Lapatinib 250mg tablets

ObjectiveThis study aimed to evaluate the efficacy and safety of small-molecule TKIs in neoadjuvant treatment of HER2-positive breast cancer using a network meta-analysis approach.MethodsA systematic literature search was conducted in the Medline, Embase, and Web of Science databases. Eligible studies that included HER2-positive breast cancer patients receiving neoadjuvant treatment with small-molecule TKIs before surgery were included. A Bayesian framework within a random-effects model was used for network meta-analysis to summarize direct and indirect evidence. Outcome measures included breast pathological complete response (breast pCR), total pathological complete response (total pCR) of the breast and lymph nodes, and selected safety endpoints.ResultsEight eligible studies involving a total of 1,841 participants were included. The most common treatment regimens were Trastuzumab (n = 8), Lapatinib (n = 6), and Lapatinib plus Trastuzumab (n = 6), while there were fewer studies on Pyrotinib plus Trastuzumab (n = 2). No studies about tucatinib and neratinib were enrolled. The rankings of efficacy for the breast pCR and total pCR endpoints were as follows: (i) Pyrotinib plus Trastuzumab, (ii) Lapatinib plus Trastuzumab, (iii) Trastuzumab, (iv) Lapatinib. Regarding safety endpoints of grade 3 or higher diarrhea, neutropenia, fatigue, and skin disorders, the rankings were as follows: (i) Trastuzumab, (ii) Lapatinib, (iii) Lapatinib plus Trastuzumab, (iv) Pyrotinib plus Trastuzumab for diarrhea; (i) Pyrotinib plus Trastuzumab, (ii) Trastuzumab, (iii) Lapatinib plus Trastuzumab, (iv) Lapatinib for neutropenia; (i) Lapatinib plus Trastuzumab, (ii) Trastuzumab, (iii) Lapatinib for fatigue; (i) Trastuzumab, (ii) Lapatinib plus Trastuzumab, (iii) Lapatinib for skin disorders.ConclusionFor HER2-positive breast cancer patients, the use of small-molecule TKIs in combination with trastuzumab as neoadjuvant treatment has certain advantages in improving the rate of pathological response. Dual-targeted therapy with pyrotinib shows objective efficacy and acceptable safety; however, further research is still needed to confirm these findings.

Abstract licence: CC BY-NC-ND

Abstract Introduction Trastuzumab, as the gold standard for HER2-positive BC treatment, was the first-line HER2 targeted drug. However, some studies reported patients benefited more from lapatinib and lapatinib plus trastuzumab therapy than standard trastuzumab therapy. This study presents an update of a systematic review and meta-analysis involving comparison of lapatinib and lapatinib plus trastuzumab therapy versus trastuzumab therapy. Aim We determined whether trastuzumab plus lapatinib or lapatinib therapy is not inferior to trastuzumab therapy in HER2-positive breast cancer patients. Methods Relevant trials were searched in CNKI, Wanfang, VIP, Sinomed, PubMed, Embase, and Cochrane CENTRAL databases from inception until October 25, 2021. Primary outcomes were OS, DFS/EFS, and PFS while secondary outcomes were pCR (ypT0/is ypN0), pCR (ypT0/is ypN0/+), ORR, DCR, rate of BCS, RFS, cardiac toxicities, and other toxicities. Results Thirteen randomized controlled trials were included in this study. Trastuzumab combined with lapatinib therapy was found to be superior to standard trastuzumab therapy alone with regard to overall survival, disease-free survival/event-free survival, pathologic complete response (ypT0/is ypN0), pathologic complete response (ypT0/is ypN0/+), recurrence-free survival, higher incidences of diarrhea, and rash/skin toxicity. Lapatinib therapy was established to be inferior to trastuzumab therapy in overall survival, progression-free survival, disease-free survival/event-free survival, pathologic complete response (ypT0/is ypN0) and pathologic complete response (ypT0/is ypN0/+), diarrhea, and rash/skin toxicity and had a low incidence of left ventricular ejection fraction decline. Conclusions The efficacy of trastuzumab combined with lapatinib therapy is superior to standard trastuzumab therapy alone; however, it has more non-cardiac grade III/IV toxicities. Moreover, the efficacy of lapatinib therapy is inferior to that of standard trastuzumab therapy alone.

Abstract licence: CC BY 4.0

PurposeTrastuzumab-based chemotherapy has improved outcomes in human epidermal growth factor receptor 2 (HER2)-positive breast cancer, but treatment benefit varies among patients. Predictive signatures are needed to identify patients most likely to respond to these therapies.Experimental designWe developed Density and Spatial architecture of Tumor-Infiltrating Lymphocytes (DeSTIL), a computational signature derived from hematoxylin and eosin slides. The signature captures spatial organization of immune cells and interactions with nonimmune cells. DeSTIL was trained on HER2+ breast cancer slides from The Cancer Genome Atlas (n = 250) and validated in a phase III National Surgical Adjuvant Breast and Bowel Project (NSABP) B-41 randomized clinical trial (n = 221), which compared chemotherapy plus trastuzumab, lapatinib, or combination. The DeSTIL scores were dichotomized into positive and negative groups, and event-free survival (EFS) was assessed using Cox proportional hazards with interaction terms.ResultsIn NSABP B-41, DeSTIL-positive patients (n = 61) showed significantly improved event-free survival (EFS) with trastuzumab compared with the combination arm [hazard ratio (HR) = 0.09; 95% confidence interval (CI) = 0.01-0.77; P = 0.006] and a significant signature-treatment interaction (P = 0.024). No EFS difference was observed in DeSTIL-negative patients (n = 160). Gene expression analysis supported the image-derived signature stratifying DeSTIL-positive and DeSTIL-negative tumors. In an exploratory pathologic complete response analysis, a classifier trained on University Hospitals Cleveland slides achieved AUCs of 0.70 in the training cohort and 0.63 in the trastuzumab arm of the NSABP B-41 validation cohort.ConclusionsDeSTIL identifies a subset of HER2+ patients who derive greater benefit from trastuzumab. These findings support the potential of computationally derived immune architecture to inform selection of standard HER2-targeted therapies.

Abstract licence: CC BY-NC-ND

BackgroundHuman metapneumovirus (HMPV) is an emerging respiratory pathogen affecting children, elderly individuals, and immunocompromised patients. Despite its disease burden, no antiviral treatment has been approved to date.ObjectiveThe present study aimed to identify the Food and Drug Administration-approved drugs with potential for repurposing against HMPV by targeting its key structural proteins-fusion (F) and nucleoprotein (N).Materials and methodsThe crystallographic structures of HMPV fusion (Protein Data Bank [PDB] ID: 5WB0) and nucleoprotein (PDB ID: 5FVD) were retrieved, validated, and subjected to molecular docking. Ligands with favorable binding scores were further evaluated using molecular dynamics simulations and binding-free-energy calculations. Pharmacokinetic and toxicity profiles were predicted to assess their translational viability.ResultsFor the fusion protein, rutin, carbetocin, and acarbose showed strong binding affinities and stable molecular interactions. For the nucleoprotein, mobocertinib, lapatinib, and levetiracetam emerged as top candidates, with mobocertinib showing the most favorable binding energy. Among all, levetiracetam displayed the most drug-like characteristics, including high gastrointestinal absorption, no major cytochrome P450 inhibition, and no violations of Lipinski's rule.ConclusionThe study highlights mobocertinib, rutin, and levetiracetam as promising repurposed drugs against HMPV. While mobocertinib exhibited the strongest predicted binding affinity, levetiracetam demonstrated the best pharmacokinetic profile, making it a particularly viable candidate for further experimental validation. These results validate the usefulness of in silico drug repurposing in addressing unmet antiviral needs and warrant preclinical studies to evaluate therapeutic efficacy.

Abstract licence: CC BY-NC-SA

IntroductionDrug resistance is a major obstacle to the long-term effectiveness of cancer therapies. Approximately 70% of breast cancer patients relapse after 5 years of treatment, and the lack of biomarkers associated with drug resistance translates to poor prognosis in the clinic. Previous research has utilised omics approaches to uncover biomarkers driving drug resistance, with a strong emphasis on genetic mutations.MethodsHere, we identified a nine-marker signature associated with resistance to lapatinib in a HER2-positive breast cancer model using a target discovery approach by employing an integrative multi-omics strategy, combining ATAC-seq, RNA-seq and proteomics.ResultsWe found that seven markers in the drug resistance-signature had not been previously found to be implicated in HER2-positive breast cancer, some of which we further validated using an additional lung cancer model. We counterintuitively found that drug-resistant cells have restrictive chromatin accessibility with reduced gene expression associated with limited total proteome changes. However, upon closer look, we identified that the drug resistance-signature had increased chromatin accessibility near the transcriptional start sites of those seven markers and was highly differentially expressed across the three datasets. Our data show that despite the overall transcriptional and proteomic landscape showing limited changes, there are several markers that are highly expressed, which correlate with increased anchorage-independent and invasive phenotype in vitro in lapatinib-resistant cells compared to cancer cells.ConclusionsOur results demonstrate that disease aggressiveness can be related to reduced chromatin and gene expression dynamics. We anticipate that the resistant signature identified here using an integrative target discovery approach can be applied to complex, more representative models and validated before they can be targeted by suitable therapeutic agents.

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It is now recognized that mitochondria play a crucial role in tumorigenesis; however, it has become clear that tumor metabolism varies significantly between cancer types. The failure of recent clinical trials aimed at directly targeting tumor respiration through oxidative phosphorylation inhibitors underscores the critical need for further studies providing an in-depth evaluation of mitochondrial bioenergetics. Accordingly, we comprehensively assessed the bulk tumor and mitochondrial metabolic phenotype in murine HER2-driven mammary cancer tumors and benign mammary tissue. Transcriptomic and proteomic profiling revealed a broad downregulation of mitochondrial genes/proteins in tumors, including OXPHOS subunits comprising Complexes I-IV. Despite reductions in tumor mitochondrial proteins, mitochondrial respiration was several-fold higher compared to benign mammary tissue, which persisted regardless of normalization method (wet weight, total protein content, and when corrected for mitochondrial content). This upregulated respiratory capacity could not be explained by OXPHOS uncoupling, suggesting HER2 signaling regulates intrinsic mitochondrial bioenergetics. In further support, lapatinib, an EGFR/HER2 tyrosine kinase inhibitor, attenuated mitochondrial respiration in NF639 murine mammary tumor epithelial cells. Together, this data highlights that the typical correlation between mitochondrial content and respiratory capacity may not apply to all tumor types and implicates HER2-linked activation of mitochondrial respiration supporting tumorigenesis in this model.

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