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Nature Communications Sep 2022Chemotherapy and targeted therapy are the major treatments for gastric cancer (GC), but drug resistance limits its effectiveness. Here, we profile the proteome of 206...
Chemotherapy and targeted therapy are the major treatments for gastric cancer (GC), but drug resistance limits its effectiveness. Here, we profile the proteome of 206 tumor tissues from patients with GC undergoing either chemotherapy or anti-HER2-based therapy. Proteome-based classification reveals four subtypes (G-I-G-IV) related to different clinical and molecular features. MSI-sig high GC patients benefit from docetaxel combination treatment, accompanied by anticancer immune response. Further study reveals patients with high T cell receptor signaling respond to anti-HER2-based therapy; while activation of extracellular matrix/PI3K-AKT pathway impair anti-tumor effect of trastuzumab. We observe CTSE functions as a cell intrinsic enhancer of chemosensitivity of docetaxel, whereas TKTL1 functions as an attenuator. Finally, we develop prognostic models with high accuracy to predict therapeutic response, further validated in an independent validation cohort. This study provides a rich resource for investigating the mechanisms and indicators of chemotherapy and targeted therapy in GC.
Topics: Docetaxel; Humans; Phosphatidylinositol 3-Kinases; Proteome; Proteomics; Proto-Oncogene Proteins c-akt; Receptors, Antigen, T-Cell; Stomach Neoplasms; Transketolase; Trastuzumab
PubMed: 36175412
DOI: 10.1038/s41467-022-33282-0 -
Clinical Cancer Research : An Official... Nov 2023Cyclin E (CCNE1) has been proposed as a biomarker of sensitivity to adavosertib, a Wee1 kinase inhibitor, and a mechanism of resistance to HER2-targeted therapy.
PURPOSE
Cyclin E (CCNE1) has been proposed as a biomarker of sensitivity to adavosertib, a Wee1 kinase inhibitor, and a mechanism of resistance to HER2-targeted therapy.
EXPERIMENTAL DESIGN
Copy number and genomic sequencing data from The Cancer Genome Atlas and MD Anderson Cancer Center databases were analyzed to assess ERBB2 and CCNE1 expression. Molecular characteristics of tumors and patient-derived xenografts (PDX) were assessed by next-generation sequencing, whole-exome sequencing, fluorescent in situ hybridization, and IHC. In vitro, CCNE1 was overexpressed or knocked down in HER2+ cell lines to evaluate drug combination efficacy. In vivo, NSG mice bearing PDXs were subjected to combinatorial therapy with various treatment regimens, followed by tumor growth assessment. Pharmacodynamic markers in PDXs were characterized by IHC and reverse-phase protein array.
RESULTS
Among several ERBB2-amplified cancers, CCNE1 co-amplification was identified (gastric 37%, endometroid 43%, and ovarian serous adenocarcinoma 41%). We hypothesized that adavosertib may enhance activity of HER2 antibody-drug conjugate trastuzumab deruxtecan (T-DXd). In vitro, sensitivity to T-DXd was decreased by cyclin E overexpression and increased by knockdown, and adavosertib was synergistic with topoisomerase I inhibitor DXd. In vivo, the T-DXd + adavosertib combination significantly increased γH2AX and antitumor activity in HER2 low, cyclin E amplified gastroesophageal cancer PDX models and prolonged event-free survival (EFS) in a HER2-overexpressing gastroesophageal cancer model. T-DXd + adavosertib treatment also increased EFS in other HER2-expressing tumor types, including a T-DXd-treated colon cancer model.
CONCLUSIONS
We provide rationale for combining T-DXd with adavosertib in HER2-expressing cancers, especially with co-occuring CCNE1 amplifications. See related commentary by Rolfo et al., p. 4317.
Topics: Humans; Animals; Mice; Cyclin E; In Situ Hybridization, Fluorescence; Trastuzumab; Receptor, ErbB-2; Camptothecin; Immunoconjugates; Neoplasms
PubMed: 37279095
DOI: 10.1158/1078-0432.CCR-23-0103 -
Nature Communications Sep 2022About 50% of human epidermal growth factor receptor 2 (HER2)+ breast cancer patients do not benefit from HER2-targeted therapy and almost 20% of them relapse after...
About 50% of human epidermal growth factor receptor 2 (HER2)+ breast cancer patients do not benefit from HER2-targeted therapy and almost 20% of them relapse after treatment. Here, we conduct a detailed analysis of two independent cohorts of HER2+ breast cancer patients treated with trastuzumab to elucidate the mechanisms of resistance to anti-HER2 monoclonal antibodies. In addition, we develop a fully humanized immunocompetent model of HER2+ breast cancer recapitulating ex vivo the biological processes that associate with patients' response to treatment. Thanks to these two approaches, we uncover a population of TGF-beta-activated cancer-associated fibroblasts (CAF) specific from tumors resistant to therapy. The presence of this cellular subset related to previously described myofibroblastic (CAF-S1) and podoplanin+ CAF subtypes in breast cancer associates with low IL2 activity. Correspondingly, we find that stroma-targeted stimulation of IL2 pathway in unresponsive tumors restores trastuzumab anti-cancer efficiency. Overall, our study underscores the therapeutic potential of exploiting the tumor microenvironment to identify and overcome mechanisms of resistance to anti-cancer treatment.
Topics: Breast Neoplasms; Cancer-Associated Fibroblasts; Female; Humans; Immunologic Factors; Immunotherapy; Interleukin-2; Receptor, ErbB-2; Trastuzumab; Tumor Microenvironment
PubMed: 36085201
DOI: 10.1038/s41467-022-32782-3 -
Proceedings of the National Academy of... Apr 2023Human epidermal growth factor receptor 2 (HER2) is overexpressed in various cancer types. HER2-targeting trastuzumab plus chemotherapy is used as first-line therapy for...
Human epidermal growth factor receptor 2 (HER2) is overexpressed in various cancer types. HER2-targeting trastuzumab plus chemotherapy is used as first-line therapy for HER2-positive recurrent or primary metastatic gastric cancer, but intrinsic and acquired trastuzumab resistance inevitably develop over time. To overcome gastric cancer resistance to HER2-targeted therapies, we have conjugated trastuzumab with a beta-emitting therapeutic isotope, lutetium-177, to deliver radiation locally to gastric tumors with minimal toxicity. Because trastuzumab-based targeted radioligand therapy (RLT) requires only the extramembrane domain binding of membrane-bound HER2 receptors, HER2-targeting RLT can bypass any resistance mechanisms that occur downstream of HER2 binding. Leveraging our previous discoveries that statins, a class of cholesterol-lowering drugs, can enhance the cell surface-bound HER2 to achieve effective drug delivery in tumors, we proposed that the combination of statins and [Lu]Lu-trastuzumab-based RLT can enhance the therapeutic efficacy of HER2-targeted RLT in drug-resistant gastric cancers. We demonstrate that lovastatin elevates cell surface HER2 levels and increases the tumor-absorbed radiation dose of [Lu]Lu-DOTA-trastuzumab. Furthermore, lovastatin-modulated [Lu]Lu-DOTA-trastuzumab RLT durably inhibits tumor growth and prolongs overall survival in mice bearing NCI-N87 gastric tumors and HER2-positive patient-derived xenografts (PDXs) of known clinical resistance to trastuzumab therapy. Statins also exhibit a radioprotective effect, reducing radiotoxicity in a mice cohort given the combination of statins and [Lu]Lu-DOTA-trastuzumab. Since statins are commonly prescribed to patients, our results strongly support the feasibility of clinical studies that combine lovastatin with HER2-targeted RLT in HER2-postive patients and trastuzumab-resistant HER2-positive patients.
Topics: Humans; Animals; Mice; Stomach Neoplasms; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Pharmaceutical Preparations; Receptor, ErbB-2; Trastuzumab; Lovastatin; Cell Line, Tumor
PubMed: 36972439
DOI: 10.1073/pnas.2220413120 -
Expert Opinion on Biological Therapy Oct 2019: Cancer treatment has evolved significantly with the introduction of biologic agents, especially in the breast cancer (BC) area. The use of trastuzumab for HER2... (Review)
Review
: Cancer treatment has evolved significantly with the introduction of biologic agents, especially in the breast cancer (BC) area. The use of trastuzumab for HER2 amplified BCsignificantly improves survival in both metastatic and early stage disease. Although the efficacy of biologics is undeniable, their high costs increased the expenses of cancer care, becoming a problem to health-care systems, mainly in low and middle-income, but also for high-income countries. In an attempt to lower the costs and allow a greater access of biologics to cancer patients, biosimilars are rapidly being developed as an alternative to the reference biologics. : A literature review based on the MEDLINE/PubMed search about biosimilars allied with the FDA and EMA's latest statements of this topic were conducted to summarize the development and the use of currently available biosimilars for BC, with a focus on trastuzumab. : Biosimilars are drugs that have similar efficacy and safety profile to those of the original biological product with equivalent immunogenicity and, as these agents hold the potential to improve patient´s access to monoclonal antibodies because their production costs are estimated to be 20-30% lower compared to the reference product, they are progressively being incorporated into clinical practice.
Topics: Antineoplastic Agents, Immunological; Biosimilar Pharmaceuticals; Breast Neoplasms; Humans; Randomized Controlled Trials as Topic; Trastuzumab
PubMed: 31248290
DOI: 10.1080/14712598.2019.1638362 -
Molecular Therapy : the Journal of the... Jul 2023Antibody-drug conjugates (ADCs) are a promising class of cancer biopharmaceuticals that exploit the specificity of a monoclonal antibody (mAb) to selectively deliver... (Review)
Review
Antibody-drug conjugates (ADCs) are a promising class of cancer biopharmaceuticals that exploit the specificity of a monoclonal antibody (mAb) to selectively deliver highly cytotoxic small molecules to targeted cancer cells, leading to an enhanced therapeutic index through increased antitumor activity and decreased off-target toxicity. ADCs hold great promise for the treatment of patients with human epidermal growth factor receptor 2 (HER2)-positive breast cancer after the approval and tremendous success of trastuzumab emtansine and trastuzumab deruxtecan, representing a turning point in both HER2-positive breast cancer treatment and ADC technology. Additionally and importantly, a total of 29 ADC candidates are now being investigated in different stages of clinical development for the treatment of HER2-positive breast cancer. The purpose of this review is to provide an insight into the ADC field in cancer treatment and present a comprehensive overview of ADCs approved or under clinical investigation for the treatment of HER2-positive breast cancer.
Topics: Humans; Female; Breast Neoplasms; Trastuzumab; Antineoplastic Agents; Ado-Trastuzumab Emtansine; Receptor, ErbB-2; Antibodies, Monoclonal; Immunoconjugates
PubMed: 36950736
DOI: 10.1016/j.ymthe.2023.03.019 -
Journal of Clinical Pharmacy and... Nov 2022This study aimed to explore the safety profile of trastuzumab deruxtecan (T-DXd, formerly DS-8201a) using multi-source medical data. (Meta-Analysis)
Meta-Analysis
WHAT IS KNOWN AND OBJECTIVE
This study aimed to explore the safety profile of trastuzumab deruxtecan (T-DXd, formerly DS-8201a) using multi-source medical data.
METHODS
We explored trastuzumab deruxtecan related adverse events (AEs) in clinical trials available in ClinicalTrials.gov and electronic databases (MEDLINE, EMBASE and PubMed) up to July 16, 2022. Meta-analysis was performed by using incidence rate with 95%CIs. In the pharmacovigilance study of FDA Adverse Event Reporting System (FAERS), the reporting odds ratio (ROR) and the medicines and healthcare products regulatory agency (MHRA) methods were used to analyse the real-world AEs (up to June 28, 2022).
RESULTS AND DISCUSSION
A 8 clinical trials enrolled 1457 patients were included. The most common AEs of any grade were gastrointestinal disorders and blood and lymphatic system disorders. The most common AE of grade 3 or higher was neutropenia (21.4%, 95%CI: 14.7%-28.1%, I = 91%). The incidence of interstitial lung disease (ILD) and decreased left ventricular ejection fraction were 10.9% (95%CI: 7.2%-14.5%, I = 82%) and 1.2% (95%CI: 0.7%-2.2%, I = 98%), respectively. A total of 1244 AE reports were identified in the pharmacovigilance study. Gastrointestinal toxicity (ROR = 21.65), myelosuppression (ROR = 36.88), interstitial lung disease (ROR = 50.30), pneumonitis (ROR = 36.59), decreased ejection fraction (ROR = 16.08), and taste disorder (ROR = 14.06) mentioned in the instructions showed strong signals. Also, ascites (ROR = 14.90), lung opacity (ROR = 78.80), pulmonary fibrosis (ROR = 5.59), and increased KL-6 (ROR = 1761.97), which were not mentioned in the instructions, showed strong signals.
WHAT IS NEW AND CONCLUSION
Trastuzumab deruxtecan was well tolerated, and more attention should be paid on ILD as well as decreased ejection fraction.
Topics: Humans; Pharmacovigilance; Stroke Volume; Ventricular Function, Left; Trastuzumab; Lung Diseases, Interstitial
PubMed: 36200429
DOI: 10.1111/jcpt.13777 -
Future Medicinal Chemistry Sep 2021Preclinical comparative similarity studies of trastuzumab-dkst, a Herceptin biosimilar, are reported. Primary sequence and higher order structure and pharmacological...
Preclinical comparative similarity studies of trastuzumab-dkst, a Herceptin biosimilar, are reported. Primary sequence and higher order structure and pharmacological mechanisms of action were compared using multiple techniques. Pharmacokinetics and repeat-dose toxicity were assessed in cynomolgus monkeys. Primary structures were identical; secondary and tertiary structures were highly similar. Non-significant differences were observed for charge heterogeneity. Twelve of 13 glycan species were highly similar, with slightly higher total mannose levels in trastuzumab-dkst. FcγR and FcRn binding activity was highly similar. Each drug equally inhibited HER2 cell proliferation, demonstrating equivalent relative potency in mediating HER2 cell cytolysis by antibody-dependent cellular cytotoxicity. Pharmacokinetic and toxicological profiles in cynomolgus monkeys were similar. Trastuzumab-dkst, US-licensed trastuzumab and EU-approved trastuzumab demonstrate high structural and functional similarity.
Topics: Animals; Antineoplastic Agents, Immunological; Apoptosis; Biosimilar Pharmaceuticals; Breast Neoplasms; Cell Line, Tumor; Cell Proliferation; Disulfides; Dose-Response Relationship, Drug; Drug Discovery; Female; Haplorhini; Humans; Polysaccharides; Protein Binding; Protein Conformation; Receptor, ErbB-2; Structure-Activity Relationship; Tandem Mass Spectrometry; Trastuzumab
PubMed: 34289749
DOI: 10.4155/fmc-2021-0113 -
Journal Francais D'ophtalmologie Apr 2021
Topics: Humans; Papilledema; Trastuzumab
PubMed: 33419593
DOI: 10.1016/j.jfo.2020.06.018 -
BMC Cancer Apr 2021Over than one third (28-58%) of pregnancy-associated breast cancer (PABC) cases are characterized by positive epidermal growth factor receptor 2-positive (HER2)...
BACKGROUND
Over than one third (28-58%) of pregnancy-associated breast cancer (PABC) cases are characterized by positive epidermal growth factor receptor 2-positive (HER2) expression. Trastuzumab anti-HER2 monoclonal antibody is still the benchmark treatment of HER2-positive breast tumors. However, FDA has categorized Trastuzumab as a category D drug for pregnant patients with breast cancer. This systemic review aims to synthesize all currently available data of trastuzumab administration during pregnancy and provide an updated view of the effect of trastuzumab on fetal and maternal outcome.
METHODS
Eligible articles were identified by a search of MEDLINE bibliographic database and ClinicalTrials.gov for the period up to 01/09/2020; The algorithm consisted of a predefined combination of the words "breast", "cancer", "trastuzumab" and "pregnancy". This study was performed in accordance with the PRISMA guidelines.
RESULTS
A total of 28 eligible studies were identified (30 patients, 32 fetuses). In more than half of cases, trastuzumab was administered in the metastatic setting. The mean duration of trastuzumab administration during gestation was 15.7 weeks (SD: 10.8; median: 17.5; range: 1-32). Oligohydramnios or anhydramnios was the most common (58.1%) adverse event reported in all cases. There was a statistically significant decrease in oligohydramnios/anhydramnios incidence in patients receiving trastuzumab only during the first trimester (P = 0.026, Fisher's exact test). In 43.3% of cases a completely healthy neonate was born. 41.7% of fetuses exposed to trastuzumab during the second and/or third trimester were born completely healthy versus 75.0% of fetuses exposed exclusively in the first trimester. All mothers were alive at a median follow-up of 47.0 months (ranging between 9 and 100 months). Of note, there were three cases (10%) of cardiotoxicity and decreased ejection fraction during pregnancy.
CONCLUSIONS
Overall, treatment with trastuzumab should be postponed until after delivery, otherwise pregnancy should be closely monitored.
Topics: Adult; Amniotic Fluid; Antineoplastic Agents, Immunological; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Cardiotoxicity; Female; Fetus; Humans; Middle Aged; Oligohydramnios; Pregnancy; Pregnancy Complications, Neoplastic; Pregnancy Trimesters; Receptor, ErbB-2; Time Factors; Trastuzumab; Young Adult
PubMed: 33902516
DOI: 10.1186/s12885-021-08162-3