synovial tissues and cells. Western blot was performed to detect the cellular expression levels of HDAC1 protein, and apoptosis and invasion-related proteins. The proliferation, invasion, and apoptosis of RASFs were detected by MTT assay, Transwell assay, and flow cytometry. The dual-luciferase reporter gene was used to test the targeting relationship between inflammatory miR-449 and HDAC1. RESULTS: Compared with normal synovial tissue and OASFs, the levels of HDAC1 messenger RNA in RA synovial tissue and RASF cells were significantly increased (P<0.01), while the expression levels of miR-449 were significantly decreased (P<0.01). The dual-luciferase reporter gene experiment confirmed that miR-449 could specifically bind to the 3' untranslated region of HDAC1 to inhibit its luciferase activity (P<0.05). HDAC1 inhibition or miR-449 overexpression significantly inhibited the proliferation and invasion of RASFs (P<0.001), while inducing their apoptosis (P<0.001). HDAC1 overexpression reversed the biological effects of miR-449 on RASFs (P<0.001). CONCLUSIONS: miR-449 inhibits the proliferation and invasion of RASFs and induces their apoptosis by targeting HDAC1, thereby exerting a protective effect against RA.

[Male breast cancer: a pairing comparison of survival with women breast cancer].

OBJECTIVE: To investigate clinicopathological characteristics of male breast cancer patients and women breast cancer patients, compare disease-free survival and overall survival in a group of matched men and women with breast cancer. METHODS: The clinical data and survival status of 45 cases operable male breast cancer treated in our hospital from 1982.9 to 2006.12 were collected. Each man with breast cancer recorded in the database was matched with two women. Matching was done based on age, year of diagnosis, stage and pathology. SPSS16.0 software was used for statistic treatment. Chi-square test was used for the comparison of frequency data between groups. Kaplan-Meier method was applied to analyze survivals. And Log-Rank was used to compare curves between groups. Statistical significance was considered at P < 0.05. RESULTS: The 45 male breast cancer patients were matched with 90 female patients. The median age at diagnosis was 59 (26 ∼ 75) years for men and 57 (22 ∼ 76) years for women. The median follow-up was 61 (5 ∼ 262) months for men and 71 (29 ∼ 283) months for women. Mass location, receptor status, chemotherapy and hormonal therapy were statistically significant between male BC and female BC groups. About male BC patients, monofactorial analysis showed tumor size, lymph node state and TNM stage were prognostic factors. The 5-year disease-free survival of male BC and women BC were respectively 62.3% and 78.8%, 10-year DFS were 35.3% and 45.3%;The 5-year overall survival of male BC and female BC were respectively 70.5% and 82.5%, 10-year OS were 42.8%and 62.4%. CONCLUSIONS: After the matching of age, year of diagnosis, stage and pathology, the prognosis for men with breast carcinoma is significantly poor comparing with women. We should play more emphasize on early diagnosis and early therapy, and think highly of chemotherapy and hormonal therapy to improve the prognosis of male BC patients.

[Prognostic analysis of patients with metastatic triple-negative breast cancer: a report of 120 cases].

OBJECTIVE: To analyze the clinical features and survival for patients with metastatic triple negative breast cancer (MTNBC), especially such a metastatic site as brain. METHODS: The clinical data and survival status of 120 cases of operable MTNBC treated at our hospital from January 2002 to December 2004 were collected. SPSS 13.0 software was used for statistic treatment. Statistical significance was considered at P < 0.05. RESULTS: At the time of last follow-up, the median time after metastasis was 22 months. Nine deaths (65.8%) were recorded. In terms of all metastatic sites (initial + subsequent), lung (58.3%), liver (41.7%) and brain (40.8%) were most common sites. The patients with brain metastasis had a worse survival than those with non-brain metastases. Twenty-two (18.3%) patients were found to have brain metastasis at the time of first metastatic presentation. The initial metastatic site in patients with brain metastasis had a worse survival than those with non-brain metastases. The median survival time after metastasis was 8 and 31 months respectively (P = 0.000). CONCLUSION: Triple-negative breast cancer is associated with a poor survival after metastases. The patients with brain metastases have a worse survival than those with non-brain metastases. New treatment strategies are needed.

A randomized controlled Phase II trial of vinorelbine plus capecitabine versus docetaxel plus capecitabine in anthracycline-pretreated women with metastatic breast cancer.

BACKGROUND: Previous studies have shown that vinorelbine/capecitabine (NX) and docetaxel/capecitabine (TX) chemotherapy has a certain effect in advanced breast cancer. However, there are few clinical studies directly comparing TX and NX regimen chemotherapy, especially in patients with advanced breast cancer previously treated with anthracycline and taxane. The purpose of this Phase II study was to compare survival and side effects between patients with anthracycline- and taxane-resistant advanced breast cancer treated with NX and those treated with TX chemotherapy. PATIENTS AND METHODS: From February 2012 to March 2014, a total number of 97 patients were randomly assigned to NX (n = 55) or TX (n = 42). Baseline characteristics were relatively well-balanced in the two treatment arms. The clinical trial registration number (clincaltrials.gov) is NCT01635465. RESULTS: After a median follow-up of 46.0 months, there was no significant difference between the NX and TX arms in objective response rate (17.9% vs. 21.1%; P = 0.686) and progression-free survival (6 months vs. 7 months; P = 0.560). The overall survival period of the TX arm was longer than that of the NX arm (32 months vs. 27 months) but without statistical significance. Both regimens were well-tolerated. The main toxicities were neutropenia, leukopenia, and anemia. In the TX arm, hand-foot syndrome occurred more frequently than in the NX arm (P < 0.01), but frequencies of other minor adverse effects were similar between the two arms. CONCLUSION: NX and TX regimens are both alternative treatments for patients with anthracycline- and taxane-resistant advanced breast cancer, but the safety profile was more favorable and manageable with the NX regimen. TRIAL REGISTRATIONS: ClinicalTrials.gov NCT01635465. Registered 09 July 2012.

Tumor necrosis factor receptor-associated factor 6 (TRAF6) inhibition modulates bone loss and matrix metalloproteinase expression levels in collagen-induced rheumatoid arthritis rat.

BACKGROUND: Rheumatoid arthritis (RA) is a main characterized by persistent synovitis, systemic inflammation, and autoantibodies. Tumor necrosis factor receptor-associated factor 6 (TRAF6) is an E3 ubiquitin ligase and is a crucial cytoplasm signal adaptor that can regulate critical biological processes. This research aims to explore the function of TRAF6 on bone loss and matrix metalloproteinase (MMP) expression in collagen-induced RA rats. METHODS: The RA model in rats (Sprague Dawley rat, 5-6 weeks old, weight 246.88±8.31 g) was set up via using collagen-induced RA. The shRNA-TRAF6 knockdown efficiency was tested using real-time reverse transcription-polymerase chain reaction (qRT-PCR) and western blot, respectively. The rats were divided into four groups: the control group, RA group, RA + shRNA-NC group, and RA + TRAF6-shRNA group. The tartrate-resistant acidic phosphatase (TRAP), hematoxylin and eosin (H&E), and Saffron O staining were employed to test the bone injury. The mRNA and protein expressive of Osteoclast-associated receptor (OSCAR), TRAP, Osterix (Osx), Collagen type I alpha 1 (COL1A1), Distal-less homeobox2 (Dlx2), tissue inhibitor of metalloproteinase (TIMP), matrix metalloproteinase-1(MMP-1), Cyclooxygenase 2 (COX2) and qRT-PCR performed MMP-13 and western blot, respectively. RESULTS: The mRNA and protein expression levels of TRAF6 were down-regulated in the RA + TRAF6- shRNA group. After the levels of TRAF6 were inhibited, the levels of bone volume/total volume (BV/TV), trabecular bone thickness (Tb.Th), and trabecular bone number (Tb.N) were increased, while the levels of trabecular bone space (Tb.Sp), Osteocalcin and ALP were deceased. The mRNA and protein expression levels of OSCAR, TRAP, MMP-1, COX2, and MMP-13 were reduced obviously in the RA + TRAF6- shRNA group compared with the RA + shRNA-NC group, while the levels of TIMP-1, OSX, CoL1A1, and DLx2 were enhanced obviously. CONCLUSIONS: Inhibition of TRAF6 reduces bone loss and MMP expression levels in collagen-induced RA rat, and supplies an alternative treatment method in RA.