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ESMO Open Aug 2023Human epidermal growth factor receptor 2 (HER2) is a widely explored therapeutic target in solid tumors. We evaluated the efficacy and safety of trastuzumab-pkrb, a...
BACKGROUND
Human epidermal growth factor receptor 2 (HER2) is a widely explored therapeutic target in solid tumors. We evaluated the efficacy and safety of trastuzumab-pkrb, a biosimilar of trastuzumab, in combination with paclitaxel, in HER2-positive recurrent or metastatic urothelial carcinoma (UC).
PATIENTS AND METHODS
We enrolled 27 patients; they were administered a loading dose of 8 mg/kg trastuzumab-pkrb on day 1, followed by 6 mg/kg and 175 mg/m paclitaxel on day 1 every 3 weeks, intravenously. All patients received six cycles of the combination treatment and continued to receive trastuzumab-pkrb maintenance until disease progression, unacceptable toxicity, or for up to 2 years. HER2 positivity (based on immunohistochemistry analysis) was determined according to the 2013 American Society of Clinical Oncology /College of American Pathologists HER2 testing guidelines. The primary endpoint was objective response rate (ORR); the secondary endpoints were overall survival (OS), progression-free survival (PFS), and safety.
RESULTS
Twenty-six patients were evaluated via primary endpoint analysis. The ORR was 48.1% (1 complete and 12 partial responses) and the duration of response was 6.9 months [95% confidence interval (CI) 4.4-9.3 months]. With a median follow-up of 10.5 months, the median PFS and OS were 8.4 months (95% CI 6.2-8.8 months) and 13.5 months (95% CI 9.8 months-not reached), respectively. The most common treatment-related adverse event (TRAE) of any grade was peripheral neuropathy (88.9%). The most common grade 3/4 TRAEs were neutropenia (25.9%), thrombocytopenia (7.4%), and anemia (7.4%).
CONCLUSIONS
Trastuzumab-pkrb plus paclitaxel demonstrates promising efficacy with manageable toxicity profiles in patients with HER2-positive recurrent or metastatic UC.
Topics: Humans; Trastuzumab; Biosimilar Pharmaceuticals; Carcinoma, Transitional Cell; Paclitaxel; Urinary Bladder Neoplasms
PubMed: 37385153
DOI: 10.1016/j.esmoop.2023.101588 -
Redox Biology Nov 2023Trastuzumab notably improves the outcome of human epidermal growth factor receptor 2 (HER2)-positive breast cancer patients, however, resistance to trastuzumab remains a...
Trastuzumab notably improves the outcome of human epidermal growth factor receptor 2 (HER2)-positive breast cancer patients, however, resistance to trastuzumab remains a major hurdle to clinical treatment. In the present study, we identify a circular RNA intimately linked to trastuzumab resistance. circ-β-TrCP, derived from the back-splicing of β-TrCP exon 7 and 13, confers trastuzumab resistance by regulating NRF2-mediated antioxidant pathway in a KEAP1-independent manner. Concretely, circ-β-TrCP encodes a novel truncated 343-amino acid peptide located in the nucleus, referred as β-TrCP-343aa, which competitively binds to NRF2, blocks SCF-mediated NRF2 proteasomal degradation, and this protective effect of β-TrCP-343aa on NRF2 protein requires GSK3 activity. Subsequently, the elevated NRF2 transcriptionally upregulates a cohort of antioxidant genes, giving rise to trastuzumab resistance. Moreover, the translation ability of circ-β-TrCP is inhibited by eIF3j under both basal and oxidative stress conditions, and eIF3j is transcriptionally repressed by NRF2, thus forming a positive feedback circuit between β-TrCP-343aa and NRF2, expediting trastuzumab resistance. Collectively, our data demonstrate that circ-β-TrCP-encoded β-TrCP protein isoform drives HER2-targeted therapy resistance in a NRF2-dependent manner, which provides potential therapeutic targets for overcoming trastuzumab resistance.
Topics: Humans; Female; Kelch-Like ECH-Associated Protein 1; Antioxidants; beta-Transducin Repeat-Containing Proteins; RNA, Circular; Trastuzumab; Breast Neoplasms; NF-E2-Related Factor 2; Glycogen Synthase Kinase 3; Protein Isoforms; Drug Resistance, Neoplasm; Cell Line, Tumor
PubMed: 37783059
DOI: 10.1016/j.redox.2023.102896 -
Clinics (Sao Paulo, Brazil) 2023Trastuzumab is the preferred drug for the treatment of breast cancer. However, research on the cellular mechanisms of trastuzumab's potential cardiotoxicity is...
OBJECTIVE
Trastuzumab is the preferred drug for the treatment of breast cancer. However, research on the cellular mechanisms of trastuzumab's potential cardiotoxicity is insufficient. The purpose of this study was to explore the toxic effects and potential mechanism of action of trastuzumab on cardiomyocytes.
METHOD
Human Cardiomyocyte (HCM) viability was assessed using the MTT method. HCM apoptosis was detected using the Hoechst33342/PI Fluorescent staining. The LDH and CK activities of the cell were measured using commercially available LDH and CK assay kits. The expression levels of Notch2, JAK2, STAT3, cleaved caspase 3, bax, and bcl 2 in HCMs were detected using western blotting.
RESULTS
The results showed that 250 mg/L trastuzumab induced cardiomyocyte injury and apoptosis, inhibited viability, activated the Notch2 receptor, and inhibited JAK2/STAT3 expression in HCM. Inhibition of Notch2 expression in HCM by targeted siNotch2 transfection reversed the trastuzumab-induced injury and apoptosis, and the expression of JAK2/STAT3 returned to normal levels.
CONCLUSIONS
Trastuzumab induces Notch2 expression by inhibiting the JAK2/STAT3 pathway of HCMs, promotes cell apoptosis, and causes cardiomyocyteinjury. Notch2 may be a potential target of trastuzumab-inducedmyocardial injury. This experiment reveals the mechanism of trastuzumab-induced cardiotoxicity, providing a theoretical basis for the application of trastuzumab.
Topics: Humans; Myocytes, Cardiac; Trastuzumab; Cardiotoxicity; Receptor, Notch2; Apoptosis; Janus Kinase 2; STAT3 Transcription Factor
PubMed: 37567042
DOI: 10.1016/j.clinsp.2023.100268 -
MAbs 2023We designed and developed a novel DNA topoisomerase I inhibitor MF-6, which was a more potent cytotoxin and a more potent inducer of immunogenic cell death compared with...
We designed and developed a novel DNA topoisomerase I inhibitor MF-6, which was a more potent cytotoxin and a more potent inducer of immunogenic cell death compared with DXd. To utilize MF-6's ability to induce antitumor immunity, a human epidermal growth factor receptor 2 (HER2)-targeted antibody-drug conjugate (ADC) trastuzumab-L6 that included a cleavable linker and MF-6 was developed. Different from traditional cytotoxic ADC, the antitumor activity of trastuzumab-L6 was assessed by inducing tumor cell immunogenic cell death, activating dendritic cells and cytotoxic CD8+ T cells to acquire durable adaptive immune memory. Tumor cells treated with trastuzumab-L6 were committed to immunogenic cell death, with upregulation of damage-associated molecular patterns and antigen presentation molecules. In a syngeneic tumor model with a mouse cell line that expressed human HER2, immunocompetent mice showed greater antitumor efficacy compared with nude mice. The trastuzumab-L6-cured immunocompetent mice acquired adaptive antitumor memory and rejected subsequent tumor cell challenge. The trastuzumab-L6 efficacy was abrogated when cytotoxic CD8+ T cells were depleted and enhanced when regulatory CD4+ T cells were depleted. The combination of trastuzumab-L6 with immune checkpoint inhibitors significantly increased antitumor efficacy. Enhanced T cell infiltration, dendritic cell activation, and decreased type M2 macrophages in tumor post trastuzumab-L6 administration confirmed the immune-activating responses. In conclusion, trastuzumab-L6 was considered to be an immunostimulatory agent, rather than a traditional cytotoxic ADC, and its antitumor efficacy was enhanced when combined with an anti-PD-L1 and anti-CTLA-4 antibody, which suggested a potential therapeutic strategy.
Topics: Humans; Animals; Mice; Topoisomerase I Inhibitors; Mice, Nude; Antibodies; Immunoconjugates; Trastuzumab; Dendritic Cells
PubMed: 37314961
DOI: 10.1080/19420862.2023.2220466 -
ESMO Open Aug 2021Two new antibody-drug conjugates (ADCs) containing a topoisomerase I inhibitor payload have recently emerged in the breast cancer (BC) treatment landscape. Sacituzumab... (Review)
Review
BACKGROUND
Two new antibody-drug conjugates (ADCs) containing a topoisomerase I inhibitor payload have recently emerged in the breast cancer (BC) treatment landscape. Sacituzumab govitecan-hziy (SG) is a first-in-class anti-trophoblast cell-surface antigen 2 ADC approved for pretreated metastatic triple-negative breast cancer (mTNBC) and trastuzumab deruxtecan (T-DXd) gained approval for human epidermal growth factor receptor-2 (HER2)-positive advanced BC (aBC). We aim to provide a contemporary review and the current clinical trial landscape of SG and T-DXd in BC.
MATERIALS AND METHODS
We conducted a literature search from Medline database through PubMed, major conference proceedings [abstracts from European Society for Medical Oncology (Breast) Congress, American Society of Clinical Oncology annual meeting, San Antonio Breast Cancer Symposium] and ClinicalTrials.gov with search terms 'sacituzumab govitecan', 'IMMU-132', 'trastuzumab deruxtecan' and 'DS-8201a' up to 21 March 2021.
RESULTS
We assessed 293 records for eligibility, of which 153 were included in this review after screening and exclusion. For SG, efficacy and safety data are available from a phase III trial in pretreated mTNBC and from a phase I/II basket study in mTNBC and hormone receptor-positive/HER2-negative aBC. Thirteen trials with pending primary analysis are ongoing with SG as single agent or in combination, of which 11 are enrolling (2/11 in the early setting). For T-DXd, efficacy/safety data are available as single agent in pretreated HER2-positive (phase Ib and phase II) and in HER2-low aBC (phase Ib), and in combination with nivolumab in HER2-low/positive aBC (phase Ib). Of 23 ongoing trials with T-DXd, 12 are open for enrollment and 3 phase III trials have completed recruitment. The distinct safety profiles of both drugs and their management are discussed.
CONCLUSION
Given their robust single-agent activity, SG and T-DXd are expected to substantially impact treatment standards, both in and far beyond the currently approved indications. Several trials are investigating new treatment settings for both drugs, including a transition to earlier lines and combinations with other anticancer treatments such as immune checkpoint inhibitors.
Topics: Antibodies, Monoclonal, Humanized; Camptothecin; Humans; Immunoconjugates; Trastuzumab; Triple Negative Breast Neoplasms
PubMed: 34225076
DOI: 10.1016/j.esmoop.2021.100204 -
Frontiers in Public Health 2023Breast cancer is a rapidly raising healthcare problem worldwide. DESTINY-Breast04 demonstrated that trastuzumab deruxtecan (T-Dxd) had a survival advantage comparing to...
BACKGROUND AND PURPOSE
Breast cancer is a rapidly raising healthcare problem worldwide. DESTINY-Breast04 demonstrated that trastuzumab deruxtecan (T-Dxd) had a survival advantage comparing to the physician's choice of chemotherapy for patients with HER2-low metastatic breast cancer. But at the same time, this expensive novel treatment also brought an economic burden. This study assessed the cost-effectiveness of T-Dxd based on results of DESTINY-Breast04 from the perspective of Chinese healthcare system.
MATERIALS AND METHODS
A three-state partitioned-survival model [progression-free survival (PFS), progressive disease (PD) and death] based on data from DESTINY-Breast04 and Chinese healthcare system was used to estimate the incremental cost-effectiveness ratio (ICER) of T-Dxd vs. the physician's choice of chemotherapy for HER2-low metastatic breast cancer. Costs, quality-adjusted life-years (QALYs) and the ICER in terms of 2022 US$ per QALY gained were calculated for both hormone receptor-positive cohort and all patients. One-way and probabilistic sensitivity analyses were performed to assess the model robustness.
RESULTS
Compared with the physician's choice of chemotherapy, T-Dxd increased costs by $104,168.30, while gaining 0.31 QALYs, resulting in an ICER of $336,026.77 per QALY in all patients. The costs of T-Dxd and the utility of PFS were the crucial factors in determining the ICER. In the hormone receptor-positive cohort, the ICER was lower than that in all patients, with the ICER of $274,905.72 per QALY. The ICER was much higher than the commonly accepted willingness-to-pay threshold ($357,96.83 per QALY).
CONCLUSION
T-Dxd as second- or subsequent-line treatment is not a cost-effective treatment option for HER2-low metastatic breast cancer from the perspective of the Chinese healthcare system.
Topics: Humans; Female; Breast Neoplasms; Cost-Effectiveness Analysis; Trastuzumab; Immunoconjugates
PubMed: 37457280
DOI: 10.3389/fpubh.2023.1049947 -
Eastern Mediterranean Health Journal =... Oct 2022There have been system inefficiencies in the profiling and management of female breast cancer in Alexandria, Egypt.
BACKGROUND
There have been system inefficiencies in the profiling and management of female breast cancer in Alexandria, Egypt.
AIMS
To identify barriers to full implementation of international guidelines for the management of female breast cancer patients.
METHODS
Female breast cancer data were extracted from records of 3 public oncology services in Alexandria, Egypt, from 2007 to 2016 and analysed.
RESULTS
A total of 5236 of the available 7125 records were usable. Median age of the patients was 54 years, and the median duration of pre-diagnosis complaint was 3.1 months. Some 522 (31.5%) of the patients had a family history of cancer. For tumour stage, 2527 (55.2%) were early, 1717 (37.6%) were locally advanced, and 331 (7.2%) were at stage IV. Estrogen receptor, progesterone receptor, and HER2 were positive in 3869 (85%), 3545 (78%), and 461 (15.3%) patients, respectively. Chemotherapy started after a median 1.03 months. Adjuvant chemotherapy was given to 3667 (91.7 %) patients and neoadjuvant chemotherapy to 333 (8.3%); 3686 (92.1%) received anthracycline-based combination chemotherapy, and 3613 (86%) received hormonal treatment. One hundred and eighty of 317 eligible patients received Trastuzumab. Local and/or distant recurrence was seen in 1109 (21.2%) patients. In nonmetastatic cases, median overall and disease-free survival were 149.1 and 77.1 months, respectively. In metastatic cases, median progression-free survival was 19.6 months.
CONCLUSION
We observed defects in the record system, there was delay in diagnosis and treatment, and nonadherence to targeted therapy in many patients. Strengthening of national and hospital-based registries is needed in Alexandria, Egypt, with a robust patient navigation system and targeted information, education and communication strategies. Continuous outcomes monitoring and adaptation to implementation needs should be sustained.
Topics: Humans; Female; Middle Aged; Breast Neoplasms; Receptor, ErbB-2; Egypt; Antineoplastic Combined Chemotherapy Protocols; Trastuzumab; Treatment Outcome
PubMed: 36382727
DOI: 10.26719/emhj.22.076 -
Vascular Health and Risk Management 2015Breast cancer is the most common cancer in the UK. Advances in the methods of early diagnosis as well as newer and more effective treatments have led to improvements of... (Review)
Review
Breast cancer is the most common cancer in the UK. Advances in the methods of early diagnosis as well as newer and more effective treatments have led to improvements of disease-free and overall survival over the last decade. Almost one-third of breast cancers present with an aggressive form characterized by increased expression of human epidermal growth receptor 2 (HER2) proteins. A targeted treatment using monoclonal antibodies against HER2 expression such as trastuzumab has been shown to improve survival. Unfortunately, there is a degree of cardiotoxicity associated with these agents, as inhibition of HER2 pathways can also impair cardioprotective pathways. In the present review, we discuss the mechanisms by which trastuzumab might affect vascular homeostasis leading to endothelial dysfunction. We also provide suggestions for future research examining the effects of trastuzumab on the vasculature in breast cancer.
Topics: Antineoplastic Agents; Breast Neoplasms; Endothelium, Vascular; Genes, erbB-2; Heart Failure; Homeostasis; Humans; Oxidative Stress; Reactive Oxygen Species; Trastuzumab
PubMed: 25897242
DOI: 10.2147/VHRM.S69641 -
Frontiers in Immunology 2023Pancreatic cancer is associated with poor prognosis, and limited treatment options are available for the majority of patients. Natural killer (NK) cells in combination...
INTRODUCTION
Pancreatic cancer is associated with poor prognosis, and limited treatment options are available for the majority of patients. Natural killer (NK) cells in combination with antibodies inducing antibody-dependent cell-mediated cytotoxicity (ADCC) could be a highly effective new therapeutic option in pancreatic cancer. Accurate predictive preclinical models are needed to develop successful NK cell immunotherapy. Tumor organoids, in vitro 3D organ-like structures that retain important pathophysiological characteristics of the in vivo tumor, may provide such a model. In the current study, we assessed the cytotoxic potential of adoptive NK cells against human pancreatic cancer organoids. We hypothesized that NK cell anti-tumor responses could be enhanced by including ADCC-triggering antibodies.
METHODS
We performed cytotoxicity assays with healthy donor-derived IL-2-activated NK cells and pancreatic cancer organoids from four patients. A 3D cytotoxicity assay using live-cell-imaging was developed and enabled real-time assessment of the response.
RESULTS
We show that NK cells migrate to and target pancreatic cancer organoids, resulting in an increased organoid death, compared to the no NK cell controls (reaching an average fold change from baseline of 2.1±0.8 vs 1.4±0.6). After 24-hours of co-culture, organoid 2D growth increased. Organoids from 2 out of 4 patients were sensitive to NK cells, while organoids from the other two patients were relatively resistant, indicating patient-specific heterogeneity among organoid cultures. The ADCC-inducing antibodies avelumab (anti-PD-L1) and trastuzumab (anti-HER2) increased NK cell-induced organoid cell death (reaching an average fold change from baseline of 3.5±1.0 and 4.5±1.8, respectively). Moreover, combination therapy with avelumab or trastuzumab resulted in complete disintegration of organoids. Finally, inclusion of ADCC-inducing antibodies was able to overcome resistance in NK-organoid combinations with low or no kill.
DISCUSSION
These results support the use of organoids as a relevant and personalized model to study the anti-tumor response of NK cells and the potential of ADCC-inducing antibodies to enhance NK cell effector function.
Topics: Humans; Antibodies, Monoclonal; Antibody-Dependent Cell Cytotoxicity; Trastuzumab; Killer Cells, Natural; Pancreatic Neoplasms
PubMed: 37520563
DOI: 10.3389/fimmu.2023.1133796 -
Targeted Oncology Dec 2019ABP 980 was developed as a biosimilar to trastuzumab, a monoclonal antibody targeting human epidermal growth factor receptor 2 (HER2), that is indicated for the... (Review)
Review
ABP 980 was developed as a biosimilar to trastuzumab, a monoclonal antibody targeting human epidermal growth factor receptor 2 (HER2), that is indicated for the treatment of HER2-positive metastatic breast cancer, early breast cancer (EBC), and metastatic gastric cancer. ABP 980 is approved in the United States, European Union, and Japan for all the indications of trastuzumab, based on the totality of evidence (TOE) gathered by the systematic step-wise accumulation of comparative analytical, preclinical, and clinical (pharmacokinetics [PK], efficacy, safety and immunogenicity) data for ABP 980 and trastuzumab reference product (RP). As a key first step of the ABP 980 biosimilar program, comprehensive analytical characterization of critical quality attributes established that ABP 980 is structurally and functionally similar to trastuzumab RP. Complementing these data, results of non-clinical pharmacology, toxicology, and toxicokinetic studies supported similarity between ABP 980 and trastuzumab RP. A randomized study in healthy subjects demonstrated clinical PK equivalence of ABP 980 relative to trastuzumab RP in these subjects. In the final clinical evaluation step, a randomized comparative study (LILAC) confirmed the lack of clinically meaningful differences between ABP 980 and trastuzumab RP in efficacy, safety, and immunogenicity in women with HER2-positive EBC in the neoadjuvant-adjuvant setting. Neoadjuvant EBC represented a sensitive homogenous population for biosimilar demonstrations, and the primary endpoint of pathologic complete response served as a sensitive surrogate endpoint. An important aspect of the LILAC study design is that it is the only study that evaluated the effect of switching from the trastuzumab RP to a trastuzumab biosimilar during the adjuvant phase. No new or unexpected safety signals emerged in the clinical evaluations, with the safety profile of ABP 980 consistent with that previously described for trastuzumab. Overall, the TOE data generated for ABP 980 support the conclusion that it is highly similar to trastuzumab RP, thus providing the scientific justification for extrapolation to all the approved indications of trastuzumab.
Topics: Adult; Antineoplastic Agents, Immunological; Biosimilar Pharmaceuticals; Breast Neoplasms; Comparative Effectiveness Research; Female; Humans; Randomized Controlled Trials as Topic; Receptor, ErbB-2; Trastuzumab
PubMed: 31620980
DOI: 10.1007/s11523-019-00675-z