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1.
Nan Fang Yi Ke Da Xue Xue Bao ; 42(4): 498-508, 2022 Apr 20.
Artigo em Chinês | MEDLINE | ID: mdl-35527485

RESUMO

OBJECTIVE: To explore the role of Runt-related transcription factor 3 (RUNX3) in metabolic regulation of trastuzumab-resistant gastric cancer cells and investigate the mechanism of RUNX3 knockdown-mediated reversal of trastuzumab resistance. METHODS: We performed a metabolomic analysis of trastuzumab-resistant gastric cancer cells (NCI N87R) and RUNX3 knockdown cells (NCI N87R/RUNX3) using ultra performance liquid chromatography (UPLC) coupled with Q Exactive Focus Orbitrap mass spectrometry (MS). Multivariate combined with univariate analyses and MS/MS ion spectrums were used to screen the differential variables. MetaboAnalyst 5.0 database was employed for pathway enrichment analysis. Differential metabolites-genes regulatory relationships were constructed based on OmicsNet database. The changes in GSH/GSSG and NADPH/NADP ratios in NCI N87R/RUNX3 cells were measured using detection kits. RESULTS: The metabolic profile of NCI N87R cells was significantly altered after RUNX3 knockdown, with 81 differential metabolites identified to contribute significantly to the classification, among which 43 metabolites were increased and 38 were decreased (P < 0.01). In NCI N87R cells, RUNX3 knockdown resulted in noticeable alterations in 8 pathways involving glutamine metabolism, glycolysis, glycerophospholipid, nicotinate-nicotinamide and glutathione metabolism, causing also significant reduction of intracellular GSH/GSSG and NADPH/NADP ratios (P < 0.01). The differential metabolites-genes network revealed a regulatory relationship between the metabolic molecules and genes. CONCLUSION: RUNX3 reverses trastuzumab resistance in gastric cancer cells by regulating energy metabolism and oxidation-reduction homeostasis and may serve as a potential therapeutic target for trastuzumab-resistant gastric cancer.


Assuntos
Subunidade alfa 3 de Fator de Ligação ao Core , Neoplasias Gástricas , Trastuzumab , Cromatografia Líquida de Alta Pressão , Subunidade alfa 3 de Fator de Ligação ao Core/genética , Dissulfeto de Glutationa , Humanos , Metabolômica , NADP , Neoplasias Gástricas/genética , Espectrometria de Massas em Tandem , Trastuzumab/farmacologia
2.
Cancer Control ; 29: 10732748221099230, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35499382

RESUMO

Human epidermal growth factor receptor 2-positive breast cancer (HER2+BC) is a common malignancy that is prone to recurrence and metastasis in the early stages, resulting in a poor prognosis for patients. Many studies have suggested that targeted therapy promotes clinical outcomes in HER2+BC. With the introduction of trastuzumab in 1998, the prognosis of patients with early HER2+BC has improved significantly. However, owing to obstinate drug resistance and adverse events, the addition of new agents in standardized treatment has become a research hotspot. These promising agents include antibodies, antibody-drug conjugates, tyrosine kinase inhibitors, and anti-HER2 combined therapies. This article provides a brief description of the biology of BC and the expression of HER2, with the aim to provide an overview of the therapeutic landscape of HER2+BC by reviewing research results and introducing the latest evidence to provide a reference for clinical treatment.


Assuntos
Neoplasias da Mama , Neoplasias da Mama/patologia , Feminino , Humanos , Terapia de Alvo Molecular , Receptor ErbB-2/metabolismo , Trastuzumab/uso terapêutico
3.
PLoS One ; 17(5): e0267027, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35503762

RESUMO

ErbB3 (HER3), a member of the HER family, is overexpressed in various cancers and plays an important role in cell proliferation and survival. Certain HER3 mutations have also been identified as oncogenic drivers, making them potential therapeutic targets. In the current study, antitumor activity of patritumab deruxtecan (HER3-DXd), a HER3 directed antibody drug conjugate, was evaluated in tumor models with clinically reported HER3 mutations. MDA-MB-231, a HER3-negative human triple-negative breast cancer cell line, was transduced with lentiviral vectors encoding HER3 wild type (HER3WT), one of 11 HER3 mutations, or HER3 empty vector (HER3EV), in the presence/absence of HER2 overexpression. Targeted delivery of HER3-DXd was assessed using cell-surface binding, lysosomal trafficking, and cell-growth inhibition assays. HER3-DXd bound to the surface of HER3WT and mutant cells in a similar, concentration-dependent manner but not to HER3EV. HER3-DXd was translocated to the lysosome, where time- and concentration-dependent signals were observed in the HER3 mutant and HER3WT cells. HER3-DXd inhibited the growth of HER3WT and HER3 mutant cells. HER3-DXd activity was observed in the presence and absence of HER2 overexpression. These data suggest that HER3-DXd may have activity against tumors expressing wild type HER3 or clinically observed HER3 mutations, supporting further clinical evaluation.


Assuntos
Neoplasias da Mama , Imunoconjugados , Neoplasias de Mama Triplo Negativas , Anticorpos Monoclonais Humanizados , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Camptotecina/análogos & derivados , Linhagem Celular Tumoral , Feminino , Humanos , Imunoconjugados/uso terapêutico , Mutação , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismo , Receptor ErbB-3/metabolismo , Trastuzumab/genética , Trastuzumab/farmacologia , Neoplasias de Mama Triplo Negativas/tratamento farmacológico
7.
Einstein (Sao Paulo) ; 20: eGS6655, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35544899

RESUMO

OBJECTIVE: Human epidermal growth factor receptor 2 (HER2) overexpression occurs in up to 30% of breast cancer cases. Ado-trastuzumab emtansine (T-DM1) is approved to treat residual HER2-positive breast cancer after neoadjuvant therapy. The aim of this study was to determine the quality-adjusted time with symptoms or toxicity and without symptoms or toxicity (Q-TWiST) of T-DM1 compared to trastuzumab for residual invasive HER2-positive breast cancer. METHODS: The authors developed an analytical model extracting individual patient data and estimated invasive disease-free survival and overall survival over a 30-year time horizon. Only direct costs from adjuvant treatment were considered as well as relapse treatment from Brazilian and American payer perspectives. Heart events were considered for utility and cost analysis. RESULTS: The 30-year projection utilizing the Weibull method estimated a mean invasive disease-free survival of 16.4 years for T-DM1 and 10.4 for Trastuzumab, in addition to a mean overall survival of 18.1 and 15.4 years, respectively. We determined a Q-TWiST gain of 3,812 years for the T-DM1 arm when compared to trastuzumab and an Incremental cost-effectiveness ratio per Q-TWiST of US$ 11,467.65 in the United States and US$ 3,332.73 in Brazil. CONCLUSION: Ado-trastuzumab emtansine is cost-effective from both Brazilian and American perspectives.


Assuntos
Neoplasias da Mama , Ado-Trastuzumab Emtansina , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Análise Custo-Benefício , Feminino , Humanos , Terapia Neoadjuvante , Receptor ErbB-2/metabolismo , Receptor ErbB-2/uso terapêutico , Trastuzumab/uso terapêutico , Estados Unidos
8.
Sci Adv ; 8(20): eabk2746, 2022 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-35594351

RESUMO

Anti-HER2 therapies have markedly improved prognosis of HER2-positive breast cancer. However, different mechanisms play a role in treatment resistance. Here, we identified AXL overexpression as an essential mechanism of trastuzumab resistance. AXL orchestrates epithelial-to-mesenchymal transition and heterodimerizes with HER2, leading to activation of PI3K/AKT and MAPK pathways in a ligand-independent manner. Genetic depletion and pharmacological inhibition of AXL restored trastuzumab response in vitro and in vivo. AXL inhibitor plus trastuzumab achieved complete regression in trastuzumab-resistant patient-derived xenograft models. Moreover, AXL expression in HER2-positive primary tumors was able to predict prognosis. Data from the PAMELA trial showed a change in AXL expression during neoadjuvant dual HER2 blockade, supporting its role in resistance. Therefore, our study highlights the importance of targeting AXL in combination with anti-HER2 drugs across HER2-amplified breast cancer patients with high AXL expression. Furthermore, it unveils the potential value of AXL as a druggable prognostic biomarker in HER2-positive breast cancer.


Assuntos
Neoplasias da Mama , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos/genética , Feminino , Humanos , Fosfatidilinositol 3-Quinases/metabolismo , Receptor ErbB-2/genética , Trastuzumab/farmacologia , Trastuzumab/uso terapêutico
9.
Croat Med J ; 63(2): 126-140, 2022 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-35505646

RESUMO

AIM: To determine the predictive value of phosphorylated human epidermal growth factor receptor 2 (pHER2Y1248) status in breast cancer (BC) patients undergoing trastuzumab-based adjuvant therapy. METHODS: Immunohistochemical status of pHER2Y1248, EGFR/HER1, HER3, and HER4 was determined in 124 consecutive HER2-positive BC patients (median age [range]=57 years [49.0-64.0]) treated at the University Hospital for Tumors, Zagreb, between 2008 and 2011. The median follow-up was 84 months (60.0-84.0). Prognostic factors of disease free survival (DFS) rate were evaluated with Kaplan-Meier/log-rank test and Cox regression analysis. RESULTS: pHER2Y1248, HER1, HER3, and HER4 were expressed in 66.1%, 9.7%, 70.2%, and 71.0% of patients, respectively. Disease progression (DP) was observed in 17.1% of pHER2Y1248-positive and 47.6% of pHER2Y1248-negative BCs (P=0.001). Kaplan-Meier analysis showed a worse five-year DFS in pHER2Y1248-negative patients who were older than 60 years (P<0.001) and had positive lymph node status (P<0.001); tumor size >2.0 cm (P<0.001); higher histological grade (P<0.001); HER2E intrinsic subtype (P<0.001), negative hormone receptors (P<0.001); negative HER1 status (P<0.001), positive HER3 (P=0.002); and/or positive HER4 (P=0.002) status. The only negative prognostic factor for five-year DFS in multivariate Cox regression analysis was pHER2Y1248-negative (hazard ratio [HR] 3.6, 95% confidence interval [CI] 1.8-7.2, P<0.001) and lymph node-positive status (HR 3.6, 95% CI 1.3-9.8, P=0.014). CONCLUSION: pHER2Y1248 predicts sensitivity to trastuzumab and a better five-year DFS regardless of any other prognostic parameter. In HER2-positive BC patients. Non-phosphorylated HER2Y1248 is a strong predictor of trastuzumab resistance and a poor DFS.


Assuntos
Neoplasias da Mama , Neoplasias da Mama/tratamento farmacológico , Intervalo Livre de Doença , Feminino , Humanos , Pessoa de Meia-Idade , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismo , Trastuzumab/uso terapêutico
10.
Nat Commun ; 13(1): 2526, 2022 May 09.
Artigo em Inglês | MEDLINE | ID: mdl-35534471

RESUMO

Resistance mechanisms and heterogeneity in HER2-positive gastric cancers (GC) limit Trastuzumab benefit in 32% of patients, and other targeted therapies have failed in clinical trials. Using patient samples, patient-derived xenografts (PDXs), partially humanized biological models, and HER2-targeted imaging technologies we demonstrate the role of caveolin-1 (CAV1) as a complementary biomarker in GC selection for Trastuzumab therapy. In retrospective analyses of samples from patients enrolled on Trastuzumab trials, the CAV1-high profile associates with low membrane HER2 density and low patient survival. We show a negative correlation between CAV1 tumoral protein levels - a major protein of cholesterol-rich membrane domains - and Trastuzumab-drug conjugate TDM1 tumor uptake. Finally, CAV1 depletion using knockdown or pharmacologic approaches (statins) increases antibody drug efficacy in tumors with incomplete HER2 membranous reactivity. In support of these findings, background statin use in patients associates with enhanced antibody efficacy. Together, this work provides preclinical justification and clinical evidence that require prospective investigation of antibody drugs combined with statins to delay drug resistance in tumors.


Assuntos
Neoplasias da Mama , Inibidores de Hidroximetilglutaril-CoA Redutases , Neoplasias Gástricas , Neoplasias da Mama/tratamento farmacológico , Caveolina 1/genética , Caveolina 1/metabolismo , Feminino , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Estudos Prospectivos , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismo , Estudos Retrospectivos , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/genética , Neoplasias Gástricas/patologia , Trastuzumab/farmacologia , Trastuzumab/uso terapêutico
11.
Breast Dis ; 41(1): 255-260, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35599460

RESUMO

Inflammatory breast cancer (IBC) is a rare variety of breast cancer accounting for two percent of breast cancer diagnoses in the United States. It is characterized by peau d'orange, breast edema and erythema on physical examination and dermal lymphatic invasion by tumor emboli on histological examination. Micrometastases to lymphatics and bone marrow at the time of diagnosis and angiogenic properties of IBC explain the high propensity of this cancer to relapse and metastasize, its aggressiveness and poor prognosis. Preoperative sequential anthracycline and taxane (plus trastuzumab and pertuzumab if HER2-positive) based chemotherapy is the current standard of care for IBC. We herein report a case of stage IIIC triple-negative IBC treated with pembrolizumab plus chemotherapy based neoadjuvant therapy with a complete clinical and complete pathological response. This is the first case of triple-negative IBC treated with this regimen reported in the literature, thereby providing clinical data on the tolerability and efficacy of pembrolizumab plus chemotherapy based neoadjuvant regimen for the treatment of IBC.


Assuntos
Neoplasias da Mama , Neoplasias Inflamatórias Mamárias , Neoplasias de Mama Triplo Negativas , Anticorpos Monoclonais Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Feminino , Humanos , Neoplasias Inflamatórias Mamárias/diagnóstico , Neoplasias Inflamatórias Mamárias/tratamento farmacológico , Terapia Neoadjuvante , Recidiva Local de Neoplasia , Receptor ErbB-2/genética , Trastuzumab/uso terapêutico , Neoplasias de Mama Triplo Negativas/tratamento farmacológico
12.
Mol Cancer Ther ; 21(5): 751-761, 2022 May 04.
Artigo em Inglês | MEDLINE | ID: mdl-35417017

RESUMO

Pharmacologically targeting the HER2 oncoprotein with therapeutics such as the mAb, trastuzumab, provides clinical benefit for patients with HER2-positive (HER2+) cancers. However, a significant number of patients eventually progress on these therapies. Efforts to overcome therapeutic resistance through combination therapy with small-molecule inhibitors of HER2 have been limited by toxicities associated with off-target activity and/or limited efficacy. In this preclinical study, we explore single-agent and combined activity of tucatinib, a novel HER2-selective small-molecule inhibitor. Tucatinib demonstrated potent, selective activity in a panel of 456 human cancer cell lines, with activity restricted to cell lines (breast and non-breast) with HER2-amplification, including models of acquired resistance to trastuzumab. Within the HER2+ population, tucatinib response tracked strongly with HER2-driven signaling. Single-agent tucatinib induced tumor regressions in xenograft models of HER2+ breast cancer and combination with trastuzumab induced a complete and sustained blockade of HER2/PI3K/AKT signaling. Efficacy of the tucatinib/trastuzumab combination matched that induced by current standard-of-care trastuzumab/pertuzumab/docetaxel combination, with the exception that the chemotherapy-sparing tucatinib/trastuzumab combination did not require a dosing holiday to achieve the same efficacy. In xenograft models of HER2+ breast cancer that also express estrogen receptor (ER; HER2+/ER+), tucatinib showed combined efficacy with inhibitors of CDK4/6 and ER, indicating potential novel therapeutic strategies for difficult-to-treat subtypes of HER2+ breast cancer. These data support expanded clinical investigations of tucatinib as a combination partner for other novel and approved targeted therapies for HER2-driven malignancies.


Assuntos
Neoplasias da Mama , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/patologia , Feminino , Humanos , Oxazóis , Fosfatidilinositol 3-Quinases/uso terapêutico , Piridinas , Quinazolinas , Receptor ErbB-2/metabolismo , Receptores de Estrogênio/uso terapêutico , Trastuzumab
13.
J Am Chem Soc ; 144(17): 7852-7860, 2022 May 04.
Artigo em Inglês | MEDLINE | ID: mdl-35438502

RESUMO

Carboranes represent a class of compounds with increasing therapeutic potential. However, few general approaches to readily embed carboranes into small molecules, peptides, and proteins are available. We report a strategy based on palladium-mediated C-X (X = C, S, and N) bond formation for the installation of carborane-containing moieties onto small molecules and peptides. We demonstrate the ability of Pd-based reagents with appropriate ligands to overcome the high hydrophobicity of the carborane group and enable chemoselective conjugation of cysteine residues at room temperature in aqueous buffer. Accordingly, carboranes can be efficiently installed on proteins by employing a combination of a bis-sulfonated biarylphosphine-ligated Pd reagent in an aqueous histidine buffer. This method is successfully employed on nanobodies, a fully synthetic affibody, and the antibody therapeutics trastuzumab and cetuximab. The conjugates of the affibody ZHER2 and the trastuzumab antibody retained binding to their target antigens. Conjugated proteins maintain their activity in cell-based functional assays in HER2-positive BT-474 cell lines. This approach enables the rapid incorporation of carborane moieties into small molecules, peptides, and proteins for further exploration in boron neutron capture therapy, which requires the targeted delivery of boron-dense groups.


Assuntos
Boranos , Paládio , Boranos/química , Paládio/química , Peptídeos , Proteínas/química , Trastuzumab
14.
Expert Opin Drug Discov ; 17(5): 427-436, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-35426752

RESUMO

INTRODUCTION: Gastric cancer is common worldwide, and while multiple therapeutic options exist, the prognosis remains poor. Tumors may overexpress HER2. While targeting HER2 with trastuzumab provides a survival benefit, options following progression are limited. Subsequent trials of HER2-targeted agents failed to improve outcomes. Recently, DESTINY-Gastric01 demonstrated a survival benefit utilizing the antibody-drug conjugate (ADC) trastuzumab deruxtecan in gastric cancer patients that progressed on trastuzumab. AREAS COVERED: /The authors give background to gastric cancer/HER2 and discuss prognostic implications of HER2 overexpression. They also describe initial trials of anti-HER2 therapy, resistance mechanisms, and ADC development/optimization. Finally, the authors review DESTINY-Gastric01 and provide future perspectives. EXPERT OPINION: While the 2010 ToGA trial demonstrated efficacy of trastuzumab in HER2 positive gastric cancer, subsequent trials of HER2-directed therapy have disappointed. Downregulation of HER2 after trastuzumab may play a role; however, trastuzumab deruxtecan maintains some efficacy in low-level HER2 expressing tumors. The DESTINY-Gastric01 cohort was from South Korea/Japan; authors have reported differences in gastric cancer risk factors/physiology between Eastern and Western populations. DESTINY-Gastric02 will evaluate trastuzumab deruxtecan in Western patients to confirm generalizability. Pulmonary side effects are notable;physicians must be cognizant of overlapping toxicities with combination therapy.


Assuntos
Imunoconjugados , Neoplasias Gástricas , Camptotecina/análogos & derivados , Quimioterapia Combinada/efeitos adversos , Humanos , Imunoconjugados/uso terapêutico , Neoplasias Gástricas/tratamento farmacológico , Trastuzumab/uso terapêutico
15.
Anal Chem ; 94(17): 6502-6511, 2022 May 03.
Artigo em Inglês | MEDLINE | ID: mdl-35442636

RESUMO

Fully automated analysis of multiple structural attributes of monoclonal antibodies (mAbs) using three-dimensional liquid chromatography-mass spectrometry (3D-LC-MS) is described. The analyzer combines Protein A affinity chromatography in the first dimension (1D) with a multimethod option in the second dimension (2D) (choice between size exclusion (SEC), cation exchange (CEX), and hydrophobic interaction chromatography (HIC)) and desalting SEC-MS in the third dimension (3D). This innovative 3D-LC-MS setup allows simultaneous and sequential assessment of mAb titer, size/charge/hydrophobic variants, molecular weight (MW), amino acid (AA) sequence, and post-translational modifications (PTMs) directly from cell culture supernatants. The reported methodology that finds multiple uses throughout the biopharmaceutical development trajectory was successfully challenged by the analysis of different trastuzumab and tocilizumab samples originating from biosimilar development programs.


Assuntos
Anticorpos Monoclonais , Antineoplásicos Imunológicos , Anticorpos Monoclonais/química , Técnicas de Cultura de Células , Cromatografia Líquida , Espectrometria de Massas em Tandem , Trastuzumab
16.
Cancer Treat Rev ; 106: 102378, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-35430509

RESUMO

Trastuzumab deruxtecan (T-DXd; DS-8201) is an antibody-drug conjugate targeting human epidermal growth factor receptor 2. Interstitial lung disease (ILD)/pneumonitis is an adverse event associated with T-DXd; in most cases, it is low grade (grade ≤ 2) and can be treated effectively but may develop to be fatal in some instances. It is important to increase patient and provider understanding of T-DXd-related ILD/pneumonitis to improve patient outcomes. Drug-related ILD/pneumonitis is a diagnosis of exclusion; other possible causes of lung injury/imaging findings must be ruled out for an accurate diagnosis. Symptoms can be nonspecific, and identifying early symptoms is challenging; therefore, diagnosis is often delayed. We reviewed characteristics of patients who developed T-DXd-related ILD/pneumonitis and its patterns, produced multidisciplinary guidelines on diagnosis and management, and described areas for future investigation. Ongoing studies are collecting data on T-DXd-related ILD/pneumonitis to further our understanding of its clinical patterns and mechanisms. SEARCH STRATEGY AND SELECTION CRITERIA: References were identified based on the guidelines used by the authors in treating interstitial lung disease and pneumonitis. Searches of the authors' own files were also completed. A search of PubMed with the search terms (trastuzumab deruxtecan) AND (interstitial lung disease) AND (guidelines) was conducted on November 1, 2021, with no restrictions based on publication date, and the two articles yielded by the search were included.


Assuntos
Imunoconjugados , Doenças Pulmonares Intersticiais , Pneumonia , Camptotecina/análogos & derivados , Humanos , Imunoconjugados/uso terapêutico , Doenças Pulmonares Intersticiais/complicações , Doenças Pulmonares Intersticiais/diagnóstico , Doenças Pulmonares Intersticiais/tratamento farmacológico , Pneumonia/complicações , Pneumonia/tratamento farmacológico , Trastuzumab/efeitos adversos
17.
Lancet Oncol ; 23(5): 625-635, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-35405088

RESUMO

BACKGROUND: Several de-escalation neoadjuvant strategies have been investigated to reduce the use of chemotherapy in HER2-positive early breast cancer using pathological complete response as a surrogate endpoint; there are few survival data from these trials. Here, we report 5-year survival data in the WSG-ADAPT-HER2+/HR- trial and address the effect of pathological complete response, early therapy response, and molecular subtype. METHODS: WSG-ASAPT-HER2+/HR-, a part of the ADAPT umbrella trial performed in patients with different subtypes of early breast cancer, was an investigator-initiated, multicentre, open-label, randomised, phase 2 trial done at 40 Breast Cancer Centres in Germany. Eligible patients were aged 18 years or older with histologically confirmed, unilateral, primary invasive, non-inflammatory early breast cancer, hormone receptor-negative and HER2-positive status, and an Eastern Cooperative Oncology Group performance status of 0 or 1 or a Karnofsky performance status of at least 80%. Patients were randomly assigned (5:2, block size 21, stratified by centre and clinical nodal status) to 12 weeks of either trastuzumab (8 mg/kg loading dose, then 6 mg/kg every 3 weeks) plus pertuzumab (840 mg loading dose, then 420 mg every 3 weeks) or trastuzumab plus pertuzumab plus paclitaxel (80 mg/m2 weekly); all drugs were administered intravenously. The primary objective of the trial was to compare the number of patients with a pathological complete response at surgery (ie, no invasive tumour cells in breast and lymph nodes [ypT0/is ypN0], the primary endpoint) in early responders (ie, low cellularity or Ki67 decrease ≥30% after 3 weeks) in the trastuzumab plus pertuzumab group versus all patients (irrespective of an early response) in the trastuzumab plus pertuzumab plus paclitaxel group. Non-inferiority was defined as a pathological complete response no worse than 23% lower in the early-responder proportion of patients in the trastuzumab plus pertuzumab group than in the entire trastuzumab plus pertuzumab plus paclitaxel group. The primary endpoint has been reported previously. Additionally, the primary objective of the ADAPT umbrella trial was the evaluation of the effect of pathological complete response on invasive disease-free survival. At investigator's discretion, further chemotherapy could be omitted in patients with a pathological complete response. Secondary survival endpoints were 5-year invasive disease-free survival, relapse-free survival, locoregional relapse-free survival, distant disease-free survival, and overall survival. The effect of pathological complete response on survival was estimated by Cox regression analysis. All analyses are reported in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT01817452, and is closed to recruitment. FINDINGS: Between March 3, 2014, and Oct 6, 2015, 134 patients were recruited and randomly assigned to treatment, 92 to trastuzumab plus pertuzumab and 42 to trastuzumab plus pertuzumab plus paclitaxel. Median follow-up in survivors was 59·9 months (IQR 53·4-61·4). There were no significant differences between the treatment groups in invasive disease-free survival, relapse-free survival, locoregional relapse-free survival, distant disease-free survival, and overall survival. In the trastuzumab plus pertuzumab plus paclitaxel group and in the trastuzumab plus pertuzumab group, the proportions of patients achieving 5-year survival respectively were 98% (95% CI 84-100) and 87% (78-93) for invasive disease-free survival (hazard ratio [HR] 0·32, 95% CI 0·07-1·49; p=0·15); 98% (95% CI 84-100) and 89% (79-94) for relapse-free survival (HR 0·41, 95% CI 0·09-1·91; p=0·25); 100% (95% CI not estimable) and 95% (88-98) for locoregional relapse-free survival (HR 0·41, 95% CI 0·05-3·75; p=0·43); 98% (95% CI 84-100) and 92% (83-96) for distant disease-free survival (HR 0·35, 95% CI 0·04-3·12; p=0·36), and 98% (95% CI 84-100) and 94% (86-97) for overall survival (HR 0·41, 95% CI 0·05-3·63; p=0·43). Pathological complete response was associated with improved invasive disease-free survival (HR 0·14, 95% CI 0·03-0·64; p=0·011). Two invasive disease-free survival events occurred after a pathological complete response (one in each treatment group). INTERPRETATION: The WSG-ADAPT-HER2+/HR- trial showed good survival rates in patients with a pathological complete response after de-escalated 12-week trastuzumab plus pertuzumab with or without weekly paclitaxel. Omission of further chemotherapy did not affect invasive disease-free survival in patients with a pathological complete response. 12 weeks of weekly paclitaxel plus dual HER2 blockade could be an efficacious de-escalated neoadjuvant regimen in patients with hormone receptor-negative, HER2-positive early breast cancer with high pathological complete response rates and good 5-year outcomes. Further trials of this approach are ongoing. FUNDING: Roche, Bayer. TRANSLATION: For the German translation of the abstract see Supplementary Materials section.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias da Mama , Terapia Neoadjuvante , Anticorpos Monoclonais Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Feminino , Hormônios/uso terapêutico , Humanos , Recidiva Local de Neoplasia/patologia , Estadiamento de Neoplasias , Paclitaxel , Trastuzumab
18.
Biochim Biophys Acta Gen Subj ; 1866(7): 130155, 2022 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-35469978

RESUMO

BACKGROUND: Site-specific coupling of toxin entities to antibodies has become a popular method of synthesis of antibody-drug conjugates (ADCs), as it leads to a homogenous product and allows a free choice of a convenient site for conjugation. METHODS: We introduced a short motif, containing a single cysteine surrounded by aromatic residues, into the N-terminal FG-loop of the CH2 domain of two model antibodies, cetuximab and trastuzumab. The extent of conjugation with toxic payload was examined with hydrophobic interaction chromatography and mass spectrometry and the activity of resulting conjugates was tested on antigen-overexpressing cell lines. RESULTS: Antibody mutants were amenable for rapid coupling with maleimide-based linker endowed toxin payload and the modifications did not impair their reactivity with target cell lines or negatively impact their biophysical properties. Without any previous reduction, up to 50% of the antibody preparation was found to be coupled with two toxins per molecule. After the isolation of this fraction with preparative hydrophobic interaction chromatography, the ADC could elicit a potent cytotoxic effect on the target cell lines. CONCLUSION: By fine-tuning the microenvironment of the reactive cysteine residue, this strategy offers a simplified protocol for production of site-selectively coupled ADCs. GENERAL SIGNIFICANCE: Our unique approach allows the generation of therapeutic ADCs with controlled chemical composition, which facilitates the optimization of their pharmacological activity. This strategy for directional coupling could in the future simplify the construction of ADCs with double payloads ("dual warheads") introduced with orthogonal techniques.


Assuntos
Antineoplásicos , Imunoconjugados , Antineoplásicos/farmacologia , Cisteína/química , Imunoconjugados/química , Imunoconjugados/farmacologia , Imunoconjugados/uso terapêutico , Espectrometria de Massas , Trastuzumab/farmacologia
19.
Artigo em Inglês | MEDLINE | ID: mdl-35457445

RESUMO

The Chinese government has launched six rounds of national drug price negotiation since 2016 to lower the price and expand access to innovative drugs, many of which are anticancer drugs. This study aims to examine the effect of the second round of negotiation at the provincial level on the expenditure, volume, and availability of anti-cancer drugs. Procurement data at the provincial level from January 2017 to September 2018 were extracted from the China Drug Supply Information Platform (CDSIP). The volume, expenditure, and availability of three targeted anti-cancer drugs, rituximab, trastuzumab, and recombinant human endostatin (RHE), in 11 provinces that implemented the policy in September 2017 were analyzed through a controlled interrupted time series (ITS) analysis. A significant 6.0% increase (p < 0.1) in monthly average expenditure, an increase in the volume of 99.51 DDDs (defined daily doses) (p < 0.1), and a 0.24% (p < 0.1) increase in availability were observed for rituximab following the implementation of the policy. The volume and availability of rituximab increased by 949.6 DDDs (p < 0.05) and 1.56%, respectively, immediately after implementation. The availability of trastuzumab increased by 5.14% (p < 0.01) immediately after the implementation while no instant changes in expenditure and volume were observed. A 15% (p < 0.01) increase in monthly expenditure, 3673.17 DDDs increase in volume, and 0.66% increase in availability were observed after the inclusion of Trastuzumab. However, for RHE, only a 0.32% (p < 0.01) increase was observed after its inclusion. Eastern and middle provinces benefited more than western provinces. National negotiation related to the drug price significantly increased the volume and expenditure of anti-cancer drugs and improved their availability. The effect of the policy might be different across different regions and across different anticancer drugs.


Assuntos
Antineoplásicos , Gastos em Saúde , Antineoplásicos/uso terapêutico , China , Humanos , Análise de Séries Temporais Interrompida , Negociação , Rituximab , Trastuzumab/uso terapêutico
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