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1.
ESMO Open ; 9(3): 102388, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38442452

RESUMO

BACKGROUND: The HER2DX risk-score has undergone rigorous validation in prior investigations involving patients with early-stage human epidermal growth factor receptor 2 (HER2)-positive (HER2+) breast cancer. In this study, we present the outcomes of the HER2DX risk-score within the most recent release of the Sweden Cancerome Analysis Network-Breast (SCAN-B) HER2+ cohort. This updated examination benefits from a larger patient sample, an extended follow-up duration, and detailed treatment information. MATERIALS AND METHODS: Clinical and RNAseq data from the SCAN-B dataset were retrieved from Gene Expression Omnibus (GSE81538). Among the 6600 patients, 819 had HER2+ breast cancer, with 757 individuals with research-based HER2DX risk-scores and corresponding survival outcomes. The HER2DX risk-score was evaluated (i) as a continuous variable and (ii) using predefined cut-offs. The primary endpoint for this study was overall survival (OS). The Kaplan-Meier method and Cox models were used to estimate OS and a multistate model with four states was fitted to better characterize patients' follow-up. RESULTS: The median follow-up time was 7.5 years (n = 757). The most common systemic therapy was chemotherapy with trastuzumab (82.0%) and most tumors were classified as T1-T2 (97.1%). The HER2DX risk-score as a continuous variable was significantly associated with OS after adjustment for clinical variables and treatment regimen [hazard ratios (HR) per 10-unit increment = 1.31, 95% confidence interval (CI) 1.13-1.51, P < 0.001] as well as within predefined risk groups (high versus low; HR = 2.57, 95% CI 1.36-4.85, P < 0.001). Patients classified as HER2DX high-risk also had higher risk of (i) breast cancer recurrence and (ii) death without previous recurrence. Within the subgroup of HER2+ T1N0 tumors (n = 297), those classified as high-risk demonstrated inferior OS compared to low-risk tumors (7-year OS 77.8% versus 96.8%, P < 0.001). The HER2DX mRNA ERBB2 score was associated with clinical HER2 status (area under the receiver operating characteristic curve = 0.91). CONCLUSIONS: In patients with early-stage HER2+ breast cancer, HER2DX risk-score provides prognostic information beyond clinicopathological variables, including treatment regimen with or without trastuzumab.


Assuntos
Neoplasias da Mama , Humanos , Feminino , Neoplasias da Mama/tratamento farmacológico , Prognóstico , Suécia/epidemiologia , Recidiva Local de Neoplasia/tratamento farmacológico , Trastuzumab/farmacologia , Trastuzumab/uso terapêutico
2.
OMICS ; 28(3): 103-110, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38466948

RESUMO

Trastuzumab is a monoclonal antibody used in oncotherapy for HER2-positive tumors. However, as an adverse effect, trastuzumab elevates the risk of heart failure, implying the involvement of energy production and mitochondrial processes. Past studies with transcriptome analysis have offered insights on pathways related to trastuzumab safety and toxicity but limited study sizes hinder conclusive findings. Therefore, we meta-analyzed mitochondria-related gene expression data in trastuzumab-treated cardiomyocytes. We searched the transcriptome databases for trastuzumab-treated cardiomyocytes in the ArrayExpress, DDBJ Omics Archive, Gene Expression Omnibus, Google Scholar, PubMed, and Web of Science repositories. A subset of 1270 genes related to mitochondrial functions (biogenesis, organization, mitophagy, and autophagy) was selected from the Kyoto Encyclopedia of Genes and Genomes and Gene Ontology Resource databases to conduct the present meta-analysis using the Metagen package (Study register at PROSPERO: CRD42021270645). Three datasets met the inclusion criteria and 1243 genes were meta-analyzed. We observed 69 upregulated genes after trastuzumab treatment which were related mainly to autophagy (28 genes) and mitochondrial organization (28 genes). We also found 37 downregulated genes which were related mainly to mitochondrial biogenesis (11 genes) and mitochondrial organization (24 genes). The present meta-analysis indicates that trastuzumab therapy causes an unbalance in mitochondrial functions, which could, in part, help explain the development of heart failure and yields a list of potential molecular targets. These findings contribute to our understanding of the molecular mechanisms underlying the cardiotoxic effects of trastuzumab and may have implications for the development of targeted therapies to mitigate such effects.


Assuntos
Insuficiência Cardíaca , Miócitos Cardíacos , Humanos , Miócitos Cardíacos/metabolismo , Cardiotoxicidade/genética , Cardiotoxicidade/metabolismo , Receptor ErbB-2/metabolismo , Anticorpos Monoclonais Humanizados/efeitos adversos , Trastuzumab/efeitos adversos , Insuficiência Cardíaca/metabolismo , Expressão Gênica
3.
Med ; 5(3): 173-175, 2024 Mar 08.
Artigo em Inglês | MEDLINE | ID: mdl-38460494

RESUMO

We analyzed the potential of HER2-targeted antibody-drug conjugates (ADCs) in treating NSCLC with activating HER2 mutations. We identified specific mutations, notably G776delinsVC, that are associated with higher therapeutic response rates, suggesting a refined approach for precision treatment. Further validation and exploration are crucial for potential breakthroughs in ADC therapy.


Assuntos
Antineoplásicos , Imunoconjugados , Trastuzumab/uso terapêutico , Antineoplásicos/uso terapêutico , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismo , Linhagem Celular Tumoral , Imunoconjugados/uso terapêutico
4.
J Immunother Cancer ; 12(3)2024 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-38490714

RESUMO

BACKGROUND: In a prior report, we detailed the isolation and engineering of a bispecific killer cell engager, referred to as BiKE:E5C1. The BiKE:E5C1 exhibits high affinity/specificity for the CD16a activating receptor on natural killer (NK) cells and human epidermal growth factor receptor 2 (HER2) on cancer cells. In vitro studies have demonstrated that BiKE:E5C1 can activate the NK cells and induce the killing of HER2+ ovarian and breast cancer cells, surpassing the performance of the best-in-class monoclonal antibody, Trazimera (trastuzumab). To advance this BiKE technology toward clinical application, the objective of this research was to demonstrate the ability of BiKE:E5C1 to activate CD16+ immune cells such as NK cells and macrophages to kill cancer cells, and eradicate metastatic HER2+ tumors in NK humanized NOG mice. METHODS: We assessed BiKE:E5C1's potential to activate CD16-expressing peripheral blood (PB)-NK cells, laNK92 cells, and THP-1-CD16A monocyte-macrophages through flowcytometry and antibody-dependent cell-mediated cytotoxicity/phagocytosis (ADCC) assays. Subsequently, laNK92 cells were selected as effector cells and genetically modified to express the nanoluciferase gene, enabling the monitoring of their viability in NK humanized NOG mice using quantitative bioluminescent imaging (qBLI). To evaluate the functionality of BiKE:E5C1 in vivo, we introduced firefly luciferase-expressing ovarian cancer cells via intraperitoneal injection into hIL-15 and hIL-2 NOG mice, creating a model of ovarian cancer metastasis. Once tumor establishment was confirmed, we treated the mice with laNK92 cells plus BiKE:E5C1 and the response to therapy was assessed using qBLI. RESULTS: Our data demonstrate that BiKE:E5C1 activates not only laNK92 cells but also PB-NK cells and macrophages, significantly enhancing their anticancer activities. ADCC assay demonstrated that IgG1 Fc region had no impact on BiKE:E5C1's anticancer activity. In vivo results reveal that both hIL-15 and hIL-2 NOG mouse models support the viability and proliferation of laNK92 cells. Furthermore, it was observed that BiKE:E5C1 activates laNK92 cells in mice, leading to eradication of cancer metastasis in both NK humanized hIL-15 and hIL-2 NOG mouse models. CONCLUSIONS: Collectively, our in vivo findings underscore BiKE:E5C1's potential as an immune cell engager capable of activating immune cells for cancer cell elimination, thereby expanding the arsenal of available BiKEs for cancer immunotherapy.


Assuntos
Células Matadoras Naturais , Neoplasias Ovarianas , Feminino , Camundongos , Humanos , Animais , Citotoxicidade Celular Dependente de Anticorpos , Trastuzumab , Macrófagos , Neoplasias Ovarianas/metabolismo
5.
PLoS One ; 19(3): e0300416, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38483950

RESUMO

About 30% of the FDA approved drugs in 2021 were protein-based therapeutics. However, therapeutic proteins can be unstable and rapidly eliminated from the blood, compared to conventional drugs. Furthermore, on-target but off-tumor protein binding can lead to off-tumor toxicity, lowering the maximum tolerated dose. Thus, for effective treatment therapeutic proteins often require continuous or frequent administration. To improve protein stability, delivery and release, proteins can be encapsulated inside drug delivery systems. These drug delivery systems protect the protein from degradation during (targeted) transport, prevent premature release and allow for long-term, sustained release. However, thus far achieving high protein loading in drug delivery systems remains challenging. Here, the use of protein desolvation with acetonitrile as an intermediate step to concentrate monoclonal antibodies for use in drug delivery systems is reported. Specifically, trastuzumab, daratumumab and atezolizumab were desolvated with high yield (∼90%) into protein nanoparticles below 100 nm with a low polydispersity index (<0.2). Their size could be controlled by the addition of low concentrations of sodium chloride between 0.5 and 2 mM. Protein particles could be redissolved in aqueous solutions and redissolved antibodies retained their binding activity as evaluated in cell binding assays and exemplified for trastuzumab in an ELISA.


Assuntos
Nanopartículas , Neoplasias , Humanos , Cloreto de Sódio/uso terapêutico , Sistemas de Liberação de Medicamentos , Trastuzumab/uso terapêutico , Neoplasias/tratamento farmacológico , Acetonitrilas
6.
PLoS One ; 19(3): e0300474, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38489305

RESUMO

BACKGROUND: In Vietnam, trastuzumab is included in social health insurance's benefits package with a reimbursement rate of 60%, but policymakers have been concerned about its cost-effectiveness. The research aims to evaluate the cost-effectiveness of one-year adjuvant trastuzumab therapy for early-stage breast cancer patients with human epidermal growth receptor 2 (HER2+) from a societal perspective. METHOD: A Markov model was developed and validated to estimate the lifetime cost and effectiveness (using life year and quality-adjusted life year) of one-year adjuvant trastuzumab therapy compared to chemotherapy (using paclitaxel) alone. Treatment efficacy and transition probabilities were estimated based on published trials (i.e., N9831, NSABP B-31, HERA, and BCIRG 006). Local cost and utility data were employed to capture the Vietnam context. One-way sensitivity analysis, probabilistic sensitivity analysis, threshold, and scenario analysis were also performed. RESULTS: One-year adjuvant trastuzumab therapy combined with chemotherapy compared to chemotherapy alone yielded an additional cost of 888,453,971VND (39,062 US$) with an additional 3.09 LYs and 1.61 QALYs, resulting in an ICER of 287,390,682 VND (12,635 US$) per LY gained, or 519,616,972 VND (22,845 US$) per QALY gained. The ICER exceeds the cost-effective threshold of 1- and 3-time GDP per capita by 6.3 and 2.1 times. The probabilistic sensitivity analysis shows similar results. According to one-way sensitivity analysis, ICERs were driven mainly by transition probabilities and trastuzumab price. One-year adjuvant trastuzumab therapy would be cost-effective at the 3-time GDP per capita threshold if the cost of Herceptin 150mg and 450mg vials were reduced by 56% and 54%, correspondingly. CONCLUSION: In Vietnam, one-year adjuvant trastuzumab therapy for early-stage breast cancer with HER2+ is not cost-effective. The research provided reliable and updated evidence to support policymakers in revising the health insurance benefit package. The policymakers should consider the options to reduce the cost of trastuzumab (e.g., regarding the use of trastuzumab biosimilars, price negotiation options, and options of optimizing the use of Herceptin vials among concurrent hospitalized breast cancer patients).


Assuntos
Medicamentos Biossimilares , Neoplasias da Mama , Humanos , Feminino , Trastuzumab/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Análise Custo-Benefício , Medicamentos Biossimilares/uso terapêutico , Vietnã , Receptor ErbB-2 , Anticorpos Monoclonais Humanizados/uso terapêutico , Quimioterapia Adjuvante , Anos de Vida Ajustados por Qualidade de Vida
7.
Sci Rep ; 14(1): 6578, 2024 03 19.
Artigo em Inglês | MEDLINE | ID: mdl-38503890

RESUMO

The prognostic value of SII (Systemic Immune-Inflammation Index) in HER-2-positive breast cancer (BC) patients, regardless of whether they receive trastuzumab treatment, and its potential value to distinguish patients who may benefit from trastuzumab therapy, warrant further investigation. Clinical data was collected from 797 HER-2-positive BC patients between July 2013 and March 2018. Baseline data differences were adjusted with propensity score matching. Univariate and multivariate analyses explored the correlation between clinical pathological factors, SII, and DFS. Four groups were established. Based on the baseline SII values of the participants, patients who did not receive trastuzumab treatment were divided into Group 1 (Low-SII) and Group 2 (High-SII), where SII had no predictive value for prognosis between groups. Participants who received trastuzumab treatment were also divided into two groups: the Low-SII group (Group 3) and the High-SII group (Group 4). The 5-year DFS was significantly higher in Group 3 than in Group 4 (91.76% vs. 82.76%, P = 0.017). Furthermore, multivariate analysis demonstrated a significant association between high SII and shorter DFS (HR = 3.430, 95% CI = 1.830-6.420, P < 0.001). In HER-2-positive BC patients treated with trastuzumab, those with lower SII showed a longer DFS, suggesting that SII may help in identifying patients who benefit from trastuzumab therapy.


Assuntos
Neoplasias da Mama , Humanos , Feminino , Trastuzumab/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Prognóstico , Receptor ErbB-2 , Inflamação/tratamento farmacológico , Estudos Retrospectivos
8.
Cancer Rep (Hoboken) ; 7(3): e1954, 2024 03.
Artigo em Inglês | MEDLINE | ID: mdl-38441358

RESUMO

BACKGROUND: Overexpression of HER2 plays an important role in cancer progression and is the target of multiple therapies in HER2-positive breast cancer. Recent studies have also highlighted the presence of activating mutations in HER2, and HER3 that are predicted to enhance HER2 downstream pathway activation in a HER2-dependent manner. METHODS: In this report, we present two exceptional responses in hormone receptor-positive, HER2-nonamplified, HER2/HER3 co-mutated metastatic breast cancer patients who were treated with the anti-HER2-directed monoclonal antibodies, trastuzumab and pertuzumab. RESULTS: Both patients acheived exceptional responses to treatment, suggesting that combined trastuzumab, pertuzumab, and endocrine therapy could be a highly effective therapy for these patients and our observations could help prioritize trastuzumab deruxtecan as an early therapeutic choice for patients whose cancers have activating mutations in HER2.


Assuntos
Neoplasias da Mama , Feminino , Humanos , Anticorpos Monoclonais Humanizados , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Mutação , Trastuzumab/uso terapêutico
9.
Nat Commun ; 15(1): 2153, 2024 Mar 09.
Artigo em Inglês | MEDLINE | ID: mdl-38461323

RESUMO

The randomized, multicenter, double-blind, placebo-controlled, phase III PEONY trial (NCT02586025) demonstrated significantly improved total pathologic complete response (primary endpoint) with dual HER2 blockade in HER2-positive early/locally advanced breast cancer, as previously reported. Here, we present the final, long-term efficacy (secondary endpoints: event-free survival, disease-free survival, overall survival) and safety analysis (62.9 months' median follow-up). Patients (female; n = 329; randomized 2:1) received neoadjuvant pertuzumab/placebo with trastuzumab and docetaxel, followed by adjuvant 5-fluorouracil, epirubicin, and cyclophosphamide, then pertuzumab/placebo with trastuzumab until disease recurrence or unacceptable toxicity, for up to 1 year. Five-year event-free survival estimates are 84.8% with pertuzumab and 73.7% with placebo (hazard ratio 0.53; 95% confidence interval 0.32-0.89); 5-year disease-free survival rates are 86.0% and 75.0%, respectively (hazard ratio 0.52; 95% confidence interval 0.30-0.88). Safety data are consistent with the known pertuzumab safety profile and generally comparable between arms, except for diarrhea. Limitations include the lack of ado-trastuzumab emtansine as an option for patients with residual disease and the descriptive nature of the secondary, long-term efficacy endpoints. PEONY confirms the positive benefit:risk ratio of neoadjuvant/adjuvant pertuzumab, trastuzumab, and docetaxel treatment in this patient population.


Assuntos
Anticorpos Monoclonais Humanizados , Neoplasias da Mama , Paeonia , Humanos , Feminino , Neoplasias da Mama/patologia , Docetaxel/uso terapêutico , Receptor ErbB-2/uso terapêutico , Terapia Neoadjuvante , Recidiva Local de Neoplasia/patologia , Trastuzumab/efeitos adversos , Adjuvantes Imunológicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos
10.
Future Oncol ; 20(13): 821-832, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38305004

RESUMO

Aim: Trastuzumab-anns is an intravenously administered biosimilar to trastuzumab approved by the EMA and US FDA for treatment of HER2+ early and metastatic breast cancer as well as metastatic gastric cancer. Lack of real-world characterization of biosimilar use has hindered uptake. Methods: This observational chart review characterizes 488 patients who received trastuzumab-anns in EU clinical practice settings. Results: Approximately 2/3rds of patients initiated trastuzumab-anns in adjuvant and neoadjuvant settings and most were naive new starters (70%). 30% were switchers from another trastuzumab, among whom 48% switched from trastuzumab iv. reference product. Common reasons for trastuzumab-anns discontinuation were a switch to another biosimilar product (34.8%, n = 85) or to trastuzumab reference product (15.6%, n = 38). Conclusion: Trastuzumab-anns was widely used in various treatment settings for HER2+ breast cancer.


Some patients have a type of breast cancer caused by abnormal amounts of a normal growth factor receptor. This growth factor receptor, known as human epidermal growth factor receptor-2 (HER-2), plays a role in normal life changes that occur in breast tissue, including during pregnancy. HER-2 exists on the surface of breast cells and sends a signal inside cells for growth and proliferation. Sometimes an abnormal amount of HER-2 appears on breast cell surfaces, which causes HER-2 to promote excessive growth and proliferation and leads to HER2+ breast cancer. HER2+ breast cancer can be treated with trastuzumab, a medicine that specifically blocks HER-2 signals, and stops cancer cell growth. Trastuzumab has greatly improved outcomes for women worldwide with HER2+ breast cancer but trastuzumab is not always available due, in part, to its high cost. Biosimilars are medicines that are highly similar, but not identical, to the brand name (original) product and have been shown in clinical trials to result in no meaningful difference in efficacy and safety compared with the original product. Trastuzumab-anns is an intravenously administered biosimilar to trastuzumab. Biosimilars are as effective and safe as original products, although more cost-effective, such that physicians and patients can benefit from more information about their use in the real world. This study provided information about trastuzumab-anns use from clinical oncology practices in seven European countries. The study provides real world evidence that trastuzumab-anns is used widely across different patients with HER2+ breast cancer, including those with metastatic disease.


Assuntos
Medicamentos Biossimilares , Neoplasias da Mama , Humanos , Feminino , Trastuzumab/efeitos adversos , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Medicamentos Biossimilares/efeitos adversos , União Europeia , Receptor ErbB-2/genética
11.
Breast Cancer Res ; 26(1): 24, 2024 02 07.
Artigo em Inglês | MEDLINE | ID: mdl-38321542

RESUMO

BACKGROUND: Overexpression of human epidermal growth factor receptor 2 (HER2) caused by HER2 gene amplification is a driver in breast cancer tumorigenesis. We aimed to investigate the prognostic significance of manual scoring and digital image analysis (DIA) algorithm assessment of HER2 copy numbers and HER2/CEP17 ratios, along with ERBB2 mRNA levels among early-stage HER2-positive breast cancer patients treated with trastuzumab. METHODS: This retrospective study comprised 371 early HER2-positive breast cancer patients treated with adjuvant trastuzumab, with HER2 re-testing performed on whole tumor sections. Digitized tumor tissue slides were manually scored and assessed with uPath HER2 Dual ISH image analysis, breast algorithm. Targeted ERBB2 mRNA levels were assessed by the Xpert® Breast Cancer STRAT4 Assay. HER2 copy number and HER2/CEP17 ratio from in situ hybridization assessment, along with ERBB2 mRNA levels, were explored in relation to recurrence-free survival (RFS). RESULTS: The analysis showed that patients with tumors with the highest and lowest manually counted HER2 copy number levels had worse RFS than those with intermediate levels (HR = 2.7, CI 1.4-5.3, p = 0.003 and HR = 2.1, CI 1.1-3.9, p = 0.03, respectively). A similar trend was observed for HER2/CEP17 ratio, and the DIA algorithm confirmed the results. Moreover, patients with tumors with the highest and the lowest values of ERBB2 mRNA had a significantly worse prognosis (HR = 2.7, CI 1.4-5.1, p = 0.003 and HR = 2.8, CI 1.4-5.5, p = 0.004, respectively) compared to those with intermediate levels. CONCLUSIONS: Our findings suggest that the association between any of the three HER2 biomarkers and RFS was nonlinear. Patients with tumors with the highest levels of HER2 gene amplification or ERBB2 mRNA were associated with a worse prognosis than those with intermediate levels, which is of importance to investigate in future clinical trials studying HER2-targeted therapy.


Assuntos
Neoplasias da Mama , Humanos , Feminino , Trastuzumab/uso terapêutico , Neoplasias da Mama/patologia , Prognóstico , Estudos Retrospectivos , Receptor ErbB-2/metabolismo , RNA Mensageiro
12.
Sci Rep ; 14(1): 2908, 2024 02 05.
Artigo em Inglês | MEDLINE | ID: mdl-38316885

RESUMO

Breast cancer is the most common diagnosed cancer, the HER2-positive subtype account for 15% of all breast cancer. HER2-targeted therapy is the mainstay treatment for HER2-positive breast cancer. Cuproptosis is a novel form of programmed cell death, and is caused by mitochondrial lipoylation and destabilization of iron-sulfur proteins triggered by copper, which was considered as a key player in various biological processes. However, the roles of cuproptosis-related genes in HER2-positive breast cancer remain largely unknown. In the present study, we constructed a prognostic prediction model of HER2-positive breast cancer patients using TCGA database. Dysregulated genes for cells resistant to HER2-targeted therapy were analyzed in the GEO dataset. KEGG pathway, GO enrichment and GSEA was performed respectively. The immune landscape of DLAT was analyzed by CIBERSORT algorithm and TIDE algorithm. HER2-positive breast cancer patients with high CRGs risk score showed shorter OS. DLAT was downregulated and correlated with better survival of HER2-positive breast cancer patients (HR = 3.30, p = 0.022). High expressed DLAT was associated with resistant to HER2-targeted therapy. Knocking down DLAT with siRNA increased sensitivity of breast cancer to trastuzumab. KEGG pathway and GO enrichment of DEGs indicated that DLAT participates in various pathways correlated with organelle fission, chromosome segregation, nuclear division, hormone-mediated signaling pathway, regulation of intracellular estrogen receptor signaling pathway, condensed chromosome and PPAR signaling pathway. There was a negative correlation between TIDE and DLAT expression (r = - 0.292, p < 0.001), which means high DLAT expression is an indicator of sensitivity to immunotherapy. In conclusion, our study constructed a four CRGs signature prognostic prediction model and identified DLAT as an independent prognostic factor and associated with resistant to HER2-targeted therapy for HER2-positive breast cancer patients.


Assuntos
Neoplasias da Mama , Humanos , Feminino , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Trastuzumab/farmacologia , Trastuzumab/uso terapêutico , Prognóstico , Algoritmos , Apoptose , Cobre
13.
Biol Pharm Bull ; 47(2): 411-416, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38346748

RESUMO

Trastuzumab deruxtecan (T-DXd) has displayed demonstrable efficacy and manageable toxicity in previously treated patients with advanced gastric and breast cancer, and it has been approved in Japan. However, there is a lack of data on the optimal management in clinical practice. Therefore, we assessed the adverse event (AE) profiles of T-DXd in patients with advanced gastric or breast cancer to provide guidance for appropriate management. This retrospective study was conducted at the Cancer Institute Hospital of the Japanese Foundation for Cancer Research. We reviewed the medical records of patients with advanced gastric or breast cancer who received T-DXd between May 2020 and December 2021. AEs occurring within the first three cycles of T-DXd were evaluated according to Common Terminology Criteria for Adverse Events version 5.0. Thirty-six patients were enrolled (gastric: n = 19, breast: n = 17). All 15 males had gastric cancer, whereas 4 and 17 females had gastric and breast cancer, respectively. Interstitial lung disease (ILD) occurred in five patients (14%), but no patients had severe ILD. Gastrointestinal (GI) toxicities, including nausea (61%), vomiting (22%), decreased appetite (33%), and diarrhea (39%), were the most common AEs. The incidence of GI toxicities did not differ by cancer type; however, nausea was significantly more common in females (81 vs. 33%; p < 0.01). T-DXd was safely administered in clinical practice in patients with previously treated advanced gastric or breast cancer. The management of GI toxicities is important in the clinical implementation of T-DXd.


Assuntos
Neoplasias da Mama , Camptotecina/análogos & derivados , Imunoconjugados , Doenças Pulmonares Intersticiais , Feminino , Masculino , Humanos , Neoplasias da Mama/tratamento farmacológico , Estudos Retrospectivos , Trastuzumab/efeitos adversos , Náusea/induzido quimicamente , Receptor ErbB-2
14.
Sci Rep ; 14(1): 3771, 2024 02 14.
Artigo em Inglês | MEDLINE | ID: mdl-38355949

RESUMO

Epidermal growth factor receptor (EGFR), human epidermal growth factor receptor 2 (HER2), and hypoxia are associated with radioresistance. The goal of this study is to study the synergy of anti-HER2, trastuzumab, and anti-EGFR, cetuximab, and characterize the tumor microenvironment components that may lead to increased radiation sensitivity with dual anti-HER2/EGFR therapy in head and neck squamous cell carcinoma (HNSCC). Positron emission tomography (PET) imaging ([89Zr]-panitumumab and [89Zr]-pertuzumab) was used to characterize EGFR and HER2 in HNSCC cell line tumors. HNSCC cells were treated with trastuzumab, cetuximab, or combination followed by radiation to assess for viability and radiosensitivity (colony forming assay, immunofluorescence, and flow cytometry). In vivo, [18F]-FMISO-PET imaging was used to quantify changes in oxygenation during treatment. Bliss Test of Synergy was used to identify combination treatment synergy. Quantifying EGFR and HER2 receptor expression revealed a 50% increase in heterogeneity of HER2 relative to EGFR. In vitro, dual trastuzumab-cetuximab therapy shows significant decreases in DNA damage response and increased response to radiation therapy (p < 0.05). In vivo, tumors treated with dual anti-HER2/EGFR demonstrated decreased tumor hypoxia, when compared to single agent therapies. Dual trastuzumab-cetuximab demonstrates synergy and can affect tumor oxygenation in HNSCC. Combination trastuzumab-cetuximab modulates the tumor microenvironment through reductions in tumor hypoxia and induces sustained treatment synergy.


Assuntos
Neoplasias de Cabeça e Pescoço , Humanos , Cetuximab/farmacologia , Cetuximab/uso terapêutico , Carcinoma de Células Escamosas de Cabeça e Pescoço/tratamento farmacológico , Trastuzumab/farmacologia , Trastuzumab/uso terapêutico , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Linhagem Celular Tumoral , Microambiente Tumoral , Receptores ErbB
15.
AAPS J ; 26(1): 25, 2024 Feb 14.
Artigo em Inglês | MEDLINE | ID: mdl-38355847

RESUMO

Degradation of therapeutic monoclonal antibodies (mAbs) is a major concern as it affects efficacy, shelf-life, and safety of the product. Taurine, a naturally occurring amino acid, is investigated in this study as a potential mAb stabilizer with an extensive analytical characterization to monitor product degradation. Forced degradation of trastuzumab biosimilar (mAb1)-containing samples by thermal stress for 30 min resulted in high-molecular-weight species by more than 65% in sample without taurine compared to the sample with taurine. Samples containing mAb1 without taurine also resulted in higher Z-average diameter, altered protein structure, higher hydrophobicity, and lower melting temperature compared to samples with taurine. The stabilizing effect of taurine was retained at different mAb and taurine concentrations, time, temperatures, and buffers, and at the presence of polysorbate 80 (PS80). Even the lowest taurine concentration (10 mM) considered in this study, which is in the range of taurine levels in amino acid injections, resulted in enhanced mAb stability. Taurine-containing samples resulted in 90% less hemolysis than samples containing PS80. Additionally, mAb in the presence of taurine showed enhanced stability upon subjecting to stress with light of 365 nm wavelength, combination of light and H2O2, and combination of Fe2+ and H2O2, as samples containing mAb without taurine resulted in increased degradation products by more than 50% compared to samples with taurine upon subjecting to these stresses for 60 min. In conclusion, the presence of taurine enhanced physical stability of mAb by preventing aggregate formation, and the industry can consider it as a new mAb stabilizer.


Assuntos
Anticorpos Monoclonais , Taurina , Anticorpos Monoclonais/química , Peróxido de Hidrogênio , Trastuzumab , Polissorbatos/química , Excipientes , Aminoácidos
16.
Front Immunol ; 15: 1321946, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38361930

RESUMO

HER2 overexpression/amplification is a prevalent driver in various types of cancer, including gastric cancer (GC). Limited options are available for patients with HER2-positive metastatic gastric cancer, particularly those who do not respond to the standard therapy of HER2 antibody trastuzumab combined with chemotherapy. Previous research suggests that combining a PD-1 inhibitor with radiotherapy and granulocyte macrophage-colony stimulating factor (PRaG regimen) may enhance the antitumor effects in patients with chemotherapy-resistant metastatic solid tumors. In this case study, we presented a potential treatment strategy of a patient having HER2-positive and PD-L1-negative gastric adenocarcinoma. The patient showed rapid tumor progression even after surgery and multiple trastuzumab plus chemotherapy treatments. To address this, we employed a novel anti-HER2 antibody called RC48 in combination with PRaG regimen therapy (PRaG3.0). The patient demonstrated a positive response after two treatment cycles and achieved a progression-free survival time of 6.5 months. This case highlights the potential of four-combination therapies for treating refractory, multiorgan, HER2-positive, PD-L1-negative metastatic gastric cancer. Additionally, varying radiation doses in targeting dual foci is critical to enhance tumor immunotherapy.


Assuntos
Neoplasias Gástricas , Humanos , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/etiologia , Inibidores de Checkpoint Imunológico/uso terapêutico , Fator Estimulador de Colônias de Granulócitos e Macrófagos/uso terapêutico , Antígeno B7-H1 , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Trastuzumab/uso terapêutico , Granulócitos , Macrófagos
17.
Int J Mol Sci ; 25(3)2024 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-38339219

RESUMO

Monoclonal antibody (mAb)-based and/or cell-based immunotherapies provide innovative approaches to cancer treatments. However, safety concerns over targeting normal cells expressing reactive antigens still exist. Therefore, the development of cancer-specific mAbs (CasMabs) that recognize cancer-specific antigens with in vivo antitumor efficacy is required to minimize the adverse effects. We previously screened anti-human epidermal growth factor receptor 2 (HER2) mAbs and successfully established a cancer-specific anti-HER2 mAb, H2Mab-250/H2CasMab-2 (IgG1, kappa). In this study, we showed that H2Mab-250 reacted with HER2-positive breast cancer cells but did not show reactivity to normal epithelial cells in flow cytometry. In contrast, a clinically approved anti-HER2 mAb, trastuzumab, recognized both breast cancer and normal epithelial cells. We further compared the affinity, effector activation, and antitumor effect of H2Mab-250 with trastuzumab. The results showed that H2Mab-250 exerted a comparable antitumor effect with trastuzumab in the mouse xenograft models of BT-474 and SK-BR-3, although H2Mab-250 possessed a lower affinity and effector activation than trastuzumab in vitro. H2Mab-250 could contribute to the development of chimeric antigen receptor-T or antibody-drug conjugates without adverse effects for breast cancer therapy.


Assuntos
Anticorpos Monoclonais , Antineoplásicos , Neoplasias da Mama , Animais , Feminino , Humanos , Camundongos , Anticorpos Monoclonais/farmacologia , Anticorpos Monoclonais/uso terapêutico , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Linhagem Celular Tumoral , Xenoenxertos , Receptor ErbB-2/imunologia , Trastuzumab/farmacologia , Trastuzumab/uso terapêutico , Ensaios Antitumorais Modelo de Xenoenxerto
18.
J Immunother Cancer ; 12(2)2024 Feb 27.
Artigo em Inglês | MEDLINE | ID: mdl-38417916

RESUMO

BACKGROUND: The antitumor activity of natural killer (NK) cells can be enhanced by specific targeting with therapeutic antibodies that trigger antibody-dependent cell-mediated cytotoxicity (ADCC) or by genetic engineering to express chimeric antigen receptors (CARs). Despite antibody or CAR targeting, some tumors remain resistant towards NK cell attack. While the importance of ICAM-1/LFA-1 interaction for natural cytotoxicity of NK cells is known, its impact on ADCC induced by the ErbB2 (HER2)-specific antibody trastuzumab and ErbB2-CAR-mediated NK cell cytotoxicity against breast cancer cells has not been investigated. METHODS: Here we used NK-92 cells expressing high-affinity Fc receptor FcγRIIIa in combination with trastuzumab or ErbB2-CAR engineered NK-92 cells (NK-92/5.28.z) as well as primary human NK cells combined with trastuzumab or modified with the ErbB2-CAR and tested cytotoxicity against cancer cells varying in ICAM-1 expression or alternatively blocked LFA-1 on NK cells. Furthermore, we specifically stimulated Fc receptor, CAR and/or LFA-1 to study their crosstalk at the immunological synapse and their contribution to degranulation and intracellular signaling in antibody-targeted or CAR-targeted NK cells. RESULTS: Blockade of LFA-1 or absence of ICAM-1 significantly reduced cell killing and cytokine release during trastuzumab-mediated ADCC against ErbB2-positive breast cancer cells, but not so in CAR-targeted NK cells. Pretreatment with 5-aza-2'-deoxycytidine induced ICAM-1 upregulation and reversed NK cell resistance in ADCC. Trastuzumab alone did not sufficiently activate NK cells and required additional LFA-1 co-stimulation, while activation of the ErbB2-CAR in CAR-NK cells induced efficient degranulation independent of LFA-1. Total internal reflection fluorescence single molecule imaging revealed that CAR-NK cells formed an irregular immunological synapse with tumor cells that excluded ICAM-1, while trastuzumab formed typical peripheral supramolecular activation cluster (pSMAC) structures. Mechanistically, the absence of ICAM-1 did not affect cell-cell adhesion during ADCC, but rather resulted in decreased signaling via Pyk2 and ERK1/2, which was intrinsically provided by CAR-mediated targeting. Furthermore, while stimulation of the inhibitory NK cell checkpoint molecule NKG2A markedly reduced FcγRIIIa/LFA-1-mediated degranulation, retargeting by CAR was only marginally affected. CONCLUSIONS: Downregulation of ICAM-1 on breast cancer cells is a critical escape mechanism from trastuzumab-triggered ADCC. In contrast, CAR-NK cells are able to overcome cancer cell resistance caused by ICAM-1 reduction, highlighting the potential of CAR-NK cells in cancer immunotherapy.


Assuntos
Neoplasias da Mama , Receptores de Antígenos Quiméricos , Humanos , Feminino , Molécula 1 de Adesão Intercelular , Receptores de Antígenos Quiméricos/metabolismo , Antígeno-1 Associado à Função Linfocitária/metabolismo , Regulação para Baixo , Evasão Tumoral , Linhagem Celular Tumoral , Células Matadoras Naturais , Trastuzumab/farmacologia , Anticorpos , Receptores Fc/metabolismo , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo
19.
Clin Nucl Med ; 49(4): e149-e155, 2024 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-38350067

RESUMO

OBJECTIVE: The aim of this study was to assess the biodistribution and dosimetry of 177 Lu-DOTA-trastuzumab in patients with HER2-positive breast carcinoma using whole-body (WB) planar imaging at multiple time points. PATIENTS AND METHODS: This study was a prospective evaluation of HER2-positive metastatic/locally advanced breast carcinoma patients who underwent gamma camera imaging for dosimetry and biodistribution studies by using 177 Lu-DOTA-trastuzumab. The standard diagnostic dosimetry protocol was followed, which included cold trastuzumab injection followed by in-house produced 177 Lu-DOTA-trastuzumab. Serial WB planar images (anterior and posterior) were obtained on gamma camera after the infusion of 177 Lu-DOTA-trastuzumab at multiple time points. Whole-body and organ regions of interest were drawn, and the numbers of disintegrations were obtained. The mean absorbed doses for the liver, spleen, kidneys, heart, red marrow, and tumor were obtained from OLINDA EXM v2.1.1 and ORIGIN software. RESULTS: The study included a cohort of 21 female breast carcinoma patients. Tracer activity ( 177 Lu-DOTA-trastuzumab) was noted in the physiological organs such as the liver, spleen, kidneys, heart, as well as in the tumors. On visual analysis of 177 Lu-DOTA-trastuzumab biodistribution, the liver activity showed gradual clearance over time, and although spleen was comparatively faintly visualized than liver and similarly, kidneys were faintly visualized suggestive of the alternate route of tracer excretion. The maximum number of patients (n = 12) showed 2 components of clearance, namely, fast and slow. The average effective half-life of all the patients (including single and 2 components of clearance) was 106.25 ± 22.14 hours (84.11-128.39 hours). The mean absorbed dose for the liver, spleen, kidneys, heart, whole body, and red marrow was 1.0702 ± 0.731, 1.4114 ± 0.462, 1.4232 ± 0.364, 1.4719 ± 0.602, 0.2412 ± 0.0295, and 0.1485 ± 0.0213 mGy/MBq, respectively, by OLINDA EXM and 0.5741 ± 0.333, 0.8096 ± 0.224, 0.7943 ± 0.235, 1.8971 ± 0.713, and 0.09619 ± 0.0144 for liver, spleen, kidneys, heart and whole body respectively by ORIGIN. The absorbed radiation dose for tumor was 1.94E+2 by OLINDA EXM software and 1.78E+2 by ORIGIN software. In this study, during and after infusion of 177 Lu-DOTA-trastuzumab, no major adverse effects were noted in any patient except 1 patient who had grade 1 nausea and managed conservatively by antiemetic drug. CONCLUSIONS: The results of our study demonstrated expected and favorable biodistribution and dosimetry with 177 Lu-DOTA-trastuzumab in HER2-positive breast carcinoma patients. We noticed the mean absorbed dose to the normal organs within the limits of maximum tolerable dose, and also tumor dose was higher than the normal liver dose. Therefore, we conclude that 177 Lu-DOTA-trastuzumab radioimmunotherapy is feasible and a safe treatment option for treating HER2-positive breast carcinoma patients.


Assuntos
Neoplasias da Mama , Compostos Heterocíclicos com 1 Anel , Lutécio , Radioisótopos , Humanos , Feminino , Distribuição Tecidual , Trastuzumab/uso terapêutico , Neoplasias da Mama/diagnóstico por imagem , Neoplasias da Mama/terapia
20.
Breast Cancer ; 31(2): 185-194, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38319565

RESUMO

This is a prognostic report by the Japanese Breast Cancer Society on breast cancer extracted from the National Clinical Database-Breast Cancer Registry of Japan. Here, we present a summary of 457,878 breast cancer cases registered between 2004 and 2016. The median follow-up duration was 5.6 years. The median age at the start of treatment was 59 years (5-95%: 38-82 years) and increased from 57 years between 2004 and 2008 to 60 years between 2013 and 2016. The proportion of patients with Stage 0-II disease increased from 74.5% to 78.3%. The number of cases with estrogen and progesterone receptor positivity increased from 74.8% to 77.9% and 60.5% to 68.1%, respectively. Regarding (neo-)adjuvant chemotherapy, the taxane (T) or taxane-cyclophosphamide (C) regimen increased by 2.4% to 8.2%, but the (fluorouracil (F)) adriamycin (A)-C-T/(F) epirubicin (E)C-T and (F)AC/(F)EC regimens decreased by 18.6% to 15.2% and 13.5% to 5.0%, respectively. Regarding (neo-)adjuvant anti-human epidermal growth factor-2 (HER2)-targeted therapy, the use of trastuzumab increased from 4.6% to 10.5%. The rate of sentinel lymph node biopsy increased from 37.1% to 60.7%, while that of axillary dissection decreased from 54.5% to 22.6%. Improvements in disease-free and overall survival were observed in patients with HER2-positive breast cancer, but there was no apparent trend in patients with hormone receptor-positive, HER2-negative, or triple-negative breast cancers.


Assuntos
Neoplasias da Mama , Neoplasias de Mama Triplo Negativas , Humanos , Pessoa de Meia-Idade , Feminino , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/epidemiologia , Neoplasias da Mama/patologia , Japão/epidemiologia , Receptor ErbB-2 , Epirubicina , Ciclofosfamida , Trastuzumab/uso terapêutico , Taxoides/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Quimioterapia Adjuvante , Sistema de Registros
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