BACKGROUND Trastuzumab constitutes the fundamental component of initial therapy for patients with advanced human epidermal growth factor receptor 2(HER-2)-positive gastric cancer(GC).However,the efficacy of this treat...BACKGROUND Trastuzumab constitutes the fundamental component of initial therapy for patients with advanced human epidermal growth factor receptor 2(HER-2)-positive gastric cancer(GC).However,the efficacy of this treatment is hindered by substantial challenges associated with both primary and acquired drug resistance.While S-phase kinase associated protein 2(Skp2)overexpression has been implicated in the malignant progression of GC,its role in regulating trastuzumab resistance in this context remains uncertain.Despite the numerous studies investigating Skp2 inhibitors among small molecule compounds and natural products,there has been a lack of successful commercialization of drugs specifically targeting Skp2.AIM To discover a Skp2 blocker among currently available medications and develop a therapeutic strategy for HER2-positive GC patients who have experienced progression following trastuzumab-based treatment.METHODS Skp2 exogenous overexpression plasmids and small interfering RNA vectors were utilized to investigate the correlation between Skp2 expression and trastuzumab resistance in GC cells.Q-PCR,western blot,and immunohistochemical analyses were conducted to evaluate the regulatory effect of thioridazine on Skp2 expression.A cell counting kit-8 assay,flow cytometry,a amplex red glucose/glucose oxidase assay kit,and a lactate assay kit were utilized to measure the proliferation,apoptosis,and glycolytic activity of GC cells in vitro.A xenograft model established with human GC in nude mice was used to assess thioridazine's effectiveness in vivo.RESULTS The expression of Skp2 exhibited a negative correlation with the sensitivity of HER2-positive GC cells to trastuzumab.Thioridazine demonstrated the ability to directly bind to Skp2,resulting in a reduction in Skp2 expression at both the transcriptional and translational levels.Moreover,thioridazine effectively inhibited cell proliferation,exhibited antiapoptotic properties,and decreased the glucose uptake rate and lactate production by suppressing Skp2/protein kinase B/mammalian target of rapamycin/glucose transporter type 1 signaling pathways.The combination of thioridazine with either trastuzumab or lapatinib exhibited a more pronounced anticancer effect in vivo,surpassing the efficacy of either monotherapy.CONCLUSION Thioridazine demonstrates promising outcomes in preclinical GC models and offers a novel therapeutic approach for addressing trastuzumab resistance,particularly when used in conjunction with lapatinib.This compound has potential benefits for patients with Skp2-proficient tumors.展开更多
Background: Trastuzumab resistance accounts for chemotherapy failure in gastric cancer patients in clinicalpractice. The significance of long non-coding RNAs (lncRNAs) in the maintenance of drug resistance in gastricc...Background: Trastuzumab resistance accounts for chemotherapy failure in gastric cancer patients in clinicalpractice. The significance of long non-coding RNAs (lncRNAs) in the maintenance of drug resistance in gastriccancer has been already underlined. Method: This study aimed to identify the specific role of lncRNA-ATB in gastriccancer progression and trastuzumab resistance. The downstream miRs of lncRNA-ATB and target genes of miRs werepredicted by bioinformatics analysis and verified using dual luciferase reporter assay. Loss- and gain-function assayswere performed to explore the roles of lncRNA-ATB, miR-200c, and zinc-finger protein 217 (ZNF217) in the cellfunctions and trastuzumab resistance of a trastuzumab-resistant gastric cancer cell line (NCI-N87-TR). Result:LncRNA-ATB was upregulated, while miR-200c was downregulated. Depletion of lncRNA-ATB or miR-200celevation led to a decrease in malignant properties of NCI-N87-TR cells. LncRNA-ATB could negatively target miR-200c, which in turn inversely targeted and reduced the expression of ZNF217. Silencing of ZNF217 could inhibit cellviability and migration. Conclusion: lncRNA-ATB promoted the progression and trastuzumab resistance of gastriccancer by repressing miR-200c via ZNF217 upregulation.展开更多
Objective: To assess the long-term effectiveness and safety of trastuzumab in adjuvant therapy for Chinese patients with early-stage human epidermal growth factor 2(HER2)-positive breast cancer in a real-world setting...Objective: To assess the long-term effectiveness and safety of trastuzumab in adjuvant therapy for Chinese patients with early-stage human epidermal growth factor 2(HER2)-positive breast cancer in a real-world setting.Methods: This retrospective observational study analyzed the medical records of HER2-positive breast cancer patients between 2000 and 2012 at the Chinese Academy of Medical Sciences. Patients who received adjuvant chemotherapy alone or adjuvant chemotherapy followed by/combined with trastuzumab were included. The Kaplan-Meier method was used to estimate disease-free survival(DFS) and overall survival(OS). Hazard ratios(HR) and 95% confidence intervals(95% CI) were calculated using the Cox regression model.Results: Of the 1,348 patients analyzed, 909 received chemotherapy alone and 439 received chemotherapy plus trastuzumab. The 3-year, 5-year and 10-year DFS rates were 83.70%, 76.38% and 68.94%, respectively, in the chemotherapy-alone cohort, and 90.21%, 86.19% and 83.45% in the chemotherapy plus trastuzumab cohort. The3-year, 5-year and 10-year OS rates were 96.10%, 91.40% and 81.88% in the chemotherapy-alone cohort, and98.17%, 94.91% and 90.01% in the chemotherapy plus trastuzumab cohort. The chemotherapy plus trastuzumab group had a significantly lower risk of disease recurrence and death than the chemotherapy-alone group(DFS:HR=0.50, 95% CI, 0.37-0.68;P<0.001;OS: HR=0.53, 95% CI, 0.34-0.81;P=0.004) after adjusting for covariates.In the 439 patients treated with trastuzumab, multivariate analysis suggested that lymph node positivity, higher T stages, and hormone receptor-negative status were significantly associated with higher risks of disease recurrence,and lymph node positivity and hormone receptor-negative status were significantly associated with higher risks of death. Grade 3/4 adverse events(incidence ≥1%) were more common in patients receiving trastuzumab(54.44% vs.15.73%).Conclusions: Early-stage HER2-positive breast cancer patients treated with trastuzumab plus adjuvant chemotherapy have a significant survival benefit compared with chemotherapy-alone in real-world settings. Lymph node positivity, hormone receptor-negative status, and higher T stages may be associated with higher risks of recurrence, and effective therapy for patients with these factors is required.展开更多
Late-stage gastric adenocarcinoma patients have a poor prognosis because of high recurrence rates.To improve long-term outcomes,perioperative chemotherapies are combined with surgery.Human epidermal growth factor rece...Late-stage gastric adenocarcinoma patients have a poor prognosis because of high recurrence rates.To improve long-term outcomes,perioperative chemotherapies are combined with surgery.Human epidermal growth factor receptor 2(HER2)overexpression had been noted in gastric cancer;therefore,trastuzumab has been used occasionally in this setting.A 63-year-old male Chinese patient,who was diagnosed with adenocarcinoma in the gastric antrum,as well as lymph node metastases along the left gastric and hepatic artery,and left adrenal area,was admitted to our hospital.HER2 expression was positive,and cluster amplification was detected in a fluorescence in situ hybridization assay.The patient received three cycles of a neoadjuvant trastuzumab/oxaliplatin/capecitabine regimen.He subsequently underwent distal gastrectomy,D2+lymphadenectomy,left adrenalectomy,cholecystectomy and BillrothⅡanastomosis.Treatment was continued with another five postoperative cycles of the same medication and trastuzumab application for 1 year.No recurrence has been observed 18 mo after the operation.Trastuzumab as perioperative and adjuvant medication,in combination with oxaliplatin and capecitabine for a HER2-overexpressing advanced gastric adenocarcinoma,led to recurrence-free survival of at least 18 mo after surgery.展开更多
BACKGROUND Targeted treatments may greatly affect the natural history of urothelial carcinoma based on their pharmacokinetics. A phase II trial has explored the combination of cytotoxic chemotherapy with the anti-HER-...BACKGROUND Targeted treatments may greatly affect the natural history of urothelial carcinoma based on their pharmacokinetics. A phase II trial has explored the combination of cytotoxic chemotherapy with the anti-HER-2 monoclonal antibody trastuzumab in selected patients with metastatic bladder cancer, but it failed.CASE SUMMARY Here, we report a case of recurrent urothelial bladder carcinoma(UBC) in a patient who has undergone three operations, and further illuminate its diagnosis and treatment. The diagnosis of UBC was rendered according to the pathological indices. Next-generation sequencing on formalin fixed paraffin-embedded(FFPE)tissue was also performed and suggested HER2 gene amplification in the FFPE tissue. Based on HER2 gene amplification in FFPE, the patient was treated with chemotherapy in combination with trastuzumab after his third surgery.Fortunately, the patient got a clinically complete remission to trastuzumab for 34 mo.CONCLUSION There is not enough clinical evidence for incorporating trastuzumab in routine treatment of UBC. This case hinted that recurrent UBC patients with HER2 gene amplification may benefit from targeted trastuzumab. Further studies are needed to further investigate the status of HER2 gene and better determine trastuzumab in the management of UBC.展开更多
Wie present a 29-year-old woman with pT2N0M0 breast cancer,histological diagnosis of invasive ductal carcinoma,ER and PR low positive,and HER-2(3+).The patient developed trastuzumab-induced thrombocytopenia in 6 hours...Wie present a 29-year-old woman with pT2N0M0 breast cancer,histological diagnosis of invasive ductal carcinoma,ER and PR low positive,and HER-2(3+).The patient developed trastuzumab-induced thrombocytopenia in 6 hours after an intravenous infusion of trastuzumab at the second cycle of trastuzumab treatment with the symptom of abnormal uterine bleeding.Laboratory exam revealed a sharp drop of platelet count down to 3X109/L.With the treatment of single-donor platelet transfusions,glucocorticoids,oxytocin and thrombopoietic drugs,the platelet count recovered completely in 11 days.This case was confirmed to be severe thrombocytopenia induced by trastuzumab,and retreatment with trastuzumab was not attempted.With increasing clinical utilization of trastuzumab,clinicians are likely to encounter more life-threatening trastuzumab induced severe thrombocytopenia.By this case report and literature review we hope to increase the awareness,attach the attentions to this condition,and help with the effective treatment.展开更多
Objective:Several studies have demonstrated different benefits for patients whose disease progressed despite previous trastuzumab treatment.Due to limited real-world data,we evaluate the effectiveness of anti-human ep...Objective:Several studies have demonstrated different benefits for patients whose disease progressed despite previous trastuzumab treatment.Due to limited real-world data,we evaluate the effectiveness of anti-human epidermal growth factor receptor 2(HER2)therapy(lapatinib or trastuzumab)plus chemotherapy or chemotherapy alone in patients who were previously treated with trastuzumab-containing regimens and investigate factors associated with effectiveness.And we further show the effectiveness of the two anti-HER2 therapy groups.Methods:A total of 342 HER2-positive metastatic breast cancer(MBC)patients whose disease progressed during prior anti-HER2(trastuzumab)and standard chemotherapy therapy from Department of Breast Oncology,the Fifth Medical Center of Chinese PLA General Hospital,from August 2010 to December 2016 were included.Seventy-eight patients received standard chemotherapy only,148 patients continued to receive trastuzumab and switched to other chemotherapy drugs,and 116 patients received tyrosine-kinase inhibitors(TKIs;lapatinib)and chemotherapy.The main outcome measures were progression-free survival(PFS),overall response rate(ORR),and clinical benefit rate(CBR).Subgroup analyses were conducted to identify patient characteristics associated with the greatest clinical benefit.Results:After a median follow-up of 26.2(range,2.0-56.0)months,PFS significantly improved with anti-HER2 therapy compared with chemotherapy alone:median 6.0 months with lapatinib[95%confidence interval(95%CI),4.53-7.47],4.5 months with trastuzumab(95%CI,3.99-5.01)vs.3.0 months with chemotherapy alone(95%CI,2.42-3.58);stratified hazard ratio(HR)=0.70,95%CI,0.60-0.81;P<0.0001.The ORR values were 33.6%,25.0%and 12.8%,respectively,the CBR values were 60.3%,48.6%and 26.9%,respectively.The effectiveness of lapatinib group and trastuzumab group were further analyzed.In multivariate analysis,lapatinib group was associated with a longer PFS,after controlling other potential confounders(HR=0.68,95%CI,0.52-0.90;P=0.006).Conclusions:The combination of TKIs and chemotherapy was effective in this cohort previously treated with trastuzumab treatment.Therefore,TKIs combined with chemotherapy is an option for Chinese HER2-positive MBC patients previously treated with trastuzumab treatment.展开更多
The combination regimen of trastuzumab(Tras)plus Nab-paclitaxel(Nab)is recommended to treat HER2-positive(HER2+)cancers.However,they exert effects in different mechanisms:Tras need to stay on cell membranes,while Nab ...The combination regimen of trastuzumab(Tras)plus Nab-paclitaxel(Nab)is recommended to treat HER2-positive(HER2+)cancers.However,they exert effects in different mechanisms:Tras need to stay on cell membranes,while Nab need to be endocytosed,therefore the concurrent combination regimen may not be the best one in HER2+tumors treatment.Caveolin-1(Cav-1)is a key player in mediating their endocytosis and is associated with their efficacy,but few researches noticed the opposite effect of Cav-1 expression on the combination efficacy.Herein,we systematically studied the Cav-1 expression level on the combination efficacy and proposed an optimized and clinically feasible combination regimen for HER2+Cav-1 High tumor treatment.In the regimen,lovastatin(Lova)was introduced to modulate the Cav-1 expression and the results indicated that Lova could downregulate Cav-1 expression,increase Tras retention on cell membrane and enhance the in vitro cytotoxicity of Tras in HER2+Cav-1 High cells but not in HER2+Cav-1 Low cells.Therefore,by exchanging the dosing sequence of Nab and Tras,and by adding Lova at appropriate time points,the precise three-drug-sequential regimen(PTDS,Nab(D1)-Lova(D2)-Lova&Tras(D2+12 h))was established.Compared with the concurrent regimen,the PTDS regimen exhibited a higher in vitro cytotoxicity and a stronger tumor growth inhibition in HER2+Cav-1 High tumors,which might be a promising combination regimen for these patients in clinics.展开更多
BACKGROUND Trastuzumab is a generally safe agent prescribed in the systemic treatment of breast cancer.Tinnitus is not a currently known adverse event related to trastuzumab.Here,we describe a rare case of severe tinn...BACKGROUND Trastuzumab is a generally safe agent prescribed in the systemic treatment of breast cancer.Tinnitus is not a currently known adverse event related to trastuzumab.Here,we describe a rare case of severe tinnitus and a migraine headache induced by trastuzumab used for adjuvant therapy.CASE SUMMARY A 37-year-old woman was diagnosed with hormone receptor-positive and human epidermal growth factor receptor 2-positive breast cancer.After surgery,she was treated with four cycles of epirubicin and cyclophosphamide;she then received docetaxel and a loading dose of trastuzumab plus pertuzumab.Less than half an hour after trastuzumab infusion,the patient complained of severe tinnitus and left-sided migraine headache.Trastuzumab monotherapy was discontinued immediately,and symptoms disappeared after 10 min.Trastuzumab was readministered,and severe tinnitus and migraine headache recurred.Trastuzumab was stopped,and severe tinnitus diminished after 10 min.Pertuzumab and docetaxel therapy was then administered,and no adverse events were observed.Subsequent infusions of trastuzumab every three weeks did not show the same symptoms.CONCLUSION Although trastuzumab is well-tolerated in most patients,we should pay attention to the risk of severe tinnitus and migraine.展开更多
BACKGROUND It remains unclear whether the current arbitrary screening recommendations of trastuzumab-related cardiotoxicity provides an adequate balance between preventing heart damage and curtailing a curative treatm...BACKGROUND It remains unclear whether the current arbitrary screening recommendations of trastuzumab-related cardiotoxicity provides an adequate balance between preventing heart damage and curtailing a curative treatment.AIM To determine the incidence rate and consequences of trastuzumab-induced cardiotoxicity as adjuvant treatment in a real-world scenario.METHODS We present a retrospective analysis of cardiac function measured by echocardiogram at baseline and every 3 mo during trastuzumab treatment.Cardiotoxicity was defined as a drop in left ventricular ejection fraction(LVEF)≥10%from baseline and/or any drop<50%.RESULTS Between January 2011 and December 2014,407 patients were selected.Most(93.6%)were treated with an anthracycline followed by a taxane-based regimen and trastuzumab for 12 mo.Forty patients(9.8%)had cardiotoxicity.None of them were symptomatic,and 28(72.5%)completely recovered LVEF.Cardiotoxicity happened early as shown by LVEF measured on echocardiogram 2 to 4 as compared to 5 to 7(odds ratio=2.47,95%confidence interval:1.09,5.63,P=0.024).There were 54 deaths(13.3%)during the 70-mo follow-up period;1(0.2%)was attributed to late cardiotoxicity(4 years after treatment).The absence of symptomatic cardiotoxicity during trastuzumab treatment and moreover the early occurrence on the treatment period may translate into a strategy to evaluate less frequently.CONCLUSION We observed a 10%rate of asymptomatic cardiotoxicity,which mirrors the results from the large adjuvant trials.Despite being transient,an LVEF drop led to frequent treatment delays and interruptions.It remains unclear whether LVEF decline is predictive of late cardiotoxicity,and treatment efficacy is compromised.展开更多
Since trastuzumab monotherapy for treatment of breast cancer with HER2/ErbB2 over-expression has been shown to have limited efficacy, combined treatment of trastuzumab with chemotherapy is widely practiced in clinic. ...Since trastuzumab monotherapy for treatment of breast cancer with HER2/ErbB2 over-expression has been shown to have limited efficacy, combined treatment of trastuzumab with chemotherapy is widely practiced in clinic. However, certain combination treatments of trastuzumab and chemotherapy (i.e. doxorubicin) are not recommended due to high risk of cardiotoxicity. Antibody-drug conjugates (ADCs) offer selective delivery of cytotoxic agents into targeted cancer cells, thereby allowing for reduced general cellular cytotoxicity caused by chemotherapeutic agents through antibody mediated specific recognition of tumor antigens. In this study, we constructed a trastuzumab-doxorubicin conjugate (T-Dox) using a thioether linkage and characterized both biophysical stability and anti-cancer potency of the T-Dox using a panel of HER2 expressing cancer cell lines. The T-Dox conjugate showed significantly improved anti-cancer potency in comparison with trastuzumab. The results demonstrated for the first time that there were significant differences in the uptake of T-Dox among high HER2 expression cancer cells and higher T-Dox uptake also showed stronger anti-cancer potency. Similar to trastuzumab, T-Dox selectively bound to HER2 overexpressing cancer cells and low HER2 expression cells had no detectable uptake of T-Dox. Consistent to the uptake data, human cardiomyocyte cells had no detectable HER2 expression and T-Dox showed minimal cytotoxic effects. On the contrary, a treatment with combination of trastuzumab and doxorubicin showed severe cytotoxicity to human cardiomyocytes (>90% cell death after 3 day exposure). This study demonstrated that trastuzumab conjugated with doxorubicin (T-Dox) can provide valuable alternative to the combination treatment with doxorubicin and trastuzumab for high HER2 expressing cancer patients.展开更多
Aim: Firstly, to quantify active healthcare professional (HCP) time and costs associated with subcutaneous (SC) administration of trastuzumab (Herceptin?) compared with the standard intravenous infusion (IV) in the tr...Aim: Firstly, to quantify active healthcare professional (HCP) time and costs associated with subcutaneous (SC) administration of trastuzumab (Herceptin?) compared with the standard intravenous infusion (IV) in the treatment of patients with HER2-positive early breast cancer within the adjuvant PrefHer trial setting;secondly, to measure patient time in the care unit and patient infusion chair time for both routes of administration. Methods: A UK multi-centre prospective, observational Time and Motion study was conducted alongside the PrefHer trial (ClinicalTrials.gov id: NCT01401166). Trained observers measured the duration of each SC and IV related task that HCPs undertook and recorded patient time in the chemotherapy unit and infusion chair. The type and quantity of medical consumables used with each route of administration were also collected. Twenty-four patient episodes were recorded (12 SC, 12 IV). Mean total administration time was calculated as the mean sum of task times, both for IV and SC formulations. The mean cost of each route of administration was calculated as the mean cost of HCP time plus the mean cost of consumables used. HCP time was costed using Personal Social Services Research Unit. Consumables were costed using hospital pharmacy data and online sources. Results: Mean active HCP time for IV administration was 92.6 minutes compared with 24.6 minutes for SC administration. The mean cost for IV preparation and administration was ￡144.96 (￡132.05 of HCP time and ￡12.92 of consumables) versus ￡33.15 (￡31.99 of HCP time and ￡1.17 of consumables) for SC administration. Mean time spent in the care unit and in the infusion chair was 94.5 minutes and 75 minutes respectively for IV, and 30.3 minutes and 19.8 minutes for SC. SC administration of trastuzumab could translate to a time saving of 68 minutes (versus IV) with a total cost saving of ￡111.81 per patient episode. This equates to a potential saving of ￡2012.58 over a full course of adjuvant treatment (18 cycles). Conclusion: Substituting IV infusion with SC administration of trastuzumab may lead to a substantial reduction in active HCP time, patient chair and unit time, consumable use and overall costs. The reduced patient chair and unit time could provide increased capacity within existing resources.展开更多
Background: Agent targeting HER-2 pathway plus chemotherapy has represented a major progress in the management of patients with breast cancer. However, the role of late-line treatment in heavily pretreated patients is...Background: Agent targeting HER-2 pathway plus chemotherapy has represented a major progress in the management of patients with breast cancer. However, the role of late-line treatment in heavily pretreated patients is still largely unclear. In the last decade, nab-paclitaxel has shown significant activity and good toxicity profile in metastatic breast cancer. Case Presentation: We report the case of a 76-year-old Caucasian woman with metastatic HER-2 positive ductal infiltrating breast carcinoma treated with a combination of weekly nab-paclitaxel and trastuzumab as fifth-line therapy. She had previously received first-line paclitaxel and trastuzumab, second-line vinorelbine and trastuzumab, third-line TDM1 and fourth-line oral capecitabine and lapatinib. Clinical and radiological staging showed progression at bone, skin and soft-tissue. The patient received weekly nab-paclitaxel plus trastuzumab. Massive objective response was clinically and PET documented which lasted 8 months. Tolerance to treatment was fairly good as well as cardiac safety. Conclusion: To the best of our knowledge, this is the first reported case of efficacy of nab-paclitaxel in combination with trastuzumab as fifth-line of treatment in a patient with metastatic HER-2 positive breast cancer.展开更多
<strong>Introduction:</strong> <span style="font-family:Verdana;">Breast cancer is the most common female cancer in India and account</span><span style="font-family:Verdana;&q...<strong>Introduction:</strong> <span style="font-family:Verdana;">Breast cancer is the most common female cancer in India and account</span><span style="font-family:Verdana;">ing</span><span style="font-family:Verdana;"> for almost 1 in 4 cancer cases in women worldwide. According to GLOBOCAN 2018: breast cancer incidence is increased to 162</span><span style="font-family:Verdana;">,</span><span style="font-family:Verdana;">468 in 2018 compared to 144</span><span style="font-family:Verdana;">,</span><span style="font-family:;" "=""><span style="font-family:Verdana;">937 in 2012. Biosimilar drugs allow expanding access to the therapies in the form of cost savings and leading to better overall health outcomes. Our study evaluates the efficacy and safety of Trastuzumab biosimilars and assesses overall survival in the study population. </span><b><span style="font-family:Verdana;">Materials</span></b></span><b><span style="font-family:;" "=""> </span></b><b><span style="font-family:Verdana;">& Methods:</span></b><span style="font-family:;" "=""><span style="font-family:Verdana;"> This prospective study was conducted in Healthcare Global Enterprises Ltd., Bengaluru, India, and all female patients diagnosed with Her2 positive, metastatic (mBC) and Locally advanced breast cancer (LABC), between March 2013 and November 2014, with at least 4 years of post-treatment follow up. </span><b><span style="font-family:Verdana;">Results:</span></b><span style="font-family:Verdana;"> A total of 65 patients diagnosed with Her2 positive breast cancer and satisfied the selection criteria were included for the study. Partial Response (PR) was observed in 42 (64.6%) patients, Stable Disease (SD) in 11 (16.9%) patients and Progressive Disease (PD) in 12 (18.5%) patients. The overall response rates were 46.1% PR, 30% SD, 23.8% PD in metastatic population and 76% PR, 7.2% SD, 15% PD observed in locally advanced disease. The mean overall survival of the study population was 20.75 ± 15.20 months in metastatic and 29.2 ±</span></span><span style="font-family:;" "=""> </span><span style="font-family:;" "=""><span style="font-family:Verdana;">17.06 months in locally advanced patients. </span><b><span style="font-family:Verdana;">Conclusion:</span></b><span style="font-family:Verdana;"> This prospective study shows the effectiveness of Trastuzumab for HER2-positive in locally advanced and metastatic breast cancer. The response rates, survival and toxicity correlate with other global studies. The response and survival are </span></span><span style="font-family:Verdana;">as</span><span style="font-family:Verdana;"> same as either generic or original Trastuzumab.</span>展开更多
基金Supported by Youth Fund of National Natural Science Foundation of China,No.81803575,No.31902287Kaifeng Science and Technology Development Plan Project,No.2203008+2 种基金Key Specialized Research and Promotion Project of Henan Province in 2023,No.232102311205Henan Medical Science and Technology Research Program Project,No.LHGJ20210801College Students Innovation and Entrepreneurship Training Program of Henan University,No.20231022007.
文摘BACKGROUND Trastuzumab constitutes the fundamental component of initial therapy for patients with advanced human epidermal growth factor receptor 2(HER-2)-positive gastric cancer(GC).However,the efficacy of this treatment is hindered by substantial challenges associated with both primary and acquired drug resistance.While S-phase kinase associated protein 2(Skp2)overexpression has been implicated in the malignant progression of GC,its role in regulating trastuzumab resistance in this context remains uncertain.Despite the numerous studies investigating Skp2 inhibitors among small molecule compounds and natural products,there has been a lack of successful commercialization of drugs specifically targeting Skp2.AIM To discover a Skp2 blocker among currently available medications and develop a therapeutic strategy for HER2-positive GC patients who have experienced progression following trastuzumab-based treatment.METHODS Skp2 exogenous overexpression plasmids and small interfering RNA vectors were utilized to investigate the correlation between Skp2 expression and trastuzumab resistance in GC cells.Q-PCR,western blot,and immunohistochemical analyses were conducted to evaluate the regulatory effect of thioridazine on Skp2 expression.A cell counting kit-8 assay,flow cytometry,a amplex red glucose/glucose oxidase assay kit,and a lactate assay kit were utilized to measure the proliferation,apoptosis,and glycolytic activity of GC cells in vitro.A xenograft model established with human GC in nude mice was used to assess thioridazine's effectiveness in vivo.RESULTS The expression of Skp2 exhibited a negative correlation with the sensitivity of HER2-positive GC cells to trastuzumab.Thioridazine demonstrated the ability to directly bind to Skp2,resulting in a reduction in Skp2 expression at both the transcriptional and translational levels.Moreover,thioridazine effectively inhibited cell proliferation,exhibited antiapoptotic properties,and decreased the glucose uptake rate and lactate production by suppressing Skp2/protein kinase B/mammalian target of rapamycin/glucose transporter type 1 signaling pathways.The combination of thioridazine with either trastuzumab or lapatinib exhibited a more pronounced anticancer effect in vivo,surpassing the efficacy of either monotherapy.CONCLUSION Thioridazine demonstrates promising outcomes in preclinical GC models and offers a novel therapeutic approach for addressing trastuzumab resistance,particularly when used in conjunction with lapatinib.This compound has potential benefits for patients with Skp2-proficient tumors.
基金supported by grants from the Basic Scientific Research Fund for Heilongjiang Provincial Universities in 2018(2018-KYYWF-0105).
文摘Background: Trastuzumab resistance accounts for chemotherapy failure in gastric cancer patients in clinicalpractice. The significance of long non-coding RNAs (lncRNAs) in the maintenance of drug resistance in gastriccancer has been already underlined. Method: This study aimed to identify the specific role of lncRNA-ATB in gastriccancer progression and trastuzumab resistance. The downstream miRs of lncRNA-ATB and target genes of miRs werepredicted by bioinformatics analysis and verified using dual luciferase reporter assay. Loss- and gain-function assayswere performed to explore the roles of lncRNA-ATB, miR-200c, and zinc-finger protein 217 (ZNF217) in the cellfunctions and trastuzumab resistance of a trastuzumab-resistant gastric cancer cell line (NCI-N87-TR). Result:LncRNA-ATB was upregulated, while miR-200c was downregulated. Depletion of lncRNA-ATB or miR-200celevation led to a decrease in malignant properties of NCI-N87-TR cells. LncRNA-ATB could negatively target miR-200c, which in turn inversely targeted and reduced the expression of ZNF217. Silencing of ZNF217 could inhibit cellviability and migration. Conclusion: lncRNA-ATB promoted the progression and trastuzumab resistance of gastriccancer by repressing miR-200c via ZNF217 upregulation.
基金supported by the Chinese Academic of Medical Sciences Initiative for Innovative Medicine (No. CAMS-I2M-1-010)
文摘Objective: To assess the long-term effectiveness and safety of trastuzumab in adjuvant therapy for Chinese patients with early-stage human epidermal growth factor 2(HER2)-positive breast cancer in a real-world setting.Methods: This retrospective observational study analyzed the medical records of HER2-positive breast cancer patients between 2000 and 2012 at the Chinese Academy of Medical Sciences. Patients who received adjuvant chemotherapy alone or adjuvant chemotherapy followed by/combined with trastuzumab were included. The Kaplan-Meier method was used to estimate disease-free survival(DFS) and overall survival(OS). Hazard ratios(HR) and 95% confidence intervals(95% CI) were calculated using the Cox regression model.Results: Of the 1,348 patients analyzed, 909 received chemotherapy alone and 439 received chemotherapy plus trastuzumab. The 3-year, 5-year and 10-year DFS rates were 83.70%, 76.38% and 68.94%, respectively, in the chemotherapy-alone cohort, and 90.21%, 86.19% and 83.45% in the chemotherapy plus trastuzumab cohort. The3-year, 5-year and 10-year OS rates were 96.10%, 91.40% and 81.88% in the chemotherapy-alone cohort, and98.17%, 94.91% and 90.01% in the chemotherapy plus trastuzumab cohort. The chemotherapy plus trastuzumab group had a significantly lower risk of disease recurrence and death than the chemotherapy-alone group(DFS:HR=0.50, 95% CI, 0.37-0.68;P<0.001;OS: HR=0.53, 95% CI, 0.34-0.81;P=0.004) after adjusting for covariates.In the 439 patients treated with trastuzumab, multivariate analysis suggested that lymph node positivity, higher T stages, and hormone receptor-negative status were significantly associated with higher risks of disease recurrence,and lymph node positivity and hormone receptor-negative status were significantly associated with higher risks of death. Grade 3/4 adverse events(incidence ≥1%) were more common in patients receiving trastuzumab(54.44% vs.15.73%).Conclusions: Early-stage HER2-positive breast cancer patients treated with trastuzumab plus adjuvant chemotherapy have a significant survival benefit compared with chemotherapy-alone in real-world settings. Lymph node positivity, hormone receptor-negative status, and higher T stages may be associated with higher risks of recurrence, and effective therapy for patients with these factors is required.
文摘Late-stage gastric adenocarcinoma patients have a poor prognosis because of high recurrence rates.To improve long-term outcomes,perioperative chemotherapies are combined with surgery.Human epidermal growth factor receptor 2(HER2)overexpression had been noted in gastric cancer;therefore,trastuzumab has been used occasionally in this setting.A 63-year-old male Chinese patient,who was diagnosed with adenocarcinoma in the gastric antrum,as well as lymph node metastases along the left gastric and hepatic artery,and left adrenal area,was admitted to our hospital.HER2 expression was positive,and cluster amplification was detected in a fluorescence in situ hybridization assay.The patient received three cycles of a neoadjuvant trastuzumab/oxaliplatin/capecitabine regimen.He subsequently underwent distal gastrectomy,D2+lymphadenectomy,left adrenalectomy,cholecystectomy and BillrothⅡanastomosis.Treatment was continued with another five postoperative cycles of the same medication and trastuzumab application for 1 year.No recurrence has been observed 18 mo after the operation.Trastuzumab as perioperative and adjuvant medication,in combination with oxaliplatin and capecitabine for a HER2-overexpressing advanced gastric adenocarcinoma,led to recurrence-free survival of at least 18 mo after surgery.
基金Supported by Zhejiang Natural Science Foundation-Zhejiang Mathematical and Physical Medical Association,No.SY19H310001
文摘BACKGROUND Targeted treatments may greatly affect the natural history of urothelial carcinoma based on their pharmacokinetics. A phase II trial has explored the combination of cytotoxic chemotherapy with the anti-HER-2 monoclonal antibody trastuzumab in selected patients with metastatic bladder cancer, but it failed.CASE SUMMARY Here, we report a case of recurrent urothelial bladder carcinoma(UBC) in a patient who has undergone three operations, and further illuminate its diagnosis and treatment. The diagnosis of UBC was rendered according to the pathological indices. Next-generation sequencing on formalin fixed paraffin-embedded(FFPE)tissue was also performed and suggested HER2 gene amplification in the FFPE tissue. Based on HER2 gene amplification in FFPE, the patient was treated with chemotherapy in combination with trastuzumab after his third surgery.Fortunately, the patient got a clinically complete remission to trastuzumab for 34 mo.CONCLUSION There is not enough clinical evidence for incorporating trastuzumab in routine treatment of UBC. This case hinted that recurrent UBC patients with HER2 gene amplification may benefit from targeted trastuzumab. Further studies are needed to further investigate the status of HER2 gene and better determine trastuzumab in the management of UBC.
基金Fund supported by the President Foundation of Nanfang Hospital,Southern Medical University(2016L007).
文摘Wie present a 29-year-old woman with pT2N0M0 breast cancer,histological diagnosis of invasive ductal carcinoma,ER and PR low positive,and HER-2(3+).The patient developed trastuzumab-induced thrombocytopenia in 6 hours after an intravenous infusion of trastuzumab at the second cycle of trastuzumab treatment with the symptom of abnormal uterine bleeding.Laboratory exam revealed a sharp drop of platelet count down to 3X109/L.With the treatment of single-donor platelet transfusions,glucocorticoids,oxytocin and thrombopoietic drugs,the platelet count recovered completely in 11 days.This case was confirmed to be severe thrombocytopenia induced by trastuzumab,and retreatment with trastuzumab was not attempted.With increasing clinical utilization of trastuzumab,clinicians are likely to encounter more life-threatening trastuzumab induced severe thrombocytopenia.By this case report and literature review we hope to increase the awareness,attach the attentions to this condition,and help with the effective treatment.
基金Capital Clinical Medicine Special Project(No.Z181100001718215)National Natural Science Foundation of China(No.81602314).Research number:CSCO-BC RWS 16002。
文摘Objective:Several studies have demonstrated different benefits for patients whose disease progressed despite previous trastuzumab treatment.Due to limited real-world data,we evaluate the effectiveness of anti-human epidermal growth factor receptor 2(HER2)therapy(lapatinib or trastuzumab)plus chemotherapy or chemotherapy alone in patients who were previously treated with trastuzumab-containing regimens and investigate factors associated with effectiveness.And we further show the effectiveness of the two anti-HER2 therapy groups.Methods:A total of 342 HER2-positive metastatic breast cancer(MBC)patients whose disease progressed during prior anti-HER2(trastuzumab)and standard chemotherapy therapy from Department of Breast Oncology,the Fifth Medical Center of Chinese PLA General Hospital,from August 2010 to December 2016 were included.Seventy-eight patients received standard chemotherapy only,148 patients continued to receive trastuzumab and switched to other chemotherapy drugs,and 116 patients received tyrosine-kinase inhibitors(TKIs;lapatinib)and chemotherapy.The main outcome measures were progression-free survival(PFS),overall response rate(ORR),and clinical benefit rate(CBR).Subgroup analyses were conducted to identify patient characteristics associated with the greatest clinical benefit.Results:After a median follow-up of 26.2(range,2.0-56.0)months,PFS significantly improved with anti-HER2 therapy compared with chemotherapy alone:median 6.0 months with lapatinib[95%confidence interval(95%CI),4.53-7.47],4.5 months with trastuzumab(95%CI,3.99-5.01)vs.3.0 months with chemotherapy alone(95%CI,2.42-3.58);stratified hazard ratio(HR)=0.70,95%CI,0.60-0.81;P<0.0001.The ORR values were 33.6%,25.0%and 12.8%,respectively,the CBR values were 60.3%,48.6%and 26.9%,respectively.The effectiveness of lapatinib group and trastuzumab group were further analyzed.In multivariate analysis,lapatinib group was associated with a longer PFS,after controlling other potential confounders(HR=0.68,95%CI,0.52-0.90;P=0.006).Conclusions:The combination of TKIs and chemotherapy was effective in this cohort previously treated with trastuzumab treatment.Therefore,TKIs combined with chemotherapy is an option for Chinese HER2-positive MBC patients previously treated with trastuzumab treatment.
基金by the National Natural Science Foundation of China(Nos.81872809,82073786)the Beijing Natural Science Foundation(L212013).
文摘The combination regimen of trastuzumab(Tras)plus Nab-paclitaxel(Nab)is recommended to treat HER2-positive(HER2+)cancers.However,they exert effects in different mechanisms:Tras need to stay on cell membranes,while Nab need to be endocytosed,therefore the concurrent combination regimen may not be the best one in HER2+tumors treatment.Caveolin-1(Cav-1)is a key player in mediating their endocytosis and is associated with their efficacy,but few researches noticed the opposite effect of Cav-1 expression on the combination efficacy.Herein,we systematically studied the Cav-1 expression level on the combination efficacy and proposed an optimized and clinically feasible combination regimen for HER2+Cav-1 High tumor treatment.In the regimen,lovastatin(Lova)was introduced to modulate the Cav-1 expression and the results indicated that Lova could downregulate Cav-1 expression,increase Tras retention on cell membrane and enhance the in vitro cytotoxicity of Tras in HER2+Cav-1 High cells but not in HER2+Cav-1 Low cells.Therefore,by exchanging the dosing sequence of Nab and Tras,and by adding Lova at appropriate time points,the precise three-drug-sequential regimen(PTDS,Nab(D1)-Lova(D2)-Lova&Tras(D2+12 h))was established.Compared with the concurrent regimen,the PTDS regimen exhibited a higher in vitro cytotoxicity and a stronger tumor growth inhibition in HER2+Cav-1 High tumors,which might be a promising combination regimen for these patients in clinics.
文摘BACKGROUND Trastuzumab is a generally safe agent prescribed in the systemic treatment of breast cancer.Tinnitus is not a currently known adverse event related to trastuzumab.Here,we describe a rare case of severe tinnitus and a migraine headache induced by trastuzumab used for adjuvant therapy.CASE SUMMARY A 37-year-old woman was diagnosed with hormone receptor-positive and human epidermal growth factor receptor 2-positive breast cancer.After surgery,she was treated with four cycles of epirubicin and cyclophosphamide;she then received docetaxel and a loading dose of trastuzumab plus pertuzumab.Less than half an hour after trastuzumab infusion,the patient complained of severe tinnitus and left-sided migraine headache.Trastuzumab monotherapy was discontinued immediately,and symptoms disappeared after 10 min.Trastuzumab was readministered,and severe tinnitus and migraine headache recurred.Trastuzumab was stopped,and severe tinnitus diminished after 10 min.Pertuzumab and docetaxel therapy was then administered,and no adverse events were observed.Subsequent infusions of trastuzumab every three weeks did not show the same symptoms.CONCLUSION Although trastuzumab is well-tolerated in most patients,we should pay attention to the risk of severe tinnitus and migraine.
文摘BACKGROUND It remains unclear whether the current arbitrary screening recommendations of trastuzumab-related cardiotoxicity provides an adequate balance between preventing heart damage and curtailing a curative treatment.AIM To determine the incidence rate and consequences of trastuzumab-induced cardiotoxicity as adjuvant treatment in a real-world scenario.METHODS We present a retrospective analysis of cardiac function measured by echocardiogram at baseline and every 3 mo during trastuzumab treatment.Cardiotoxicity was defined as a drop in left ventricular ejection fraction(LVEF)≥10%from baseline and/or any drop<50%.RESULTS Between January 2011 and December 2014,407 patients were selected.Most(93.6%)were treated with an anthracycline followed by a taxane-based regimen and trastuzumab for 12 mo.Forty patients(9.8%)had cardiotoxicity.None of them were symptomatic,and 28(72.5%)completely recovered LVEF.Cardiotoxicity happened early as shown by LVEF measured on echocardiogram 2 to 4 as compared to 5 to 7(odds ratio=2.47,95%confidence interval:1.09,5.63,P=0.024).There were 54 deaths(13.3%)during the 70-mo follow-up period;1(0.2%)was attributed to late cardiotoxicity(4 years after treatment).The absence of symptomatic cardiotoxicity during trastuzumab treatment and moreover the early occurrence on the treatment period may translate into a strategy to evaluate less frequently.CONCLUSION We observed a 10%rate of asymptomatic cardiotoxicity,which mirrors the results from the large adjuvant trials.Despite being transient,an LVEF drop led to frequent treatment delays and interruptions.It remains unclear whether LVEF decline is predictive of late cardiotoxicity,and treatment efficacy is compromised.
文摘Since trastuzumab monotherapy for treatment of breast cancer with HER2/ErbB2 over-expression has been shown to have limited efficacy, combined treatment of trastuzumab with chemotherapy is widely practiced in clinic. However, certain combination treatments of trastuzumab and chemotherapy (i.e. doxorubicin) are not recommended due to high risk of cardiotoxicity. Antibody-drug conjugates (ADCs) offer selective delivery of cytotoxic agents into targeted cancer cells, thereby allowing for reduced general cellular cytotoxicity caused by chemotherapeutic agents through antibody mediated specific recognition of tumor antigens. In this study, we constructed a trastuzumab-doxorubicin conjugate (T-Dox) using a thioether linkage and characterized both biophysical stability and anti-cancer potency of the T-Dox using a panel of HER2 expressing cancer cell lines. The T-Dox conjugate showed significantly improved anti-cancer potency in comparison with trastuzumab. The results demonstrated for the first time that there were significant differences in the uptake of T-Dox among high HER2 expression cancer cells and higher T-Dox uptake also showed stronger anti-cancer potency. Similar to trastuzumab, T-Dox selectively bound to HER2 overexpressing cancer cells and low HER2 expression cells had no detectable uptake of T-Dox. Consistent to the uptake data, human cardiomyocyte cells had no detectable HER2 expression and T-Dox showed minimal cytotoxic effects. On the contrary, a treatment with combination of trastuzumab and doxorubicin showed severe cytotoxicity to human cardiomyocytes (>90% cell death after 3 day exposure). This study demonstrated that trastuzumab conjugated with doxorubicin (T-Dox) can provide valuable alternative to the combination treatment with doxorubicin and trastuzumab for high HER2 expressing cancer patients.
文摘Aim: Firstly, to quantify active healthcare professional (HCP) time and costs associated with subcutaneous (SC) administration of trastuzumab (Herceptin?) compared with the standard intravenous infusion (IV) in the treatment of patients with HER2-positive early breast cancer within the adjuvant PrefHer trial setting;secondly, to measure patient time in the care unit and patient infusion chair time for both routes of administration. Methods: A UK multi-centre prospective, observational Time and Motion study was conducted alongside the PrefHer trial (ClinicalTrials.gov id: NCT01401166). Trained observers measured the duration of each SC and IV related task that HCPs undertook and recorded patient time in the chemotherapy unit and infusion chair. The type and quantity of medical consumables used with each route of administration were also collected. Twenty-four patient episodes were recorded (12 SC, 12 IV). Mean total administration time was calculated as the mean sum of task times, both for IV and SC formulations. The mean cost of each route of administration was calculated as the mean cost of HCP time plus the mean cost of consumables used. HCP time was costed using Personal Social Services Research Unit. Consumables were costed using hospital pharmacy data and online sources. Results: Mean active HCP time for IV administration was 92.6 minutes compared with 24.6 minutes for SC administration. The mean cost for IV preparation and administration was ￡144.96 (￡132.05 of HCP time and ￡12.92 of consumables) versus ￡33.15 (￡31.99 of HCP time and ￡1.17 of consumables) for SC administration. Mean time spent in the care unit and in the infusion chair was 94.5 minutes and 75 minutes respectively for IV, and 30.3 minutes and 19.8 minutes for SC. SC administration of trastuzumab could translate to a time saving of 68 minutes (versus IV) with a total cost saving of ￡111.81 per patient episode. This equates to a potential saving of ￡2012.58 over a full course of adjuvant treatment (18 cycles). Conclusion: Substituting IV infusion with SC administration of trastuzumab may lead to a substantial reduction in active HCP time, patient chair and unit time, consumable use and overall costs. The reduced patient chair and unit time could provide increased capacity within existing resources.
文摘Background: Agent targeting HER-2 pathway plus chemotherapy has represented a major progress in the management of patients with breast cancer. However, the role of late-line treatment in heavily pretreated patients is still largely unclear. In the last decade, nab-paclitaxel has shown significant activity and good toxicity profile in metastatic breast cancer. Case Presentation: We report the case of a 76-year-old Caucasian woman with metastatic HER-2 positive ductal infiltrating breast carcinoma treated with a combination of weekly nab-paclitaxel and trastuzumab as fifth-line therapy. She had previously received first-line paclitaxel and trastuzumab, second-line vinorelbine and trastuzumab, third-line TDM1 and fourth-line oral capecitabine and lapatinib. Clinical and radiological staging showed progression at bone, skin and soft-tissue. The patient received weekly nab-paclitaxel plus trastuzumab. Massive objective response was clinically and PET documented which lasted 8 months. Tolerance to treatment was fairly good as well as cardiac safety. Conclusion: To the best of our knowledge, this is the first reported case of efficacy of nab-paclitaxel in combination with trastuzumab as fifth-line of treatment in a patient with metastatic HER-2 positive breast cancer.
文摘<strong>Introduction:</strong> <span style="font-family:Verdana;">Breast cancer is the most common female cancer in India and account</span><span style="font-family:Verdana;">ing</span><span style="font-family:Verdana;"> for almost 1 in 4 cancer cases in women worldwide. According to GLOBOCAN 2018: breast cancer incidence is increased to 162</span><span style="font-family:Verdana;">,</span><span style="font-family:Verdana;">468 in 2018 compared to 144</span><span style="font-family:Verdana;">,</span><span style="font-family:;" "=""><span style="font-family:Verdana;">937 in 2012. Biosimilar drugs allow expanding access to the therapies in the form of cost savings and leading to better overall health outcomes. Our study evaluates the efficacy and safety of Trastuzumab biosimilars and assesses overall survival in the study population. </span><b><span style="font-family:Verdana;">Materials</span></b></span><b><span style="font-family:;" "=""> </span></b><b><span style="font-family:Verdana;">& Methods:</span></b><span style="font-family:;" "=""><span style="font-family:Verdana;"> This prospective study was conducted in Healthcare Global Enterprises Ltd., Bengaluru, India, and all female patients diagnosed with Her2 positive, metastatic (mBC) and Locally advanced breast cancer (LABC), between March 2013 and November 2014, with at least 4 years of post-treatment follow up. </span><b><span style="font-family:Verdana;">Results:</span></b><span style="font-family:Verdana;"> A total of 65 patients diagnosed with Her2 positive breast cancer and satisfied the selection criteria were included for the study. Partial Response (PR) was observed in 42 (64.6%) patients, Stable Disease (SD) in 11 (16.9%) patients and Progressive Disease (PD) in 12 (18.5%) patients. The overall response rates were 46.1% PR, 30% SD, 23.8% PD in metastatic population and 76% PR, 7.2% SD, 15% PD observed in locally advanced disease. The mean overall survival of the study population was 20.75 ± 15.20 months in metastatic and 29.2 ±</span></span><span style="font-family:;" "=""> </span><span style="font-family:;" "=""><span style="font-family:Verdana;">17.06 months in locally advanced patients. </span><b><span style="font-family:Verdana;">Conclusion:</span></b><span style="font-family:Verdana;"> This prospective study shows the effectiveness of Trastuzumab for HER2-positive in locally advanced and metastatic breast cancer. The response rates, survival and toxicity correlate with other global studies. The response and survival are </span></span><span style="font-family:Verdana;">as</span><span style="font-family:Verdana;"> same as either generic or original Trastuzumab.</span>
