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Asian Pacific Journal of Cancer... May 2024The long-term use of trastuzumab (TRZ), a therapeutic agent for human epidermal growth factor receptor 2 (HER2)+ breast cancer subtype (HER2+ BC), induces resistance....
Characterization of Potential Target Genes of Borneol in Increasing Trastuzumab Sensitivity in HER2+ Trastuzumab-Resistant Breast Cancer: Bioinformatics and In Vitro Studies.
OBJECTIVE
The long-term use of trastuzumab (TRZ), a therapeutic agent for human epidermal growth factor receptor 2 (HER2)+ breast cancer subtype (HER2+ BC), induces resistance. Borneol (BOR) exerts anticancer effects on various types of cancer. However, its anticancer effect on HER2+ BC remains unknown. This study aimed to determine the potential target genes of BOR and its effect on overcoming the resistance of HER2+ BC to TRZ.
METHODS
The hub gene of BOR's potential target on HER2+ BC cells was determined via a bioinformatics approach. Resistant HCC1954 cells (HCC1954-TR) were obtained through repeated inducement of HCC1954 cancer cells with TRZ. The cells were then subjected to cytotoxic tests involving single compounds and their combinations. Then, the hub gene expression was determined using quantitative reverse-transcription polymerase chain reaction. The interaction between BOR and selected proteins was measured through molecular docking.
RESULTS
Hub genes IL6, TNF, ESR1, IL1B, CYP19A1, AR, NR3C1, RELA, CYP17A1, and GPT were obtained via a bioinformatics approach. HCC1954-TR cells were successfully established. The TRZ-BOR combination treatment of parental HCC1954 (400 µg/mL and 25 µM) and HCC1954-TR (800 µg/mL and 100 µM) yielded considerably better results compared with BOR or TRZ alone. The expressions of AR, GPT, and ESR1 under the TRZ-BOR combination were notably different compared with those under single exposure. The molecular docking study of CYP19A1, CYP17A1, NR3C1, and IL-1β highlighted the potential interaction between BOR and such proteins.
CONCLUSION
BOR improved the cytotoxic effects of TRZ on HCC1954 and HCC1954-TR cell lines, where it specifically targets AR, ESR1, and GPT genes. In addition, the BOR effect, which counteracted the resistance of HCC1954-TR cells to TRZ, was mediated by genes CYP19A1, CYP17A1, NR3C1, IL-1, and RELA. However, additional research is required to validate their role in BOR activity to circumvent the resistance of HER2+ BC to TRZ.
Topics: Humans; Breast Neoplasms; Trastuzumab; Drug Resistance, Neoplasm; Female; Receptor, ErbB-2; Computational Biology; Camphanes; Molecular Docking Simulation; Gene Expression Regulation, Neoplastic; Cell Proliferation; Antineoplastic Agents, Immunological; Tumor Cells, Cultured; Cell Line, Tumor
PubMed: 38809634
DOI: 10.31557/APJCP.2024.25.5.1623 -
Revista Peruana de Medicina... May 2024Motivation for the study. Treatment options for HER2-positive breast cancer were evaluated, focusing on the efficacy and safety of trastuzumab-emtansine (T-DM1) compared... (Meta-Analysis)
Meta-Analysis Comparative Study
OBJECTIVE.
Motivation for the study. Treatment options for HER2-positive breast cancer were evaluated, focusing on the efficacy and safety of trastuzumab-emtansine (T-DM1) compared to other anti-HER2 therapies. Main findings. Trastuzumab-deruxtecan (T-DXd) and PyroCap emerged as promising alternatives, showing substantial improvements in progression-free survival for locally advanced or metastatic breast cancer. T-DM1 showed superior efficacy to the other treatments. Implications. Our findings could inform healthcare decision-making processes to optimize strategies for HER2-positive breast cancer, and potentially improve health outcomes and quality of life. We aimed to study the efficacy and safety of trastuzumab-emtansine (T-DM1) versus other anti-HER2 therapies in HER2+ breast cancer (BC).
MATERIALS AND METHODS.
We performed a network meta-analysis (NMA) of randomized controlled trials (RCTs). Our study focused on patients undergoing treatment for unresectable locally advanced breast cancer (LABC) or metastatic breast cancer (mBC), which included regimens involving trastuzumab and taxanes. Additionally, we considered cases within the first 6 months of treatment for HER2+ early breast cancer (EBC).
RESULTS.
A total of 23 RCTs and 41 reports were included in our analysis. LABC and mBC showed no statistically significant difference in any of the comparisons of T-DM1 versus the other anti-HER2+ therapies. When assessing progression-free survival (PFS), trastuzumab-deruxtecan (T-DXd) and PyroCap demonstrated greater efficacy compared to other treatments (Hazard Ratio [HR]: 3.57; 95% confidence interval [CI]: 2.75-4.63 and HR: 1.82; 95% CI: 1.35-2.44; respectively), while T-DM1 alone exhibited superior effectiveness compared to LapCap (HR: 0.65; 95% CI: 0.55-0.77), TrasCap (HR: 0.65; 95% CI: 0.46-0.91), LapCapCitu (HR: 0.60; 95% CI: 0.33-1.10), Nera (HR: 0.55; 95% CI: 0.39-0.77), and Cap (HR: 0.37; 95% CI: 0.28-0.49).
CONCLUSIONS.
NMA allows a ranking based on the comparative efficacy and safety among the interventions available. Although superior to other schemes, T-DM1 showed a lower efficacy performance in PFS and overall response rate and a trend towards worse overall survival than T-DXd.
Topics: Humans; Breast Neoplasms; Ado-Trastuzumab Emtansine; Female; Receptor, ErbB-2; Antineoplastic Agents, Immunological; Trastuzumab; Network Meta-Analysis; Randomized Controlled Trials as Topic; Neoplasm Metastasis; Antineoplastic Combined Chemotherapy Protocols; Maytansine
PubMed: 38808848
DOI: 10.17843/rpmesp.2024.411.13351 -
Journal of Comparative Effectiveness... May 2024This systematic literature review aims to summarize the efficacy/effectiveness of treatments, including eribulin (ERI)-based and anti-human epidermal growth factor... (Review)
Review
This systematic literature review aims to summarize the efficacy/effectiveness of treatments, including eribulin (ERI)-based and anti-human epidermal growth factor receptor 2 (HER2) treatments in advanced/metastatic HER2+ breast cancer. Three databases from 2016 to September 2021 were searched for clinical trials and observational studies in patients receiving first-line (1L) standard of care (SOC), second-line (2L) SOC or third-line or subsequent lines (3L+). 2692 citations were screened, and 38 studies were included. Eleven studies were randomized-controlled trials (RCTs; 5 in 1L, 6 in 3L+), 6 were single-arm trials (5 in 1L, 1 in 3L+) and 21 were observational studies (13 in 1L, 6 in 2L, 4 in 3L+ [note that studies with subgroups for 1L, 2L, 3L+ are double-counted]). Longer overall survival (OS) was associated with 1L and 2L treatment, and for 3L+ studies that included ERI, ERI or trastuzumab (Tmab) + ERI led to longer OS than treatments of physician's choice (median OS of 11, 10 and 8.9 months, respectively). Progression-free survival was 9 months in Tmab + pertuzumab (Pmab) + ERI, 4 months in Tmab + ERI and 3.3 months in ERI. Available treatments provide a wide range of efficacy. However, later lines lack standardization and conclusions on comparative effectiveness are limited by differing trial designs. Thus, the chance of prolonged survival with new agents warrants further research.
PubMed: 38808626
DOI: 10.57264/cer-2023-0153 -
Communications Biology May 2024Epitope binning, an approach for grouping antibodies based on epitope similarities, is a critical step in antibody drug discovery. However, conventional methods are...
Epitope binning, an approach for grouping antibodies based on epitope similarities, is a critical step in antibody drug discovery. However, conventional methods are complex, involving individual antibody production. Here, we established Epitope Binning-seq, an epitope binning platform for simultaneously analyzing multiple antibodies. In this system, epitope similarity between the query antibodies (qAbs) displayed on antigen-expressing cells and a fluorescently labeled reference antibody (rAb) targeting a desired epitope is analyzed by flow cytometry. The qAbs with epitope similar to the rAb can be identified by next-generation sequencing analysis of fluorescence-negative cells. Sensitivity and reliability of this system are confirmed using rAbs, pertuzumab and trastuzumab, which target human epidermal growth factor receptor 2. Epitope Binning-seq enables simultaneous epitope evaluation of 14 qAbs at various abundances in libraries, grouping them into respective epitope bins. This versatile platform is applicable to diverse antibodies and antigens, potentially expediting the identification of clinically useful antibodies.
Topics: Humans; Epitopes; Sequence Analysis, DNA; High-Throughput Nucleotide Sequencing; Animals; Receptor, ErbB-2; Flow Cytometry; Trastuzumab; Epitope Mapping; Antibodies; Antibodies, Monoclonal, Humanized
PubMed: 38806676
DOI: 10.1038/s42003-024-06363-7 -
Scientific Reports May 2024The effect of high-dose pyridoxine (PN) on activity of 5-fluorouracil (FUra) and folinic acid (FA)-containing regimens was studied in 50 patients including 14 with...
The effect of high-dose pyridoxine (PN) on activity of 5-fluorouracil (FUra) and folinic acid (FA)-containing regimens was studied in 50 patients including 14 with digestive tract, and 36 with breast carcinomas (BC) in advanced stages with poor prognostic characteristics. Patients with colorectal, and pancreas adenocarcinoma received oxaliplatin, irinotecan, FUra, FA (Folfirinox), and patients with squamous cell carcinoma of the esophagus had paclitaxel, carboplatin, FUra, FA (TCbF). Patients with BC received AVCF (doxorubicin, vinorelbine, cyclophosphamide, FUra, FA) followed by TCbF or TCbF only, and patients who overexpressed HER2 received TCbF plus trastuzumab and pertuzumab. PN (1000-3000 mg/day iv) preceded each administration of FUra and FA. 47 patients (94%) responded, including 16 (32%) with CR. Median tumor reduction was 93%. Median event-free survival (EFS) was 37.7 months. The 25 patients with tumor shrinkage ≥ 91% had EFS of 52% from 42 months onwards. Unexpected toxicity did not occur. PN enhances potency of chemotherapy regimens comprising FUra and FA.
Topics: Humans; Fluorouracil; Leucovorin; Pyridoxine; Female; Middle Aged; Aged; Male; Antineoplastic Combined Chemotherapy Protocols; Adult; Breast Neoplasms; Neoplasm Staging; Treatment Outcome
PubMed: 38802419
DOI: 10.1038/s41598-024-62860-z -
Scientific Reports May 2024Many targeted cancer therapies rely on biomarkers assessed by scoring of immunohistochemically (IHC)-stained tissue, which is subjective, semiquantitative, and does not...
Many targeted cancer therapies rely on biomarkers assessed by scoring of immunohistochemically (IHC)-stained tissue, which is subjective, semiquantitative, and does not account for expression heterogeneity. We describe an image analysis-based method for quantitative continuous scoring (QCS) of digital whole-slide images acquired from baseline human epidermal growth factor receptor 2 (HER2) IHC-stained breast cancer tissue. Candidate signatures for patient stratification using QCS of HER2 expression on subcellular compartments were identified, addressing the spatial distribution of tumor cells and tumor-infiltrating lymphocytes. Using data from trastuzumab deruxtecan-treated patients with HER2-positive and HER2-negative breast cancer from a phase 1 study (NCT02564900; DS8201-A-J101; N = 151), QCS-based patient stratification showed longer progression-free survival (14.8 vs 8.6 months) with higher prevalence of patient selection (76.4 vs 56.9%) and a better cross-validated log-rank p value (0.026 vs 0.26) than manual scoring based on the American Society of Clinical Oncology / College of American Pathologists guidelines. QCS-based features enriched the HER2-negative subgroup by correctly predicting 20 of 26 responders.
Topics: Humans; Female; Receptor, ErbB-2; Breast Neoplasms; Trastuzumab; Patient Selection; Middle Aged; Biomarkers, Tumor; Adult; Immunoconjugates; Antineoplastic Agents, Immunological; Aged; Immunohistochemistry; Camptothecin
PubMed: 38802399
DOI: 10.1038/s41598-024-61957-9 -
Cureus Apr 2024Extramammary Paget's disease is a rare skin cancer that usually arises from the secretory cells of the apocrine glands. In most cases, an extramammary Paget's tumor...
Extramammary Paget's disease is a rare skin cancer that usually arises from the secretory cells of the apocrine glands. In most cases, an extramammary Paget's tumor occurs as a single intraepithelial form not associated with another cancer, although rarely, it may be associated with other loco-regional or distant cancer. It is generally slow-growing and diagnosed in situ. Most often, surgical excision with wide margins is curative, with the local recurrence rate being lower after the Mohs micrographic surgery technique. Nonetheless, relapses are frequent. In the metastatic setting, there are no treatment guidelines or standard therapies; additionally, the experience is limited to a few individual cases, and the efficacy of conventional chemotherapies is not well-defined. Moreover, chemotherapy can also have serious side effects; therefore, there is a need to identify more effective and less toxic therapies. In this case report, we have observed a long-lasting complete response with anti-HER2 plus paclitaxel.
PubMed: 38800219
DOI: 10.7759/cureus.58924 -
Cancer Control : Journal of the Moffitt... 2024CpG ODN is a Toll-like receptor 9 agonist with immunotherapeutic potential for many cancer types, including aggressive breast cancers. There is strong interest in...
OBJECTIVES
CpG ODN is a Toll-like receptor 9 agonist with immunotherapeutic potential for many cancer types, including aggressive breast cancers. There is strong interest in utilizing CpG ODN as an adjuvant to improve clinical efficacy of current treatments and immunogenicity of breast cancers not traditionally responsive to active immunotherapy, such as those that are human epidermal growth factor receptor 2 (HER2)-positive. This study aimed to study the efficacy and safety of combination CpG ODN plus anti-HER2 antibody trastuzumab treatment in patients with advanced/metastatic breast cancer.
METHODS
This single-arm, open-label phase II clinical trial treated patients (n = 6) with advanced/metastatic HER2-positive breast cancer with weekly subcutaneous CpG ODN and trastuzumab. Patients may have received any number of prior therapies to be enrolled (most enrolled at median 1 prior line of chemotherapy). Peripheral blood was collected at baseline and weeks 2, 6, 12, and 18 for immune analyses. Six patients were enrolled and 50% achieved stable disease (SD) response.
RESULTS
Median PFS was 8.3 months. Three of the six patients enrolled opted to stop treatment due to tolerability issues. Multiplex assay for cytokine measurements revealed significantly higher VEGF-D levels at week 2 compared to baseline. Peripheral blood mononuclear cells analyzed by flow cytometry showed a significant increase in monocytic MDSC between weeks 6 and 12. Patients with progressive disease tended to have higher levels of week 6 monocytic MDSC and PD-1+ T cells than patients with SD. NK cell populations did not significantly change throughout treatment.
CONCLUSIONS
CpG ODN and trastuzumab treatment of metastatic HER2 + breast cancer was safe but was not tolerable for all patients. This combination did induce potentially predictive immune profile changes in treated patients with metastatic HER2 + breast cancer, the significance of which needs to be further explored.
Topics: Humans; Female; Breast Neoplasms; Oligodeoxyribonucleotides; Trastuzumab; Receptor, ErbB-2; Middle Aged; Adult; Antineoplastic Combined Chemotherapy Protocols; Aged
PubMed: 38797949
DOI: 10.1177/10732748241250189 -
ESMO Open May 2024DESTINY-Breast03 is a randomized, multicenter, open-label, phase III study of trastuzumab deruxtecan (T-DXd) versus trastuzumab emtansine (T-DM1) in patients with human... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
DESTINY-Breast03 is a randomized, multicenter, open-label, phase III study of trastuzumab deruxtecan (T-DXd) versus trastuzumab emtansine (T-DM1) in patients with human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (mBC) previously treated with trastuzumab and a taxane. A statistically significant improvement in progression-free survival (PFS) versus T-DM1 was reported in the primary analysis. Here, we report exploratory efficacy data in patients with and without brain metastases (BMs) at baseline.
PATIENTS AND METHODS
Patients were randomly assigned 1 : 1 to receive T-DXd 5.4 mg/kg or T-DM1 3.6 mg/kg. Patients with clinically inactive/asymptomatic BMs were eligible. Lesions were measured as per modified RECIST, version 1.1. Outcomes included PFS by blinded independent central review (BICR), objective response rate (ORR), and intracranial ORR as per BICR.
RESULTS
As of 21 May 2021, 43/261 patients randomized to T-DXd and 39/263 patients randomized to T-DM1 had BMs at baseline, as per investigator assessment. Among patients with baseline BMs, 20/43 in the T-DXd arm and 19/39 in the T-DM1 arm had not received prior local BM treatment. For patients with BMs, median PFS was 15.0 months [95% confidence interval (CI) 12.5-22.2 months] for T-DXd versus 3.0 months (95% CI 2.8-5.8 months) for T-DM1; hazard ratio (HR) 0.25 (95% CI 0.13-0.45). For patients without BMs, median PFS was not reached (95% CI 22.4 months-not estimable) for T-DXd versus 7.1 months (95% CI 5.6-9.7 months) for T-DM1; HR 0.30 (95% CI 0.22-0.40). Confirmed systemic ORR was 67.4% for T-DXd versus 20.5% for T-DM1 and 82.1% for T-DXd versus 36.6% for T-DM1 for patients with and without BMs, respectively. Intracranial ORR was 65.7% with T-DXd versus 34.3% with T-DM1.
CONCLUSIONS
Patients with HER2-positive mBC whose disease progressed after trastuzumab and a taxane achieved a substantial benefit from treatment with T-DXd compared with T-DM1, including those with baseline BMs.
Topics: Humans; Female; Breast Neoplasms; Brain Neoplasms; Trastuzumab; Middle Aged; Ado-Trastuzumab Emtansine; Receptor, ErbB-2; Adult; Aged; Camptothecin; Antineoplastic Agents, Immunological; Immunoconjugates; Progression-Free Survival
PubMed: 38796287
DOI: 10.1016/j.esmoop.2024.102924 -
Journal of Personalized Medicine Apr 2024The article discusses the importance of accurately distinguishing HER2-low from HER2-negative breast cancer, as novel ADCs have demonstrated activity in a large... (Review)
Review
The article discusses the importance of accurately distinguishing HER2-low from HER2-negative breast cancer, as novel ADCs have demonstrated activity in a large population of patients with HER2-low-expressing BC. While current guidelines recommend a dichotomous classification of HER2 as either positive or negative, the emergence of the HER2-low concept calls for standardization of HER2 testing in breast cancer, using currently available assays to better discriminate HER2 levels. This review covers the evolution and latest updates of the ASCO/CAP guidelines relevant to this important biomarker in breast cancer, including still-evolving concepts such as HER2 low, HER2 heterogeneity, and HER2 evolution. Our group presents the latest Mexican recommendations for HER2 status evaluation in breast cancer, considering the ASCO/CAP guidelines and introducing the HER2-low concept. In the era of personalized medicine, accurate HER2 status assessment remains one of the most important biomarkers in breast cancer, and the commitment of Mexican pathologists to theragnostic biomarker quality is crucial for providing the most efficient care in oncology.
PubMed: 38793049
DOI: 10.3390/jpm14050467