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Journal of Interventional Cardiac... Aug 2023Tyrosine kinase inhibitors (TKIs) have been increasingly used as first-line therapy in hematologic and solid-organ malignancies. Multiple TKIs have been linked with the... (Review)
Review
BACKGROUND
Tyrosine kinase inhibitors (TKIs) have been increasingly used as first-line therapy in hematologic and solid-organ malignancies. Multiple TKIs have been linked with the development of cardiovascular complications, especially atrial arrhythmias, but data on ventricular arrhythmias (VAs) is scarce.
METHODS
Herein we describe five detailed cases of VAs related to TKI use in patients with varied baseline cardiovascular risk factors between 2019 and 2022 at three centers. Individual chart review was conducted retrospectively.
RESULTS
Patient ages ranged from 43 to 83 years. Three patients were on Bruton's TKI (2 ibrutinib and 1 zanubrutinib) at the time of VAs; other TKIs involved were afatinib and dasatinib. Three patients had a high burden of non-sustained ventricular tachycardia (NSVT) requiring interventions, whereas two patients had sustained VAs. While all patients in our case series had significant improvement in VA burden after TKI cessation, two patients required new long-term antiarrhythmic drug therapy, and one had an implantable defibrillator cardioverter (ICD) placed due to persistent VAs after cessation of TKI therapy. One patient reinitiated TKI therapy after control of arrhythmia was achieved with antiarrhythmic drug therapy.
CONCLUSIONS
Given the expanding long-term use of TKIs among a growing population of cancer patients, it is critical to acknowledge the association of TKIs with cardiovascular complications such as VAs, to characterize those at risk, and deploy preventive and therapeutic measures to avoid such complications and interference with oncologic therapy. Further efforts are warranted to develop monitoring protocols and optimal treatment strategies for TKI-induced VAs.
Topics: Humans; Adult; Middle Aged; Aged; Aged, 80 and over; Anti-Arrhythmia Agents; Tyrosine Kinase Inhibitors; Retrospective Studies; Arrhythmias, Cardiac; Defibrillators, Implantable; Tachycardia, Ventricular; Death, Sudden, Cardiac
PubMed: 36411365
DOI: 10.1007/s10840-022-01400-z -
Clinical & Experimental Metastasis Apr 2024Human epidermal growth factor 2 (HER2)-positive breast cancer with lung metastases resistant to targeted agents is a common therapeutic challenge. Absence of preclinical... (Comparative Study)
Comparative Study
Human epidermal growth factor 2 (HER2)-positive breast cancer with lung metastases resistant to targeted agents is a common therapeutic challenge. Absence of preclinical lung metastasis models that are resistant to multiple anti-HER2 targeted drugs hampers the development of novel therapies. We established a novel HER2-positive breast cancer cell line (L-JIMT-1) with a high propensity to form lung metastases from the parenteral JIMT-1 cell line by injecting JIMT-1 cells into immunodeficient SCID mice. Lung metastases developed in all mice injected with L-JIMT-1 cells, and more rapidly and in greater numbers compared with the parental JIMT-1 cells. L-JIMT-1 cells expressed more epidermal growth factor receptor and HER2 than JIMT-1 cells. L-JIMT-1 cells were resistant to all five tyrosine kinase inhibitors tested in vitro (afatinib, erlotinib, lapatinib, sapitinib, and tucatinib). When we compared JIMT-1 and L-JIMT-1 sensitivity to three HER2-targeting antibody-drug conjugates (ADCs) trastuzumab emtansine (T-DM1), trastuzumab deruxtecan (T-DXd), and disitamab vedotin (DV) in vitro, JIMT-1 cells were resistant T-DXd, partially sensitive to T-DM1, and sensitive to DV, while L-JIMT-1 cells were resistant to both T-DM1 and T-DXd, but moderately sensitive to DV. In a mouse model, all three ADCs inhibited the growth of L-JIMT-1 lung metastases compared to a vehicle, but DV and T-DXd more strongly than T-DM1, and DV treatment led to the smallest tumor burden. The L-JIMT breast cancer lung metastasis model developed may be useful in the evaluation of anti-cancer agents for multiresistant HER2-positive advanced breast cancer.
Topics: Animals; Female; Humans; Mice; Ado-Trastuzumab Emtansine; Antibodies, Monoclonal; Antineoplastic Agents; Breast Neoplasms; Camptothecin; Immunoconjugates; Lung Neoplasms; Mice, SCID; Oligopeptides; Receptor, ErbB-2; Trastuzumab
PubMed: 38367127
DOI: 10.1007/s10585-024-10278-2 -
Journal of Cellular and Molecular... Aug 2023Peroxisome proliferator-activated receptors (PPARs) are essential for cellular physiological processes. However, there is less research on the PPAR-related genes in lung...
Peroxisome proliferator-activated receptors (PPARs) are essential for cellular physiological processes. However, there is less research on the PPAR-related genes in lung adenocarcinoma (LUAD). Open-access data were get from the cancer genome atlas (TCGA) and gene expression omnibus (GEO) databases. All the analysis were conducted in the R software based on different R packages. In this study, we gauged the PPAR score employing a set of 72 PPAR-associated genes and probed the biological impact of this score on lung adenocarcinoma (LUAD). Subsequently, we established a unique signature composed of eight PPAR-related genes (ANGPTL4, ACSL3, ADIPOQ, FABP1, SLC27A1, ACOX2, PPARD and OLR1) to forecast the prognosis of LUAD. The signature's effectiveness in predicting survival was validated through the receiver operating characteristic curve in the TCGA-LUAD cohort. As per the pathway enrichment analysis, several crucial oncogenic pathways and metabolic processes were enriched in high-risk individuals. Further, we observed that these high-risk patients exhibited heightened genomic instability. Additionally, compared to the low-risk cohort, high-risk patients demonstrated diminished immune components and function. Intriguingly, high-risk patients exhibited a potential heightened sensitivity to immunotherapy and certain drugs, including Gefitinib, Afatinib, Erlotinib, IAP_5620, Sapitinib, LCL161, Lapatinib and AZD3759. The prognosis model based on eight PPAR-related genes has satisfactory prognosis prediction efficiency. Meanwhile, our results can provide direction for future studies in the relevant aspects.
PubMed: 37556076
DOI: 10.1111/jcmm.17877 -
Molecules (Basel, Switzerland) Mar 2024The epidermal growth factor receptor (EGFR) plays a pivotal role in cancer therapeutics, with small-molecule EGFR inhibitors emerging as significant agents in combating... (Review)
Review
The epidermal growth factor receptor (EGFR) plays a pivotal role in cancer therapeutics, with small-molecule EGFR inhibitors emerging as significant agents in combating this disease. This review explores the synthesis and clinical utilization of EGFR inhibitors, starting with the indispensable role of EGFR in oncogenesis and emphasizing the intricate molecular aspects of the EGFR-signaling pathway. It subsequently provides information on the structural characteristics of representative small-molecule EGFR inhibitors in the clinic. The synthetic methods and associated challenges pertaining to these compounds are thoroughly examined, along with innovative strategies to overcome these obstacles. Furthermore, the review discusses the clinical applications of FDA-approved EGFR inhibitors such as erlotinib, gefitinib, afatinib, and osimertinib across various cancer types and their corresponding clinical outcomes. Additionally, it addresses the emergence of resistance mechanisms and potential counterstrategies. Taken together, this review aims to provide valuable insights for researchers, clinicians, and pharmaceutical scientists interested in comprehending the current landscape of small-molecule EGFR inhibitors.
Topics: Humans; Afatinib; Carcinogenesis; Cell Transformation, Neoplastic; ErbB Receptors; Erlotinib Hydrochloride
PubMed: 38611728
DOI: 10.3390/molecules29071448 -
International Journal of General... 2024Stomach adenocarcinoma (STAD) presents a challenge given its advanced stage at diagnosis and poor prognosis. Integrin subunit alpha 11 (ITGA11) encodes alpha integrin...
BACKGROUND
Stomach adenocarcinoma (STAD) presents a challenge given its advanced stage at diagnosis and poor prognosis. Integrin subunit alpha 11 (ITGA11) encodes alpha integrin and has been implicated in promoting tumorigenesis and development by participating in cell proliferation and invasion. However, the precise mechanism of ITGA11 in STAD remains unclear.
METHODS
The differences in ITGA11 expression levels between 375 gastric cancer samples and 32 paracancerous tissue samples from the Cancer Genome Atlas (TCGA) database were examined. The relationship between ITGA11 expression and clinical features and ITGA11 diagnostic and prognostic value were evaluated using the chi-square test and receiver operating characteristic (ROC) assay. Differentially expressed genes were identified based on ITGA11 expression. Subsequently, functional enrichment analyses were conducted using Gene Ontology, the Kyoto Encyclopedia of Genes and Genomes, and Gene Set Enrichment Analysis. Furthermore, immune infiltration and the expression of ITGA11-associated immune checkpoints in patients with tumors were assessed using CIBERSORT, single-sample gene set enrichment analysis, and the TIMER database. Drug sensitivity associated with ITGA11 expression was analyzed using the R oncoPredict package to guide treatment decisions. Finally, the difference in ITGA11 expression between cancer tissue and the adjacent tissues was validated using quantitative PCR (qPCR) and immunohistochemistry.
RESULTS
The gastric cancer tissue had significantly upregulated ITGA11 expression compared to paracancerous tissues. ITGA11 demonstrated robust diagnostic and prognostic value in gastric cancer (GC) and was an independent risk factor for adverse outcomes. The patients with STAD with elevated ITGA11 expression levels had heightened immune cell infiltration and increased immune checkpoint marker expression. Notably, patients with increased ITGA11 expression demonstrated reduced responsiveness to oxaliplatin and afatinib.
CONCLUSION
The results indicated the pivotal role of ITGA11 in shaping the tumor immune microenvironment, ultimately establishing ITGA11 as an immune-related prognostic predictor within the intricate landscape of STAD.
PubMed: 38344679
DOI: 10.2147/IJGM.S444786 -
Translational Lung Cancer Research Nov 2023Data from clinical trials and real-world studies show that afatinib is effective in treating non-small cell lung cancer (NSCLC) harboring activating mutations in the...
BACKGROUND
Data from clinical trials and real-world studies show that afatinib is effective in treating non-small cell lung cancer (NSCLC) harboring activating mutations in the epidermal growth factor receptor () gene. A previous analysis of patients enrolled in the Korean Academy of Tuberculosis and Respiratory Disease (KATRD) cohort showed that first-line afatinib was well tolerated and effectiveness results were encouraging. At the time of the previous analysis, survival data were not mature. Here we briefly present updated survival data from the cohort.
METHODS
The study was a retrospective, multicenter (15 sites) review of electronic records of Korean adult patients (aged >20 years) with advanced mutation-positive NSCLC who initiated first-line afatinib (N=421). Progression-free survival (PFS) and overall survival (OS) were evaluated using Kaplan-Meier survival curves.
RESULTS
Overall, median PFS was 20.2 months and median OS was 48.6 months. OS rates at 36 and 60 months were 60.1% and 42.3%, respectively. Presence . absence of baseline brain metastases was associated with significantly reduced median PFS (14.9 . 28.0 months; P<0.001) and median OS (32.2 . 65.6 months; P<0.001). The presence of common baseline mutations (Del19, L858R) was associated with significantly prolonged median OS (49.6 . 30.1 months; P=0.017). In patients stratified by the presence/absence of T790M mutation, the T790M mutation was associated with significantly reduced median PFS (P=0.0005) but there was no significant difference between groups in survival (P=0.263). There were no significant differences in PFS or OS for patients stratified by afatinib dose reduction or by age group (<70 . ≥70 years).
CONCLUSIONS
Afatinib was effective in Korean patients with mutation-positive NSCLC with median OS over 4 years. The presence of baseline brain metastases and/or uncommon mutations were associated with reduced survival. In the absence of baseline brain metastases, median OS was more than 5 years.
PubMed: 38090523
DOI: 10.21037/tlcr-23-383 -
Medicina (Kaunas, Lithuania) Dec 2023Tumor lysis syndrome (TLS) is a potentially fatal oncological emergency that typically develops during the treatment of rapidly proliferating malignancies. It is... (Review)
Review
Tumor lysis syndrome (TLS) is a potentially fatal oncological emergency that typically develops during the treatment of rapidly proliferating malignancies. It is infrequently reported in solid tumors, such as pulmonary adenocarcinoma. A 59-year-old male patient with shortness of breath presented with a 3.3 cm × 3.0 cm mass in the right upper lobe, along with massive right-sided pleural effusion. A percutaneous needle biopsy was performed, and a diagnosis of pulmonary adenocarcinoma with an epidermal growth factor receptor () mutation was made. The patient was treated with afatinib because of the malignant pleural effusion and multiple metastases to the intrathoracic lymph nodes, left scapula, and brain. After 4 days of afatinib treatment, he developed oliguric acute kidney injury and progressively worsening dyspnea. Based on the clinical and laboratory findings, the patient was diagnosed with afatinib-induced TLS. To the best of our knowledge, this is the first reported case of afatinib-induced TLS in pulmonary adenocarcinoma.
Topics: Male; Humans; Middle Aged; Afatinib; Lung Neoplasms; Tumor Lysis Syndrome; ErbB Receptors; Adenocarcinoma of Lung
PubMed: 38138247
DOI: 10.3390/medicina59122144 -
Therapeutic Advances in Medical Oncology 2024Afatinib is indicated for advanced-stage non-small-cell lung cancer (NSCLC) with Epidermal Growth Factor Receptor (EGFR) and uncommon mutations. However, real-world...
Real-world analysis of afatinib as a first-line treatment for patients with advanced stage non-small-cell lung cancer with uncommon EGFR mutations: a multicenter study in Vietnam.
BACKGROUND
Afatinib is indicated for advanced-stage non-small-cell lung cancer (NSCLC) with Epidermal Growth Factor Receptor (EGFR) and uncommon mutations. However, real-world studies on this topic are limited. This study aimed to evaluate afatinib as first-line therapy for locally advanced and metastatic NSCLC with uncommon EGFR mutations.
PATIENTS AND METHODS
A retrospective study included 92 patients with advanced NSCLC with uncommon and compound EGFR mutations, treated with afatinib as first-line therapy. Patients were followed up and evaluated every 3 months or when symptoms of progressive disease arose. The endpoints were objective response rate (ORR), time-to-treatment failure (TTF), and adverse events.
RESULTS
The G719X EGFR mutation had the highest occurrence rate (53.3% for both monotherapy and the compound). By contrast, the compound mutation G719X-S768I was observed at a rate of 22.8%. The ORR was 75%, with 15.2% of patients achieving complete response. The overall median TTF was 13.8 months. Patients with the G719X EGFR mutation (single and compound) had a median TTF of 19.3 months, longer than that of patients with other mutations, who had a median TTF of 11.2 months. Patients with compound EGFR mutations (G719X and S768I) demonstrated a median TTF of 23.2 months compared to that of 12.3 months for other mutations. Tolerated doses of 20 or 30 mg achieved a longer median TTF of 17.1 months compared to 11.2 months with 40 mg. Median TTF differed between patients with and without brain metastasis, at 11.2 and 16.9 months, respectively. Rash (55.4%) and diarrhea (53.3%) were the most common adverse events, primarily grades 1 and 2. Other side effects occurred at a low rate.
CONCLUSION
Afatinib is effective for locally advanced metastatic NSCLC with uncommon EGFR mutations. Patients with G719X, compound G719X-S768I mutations, and tolerated doses of 20 or 30 mg had a longer median TTF than those with other mutations.
PubMed: 38736554
DOI: 10.1177/17588359241242972 -
International Journal of Molecular... May 2024We present the case of a 70-year-old never-smoking female patient with () p.L858R-mutated metastatic non-small cell lung cancer (NSCLC). After three months of...
We present the case of a 70-year-old never-smoking female patient with () p.L858R-mutated metastatic non-small cell lung cancer (NSCLC). After three months of first-line treatment with erlotinib, progression occurred and platinum/pemetrexed was initiated, followed by a response for more than two years. After the progression, the molecular testing of a vertebral metastasis revealed a () translocation and a (2) p.S310F mutation, in addition to the known p.L858R mutation. Crizotinib then led to a durable response of 17 months. The molecular retesting of the tumour cells obtained from the recurrent pleural effusion revealed the absence of the translocation, whereas the and mutations were still present. Afatinib was added to the crizotinib, and the combination treatment resulted in another durable response of more than two years. The patient died more than 7 years after the initial diagnosis of metastatic NSCLC. This case demonstrates that the repeated molecular testing of metastatic NSCLC may identify new druggable genomic alterations that can impact the patient management and improve the patient outcome.
Topics: Humans; Crizotinib; Female; Afatinib; Aged; Proto-Oncogene Mas; Receptor, ErbB-2; ErbB Receptors; Lung Neoplasms; Proto-Oncogene Proteins; Protein-Tyrosine Kinases; Adenocarcinoma of Lung; Proto-Oncogene Proteins c-met; Mutation; Antineoplastic Combined Chemotherapy Protocols
PubMed: 38891886
DOI: 10.3390/ijms25115698 -
Scientific Reports Jan 2024Lung adenocarcinoma (LUAD) is a malignant tumor with high lethality, and the aim of this study was to identify promising biomarkers for LUAD. Using the TCGA-LUAD dataset...
Lung adenocarcinoma (LUAD) is a malignant tumor with high lethality, and the aim of this study was to identify promising biomarkers for LUAD. Using the TCGA-LUAD dataset as a discovery cohort, a novel joint framework VAEjMLP based on variational autoencoder (VAE) and multilayer perceptron (MLP) was proposed. And the Shapley Additive Explanations (SHAP) method was introduced to evaluate the contribution of feature genes to the classification decision, which helped us to develop a biologically meaningful biomarker potential scoring algorithm. Nineteen potential biomarkers for LUAD were identified, which were involved in the regulation of immune and metabolic functions in LUAD. A prognostic risk model for LUAD was constructed by the biomarkers HLA-DRB1, SCGB1A1, and HLA-DRB5 screened by Cox regression analysis, dividing the patients into high-risk and low-risk groups. The prognostic risk model was validated with external datasets. The low-risk group was characterized by enrichment of immune pathways and higher immune infiltration compared to the high-risk group. While, the high-risk group was accompanied by an increase in metabolic pathway activity. There were significant differences between the high- and low-risk groups in metabolic reprogramming of aerobic glycolysis, amino acids, and lipids, as well as in angiogenic activity, epithelial-mesenchymal transition, tumorigenic cytokines, and inflammatory response. Furthermore, high-risk patients were more sensitive to Afatinib, Gefitinib, and Gemcitabine as predicted by the pRRophetic algorithm. This study provides prognostic signatures capable of revealing the immune and metabolic landscapes for LUAD, and may shed light on the identification of other cancer biomarkers.
Topics: Humans; Prognosis; Deep Learning; Adenocarcinoma of Lung; Biomarkers, Tumor; Lung Neoplasms
PubMed: 38177198
DOI: 10.1038/s41598-023-51108-x