Pharmacoeconomic evaluation of pyrotinib combined with capecitabine in the second-line treatment of HER- 2 positive patients with advanced breast cancer / 中国药房

OBJECTIVE To evaluate the cost-effectiveness of pyrotinib combined with capecitabine in the second-line treatment of human epidermal growth factor receptor- 2（HER-2）positive advanced breast cancer from the point of view of medical and health system ，and to provide reference for the selection of clinical therapy plan and national health decision. METHODS The dynamic Markov model was constructed on the basis of a multicenter ，open，randomized controlled phase Ⅲ clinical trial in 29 centers in China. The simulation time limit was 8 years，and the cycle was 21 days. The cost-effectiveness of pyrotinib combined with capecitabine （observation group ）were compared with that of lapatinib combined with capecitabine （control group ）in the second-line treatment of HER- 2 positive advanced breast cancer. The incremental cost-utility ratio （ICER）was calculated by using quality-adjusted life year （QALY）as output indicators ，and the sensitivity analysis was carried out to validate the robustness of the results of basic analysis. RESULTS The results of basic analysis showed that compared with control group ，the incremental cost per capita and incremental utility per capita of observation group were 67 953.82 yuan and 0.40 QALYs；ICER was 168 861.89 yuan/QALY，which was lower than the willing to pay （WTP）threshold（217 500 yuan/QALY）represented by 3 times of China ’s per capita GDP in 2020，indicating the treatment plan of the observation group is more cost-effective. The results of single factor sensitivity analysis showed that the proportion of patients treated with trastuzumab or pyrotinib after entering disease progression （PD）status in the control group ，the proportion of patients treated with lapatinib or trastuzumab after entering PD status in the observation group ，the cost of capecitabine and other parameters showed great impact on ICER ，but those parameters didn ’t cause the reverse of basis analysis results. The results of probabilistic sensitivity analysis showed that when the WTP threshold was 217 500 yuan/QALY，the probability that the treatment plan in the observation group was cost-effective was 94.10％. The results of partition survival model analysis were consistent with those of dynamic Markov model. CONCLUSIONS On the premise of taking 3 times of China ’s per capita GDP in 2020 as the WTP lin- threshold， the second-line treatment of HER- 2 positive wang9805@163.com advanced breast cancer with pyrotinib combined with capecitabine is more cost-effective than that with lapatinib combined with capecitabine.

The clinical efficacy and safety of Apatinib combined with radiotherapy and chemotherapy in the patients with medium-and late-stage cervical cancer / 中华老年医学杂志

Objective:To analyze the clinical efficacy and safety of Apatinib combined with radiotherapy and chemotherapy in patients with medium-and late-stage cervical cancer.Methods:A total of 58 patients with medium-and late-stage cervical cancer treated in our hospital from December 2017 to December 2020 were randomly divided into the control group(receiving the radiotherapy plus chemotherapy, n=29)and the observation group(receiving Lapatinib combined with radiotherapy plus chemotherapy, n=29). After 4 courses of continuous medication, the recent clinical efficacy, changes in tumor lesions, and adverse reactions were compared between the two group.Results:Before treatment, there was no significant difference in the size of tumor lesions between the two groups[(4.26±0.21)cm vs.(4.30±0.29)cm, P=0.550]. The tumor lesion size after treatment was significantly smaller both in observation group[(4.26±0.21) vs.(2.37±0.17)cm, P<0.01]and in the control group[(4.30±0.29) vs.(3.32±0.20)cm, P<0.01]. But image features revealed significantly smaller tumor lesion size in observation group than in the control group[(2.37±0.17)cm vs.(3.32±0.20)cm, P=0.000]. After treatment, the short-term total effective rates were significantly higher in the observation group(82.76%, 24/29)than in the control group(58.62%, 17/29), ( χ2=4.077, P=0.043). There was no statistical difference between the groups in incidences of diarrhea, rash, proteinuria, bone marrow suppression, hand-foot syndrome, hypertension, etc. Conclusions:The treatment of Lapatinib combined with radiotherapy and chemotherapy can effectively improve the clinical efficacy and reduce the size of the tumor lesions, and the adverse reactions can be tolerated in patients with medium-and late-stage cervical cancer.

Synergistic Antitumor Activity and Mechanism of Lapatinib and Paclitaxel in Esophageal Cancer Cells / 肿瘤防治研究

Objective To investigate the anti-tumor activity and mechanism of lapatinib, paclitaxel and their combination on esophageal cancer cells EC109. Methods MTT assay was used to detect the effects of lapatinib (1, 2, 4, 8 μmol/L), paclitaxel (5, 10, 20, 40 μg/L) and their combination on the proliferation of esophageal cancer cells EC109. We tested the effects of 2 μmol/L lapatinib, 10 μg/L paclitaxel and their combination on the invasion, cell cycle, apoptosis and EGFR, HER2 and downstream signaling pathways of EC109 cells. Results Lapatinib combined with paclitaxel synergistically inhibited the proliferation of EC109 cells, and the combined action index was greater than 1.15. The number of invaded cells in the combination group (62.0±9.5) was significantly less than those in the lapatinib group (152.4±16.1) and the paclitaxel group (103.6±12.7) (P < 0.05). G2/M cells in the combination group ((43.4±3.1)%) was higher than those in lapatinib group ((20.3±2.5)%) and paclitaxel group ((26.6±2.8)%) (P < 0.05). The apoptosis rate of the combination group was (47.3±8.4)%, higher than those of lapatinib ((12.7±2.3)%) and paclitaxel group ((21.4±5.2)%) (P < 0.05). Lapatinib combined with paclitaxel could synergistically inhibit the expression of phosphorylated EGFR, HER2 and AKT proteins. Conclusion Lapatinib combined with paclitaxel exert synergistic antitumor activity by synergistically inhibiting the proliferation and invasion of esophageal cancer cell line EC109, arresting cell cycle, inducing apoptosis and inhibiting the transduction of EGFR/HER downstream signaling pathway.

Development And Evaluation Of Lapatinib Solid Lipid Nanoparticles In The Management Of Breast Cancer

The current research was aimed at formulation of Lapatinib loaded solid lipid nanoparticles (SLNs) followed by evaluation for effective treatment of breast cancer. The formulations prepared by homogenization and ultrasonication and evaluated for zeta potential, particle size, polydispersity index, entrapment efficiency and in-vitro dissolution studies. Entrapment efficiency studies indicated proportional relation between concentration of lipid and the amount of drug entrapped. The physicochemical parameter evaluation data indicated 94.27% entrapment efficiency, 130 nm particle size and -19.9 zeta potential for stable formulation. The in vitro drug dissolution studies indicated that Lapatinib loaded SLNs (F6) formulated with Dynasan 116 and Egg Lecithin was suitable for anti-cancer therapy with higher drug dissolution rate.

Advances in therapy of breast cancer: overexpression and therapeutic implications of targeting human epidermal growth factor receptors

The human epidermal growth factor receptor 2 (HER2) ERbb2 gene is amplified in approximately 25% of breast cancers. Characteristics of HER2-amplified tumors include increased proliferation rates and a propensity for distant metastasis. The discovery of overexpression of HER2 in a subset of breast cancers was an important milestone in our understanding of the biology of the disease. This paved the way for the discovery of trastuzumab, a humanized monoclonal antibody targeting HER2. Trastuzumab is the foundation of treatment of HER2- positive breast cancers, demonstrating dramatic responses in patients with metastatic disease. Recent advances in our understanding of the interaction between HER2 and other members of the epidermal growth factor receptor family have led to the identification of newer agents, resulting in the expansion of the clinical armamentarium of available agents for the treatment of HER2-positive tumors. The biology of the ERbb receptor family, the use of HER2-targeted agents in breast cancer, and the advances in anti-HER2 agents that are currently in clinical development are reviewed here.

Analysis of eddicacy of HER2-enriched subtype to Trastuzumab combined with Lapatinib in treatment of early breast cancer / 国际外科学杂志

Objective To analyze the therapeutic effects of adjuvant therapy with the human epidermal growth factor receptor 2 (HER2) double-blocker Trastuzumab and Lapatinib on the differential expression of different molecular subtypes of breast cancer,especially for the HER2 overexpression.Methods A prospective study was conducted to select 227 patients with early-stage HER2-positive breast cancer who were not treated in the Yulin First Hospital from January 2014 to March 2017.The average age was 55 years old,rang from 22 to 67 years old.All patients received a double blocker treatment for consecutive 18 weeks [oral Lapatinib 1 000 mg/(time · d) and injection Trastuzumab (first 8 mg/kg,later 6 mg/kg,Intravenous drip,once every 3 weeks)].Among them,postmenopausal patients took Letrozole 2.5 mg/d,and premenopausal patients took Tamoxifen 20 mg/d.If a serious adverse reaction occurs during the administration,the amount of Lapatinib was reduced to 750 mg/(time · d).The test can continue after the adverse reaction had dropped to level 1 and below,up to 14 days.Safety tests were performed on the first day of each cycle,and biopsy was performed on the 14th day for the detection of initial gene expression changes,and the effect of the reaction was initially judged by ultrasound at 6th week.According to the Response Evaluation Criteria in Solid Tumors 1.1 of the solid tumor,if the tumor volume becomes large,it was determined that the treatment was ineffective.Ineffective patients were given an intravenous infusion of 80 mg/m2 Paclitaxel per week.The dose of lapatinib was reduced to 750 mg/(time · d) and the remaining 12 courses were continued.Normal patients underwent surgery within 1 to 3 weeks of the completion of the last course of treatment.Ineffective patients underwent surgery within 2 to 3 weeks after the end of the procedure,and the last safety examination was followed up 30 days after surgery.Clinical variables,complete response rates,and adverse events were observed in patients with different molecular subtypes.Measurement data were expressed as median (interquartile range) [M(P25,P75)],Wilcoxon rank sum test was used for comparison between groups;Chi-square test was used for compare the count data between groups.Results Of the 227 patients,207 (91.19％) completed the entire treatment process.After treatment,compared with the initial molecular subtypes,63 (41.72％) of the 151 patients with HER2 overexpression had complete remission,while only 10 of the 76 other subtypes (13.16％) were completely relapsed.Remission,the difference between the two groups was statistically significant (x2 =17.62,P ＜ 0.001);after 14 days of treatment,most of the tumor types were converted to normal breast-like type,and the patients who became normal breast-like type were completely,the response rate was 50.00％ (56/112),which was much higher than the complete response rate of other patients [14.78％ (17/115),x2 =30.66,P ＜ 0.001].Of the initial 151 HER2 overexpressing patients,115 (76.16％) patients switched to other subtypes,of which 84 (73.04％) converted to normal breast-like and 51 (60.71％) for complete remission.Most of the adverse reactions were concentrated in grades 1 to 2.Among them,liver function abnormalities,diarrhea,skin rashes,and hand-foot syndrome were the main factors.Conclusion In HER2-positive early breast cancer,adjuvant therapy with the HER2 double-blocker Trastuzumab and Lapatinib is more effective in patients with HER2 overexpression and can be used to determine the intrinsic molecular subtype of breast cancer,with its potential utilization value.

BioPATH: A Biomarker Study in Asian Patients with HER2+ Advanced Breast Cancer Treated with Lapatinib and Other Anti-HER2 Therapy / Journal of the Korean Cancer Association, 대한암학회지

PURPOSE: BioPATH is a non-interventional study evaluating the relationship of molecular biomarkers (PTEN deletion/downregulation, PIK3CA mutation, truncated HER2 receptor [p95HER2], and tumor HER2 mRNA levels) to treatment responses in Asian patients with HER2+ advanced breast cancer treated with lapatinib and other HER2-targeted agents. MATERIALS AND METHODS: Female Asian HER2+ breast cancer patients (n=154) who were candidates for lapatinib-based treatment following metastasis and having an available primary tumor biopsy specimen were included. The primary endpoint was progression-free survival (PFS). Secondary endpoints were response rate, overall survival on lapatinib, correlation between biomarker status and PFS for any previous trastuzumab-based treatment, and conversion/conservation rates of the biomarker status between tissue samples collected at primary diagnosis and at recurrence/metastasis. Potential relationships between tumor mRNA levels of HER2 and response to lapatinib-based therapy were also explored. RESULTS: p95HER2, PTEN deletion/downregulation, and PIK3CA mutation did not demonstrate any significant co-occurrence pattern and were not predictive of clinical outcomes on either lapatinib-based treatment or any previous trastuzumab-based therapy in the metastatic setting. Proportions of tumors positive for p95HER2 expression, PIK3CA mutation, and PTEN deletion/down-regulation at primary diagnosis were 32%, 31.2%, and 56.2%, respectively. Despite limited availability of paired samples, biomarker status patterns were conserved in most samples. HER2 mRNA levels were not predictive of PFS on lapatinib. CONCLUSION: The prevalence of p95HER2 expression, PIK3CA mutation, and PTEN deletion/downregulation at primary diagnosis were similar to previous reports. Importantly, no difference was observed in clinical outcome based on the status of these biomarkers, consistent with reports from other studies.

FOXO1 Suppression is a Determinant of Acquired Lapatinib-Resistance in HER2-Positive Gastric Cancer Cells Through MET Upregulation / Journal of the Korean Cancer Association, 대한암학회지

PURPOSE: Lapatinib is a candidate drug for treatment of trastuzumab-resistant, human epidermal growth factor receptor 2 (HER2)–positive gastric cancer (GC). Unfortunately, lapatinib resistance renders this drug ineffective. The present study investigated the implication of forkhead box O1 (FOXO1) signaling in the acquired lapatinib resistance in HER2-positive GC cells. MATERIALS AND METHODS: Lapatinib-resistant GC cell lines (SNU-216 LR2-8) were generated in vitro by chronic exposure of lapatinib-sensitive, HER2-positive SNU-216 cells to lapatinib. SNU-216 LR cells with FOXO1 overexpression were generated by stable transfection of a constitutively active FOXO1 mutant (FOXO1A3). HER2 and MET in SNU-216 LR cells were downregulated using RNA interference. The sensitivity of GC cells to lapatinib and/or cisplatin was determined by crystal violet assay. In addition, Western blot analysis, luciferase reporter assay and reverse transcription–polymerase chain reaction were performed. RESULTS: SNU-216 LR cells showed upregulations of HER2 and MET, but downregulation of FOXO1 compared to parental SNU-216 cells. FOXO1 overexpression in SNU-216 LR cells significantly suppressed resistance to lapatinib and/or cisplatin. In addition, FOXO1 negatively controlled HER2 and MET at the transcriptional level and was negatively controlled by these molecules at the post-transcriptional level. A positive crosstalk was shown between HER2 and MET, each of which increased resistance to lapatinib and/or cisplatin. CONCLUSION: FOXO1 serves as an important linker between HER2 and MET signaling pathways through negative crosstalks and is a key regulator of the acquired lapatinib resistance in HER2-positive GC cells. These findings provide a rationale for establishing a novel treatment strategy to overcome lapatinib resistance in a subtype of GC patients.

Phosphorylated S6 Kinase-1 as Predictive Marker of Lapatinib Efficacy in Human Epidermal Growth Factor Receptor 2-Positive Metastatic Breast Cancer Patients

PURPOSE: The 40S ribosomal protein S6 kinase-1 (S6K1) is a crucial downstream effector of the PI3K/AKT/mTOR pathway. S6K1 overexpression is found in 10% to 30% of breast cancers and is associated with aggressive disease and poor prognosis. Herein, we investigated the relationship between the expression of phosphorylated S6K1 (p-S6K1) and efficacy of lapatinib in patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer. METHODS: We retrospectively analyzed the data of 36 patients with HER2-positive metastatic breast cancer treated with lapatinib between January 2010 and September 2014. The p-S6K1 expression status of the primary tumor was assessed via immunohistochemistry using a mouse monoclonal antibody. RESULTS: Fourteen of the 36 patients (38.9%) had p-S6K1-positive tumors. The median progression-free survival (PFS) of patients with p-S6K1-positive tumors was significantly longer than that of patients with p-S6K1-negative tumors (13.4 months vs. 7.1 months, p=0.025). In multivariate analysis, p-S6K1 positivity remained an independent, favorable predictive factor for PFS (hazard ratio, 0.32; 95% confidence interval, 0.11–0.97; p=0.044). CONCLUSION: The high expression of p-S6K1 was significantly associated with prolonged PFS, suggesting that p-S6K1 can be a potential biomarker for predicting the efficacy of lapatinib in patients with HER2-positive metastatic breast cancer.

Efficacy and safety of oral lapatinib in HER2 positive metastatic breast cancer / 肿瘤

Objective: To determine the effectiveness and safety of lapatinib for patients with human epidermal growth factor receptor-2 (HER2) positive metastatic breast cancer. Methods: In this retrospective study, 40 patients with HER2 positive metastatic breast cancer (MBC) received lapatinib-based regimen. The clinical records and follow-up information were collected and analyzed. Results: Forty patients with HER2 positive MBC were enrolled in this study, and 90.0% (36/40) of the patients had received trastuzumab-based regimen during the recurrent/metastatic period, the median interval of trastuzumab treatment was 12.0 months (95% confidence interval: 10.5-13.5 months) (range: 2.0-54.0 months); 5.0% (2/40) of the patients had received adjuvant trastuzumab, but the disease-free survival (DFS) was two years or less; 5.0% (2/40) of the patients had never received trastuzumab, but the brain was the first metastatic organ. Of 40 patients, 31 (77.5%) received lapatinib combined with chemotherapy, 6 (15.0%) combined with endocrine therapy, and 3 (7.5%) combined with trastuzumab. The objective response to lapatinib-based therapy was evaluable in all patients. Ten (25.0%) patients achieved partial response (PR), 21 (52.5%) patients had stable disease (SD), 9 (22.5%) had progressive disease (PR), and no one achieved complete response (CR). The objective response rate (ORR) (CR+PR) was 25.0%, and the clinical benefit rate (CBR) (CR+PR+SD≥ 6 months) was 50.0%. The median progression-free survival (PFS) was 6.0 months (95% confidence interval: 4.6-7.5 months) (range: 1.0-20.0 months). The main toxicities related to lapatinib were grade 1-2 diarrhea in 8 patients (20.0%), and grade 1-2 rash in 6 patients (15.0%). Conclusion: Lapatinib-based therapy is an effective treatment for patients with HER2 positive metastatic breast cancer after prior exposure to trastuzumab.

Brain metastasis in human epidermal growth factor receptor 2-positive breast cancer: from biology to treatment

Overexpression of human epidermal growth factor receptor 2 (HER2) is found in about 20% of breast cancer patients. With treatment using trastuzumab, an anti-HER2 monoclonal antibody, systemic control is improved. Nonetheless, the incidence of brain metastasis does not be improved, rather seems to be increased in HER2-positive breast cancer. The mainstay treatment for brain metastases is radiotherapy. According to the number of metastatic lesions and performance status of patients, radiosurgery or whole brain radiotherapy can be performed. The concurrent use of a radiosensitizer further improves intracranial control. Due to its large molecular weight, trastuzumab has a limited ability to cross the blood-brain barrier. However, small tyrosine kinase inhibitors such as lapatinib, has been noted to be a promising agent that can be used as a radiosensitizer to affect HER2-positive breast cancer. This review will outline general management of brain metastases and will focus on preclinical findings regarding the radiosensitizing effect of small molecule HER2 targeting agents.

Factors predicting lapatinib efficacy in HER-2+ metastatic breast carcinoma: Does it work better in different histologic subtypes.

CONTEXT: Introduction of trastuzumab, a recombinant monoclonal antibody against the extracellular domain of HER‑2, is a cornerstone in the treatment of HER‑2+ breast carcinoma. However, many cancers that have an initial response to trastuzumab will progress some time later. After progression on trastuzumab‑based first‑line treatment, there are several options. Although TDM‑1 (Trastuzumab emtansine) has prolonged progression‑free survival (PFS) and overall survival in patients previously treated with trastuzumab and taxane, it is still not available in Turkey. Patients may be switched to lapatinib (an oral tyrosine kinase inhibitor targeting both HER‑1 and HER‑2), or they may re‑challenge with trastuzumab. There is no clear definition of the patients who should be switched to lapatinib. AIM: In this study, we investigated the factors predicting the efficacy of lapatinib. SUBJECTS AND METHODS: Totally, 94 patients treated with lapatinib for metastatic breast carcinoma was included in our study. Retrospective data including pathology, treatments and treatment results, metastatic sites, and laboratory tests were collected. RESULTS: Progression‑free survival was 9.1 months. Histologic subtypes other than invasive ductal carcinoma and liver metastasis were inversely related with PFS. Overall survival was 22.1 months, and patients with histologic subtypes other than invasive ductal carcinoma and who progress with brain metastasis had a worse prognosis. CONCLUSION: Clinicians should give attention to histologic subtype and metastatic sites when choosing patients for lapatinib treatment.

Lapatinib induced cell cycle arrest and apoptosis in CNE-2z cells / 解放军医学杂志

Objective To explore the effect of lapatinib on the cell cycle and apoptosis of human CNE-2Z nasopharyngeal carcinoma (NPC) cells, and to study the related mechanisms. Methods CCK-8 assay was used to assess the proliferation of CNE-2Z cells treated by lapatinib. After PI staining, the cell cycle distribution was determined by flow cytometry. Apoptosis was analyzed using Annexin V/PI double binding assay. The mRNA expression of cell cycle related molecular Cyclin D1, P21 and P53 was assessed with real time PCR. The expression of protein Cyclin D1, P21, P53, and apoptosis related protein Mcl-1 and Bax was determined by Western blotting. The enzymatic activity of caspase-3/7 was measured by using Apo-ONE Homogeneous Caspase-3/7 Assay kit. Results Lapatinib inhibited the proliferation of CNE-2Z cells in a dose-dependent manner. Various concentrations of lapatinib induced significant G0/G1 phase arrest and promoted apoptosis of CNE-2Z cells. Lapatinib significantly down-regulated Cyclin D1 expression, but up-regulated P21 and P53 expression at mRNA and protein levels. Lapatinib also induced down-regulation of Mcl-1 with up-regulation of Bax protein expression, and activated Caspase-3/7 in CNE-2Z cells. Conclusion Lapatinib may effectively inhibit proliferation, induce cell cycle arrest and promote apoptosis of CNE-2Z cells, so it may serve as a potent therapeutic agent against nasopharyngeal carcinoma.

Long-term Complete Response with Lapatinib Plus Capecitabine in a Patient with HER2-Positive Breast Cancer Metastasized to the Pancreas / 이화의대지

A 37-year-old woman underwent a total mastectomy and adjuvant chemotherapy for HER2-positive breast cancer (pT1N0M), and then recurred in the right lung followed by the pancreas. Lung lobectomy and pylorus-preserving pancreaticoduodenectomy were performed, and systemic chemotherapies including trastuzumab were sequentially administered. However, metastasis to the pancreatic tail was detected. She underwent image-guided radiation therapy, but this was not effective. Lapatinib plus capecitabine combination was administered as forth-line treatment and the metastatic lesion was disappeared. She is continuing this regimen with a complete response for 48 months until now.

The application of Lapatinib in breast cancer and its mechanism of drug resistance / 实用肿瘤学杂志

With development of molecular biology,breast cancer has entered an era of molecular classifi-cation,thus making biomarker based personalized medicine is the trend of breast cancer treatment.HER2-posi-tive breast cancer of high invasiveness and bad prognosis accounts for 20%~30%.Targeting HER2,trastuzumab is the first humanized monoclonal antibody which can improve the prognosis of HER2-positive patients and it is recommended by guidelines and expert consensus at home and abroad for anti-HER2 therapy in any stage.How-ever,the cardiotoxicity,de novo resistance and acquired resistance of trastuzumab make the clinician to explore the second line anti-HER2 therapy.Lapatinib is the first FDA approved and HER1,HER2 double-targeting tyrosine kinase inhibitor which can be a better choice after failure with trastuzumab.This article reviews the appli-cation,some clinical and mechanism of drug resistance researches of Lapatinib.

The combination of trastuzumab and lapatinib added to neoadjuvant chemotherapy for breast cancer:a meta-analysis of randomized evidence / 国际肿瘤学杂志

Objective To compare the efficacy and safety of trastuzumab versus the combination of tras-tuzumab and lapatinib added to neoadjuvant chemotherapy in HER2-positive breast cancer. Methods We searched PubMed,MEDLINE,The Cochrane Library,Web of Science,CNKI,Wanfang datebase and the abstracts of major international conferences in recent 5 years to identify randomized controlled trials which met the inclusion and exclusion criteria. Study selection and analyses were undertaken according to the Cochrane Hand-book. Meta-analysis was performed using RevMan 5. 0 software. Results Four trials were identified with 779 eli-gible patients. The results of meta-analyses showed that the rate of pathological complete response was significant-ly higher in the group receiving rastuzumab and tlapatinib than that in the group with trastuzumab alone(53. 3%vs 38. 8% ,RR =1. 39,95 % CI:1. 20-1. 63;P < 0. 001). No statistical differences were observed in regarding adverse events among patients receiving trastuzumab or the combination of trastuzumab and lapatinib,except the grade Ⅲ-Ⅳ diarrhea(2. 2% vs 25. 6% ,RR =11. 54,95% CI:5. 69-23. 41;P <0. 001). Conclusion The com-bination of trastuzumab and lapatinib added to neoadjuvant chemotherapy in HER2-positive breast cancer is more effective,without more adverse reactions except diarrhea;it ia an effective and safe treatment.

Development and In-vitro evaluation of poly (lactic acid) films for controlled release studies of Lapatinib: an anticancer drug.

Biodegradable poly (lactic acid) films containing Lapatinib were prepared by spreading polymer / Lapatinib solution on the non-solvent surface. Different drug loading polymer films can be obtained by controlling the weight ratios of drug and polymer. The synthesized Lapatinib loaded PLA films were evaluated by different parameters such as drug loading, encapsulation efficiency, surface morphology, differential scanning calorimetry, powder X-ray diffractometry and In vitro drug release kinetics. Various combinations of the polymer-drug weight ratios were used to achieve In vitro release of drug over a period of 30-35 days, with initial burst release < 25% and a steady release rate over the entire period of release. Furthermore the drug release rate of the film could be controlled by the drug loading content and pH of the release medium. Our results suggest that these Lapatinib loaded PLA film formulations could constitute a promising approach for the controlled drug delivery applications. This is the first study which shows the in-vitro release profile of Lapatinib using a polymeric delivery system.

The Inhibitory Effect of Down-Regulating Phosphorylated HER2 on Proliferation and Metastasis in U2-OS Osteosarcoma Cells / 天津医药

Objective To investigate the effects of down-regulating phosphorylated human epidermal growth factor receptor 2 (HER2) on the proliferation and metastasis in human osteosarcoma cells (U2-OS) in vitro. Methods Various concentrations of HER2 phosphorylation inhibitor lapatinib ditosylate (5, 10, 20, 30 and 40 μmol/L) were adopted to deal with U2-OS. MTT assay was performed to evaluate the cell proliferation during various times (24, 48 and 72 h), and the IC50 value in 24 h was calculated. The value of 10μmol/L (IC50=22.15μmol/L) was chosen to deal with U2-OS cells. The expres-sion level of phosphorylated HER2 (p-HER2) was measured by Western blot assay. The cell migration and invasion abilities were detected by Wound healing and Transwell invasion assays. Results The cell proliferation of U2-OS was significantly inhibited by HER2 phosphorylation inhibitor lapatinib ditosylate in a concentration- and time-dependent manner. During 24 hours, the p-HER2 level was significantly lower in lapatinib ditosylate group than that of negative control group (0.093± 0.033 vs 0.306±0.033), the cell migration rate was significantly lower in lapatinib ditosylate group than that of negative con-trol group (32.70%±3.00%and 94.52%±4.76%), and the trans-membrane cells were significantly lower than those of nega-tive control group (37/HP±5/HP and 85/HP±10/HP), respectively. Conclusion The down-regulating p-HER2 in U2-OS could efficiently inhibit the cell proliferation, migration and invasion in vitro. HER2 has the potential to become a molecular target for anti-osteosarcoma metastasis.

Compensatory activation of estrogen receptor α signaling in acquired resistance to lapatinib of HER2-overexpressing/ERα-positive breast cancer cells / 第二军医大学学报

Objective To investigate the role of compensatory activation of estrogen receptor α (ERα) signaling in acquired resistance to lapatinib of breast cancer cells BT474 and the related mechanism. Methods Real-time PCR and Western blotting analysis were used to determine the changes of HER2 and ERα pathways in BT474 cells treated by lapatinib. Acquired resistant model of rBT474 cellswas induced with increasing concentrations of lapatinib (from 0. 25 μmol/L to 5 μmol/L); the apoptosis in rBT474 cells was determined by flow cytometry. Western blotting analysis was used to evaluate the differences between BT474 and rBT474 in the HER2 and ER pathways. The growth of rBT474 cells treated by lapatinib and/or fulvestrant was detected by MTT assay, andcolony formation was used to observe the possibility of preventing acquired resistance to lapatinib in BT474 cells by double targets therapy. Results The results of real-time PCR and Western blotting analysis showed that Lapatinib inhibited phosphorylation of HER2 and induced expression of forkhead-box protein O 3A (F0X03a) and progesterone receptor (PR) in BT474 cells. Acquired resistance cell model of rBT474 was established in a 5 μmol/L lapatinib condition. Western blotting analysis showed that the phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT) pathway was inhibited in rBT474 cells compared with that in the BT474 cells, while the mitogen-activated protein kinase (MAPK) pathways, especially the ER pathway, were activated in the BT474 cells. MTT results showed that, Lapatinib combined with fulvestrant had a significantly greater inhibition on rBT474 cell vitality compared with lapatinib alone (P<0. 01). Colony formation results also showed that combination of lapatinib and fulvestrant had a significantly greater inhibition effect against colon formation of BT474 cells compared with each drug alone and DMSO (P<0. 01), showing a possible prevention ability against acquired resistance. Conclusion Compensatory activation of estrogen receptor a signaling might be one of the mechanisms of acquired resistance to lapatinib in HER2-overexpressing/ERcrpositive breast cancer cells, and inhibition of PI3K/AKT and activation of MAPK might be the main reason for compensatory activation of ERα.

Determination of related substances in lapatinib ditosylate tablets by HPLC / 中国药学杂志

OBJECTIVE: To establish a determination method of the related substances of lapatinib ditosylate tablets by HPLC. METHODS: Waters Xterra MS C18 column (4.6 mm × 250 mm, 5 μm) was selected; 0.01 mol · L-1 sodium dihydrogen phosphate solution (pH adjusted to 3.2 with phosphoric acid) was mobile phase A, acetonitrile was mobile phase B, and gradient elution was used at a flow rate of 1.0 mL · min-1. The detection wavelength was set at 265 nm, and the column temperature was 40°C. RESULTS: Lapatinib Impurity A, LAPA-2 and LAPA-1 had good linearity in the range of 0.02-8.08, 0.02-8.26 and 0.02-8.29 mg · mL-1, respectively (r≥0.9999). The limits of quantitation (LOQ) were 1.0, 1.4, and 2.1 ng, respectively. The average recovery (n=9) was in the range of 100.2%-102.9%, and RSDs (n=9) were in the range of 0.02%-0.66%. CONCLUSION: The method is simple, accurate, and specific and can quantitatively determine the related substances of lapatinib ditosylate tablets.