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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 -
BMC Cancer Sep 2023Trastuzumab is the only approved target agent for the first-line treatment of human epidermal growth factor receptor-2 (HER-2) positive gastric cancer; however,...
BACKGROUND
Trastuzumab is the only approved target agent for the first-line treatment of human epidermal growth factor receptor-2 (HER-2) positive gastric cancer; however, trastuzumab resistance is a major problem in clinical practice. To comprehend the mechanism of trastuzumab resistance, we focused on the Wnt/β-catenin signaling pathway and its influence on the phenotypes and behavior of trastuzumab-resistant gastric cancer cells.
METHODS
Trastuzumab-resistant NCI-N87R cells were established in vitro from the human gastric cancer cell line NCI-N87 by dose-escalating repeated trastuzumab treatment. We investigated the phenotypes of NCI-N87R cells, including Wnt signaling pathway activity. Gastric cancer organoid cells were incubated with complete medium and Wnt3a-depletion medium, and their resistance to trastuzumab was compared.
RESULTS
NCI-N87R exhibited stemness and epithelial-mesenchymal transition (EMT)-like phenotypes, along with decreased levels of the epithelial marker E-cadherin and increased levels of the mesenchymal markers Vimentin and Snail along with an increased Wnt signaling pathway activity. When gastric cancer cells were incubated in Wnt3a-conditioned medium. Wnt signaling pathway activity and resistance to trastuzumab increased. Gastric cancer patient-derived organoids incubated in Wnt3a-depletion medium were more susceptible to dose-dependent inhibition of cell viability by trastuzumab than those incubated in complete medium.
CONCLUSIONS
Trastuzumab-resistant gastric cancer cells exhibited EMT-like phenotype, and trastuzumab resistance was promoted by the Wnt/β-catenin signaling pathway. The Wnt/β-catenin pathway is a key signaling pathway for trastuzumab resistance in gastric cancer cells.
Topics: Humans; beta Catenin; Cell Line, Tumor; Cell Movement; Epithelial-Mesenchymal Transition; Stomach Neoplasms; Trastuzumab; Wnt Signaling Pathway; Drug Resistance, Neoplasm
PubMed: 37773114
DOI: 10.1186/s12885-023-11447-4 -
The Oncologist Oct 2023Antibody-drug conjugates (ADCs) have been the preferred regimens for human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC) after...
BACKGROUND
Antibody-drug conjugates (ADCs) have been the preferred regimens for human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC) after trastuzumab. Unfortunately, there is little data showing which ADCs should be chosen for those patients whose treatment with tyrosine kinase inhibitors (TKIs) failed. This study aims to analyze the efficacy and safety between novel anti-HER2 ADCs and trastuzumab emtansine (T-DM1) for those with TKIs failure.
MATERIALS AND METHODS
HER2-positive MBC using ADCs from January 2013 to June 2022 were included, and all of them were treated with TKIs. The primary study endpoint was progression-free survival (PFS), and the secondary study endpoints were objective response rate (ORR), clinical benefit rate (CBR), and safety.
RESULTS
A total of 144 patients with 73 patients in the novel anti-HER2 ADCs group and 71 patients in the T-DM1 group. In these novel ADCs, 30 patients received trastuzumab deruxtecan (T-Dxd), 43 patients receive other novel ADCs. The median PFS in the novel ADCs group and T-DM1 group were 7.0 months versus 4.0 months, respectively, and ORR was 54.8% versus 22.5%, CBR was 65.8% versus 47.9%, respectively. In subgroups analysis, the PFS were both significantly improved in patients receiving T-Dxd and other novel ADCs compared with T-DM1. The most common grades 3-4 adverse events in the novel anti-HER-2 ADCs group were neutropenia (20.5%) and thrombocytopenia (28.1%) in the T-DM1 group.
CONCLUSIONS
In patients with HER2-positive MBC previously treated with TKIs, both T-Dxd and other novel anti-HER2 ADCs yielded statistically significant better PFS than T-DM1 did, with tolerable toxicities.
Topics: Female; Humans; Ado-Trastuzumab Emtansine; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Immunoconjugates; Receptor, ErbB-2; Trastuzumab; Tyrosine Kinase Inhibitors
PubMed: 37218076
DOI: 10.1093/oncolo/oyad127 -
International Journal of Molecular... Nov 2023Human epidermal growth factor receptor 2 (HER2), coded by the proto-oncogene , is known to be mutated or amplified in various malignant diseases, and many HER2-targeted... (Review)
Review
Human epidermal growth factor receptor 2 (HER2), coded by the proto-oncogene , is known to be mutated or amplified in various malignant diseases, and many HER2-targeted therapies (including monoclonal antibodies and low-molecular-weight tyrosine kinase inhibitors) have been investigated. HER2 overexpression is observed in ~30% of patients with osteosarcoma, and HER2-targeted therapy for osteosarcoma has also been investigated, along with the prognostic and/or predictive value of HER2. An effective HER2-targeted therapy for osteosarcoma has not been established, however. An antibody-drug conjugate (ADC), i.e., trastuzumab deruxtecan (T-DXd), has been approved for the treatment of HER2-positive malignant diseases such as breast cancer and gastric cancer. T-DXd showed promising efficacy in a tumor-agnostic clinical trial, but even T-DXd did not demonstrate sufficient efficacy against HER2-positive osteosarcoma. In this review, the underlying reasons/mechanisms for the failure of HER2-targeted treatments for osteosarcoma (including T-DXd) are discussed, and the potential and future direction of HER2-targeted therapy is described.
Topics: Humans; Antibodies, Monoclonal, Humanized; Bone Neoplasms; Breast Neoplasms; Camptothecin; Immunoconjugates; Osteosarcoma; Receptor, ErbB-2; Trastuzumab
PubMed: 38069146
DOI: 10.3390/ijms242316823 -
Drug Resistance Updates : Reviews and... Mar 2024Trastuzumab resistance in HER2+ breast cancer (BC) is the major reason leading to poor prognosis of BC patients. Oncogenic gene overexpression or aberrant activation of...
Trastuzumab resistance in HER2+ breast cancer (BC) is the major reason leading to poor prognosis of BC patients. Oncogenic gene overexpression or aberrant activation of tyrosine kinase SRC is identified to be the key modulator of trastuzumab response. However, the detailed regulatory mechanisms underlying SRC activation-associated trastuzumab resistance remain poorly understood. In the present study, we discover that SRC-mediated YAP1 tyrosine phosphorylation facilitates its interaction with transcription factor AP-2 alpha (activating enhancer binding protein 2 alpha, TFAP2A), which in turn promotes YAP1/TEAD-TFAP2A (YTT) complex-associated transcriptional outputs, thereby conferring trastuzumab resistance in HER2+ BC. Inhibition of SRC kinase activity or disruption of YTT complex sensitizes cells to trastuzumab treatment in vitro and in vivo. Additionally, we also identify YTT complex co-occupies the regulatory regions of a series of genes related to trastuzumab resistance and directly regulates their transcriptions, including EGFR, HER2, H19 and CTGF. Moreover, YTT-mediated transcriptional regulation is coordinated by SRC kinase activity. Taken together, our study reveals that SRC-mediated YTT complex formation and transcriptions are responsible for multiple mechanisms associated with trastuzumab resistance. Therefore, targeting HER2 signaling in combination with the inhibition of YTT-associated transcriptional outputs could serve as the treatment strategy to overcome trastuzumab resistance caused by SRC activation.
Topics: Humans; Female; Trastuzumab; Breast Neoplasms; Phosphorylation; Transcription Factor AP-2; Receptor, ErbB-2; Drug Resistance, Neoplasm; Cell Line, Tumor; src-Family Kinases; Transcription Factors; Tyrosine
PubMed: 38219531
DOI: 10.1016/j.drup.2024.101051 -
Cancer Journal (Sudbury, Mass.)Antibody-drug conjugates (ADCs) are composed of monoclonal antibodies linked to a cytotoxic payload, enabling targeted delivery of more potent chemotherapy. In the past... (Review)
Review
Antibody-drug conjugates (ADCs) are composed of monoclonal antibodies linked to a cytotoxic payload, enabling targeted delivery of more potent chemotherapy. In the past decade, there has been rapid development of ADCs aimed at different types of breast cancer. The success of the monoclonal antibody trastuzumab has led to the evolution of several ADCs targeting HER2-positive breast cancer. Trastuzumab-emtansine, the first approved ADC targeting HER2-positive breast cancer, has become standard of care for patients with high-risk early-stage HER2-positive breast cancer who have residual disease after neoadjuvant chemotherapy. More recently, the observation of the bystander effect, in which ADCs target both antigen-positive cells and adjacent antigen-negative cells, has led to the reclassification of "HER2-low" breast cancer and the development of trastuzumab-deruxtecan to target this population. This article reviews the history of HER2-directed ADCs in breast cancer as well as ongoing ADCs in development.
Topics: Humans; Female; Breast Neoplasms; Receptor, ErbB-2; Trastuzumab; Immunoconjugates; Ado-Trastuzumab Emtansine; Antibodies, Monoclonal
PubMed: 36383904
DOI: 10.1097/PPO.0000000000000634 -
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 -
Journal of Experimental & Clinical... Mar 2021Although the anti-HER2 antibody trastuzumab augments patient survival in HER2+ breast cancer, a relevant number of patients progress to this treatment. In this context,...
BACKGROUND
Although the anti-HER2 antibody trastuzumab augments patient survival in HER2+ breast cancer, a relevant number of patients progress to this treatment. In this context, novel drug combinations are needed to increase its antitumor activity. In this work, we have evaluated the efficacy of proteolysis targeting chimera (PROTAC) compounds based on BET inhibitors (BETi) to augment the activity of trastuzumab in HER2+ breast cancer models.
METHODS
BT474 and SKBR3 HER2+ breast cancer cell lines were used. The effects of trastuzumab and the BET-PROTAC MZ1 either alone or in combination, were evaluated using MTT proliferation assays, three-dimensional invasion and adhesion cultures, flow cytometry, qPCR and Western blot. In vivo studies were carried out in a xenografted model in mice. Finally, a Clariom_S_Human transcriptomic array was applied to identify deregulated genes after treatments.
RESULTS
MZ1 induced a higher antiproliferative effect compared to the BETi JQ1. The combination of MZ1 and -trastuzumab significantly decreased cell proliferation, the formation of three-dimensional structures and cellular invasion compared to either of the drugs alone. Evaluation of apoptosis resulted in an increase of cell death following treatment with the combination, and biochemical studies displayed modifications of apoptosis and DNA damage components. In vivo administration of agents alone or combined, to tumors orthotopically xenografted in mice, resulted in a decrease of the tumor volume only after MZ1-Trastuzumab combination treatment. Results from a transcriptomic array indicated a series of newly described transcription factors including HOXB7, MEIS2, TCERG1, and DNAJC2, that were associated to poor outcome in HER2+ breast cancer subtype and downregulated by the MZ1-trastuzumab combination.
CONCLUSIONS
We describe an active novel combination that includes the BET-PROTAC MZ1 and trastuzumab, in HER2+ tumors. Further studies should be performed to confirm these findings and pave the way for their future clinical development.
Topics: Animals; Breast Neoplasms; Female; Humans; Mice; Prognosis; Receptor, ErbB-2; Trastuzumab
PubMed: 33741018
DOI: 10.1186/s13046-021-01907-9 -
BMC Immunology Feb 2021Immunogenicity is a major challenge in drug development and patient care. Clinicians and regulators are familiar with immunogenicity concerns of monoclonal antibody...
BACKGROUND
Immunogenicity is a major challenge in drug development and patient care. Clinicians and regulators are familiar with immunogenicity concerns of monoclonal antibody (mAb) therapeutics, growth factors and enzyme replacements. Although most small therapeutic molecules are unlikely to trigger undesirable immunogenic responses against themselves upon their administration, the biological therapeutic agents are likely to induce such kind of immunogenicity. This imparts a problem that has to be considered upon judging their risk-benefit ratio. In this article, we tested the immunogenicity developed in patients' sera due to the use of trastuzumab and that developed in laboratory animals injected with this recombinant humanized IgG1 monoclonal antibody.
METHODS
We studied trastuzumab immunogenicity by: I in vitro detection of anti-trastuzumab antibody (Ab) levels in patient's serum samples withdrawn at different points during trastuzumab treatment course; I.1 using an Affinity Capture Elution (ACE) assay, the assay is both sensitive and highly tolerant to free drug; I.2 using MTT cytotoxicity method against MCF-7 cell line as confirmatory method used in sample showed high level of anti-trastuzumab Ab and to determine neutralizing activity of the anti-trastuzumab Ab. II in vivo immunogenicity testing of trastuzumab in lab animals.
RESULTS
In vitro analysis of patients' sera for antibodies developed against trastuzumab revealed that this monoclonal antibody has low immunogenicity since most samples showed low levels of anti-trastuzumab antibodies that decreased progressively along the treatment course. Only 1% of samples showed high levels of anti-trastuzumab antibodies which might affect treatment course. In vivo immunogenicity testing in mice showed also low immunogenicity of trastuzumab that could support the in vitro clinical assessment applied in our study.
CONCLUSIONS
The study gives an evidence for the low trastuzumab immunogenicity when assessed in Egyptian patients under treatment with this biological therapeutic agent. This supports its prescription and continuous use across the approved indications as biological therapeutic agent.
Topics: Animals; Antibodies; Antineoplastic Agents, Immunological; Cell Survival; Enzyme-Linked Immunosorbent Assay; Humans; Immunoassay; MCF-7 Cells; Mice; Trastuzumab
PubMed: 33607941
DOI: 10.1186/s12865-021-00405-z -
Biochimica Et Biophysica Acta.... Nov 2022Despite the efficacy of trastuzumab in treating HER2-positive breast cancer patients, a significant proportion of patients relapse after treatment. The role of C-X-C...
Despite the efficacy of trastuzumab in treating HER2-positive breast cancer patients, a significant proportion of patients relapse after treatment. The role of C-X-C chemokine receptor type 4 (CXCR4) in trastuzumab resistance was studied only in cell lines and the underlying mechanisms remain largely unclear. This study investigated the role of CXCR4 in trastuzumab resistance in breast cancer patients and explored the possible underlying mechanisms. The study was performed retrospectively on tissue samples from 62 breast cancer patients including 42 who were treated with trastuzumab and chemotherapy and 20 who received chemotherapy alone in adjuvant setting. Expression levels of CXCR4 and its regulators hypoxia-inducible factor 1-alpha (HIF-1α), tristetraprolin (TTP), human antigen R (HuR), itchy E3 ubiquitin protein ligase (ITCH), miR-302a and miR-494 were determined and their associations with tumor recurrence and disease-free survival were analyzed. In trastuzumab-treated patients, high CXCR4 expression was associated with recurrence and was an independent predictor of progression risk after therapy. CXCR4 correlated positively with its transcriptional regulator, HIF-1α, and negatively with its post-translational regulator, ITCH. HIF-1α, HuR and ITCH were significantly associated with clinical outcome. In chemotherapy-treated patients, neither CXCR4 nor any of its regulators were associated with recurrence or predicted disease progression risk after chemotherapy. In conclusion, this study suggests a potential role for CXCR4 in recurrence after trastuzumab-based therapy in human breast cancer that could be mediated, at least in part, by hypoxia and/or decreased ubiquitination. These findings highlight the potential utility of CXCR4 as a promising target for enhancing trastuzumab therapeutic outcome.
Topics: Breast Neoplasms; Female; Humans; Hypoxia-Inducible Factor 1; MicroRNAs; Receptors, CXCR4; Retrospective Studies; Trastuzumab; Tristetraprolin; Ubiquitin-Protein Ligases
PubMed: 35985446
DOI: 10.1016/j.bbadis.2022.166520