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Translational Breast Cancer Research :... 2022Our aim was to evaluate the efficacy and safety of inetetamab plus chemotherapy in the first-line treatment of HER2-positive metastatic breast cancer.
Efficacy and safety of inetetamab in combination with chemotherapy as first-line treatment of HER2-positive metastatic breast cancer: a subgroup analysis in the HOPES study.
BACKGROUND
Our aim was to evaluate the efficacy and safety of inetetamab plus chemotherapy in the first-line treatment of HER2-positive metastatic breast cancer.
METHODS
A HOPES study was conducted on patients with HER2-positive metastatic breast cancer. Eligible patients were randomly divided into test group and control group at a 2:1 ratio. Among them, patients in test group received inetetamab plus vinorelbine. Concurrently, patients in the control group received vinorelbine. During the trial, safety evaluation was conducted every 4 weeks and efficacy evaluation was conducted every 8 weeks. As assessed by the Response Criteria Evaluation in Solid Tumors (RECIST) 1.0 criteria, the primary endpoint was progression-free survival (PFS) and the secondary endpoints included objective response rate (ORR) and disease control rate (DCR). Safety was estimated according to the National Cancer Institute Common Toxicity Criteria (NCI-CTC) version 2.0. Efficacy and safety of the postoperative recurrent-metastases first-line subgroup in the HOPES registry study of inetetamab was analyzed and compared with previous clinical studies of trastuzumab in the first-line treatment of HER2-positive metastatic breast cancer.
RESULTS
In total, we included 315 patients. Among them, 114 patients in the postoperative recurrent-metastases first-line subgroup were assigned to the full analysis set (FAS) (test group, 72; and control group, 42). The test group significantly prolonged median PFS (mPFS) (11.1 3.3 months of the control group; P<0.0001). ORR and DCR were remarkably higher than the control group (ORR, 61.5% 29.7% with an increase of 31.8%, P=0.0224; DCR, 93.8% 59.4% with an increase of 34.4%, P=0.0003). Efficacy and safety of postoperative recurrent-metastases first-line subgroup in the HOPES study was comparable to previous clinical studies of trastuzumab as first-line treatment of HER2-positive metastatic breast cancer.
CONCLUSIONS
Inetetamab has shown efficacy and safety equivalent to trastuzumab for patients in the first-line treatment of postoperative recurrence-metastases HER2-positive breast cancer, which confirms its important status and potential as first-line treatment. Inetetamab provides more first-line targeted therapy options for patients with HER2-positive metastatic breast cancer.
PubMed: 38751509
DOI: 10.21037/tbcr-21-42 -
Strahlentherapie Und Onkologie : Organ... Jan 2022Treatment of muscle-invasive bladder cancer (MIBC) remains challenging, especially for elderly and/or comorbid patients. Patients who are unfit for or refuse surgery...
PURPOSE
Treatment of muscle-invasive bladder cancer (MIBC) remains challenging, especially for elderly and/or comorbid patients. Patients who are unfit for or refuse surgery should receive bladder-preserving multimodality treatment (BPMT), consisting of transurethral resection of the bladder tumor (TURB) followed by combined chemoradiotherapy (CRT). We aimed to investigate the effectiveness of vinorelbine, a chemotherapeutic agent not routinely used for MIBC, in patients referred to CRT who are unfit for standard chemotherapy and would thus rely solely on radiotherapy (RT).
METHODS
We retrospectively analyzed 52 consecutive patients with MIBC who received standard CRT with cisplatin (n = 14), CRT with vinorelbine (n = 26), or RT alone (n = 12). Primary endpoints were median overall survival (OS) and median cancer-specific survival (CSS). Secondary endpoints were median local control (LC), median distant control (DC), and OS, CSS, LC, and DC after 1, 2, and 3 years, respectively.
RESULTS
Median OS and CSS were significantly higher for patients who received vinorelbine as compared to RT alone (OS 8 vs. 22 months, p = 0.003; CSS 11 months vs. not reached, p = 0.001). Median LC and DC did not differ significantly between groups. Vinorelbine was well tolerated with no reported side effects >grade II.
CONCLUSION
Our results suggest that CRT with vinorelbine is well tolerated and superior to RT alone in terms of OS and CSS. Therefore, this treatment regime might constitute a new treatment option for patients with MIBC who are unfit for or refuse surgery or standard chemotherapy. This study encourages a randomized controlled trial to compare this new regime to current standard therapies.
Topics: Aged; Cisplatin; Humans; Muscles; Neoplasm Invasiveness; Retrospective Studies; Treatment Outcome; Urinary Bladder; Urinary Bladder Neoplasms; Vinorelbine
PubMed: 34414475
DOI: 10.1007/s00066-021-01837-7 -
Computers in Biology and Medicine Oct 2022Whether pyroptosis, apoptosis, and necroptosis (PAN) molecular subtypes exist in gastric cancer (GC) remains unclear.
Pyroptosis, apoptosis, and necroptosis molecular subtype derived prognostic signature universal applicable for gastric cancer-A large sample and multicenter retrospective analysis.
BACKGROUND
Whether pyroptosis, apoptosis, and necroptosis (PAN) molecular subtypes exist in gastric cancer (GC) remains unclear.
METHODS
Seven independent cohorts including a total of 1901 GC patients were enrolled in our research. TCGA (n = 371) and GSE84437 (n = 433) were combined into one cohort (n = 804) to screen for prognosis-related PAN genes using a univariate Cox regression analysis. The R package "ConsensusClusterPlus" was applied to conduct a clustering analysis of the combination set based on prognosis-related PAN genes. The R package "limma" was used for the identification of differentially expressed genes (DEGs) between different PAN clusters (FDR <0.05 and |logFC|>1). The combined cohort was randomly divided into a training group (n = 484) and a test group (n = 320) at a ratio of 6:4 to establish and verify the prognostic model. A univariate Cox regression analysis, least absolute shrinkage and selection operator method (LASSO) regression analysis, and multivariate Cox regression analysis were used for the identification of prognostic genes and the construction of risk scores. Another five independent cohorts (GSE62254, n = 300; GSE15459, n = 191; GSE26901, n = 109; GSE26253, n = 432; and GSE13861, n = 65) were used for external validation to verify the accuracy and stability of the prognostic signature.
RESULTS
The internal and external validation demonstrated that the 5-gene risk score (LOXL4, SLCO2A1, CST2, PDK4, and MMP11) was an effective instrument for the prognostic risk classification of GC patients. The overall survival (OS) and relapse-free survival (RFS) in the high-risk group were significantly lower than those in the low-risk group and were accompanied by a larger proportion of macrophage and regulatory T cell infiltration. The low-risk group had a good prognosis, with a high tumor mutation burden (TMB), strong cytolytic activity, and a higher proportion of activated CD4 T cell infiltration. In addition, compared with the low-risk group, the cancer-related pathways in the high-risk group were overactivated, and the function of DNA damage repair (DDR) was significantly weakened. Regarding drug sensitivity, the high-risk group was more suitable for targeted drugs, such as axitinib, lapatinib, and nilotinib. The low-risk group was more sensitive to chemotherapy, such as cisplatin, gemcitabine, and vinorelbine.
CONCLUSION
A universally applicable prognostic signature of GC is proposed in this research based on pyroptosis, apoptosis, and necroptosis (PAN) molecular subtypes.
Topics: Apoptosis; Axitinib; Cisplatin; Gene Expression Profiling; Humans; Lapatinib; Matrix Metalloproteinase 11; Necroptosis; Organic Anion Transporters; Prognosis; Protein-Lysine 6-Oxidase; Pyroptosis; Stomach Neoplasms; Vinorelbine
PubMed: 36044785
DOI: 10.1016/j.compbiomed.2022.106037 -
Biomedicine & Pharmacotherapy =... Jun 2023Vinorelbine, the standard chemotherapy drug on advanced lung cancer, causes adverse events such as immunosuppression and bone marrow suppression. Thus, it is necessary...
Vinorelbine, the standard chemotherapy drug on advanced lung cancer, causes adverse events such as immunosuppression and bone marrow suppression. Thus, it is necessary to find drugs that could improve immune function and synergistically enhance the anti-tumor effect of vinorelbine. Thymosin is reported to inhibit tumor growth as an immunomodulator. Herein, to study the synergistic anti-cancer and attenuation effects of thymosin on vinorelbine, human lung cancer A549 cells that were labeled with CM-DiI were transplanted into zebrafish to establish the lung cancer xenotransplanted model. After treatment of vinorelbine and different concentrations of thymosin, the fluorescence intensity of CM-DiI-labeled A549 cells and the number of apoptotic muscle cells in the tumor-bearing zebrafish were detected. Besides, effects of thymosin on vinorelbine-reduced macrophages and T cells were identified in the transgenic zebrafish (Tg:zlyz-EGFP and Tg:rag2-DsRed). Then, the qRT-PCR was used to determine the alterations of the immune-related factors at the transcription level. Thymosin showed a marked synergistic anti-cancer effect with vinorelbine for the xenograft human lung cancer A549 cells, and the synergistic effect enhanced in a dose-dependent manner. Moreover, thymosin alleviated vinorelbine-induced muscle cell apoptosis, macrophage reduction, and T cell suppression. Compared with the vinorelbine group, co-administration with thymosin raised the mRNA levels of TNF-α, TNF-β, INF-γ, and GM-CSF. Thus, thymosin possesses synergistic anti-cancer effect on vinorelbine, and has protective effect on vinorelbine-induced immunosuppression. Thymosin, as an adjuvant immunomodulatory therapy, has great potential in enhancing the clinical application of vinorelbine.
Topics: Animals; Humans; Vinorelbine; Zebrafish; Thymosin; Cell Line, Tumor; Lung Neoplasms
PubMed: 37018994
DOI: 10.1016/j.biopha.2023.114633 -
Biomedicine & Pharmacotherapy =... Feb 2021Currently, epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) were approved for the treatment of non-small cell lung cancer (NSCLC) patients...
Currently, epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) were approved for the treatment of non-small cell lung cancer (NSCLC) patients harboring EGFR mutation. However, some lung cancer patients fail to respond and eventually develop drug resistance. Therefore, new therapeutic strategies are needed to improve the outcomes for substantial clinical benefit. Here we aimed to explore the combination of vinorelbine with the second EGFR-TKI afatinib in NSCLC cells with or without EGFR mutation. The three cells of H1975, HCC827, and H460 were assessed for the combination of vinorelbine and afatinib. Vinorelbine combined with afatinib synergistically inhibited the three lung cancer cells growth without aggravating adverse effect on the normal lung cells. The combination of low doses of vinorelbine and afatinib suppressed the cancer cell proliferation by cell colony formation assay and significantly induced cell apoptosis. The anti-apoptotic proteins Bcl-xL and Bcl-2 showed significant reduction after the drug combination treatment, while the pro-apoptotic protein Bax as well as apoptosis indicators cytochrome C and cleaved PARP were observed a notable increasing. EGFR downstream pathways including AKT, ERK, JNK, and p38 were highly active and p53 was inactive in the three lung cancer cells, favoring tumor growth. The low doses of vinorelbine plus afatinib blocked the phosphorylation of AKT, ERK, JNK, and p38, but restored the expression of p53. Our findings suggested that the combination of vinorelbine and afatinib could be recommended as a therapeutic regimen for treatment of NSCLC with or without EGFR mutation.
Topics: Afatinib; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Apoptosis Regulatory Proteins; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Dose-Response Relationship, Drug; Drug Synergism; ErbB Receptors; Humans; Lung Neoplasms; Signal Transduction; Tumor Suppressor Protein p53; Vinorelbine
PubMed: 33360044
DOI: 10.1016/j.biopha.2020.111144 -
Cancer Chemotherapy and Pharmacology Aug 2019Pharmacokinetics of vinorelbine is mainly known from studies conducted in European patients. Interethnic differences in drug disposition may, however, induce interethnic... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Pharmacokinetics of vinorelbine is mainly known from studies conducted in European patients. Interethnic differences in drug disposition may, however, induce interethnic variation in drug exposure. This paper aimed to evaluate the effect of ethnicity on the bioavailability and clearance of oral and intravenous vinorelbine.
METHODS
Oral and intravenous vinorelbine pharmacokinetics data in Asian patients were pooled from two-phase II studies of patients with non-small-cell lung cancer or advanced breast cancer in China. Blood vinorelbine and its active metabolite, 4'-O-deacetylvinorelbine, were quantified using liquid chromatography-tandem mass spectrometry. Bayesian pharmacokinetic parameters were calculated and vinorelbine monotherapy results (intravenous 25 mg/m; oral 60 mg/m) of the Asian data set were compared to a reference European data set (intravenous 30 mg/m; oral 80 mg/m). Subsequently, a population pharmacokinetics analysis was conducted in a combined cohort (Asian data set + historical vinorelbine pharmacokinetics database) to investigate for a potential effect of ethnicity.
RESULTS
Pharmacokinetics data from the Asian data set (oral: n = 47; intravenous: n = 34) was compared to the European reference data set (oral: n = 48; intravenous: n = 48). Mean apparent clearance of oral vinorelbine and mean absolute clearance of intravenous vinorelbine was comparable between the Asian and reference European data set. A population pharmacokinetic analysis (oral: n = 222; intravenous: n = 111) demonstrated no influence of ethnicity on oral and intravenous vinorelbine bioavailability and clearance.
CONCLUSION
Vinorelbine pharmacokinetics were found to be comparable between Asian and European patients. No relevant influence of ethnicity on vinorelbine bioavailability and clearance for oral and intravenous routes of administration was observed.
Topics: Adult; Aged; Antineoplastic Agents, Phytogenic; Ethnicity; Female; Humans; Male; Middle Aged; Prospective Studies; Vinorelbine
PubMed: 31134323
DOI: 10.1007/s00280-019-03872-9 -
Oxidative Medicine and Cellular... 2022Recent studies have demonstrated that homeobox A1 (HOXA1) is upregulated in lung cancer due to RNA modifications (N-methyladenosine), but the specific function of HOXA1...
OBJECTIVE
Recent studies have demonstrated that homeobox A1 (HOXA1) is upregulated in lung cancer due to RNA modifications (N-methyladenosine), but the specific function of HOXA1 in lung adenocarcinoma (LUAD) remains indistinct. Herein, we investigated the role of HOXA1 in LUAD biology.
METHODS
This study presented pancancer analysis of associations of HOXA1 with prognosis, TMB, and immune checkpoints. The expression of HOXA1 was detected in LUAD and normal tissues with immunohistochemistry and western blot. Through least absolute shrinkage and selection operator (LASSO) analysis, HOXA1-derived gene model was conducted in LUAD. Correlations of HOXA1 with immune cell infiltrations, immune checkpoints, HLAs, and chemotherapeutic sensitivity were evaluated. Colony formation, proliferation, and migration of LUAD cells with si-HOXA1 transfection were investigated, and the effects of HOXA1 on T cell exhaustion were assessed .
RESULTS
HOXA1 expression was a risk factor of overall survival, disease-specific survival, and progression-free interval of LUAD. HOXA1 exhibited prominent associations with immune cell infiltration, immune checkpoints, and HLAs. HOXA1-derived gene signature reliably and independently predicted LUAD outcomes. Also, high-risk cases presented increased sensitivity to cisplatin, paclitaxel, docetaxel, vinorelbine, and etoposide. HOXA1 knockdown exhibited an inhibitory effect on proliferation and migration abilities of LUAD cells. Silencing HOXA1 weakened the expression of antioxidative stress markers Nrf2/HO-1 and T cell exhaustion marker CD155 in LUAD cells. Moreover, LUAD cells with HOXA1 knockdown enhanced the CD8+ T cell response.
CONCLUSION
Our data support the oncogenic function and prognostic significance of HOXA1 that facilitates immune escape and alleviates oxidative stress of LUAD.
Topics: Adenocarcinoma of Lung; Cell Proliferation; Genes, Homeobox; Homeodomain Proteins; Humans; Lung Neoplasms; Oxidative Stress; Transcription Factors
PubMed: 35633885
DOI: 10.1155/2022/4102666 -
Molecules (Basel, Switzerland) Apr 2022The problems with anticancer therapy are resistance and toxicity. From 3000 Cisplatin derivatives tested as antitumor agents, most of them have been rejected, due to... (Review)
Review
The problems with anticancer therapy are resistance and toxicity. From 3000 Cisplatin derivatives tested as antitumor agents, most of them have been rejected, due to toxicity. The aim of current study is the comparison of therapeutic combinations of the currently applied in clinical practice: Cisplatin, Carboplatin, Oxaliplatin, Nedaplatin, Lobaplatin, Heptaplatin, and Satraplatin. The literature data show that the strategies for the development of platinum anticancer agents and bypassing of resistance to Cisplatin derivatives and their toxicity are: combination therapy, Pt IV prodrugs, the targeted nanocarriers. The very important strategy for the improvement of the antitumor effect against different cancers is synergistic combination of Cisplatin derivatives with: (1) anticancer agents-Fluorouracil, Gemcitabine, Cytarabine, Fludarabine, Pemetrexed, Ifosfamide, Irinotecan, Topotecan, Etoposide, Amrubicin, Doxorubicin, Epirubicin, Vinorelbine, Docetaxel, Paclitaxel, Nab-Paclitaxel; (2) modulators of resistant mechanisms; (3) signaling protein inhibitors-Erlotinib; Bortezomib; Everolimus; (4) and immunotherapeutic drugs-Atezolizumab, Avelumab, Bevacizumab, Cemiplimab, Cetuximab, Durvalumab, Erlotinib, Imatinib, Necitumumab, Nimotuzumab, Nivolumab, Onartuzumab, Panitumumab, Pembrolizumab, Rilotumumab, Trastuzumab, Tremelimumab, and Sintilimab. An important approach for overcoming the drug resistance and reduction of toxicity of Cisplatin derivatives is the application of nanocarriers (polymers and liposomes), which provide improved targeted delivery, increased intracellular penetration, selective accumulation in tumor tissue, and enhanced therapeutic efficacy. The advantages of combination therapy are maximum removal of tumor cells in different phases; prevention of resistance; inhibition of the adaptation of tumor cells and their mutations; and reduction of toxicity.
Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Cisplatin; Erlotinib Hydrochloride; Humans; Neoplasms
PubMed: 35458666
DOI: 10.3390/molecules27082466 -
Cells Jul 2023Metastasis, rather than the growth of the primary tumor, accounts for approximately 90% of breast cancer patient deaths. Microtentacles (McTNs) formation represents an...
Metastasis, rather than the growth of the primary tumor, accounts for approximately 90% of breast cancer patient deaths. Microtentacles (McTNs) formation represents an important mechanism of metastasis. Triple-negative breast cancer (TNBC) is the most aggressive subtype with limited targeted therapies. The present study aimed to isolate viable circulating tumor cells (CTCs) and functionally analyze them in response to drug treatment. CTCs from 20 TNBC patients were isolated and maintained in culture for 5 days. Biomarker expression was identified by immunofluorescence staining and VyCap analysis. Vinorelbine-induced apoptosis was evaluated based on the detection of M30-positive cells. Our findings revealed that the CTC absolute number significantly increased using TetherChips analysis compared to the number of CTCs in patients' cytospins ( = 0.006) providing enough tumor cells for drug evaluation. Vinorelbine treatment (1 h) on live CTCs led to a significant induction of apoptosis ( = 0.010). It also caused a significant reduction in Detyrosinated α-tubulin (GLU), programmed death ligand (PD-L1)-expressing CTCs ( < 0.001), and disruption of McTNs. In conclusion, this pilot study offers a useful protocol using TetherChip technology for functional analysis and evaluation of drug efficacy in live CTCs, providing important information for targeting metastatic dissemination at a patient-individualized level.
Topics: Humans; Neoplastic Cells, Circulating; Triple Negative Breast Neoplasms; Vinorelbine; Pilot Projects; Cell Line, Tumor; Biomarkers, Tumor
PubMed: 37566019
DOI: 10.3390/cells12151940 -
Journal of Oncology 2022Pyroptosis is a programmed cell death that may either promote or hinder cancer growth under different circumstances. Pyroptosis-related genes (PRGs) could be a useful...
Pyroptosis is a programmed cell death that may either promote or hinder cancer growth under different circumstances. Pyroptosis-related genes (PRGs) could be a useful target for cancer therapy, and are uncommon in lung adenocarcinoma (LUAD). The expression profiles, mutation data and clinical information of LUAD patients were included in this study. A pyroptosis-related prognostic risk score (PPRS) model was constructed by performing Cox regression, weighted gene co-expression network analysis (WGCNA), and least absolute shrinkage and selection operator (LASSO) analysis to score LUAD patients. Somatic mutation and copy number variation (CNV), tumor immunity, and sensitivity to immunotherapy/chemotherapy were compared between different PPRS groups. Clinical parameters of LUAD were combined with PPRS to construct a decision tree and nomogram. Red module was highly positively correlated with pyroptosis. Seven genes (FCRLB, COTL1, GNG10, CASP4, DOK1, CCR2, and AQP8) were screened from the red module to construct a PPRS model. Significantly lower overall survival (OS), higher incidence of somatic mutation and CNV, elevated infiltration level of the immune cell together with increased probability of immune escape were observed in LUAD patients with higher PPRS, and were more sensitive to Cisplatin, Docetaxel, and Vinorelbine. We constructed a new PPRS model for patients with LUAD. The model might have clinical significance in the prediction of the prognosis of patients with LUAD and in the efficacy of chemotherapy and immunotherapy.
PubMed: 35938142
DOI: 10.1155/2022/6905588