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Breast Cancer Research : BCR Jun 2024In this study, we prepared a bionic nanosystem of trastuzumab-functionalized SK-BR-3 cell membrane hybrid liposome-coated pyrotinib (Ptb-M-Lip-Her) for the treatment of...
In this study, we prepared a bionic nanosystem of trastuzumab-functionalized SK-BR-3 cell membrane hybrid liposome-coated pyrotinib (Ptb-M-Lip-Her) for the treatment of HER2-positive breast cancer. Transmission electron microscopy, dynamic light scattering, polyacrylamide gel electrophoresis (SDS-PAGE) and western blotting were used to verify the successful preparation of Ptb-M-Lip-Her. In vitro drug release experiments proved that Ptb-M-Lip-Her had a sustained release effect. Cell uptake experiments and in vivo imaging experiments proved that Ptb-M-Lip-Her had good targeting ability to homologous tumor cells (SK-BR-3). The results of cell experiments such as MTT, flow cytometry, immunofluorescence staining and in vivo antitumor experiments showed that Ptb-M-Lip-Her could significantly promote apoptosis and inhibit the proliferation of SK-BR-3 cells. These results clearly indicated that Ptb-M-Lip-Her may be a promising biomimetic nanosystem for targeted therapy of HER2-positive breast cancer.
Topics: Humans; Female; Liposomes; Trastuzumab; Breast Neoplasms; Receptor, ErbB-2; Animals; Cell Line, Tumor; Mice; Apoptosis; Xenograft Model Antitumor Assays; Cell Proliferation; Drug Liberation; Drug Delivery Systems; Molecular Targeted Therapy; Acrylamides; Aminoquinolines
PubMed: 38867302
DOI: 10.1186/s13058-024-01853-2 -
Future Oncology (London, England) Jun 2024To describe patient and treatment characteristics associated with bevacizumab BS-Pfizer, rituximab BS-Pfizer and trastuzumab BS-Pfizer and their reference products in...
To describe patient and treatment characteristics associated with bevacizumab BS-Pfizer, rituximab BS-Pfizer and trastuzumab BS-Pfizer and their reference products in Japan. This retrospective observational study used an administrative claims database to identify patients with ≥1 biosimilar or reference product prescription from 2019 to 2022 for approved indications. Descriptive statistics were calculated. Overall, 14-39% of biosimilar-prescribed patients initiated therapy with reference products. Biosimilar utilization significantly increased from 2019 to 2022. The most-commonly prescribed concomitant class of therapy with biosimilars was antineoplastic therapy. Reference products were most frequently prescribed among the Japanese cohorts, but substantial and increasing proportions received biosimilars over time. Future studies should extend our initial insights to assess biosimilar clinical outcomes in Japanese settings.
PubMed: 38864611
DOI: 10.1080/14796694.2024.2352405 -
BMC Cancer Jun 2024Evaluation of human epidermal growth factor receptor 2 (HER2) overexpression caused by erb-b2 receptor tyrosine kinase 2 (ERBB2) amplification (AMP) by...
BACKGROUND
Evaluation of human epidermal growth factor receptor 2 (HER2) overexpression caused by erb-b2 receptor tyrosine kinase 2 (ERBB2) amplification (AMP) by immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) is essential for treating unresectable metastatic gastric cancer (GC). A targeted tumour sequencing test enables comprehensive assessment of alterations in cancer-related genes, including ERBB2. This study aimed to evaluate the concordance between the targeted tumour sequencing test and IHC/FISH for detecting HER2-positive GC and to clarify the significance of ERBB2 AMP and concomitant genetic alterations in HER2 downstream pathways (DPs) in anti-HER2 therapy for unresectable metastatic GC patients.
METHODS
ERBB2 copy number alteration (CNA) was examined via a targeted tumour sequencing test in 152 formalin-fixed paraffin-embedded (FFPE) GC tissues. ERBB2 CNA was compared to HER2 status evaluated by IHC/FISH in FFPE block sections, which were identical to those subjected to the targeted tumour sequencing test. Treatment outcomes of anti-HER2 therapy in 11 patients with unresectable metastatic GC was evaluated.
RESULTS
ERBB2 AMP (≥ 2.5-fold change) was detected by the targeted tumour sequencing test in 15 patients (9.9%), and HER2 positivity (IHC 3 + or IHC 2+/FISH positive) was detected in 21 patients (13.8%). The overall percent agreement, positive percent agreement, negative percent agreement and Cohen's kappa between ERBB2 CNA and HER2 status were 94.7%, 66.7%, 99.2% and 0.75, respectively. Progression-free survival for trastuzumab therapy in patients with ERBB2 AMP was significantly longer than that in patients with no ERBB2 AMP detected by the targeted tumour sequencing test (median 14 months vs. 4 months, P = 0.007). Treatment response to trastuzumab therapy was reduced in patients with ERBB2 AMP and concomitant CNAs of genes in HER2 DPs. One patient with ERBB2 AMP and concomitant CNAs of genes in HER2 DPs achieved a durable response to trastuzumab deruxtecan as fourth-line therapy.
CONCLUSIONS
A targeted tumour sequencing test is a reliable modality for identifying HER2-positive GC. ERBB2 AMP and concomitant genetic alterations detected through the targeted tumour sequencing test are potential indicators of treatment response to trastuzumab therapy. The targeted tumour sequencing test has emerged as a plausible candidate for companion diagnostics to determine indications for anti-HER2 therapy in the era of precision medicine for GC.
Topics: Humans; Stomach Neoplasms; Receptor, ErbB-2; Female; Male; Gene Amplification; Aged; Middle Aged; In Situ Hybridization, Fluorescence; Adult; Aged, 80 and over; Immunohistochemistry; Trastuzumab; DNA Copy Number Variations; Biomarkers, Tumor
PubMed: 38862927
DOI: 10.1186/s12885-024-12482-5 -
Expert Opinion on Biological Therapy Jun 2024The prognosis of advanced esophageal squamous cell carcinoma (ESCC) is poor. Although cytotoxic drugs have been widely used in advanced ESCC, several antibody agents... (Review)
Review
INTRODUCTION
The prognosis of advanced esophageal squamous cell carcinoma (ESCC) is poor. Although cytotoxic drugs have been widely used in advanced ESCC, several antibody agents have recently been reported to be effective.
AREAS COVERED
Nivolumab and pembrolizumab are anti-PD-1 antibodies that improve immunosuppression by binding to programmed death-1 (PD-1), leading to an antitumor effect. Randomized phase III trials have found these immune checkpoint inhibitors (ICIs) to be effective as second-line treatment. ATTRACTION-3, which compared nivolumab monotherapy with taxane monotherapy in patients with previously treated advanced ESCC, reported prolonged overall survival in the nivolumab group. KEYNOTE-181 found that overall survival was longer in patients with PD-L1-positive ESCC who received second-line treatment with pembrolizumab than in those who received chemotherapy. Sym004 and amivantamab are antibodies that target the epidermal growth factor receptor and have demonstrated efficacy in the treatment of other tumors in recent phase I studies. Furthermore, clinical trials on antibody-drug conjugates such as enfortumab vedotin and DS-7300 for solid tumors are currently ongoing.
EXPERT OPINION
The standard first-line treatments for patients with advanced ESCC contain ICIs. Therefore, drugs with different mechanisms of action that can overcome resistance to ICIs are needed as second-line or later-line treatments to improve clinical outcomes in these patients.
PubMed: 38860728
DOI: 10.1080/14712598.2024.2366493 -
Modern Pathology : An Official Journal... Jun 2024The DESTINY Breast-04 Trial (DB-04) revealed survival advantages of Trastuzumab Deruxtecan for women with metastatic HER2-low breast cancer (1+ or 2+ IHC, without...
The DESTINY Breast-04 Trial (DB-04) revealed survival advantages of Trastuzumab Deruxtecan for women with metastatic HER2-low breast cancer (1+ or 2+ IHC, without amplification). While DB-04 applied the 2018 ASCO CAP HER2 IHC scoring criteria, the subjectivity and imprecision in IHC scoring have raised concerns that patients' treatment may be mis-aligned. Our group of 9 experienced breast pathologists collated a deidentified set of 60 breast cancer core biopsies from 3 laboratories, evaluated with the Ventana 4B5 HER2 assay and mostly scored locally as HER2 0 or 1+. Based on ASCO CAP 2018 criteria and our extensive experience of reporting HER2 IHC, we specified scoring conventions for cancers with low levels of HER2 protein expression, articulating specific scoring pitfalls. Each pathologist then reviewed digitised whole slide images of the IHC slides and scored the HER2 expression for each case. At a subsequent consensus workshop, we reviewed the cases jointly to i) establish consensus scores for each case and ii) determine the percentage of HER2 expressing tumour cells. Consensus was reached on all cases, 40 classified as 1+ and three as 2+ (not amplified), totalling 43 (71.7%) HER2-low cancers. The remaining cases were HER2 0. In 93.3% (56 of 60) cases the consensus score matched with the majority opinion of pathologists' independent scores. 7 of 17 (41.2%) cases reported locally as HER2 0 were classified as HER2-low. Conversely, among 32 cases with local scores of 1+, 7 (21.8%) were reclassified as ultralow or null. Individual pathologists' accuracy in matching the consensus scores ranged from 73.3-91.67% (mean 80.74%). Among HER2-low cancers those in which < 20% of the tumor cells expressed HER2 had the lowest concordance levels. Observers Cohen's Kappa coefficients for concordance was excellent for 4, good in 1 and moderate in the 4 observers. This reference set of cases with expert consensus HER2 scores will be invaluable for peer training and development of our national external quality assurance program for HER2-low cancers. For assessing breast cancers at the low end of HER2 protein expression, our targeted scoring criteria and explicit instruction on pitfalls, improved pathologists' accuracy and concordance.
PubMed: 38852812
DOI: 10.1016/j.modpat.2024.100535 -
Cancer Letters Jun 2024HER2-positive and triple-negative breast cancers (TNBC) are difficult to treat and associated with poor prognosis. Despite showing initial response, HER2-positive breast...
HER2-positive and triple-negative breast cancers (TNBC) are difficult to treat and associated with poor prognosis. Despite showing initial response, HER2-positive breast cancers often acquire resistance to HER2-targeted therapies, and TNBC lack effective therapies. To overcome these clinical challenges, we evaluated the therapeutic utility of co-targeting TrkA and JAK2/STAT3 pathways in these breast cancer subtypes. Here, we report the novel combination of FDA-approved TrkA inhibitors (Entrectinib or Larotrectinib) and JAK2 inhibitors (Pacritinib or Ruxolitinib) synergistically inhibited in vitro growth of HER2-positive breast cancer cells and TNBC cells. The Entrectinib-Pacritinib combination inhibited the breast cancer stem cell subpopulation, reduced expression of stemness genes, SOX2 and MYC, and induced apoptosis. The Entrectinib-Pacritinib combination suppressed orthotopic growth of HER2-positive Trastuzumab-refractory breast cancer xenografts and basal patient-derived xenograft (PDXs), reduced tumoral SOX2 and MYC, and induced apoptosis in both mouse models. The Entrectinib-Pacritinib combination inhibited overall metastatic burden, and brain and bone metastases of intracardially inoculated TNBC cells without toxicity. Together, our results demonstrate for the first time that co-inhibition of TrkA and JAK2 synergistically suppresses breast cancer growth and metastasis, thereby providing preclinical evidence that supports future clinical evaluations.
PubMed: 38852701
DOI: 10.1016/j.canlet.2024.217023 -
International Journal of Surgery Case... Jul 2024Radiation recall dermatitis (RRD) is a localized drug-induced inflammatory skin reaction occurring exclusively in a previously irradiated site months to years after...
INTRODUCTION AND IMPORTANCE
Radiation recall dermatitis (RRD) is a localized drug-induced inflammatory skin reaction occurring exclusively in a previously irradiated site months to years after discontinuation of ionizing radiation. The symptoms of RRD can range from mild redness to extensive dermatitis. Antineoplastic drugs such as doxorubicin, docetaxel, paclitaxel, and gemcitabine are most commonly associated with radiation recall reactions. These reactions can also occur with antibiotics and anti-tubercular drugs.
CASE PRESENTATION
A 38-years-old woman with hormone receptor-negative, HER2-positive inflammatory breast cancer (right), clinical stage cT4dN1Mx, received neoadjuvant chemotherapy with AC > TH protocol at 3 weeks intervals (Anthracycline-Doxorubicin plus Cyclophosphamide X 4 cycles, then docetaxel plus Trastuzumab X 4 cycles) followed by modified radical mastectomy followed by adjuvant locoregional radiotherapy. She received the 5th cycle and 6th cycle trastuzumab monotherapy just before the start of surgery and radiotherapy, respectively. After 1 month of completion of radiotherapy, during her seventh cycle of Trastuzumab monotherapy, she developed mild edema with erythematous change over the previously irradiated area with fever. A skin biopsy was taken to exclude any recurrence; however, no evidence of malignancy was found.
CLINICAL DISCUSSION
We diagnosed it as a case of RRD. We managed her conservatively. Later, she was rechallenged with the same dose in subsequent cycles with systemic steroid coverage, which she tolerated very well, except for the reappearance of mild erythema following each cycle of maintenance dose of Trastuzumab.
CONCLUSION
Radiation recall dermatitis is an extremely rare phenomenon; hence, an acquaintance of clinicians with this rare entity is essential for timely diagnosis and appropriate management.
PubMed: 38852571
DOI: 10.1016/j.ijscr.2024.109864 -
BMC Cancer Jun 2024Novel antibody-drug conjugates (ADCs) drugs present a promising anti-cancer treatment, although survival benefits for HER2-positive advanced breast cancer (BC) remain... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Novel antibody-drug conjugates (ADCs) drugs present a promising anti-cancer treatment, although survival benefits for HER2-positive advanced breast cancer (BC) remain controversial. The aim of this meta-analysis was to evaluate the comparative effect of ADCs and other anti-HER2 therapy on progression-free survival (PFS) and overall survival (OS) for treatment of HER2-positive locally advanced or metastatic BC.
METHODS
Relevant randomized controlled trials (RCTs) were retrieved from five databases. The risk of bias was assessed with the Cochrane Collaboration's tool for RCTs by RevMan5.4 software. The hazard ratio (HR) and 95% confidence intervals (CIs) were extracted to evaluate the benefit of ADCs on PFS and OS in HER2-positive advanced BC by meta-analysis.
RESULTS
Meta-analysis of six RCTs with 3870 patients revealed that ADCs significantly improved PFS (HR: 0.63, 95% CI: 0.49-0.80, P = 0.0002) and OS (HR: 0.79, 95% CI: 0.72-0.86, P < 0.0001) of patients with HER2-positive locally advanced or metastatic BC. Subgroup analysis showed that PFS and OS were obviously prolonged for patients who previously received HER2-targeted therapy. Sensitivity analysis and publication bias suggested that the results were stable and reliable.
CONCLUSION
Statistically significant benefits for PFS and OS were observed with ADCs in HER2-positive locally advanced or metastatic BC, especially for those who received prior anti-HER2 treatment.
Topics: Humans; Breast Neoplasms; Receptor, ErbB-2; Female; Immunoconjugates; Randomized Controlled Trials as Topic; Progression-Free Survival; Treatment Outcome; Trastuzumab; Antineoplastic Agents, Immunological
PubMed: 38851684
DOI: 10.1186/s12885-024-12478-1 -
European Journal of Pharmacology Jun 2024Receptor tyrosine kinases (RTKs) are cell surface receptors with kinase activity that play a crucial role in diverse cellular processes. Among the RTK family members,... (Review)
Review
Receptor tyrosine kinases (RTKs) are cell surface receptors with kinase activity that play a crucial role in diverse cellular processes. Among the RTK family members, Human epidermal growth factor receptor 2 (HER2) and HER3 are particularly relevant to breast cancer. The review delves into the complexities of receptor tyrosine kinase interactions, resistance mechanisms, and the potential of anti-HER3 drugs, offering valuable insights into the clinical implications and future directions in this field of study. It assesses the potential of anti-HER3 drugs, such as pertuzumab, in overcoming resistance observed in HER2-positive breast cancer therapies. The review also explores the resistance mechanisms associated with various drugs, including trastuzumab, lapatinib, and PI3K inhibitors, providing insights into the intricate molecular processes underlying resistance development. The review concludes by emphasizing the necessity for further clinical trials to assess the efficacy of HER3 inhibitors and the potential of developing safe and effective anti-HER3 treatments to improve treatment outcomes for patients with HER2-positive breast cancer.
PubMed: 38851563
DOI: 10.1016/j.ejphar.2024.176725 -
Bioorganic Chemistry Aug 2024The notable characteristics of recently emerged Antibody-Drug Conjugates (ADCs) encompass the targeting of Human Epidermal growth factor Receptor 2 (HER2) through...
The notable characteristics of recently emerged Antibody-Drug Conjugates (ADCs) encompass the targeting of Human Epidermal growth factor Receptor 2 (HER2) through monoclonal antibodies (mAbs) and a high ratio of drug to antibody (DAR). The achievements of Kadcyla® (T-DM1) and Enhertu® (T-Dxd) have demonstrated that HER2-targeting antibodies, such as trastuzumab, have shown to be competitive in terms of efficacy and price for development. Furthermore, with the arrival of T-Dxd and Trodelvy®, high-DAR (7-8) ADCs, which differ from the moderate DAR (3-4) ADCs that were formerly regarded as conventional, are being acknowledged for their worth. Following this trend of drug development, we endeavored to develop a high-DAR ADC using a straightforward approach involving the utilization of DM1, a highly potent substance, in combination with the widely recognized trastuzumab. To achieve a high DAR, DM1 was conjugated to reduced cysteine through the simple design and synthesis of various dimaleimide linkers with differing lengths. Using LC and MS analysis, we have demonstrated that our synthesis methodology is uncomplicated and efficacious, yielding trastuzumab-based ADCs that exhibit a remarkable degree of uniformity. These ADCs have been experimentally substantiated to exert an inhibitory effect on cancer cells in vitro, thus affirming their value as noteworthy additions to the realm of ADCs.
Topics: Humans; Immunoconjugates; Receptor, ErbB-2; Ado-Trastuzumab Emtansine; Trastuzumab; Molecular Structure; Cell Proliferation; Drug Screening Assays, Antitumor; Maleimides; Dose-Response Relationship, Drug; Antineoplastic Agents; Structure-Activity Relationship; Maytansine; Cell Line, Tumor; Antineoplastic Agents, Immunological
PubMed: 38850783
DOI: 10.1016/j.bioorg.2024.107504