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American Journal of Translational... 2021Evidence on the effectiveness of ErbB inhibitor interventions for women with triple-positive breast cancer (TPBC) is scarce. Exposure to hormone receptors was reported... (Review)
Review
BACKGROUND
Evidence on the effectiveness of ErbB inhibitor interventions for women with triple-positive breast cancer (TPBC) is scarce. Exposure to hormone receptors was reported to eclipse targeted intervention effectiveness. Here, we aimed to explore the optimum targeted regimen for TPBC.
METHODS
We conducted a thorough search of the literature focusing on neoadjuvant targeted therapy with both hormone receptor-positive and HER2 (ErbB2)-positive patients and performed a network meta-analysis comparing the regimens using a random-effects model. The rate of pathological complete response (pCR) (ypT0/is) was the primary outcome. The odds ratio (OR) with 95% confidence interval (CI) was used to assess the association among twelve regimens.
RESULTS
Thirteen studies meeting the inclusion criteria were included. Significantly more TPBC patients receiving ado-trastuzumab emtansine plus lapatinib experienced pCR events than other patients. In the high-performance ranking of the twelve regimens, ado-trastuzumab emtansine plus lapatinib (TDM-1+L) ranked top, followed by ado-trastuzumab emtansine (TDM-1), trastuzumab plus carboplatin, taxanes and pertuzumab (TCHP), trastuzumab plus docetaxel and lapatinib (THL), trastuzumab, taxanes and pertuzumab (THP), ado-trastuzumab emtansine plus pertuzumab (TDM1+P), trastuzumab plus taxanes (TH), trastuzumab plus taxanes and neratinib, taxanes plus pertuzumab (HP), taxanes and neratinib (HN), trastuzumab plus lapatinib (TL), trastuzumab plus pertuzumab (TP) in sequence.
CONCLUSION
Double-targeted therapy in chemotherapy-based regimens was associated with better pCR than single-targeted therapy, and TDM-1+L stood out. For either single-targeted or double-targeted therapies, regimens free of chemotherapy were always worse than those with targeted therapy. Our data support guidelines that recommend combinations of chemotherapies plus targeted therapies in the neoadjuvant setting for early TPBC.
PubMed: 34956441
DOI: No ID Found -
Frontiers in Immunology 2023Human epithelial growth factor receptor-2 (HER2) plays an oncogenic role in numerous tumors, including breast, gastric, and various other solid tumors. While anti-HER2...
Human epithelial growth factor receptor-2 (HER2) plays an oncogenic role in numerous tumors, including breast, gastric, and various other solid tumors. While anti-HER2 therapies are approved for the treatment of HER2-positive tumors, a necessity persists for creating novel HER2-targeted agents to resolve therapeutic resistance. Utilizing a synthetic nanobody library and affinity maturation, our study identified four anti-HER2 nanobodies that exhibited high affinity and specificity. These nanobodies recognized three distinct epitopes of HER2-ECD. Additionally, we constructed VHH-Fc and discovered that they facilitated superior internalization and showed moderate growth inhibition. Compared to the combination of trastuzumab and pertuzumab, the VHH-Fc combos or their combination with trastuzumab demonstrated greater or comparable antitumor activity in both ligand-independent and ligand-driven tumors. Most remarkably, A9B5-Fc, which targeted domain I of HER2-ECD, displayed significantly enhanced trastuzumab-synergistic antitumor efficacy compared to pertuzumab under trastuzumab-resistant conditions. Our findings offer anti-HER2 nanobodies with high affinity and non-overlapping epitope recognition. The novel nanobody-based HER2-targeted antibody, A9B5-Fc, binding to HER2-ECD I, mediates promising receptor internalization. It possesses the potential to serve as a potent synergistic partner with trastuzumab, contributing to overcoming acquired resistance.
Topics: Humans; Trastuzumab; Receptor, ErbB-2; Single-Domain Antibodies; Ligands; Neoplasms; Epitopes
PubMed: 37954614
DOI: 10.3389/fimmu.2023.1292839 -
Cancers May 2022Human epidermal growth factor receptor-2 (HER-2) overexpressing breast cancer is a breast cancer subtype characterized by high aggressiveness, high frequency of brain... (Review)
Review
Human epidermal growth factor receptor-2 (HER-2) overexpressing breast cancer is a breast cancer subtype characterized by high aggressiveness, high frequency of brain metastases and poor prognosis. HER-2, a glycoprotein belonging to the ErbB receptor family, is overexpressed on the outer membrane of cancer cells and has been an important therapeutic target for the development of targeted drugs, such as the monoclonal antibodies trastuzumab and pertuzumab. These therapies have been available in clinics for more than twenty years. However, despite the initial enthusiasm, a major issue emerged limiting HER-2 targeted therapy efficacy, i.e., the evolution of drug resistance, which could be tackled by nanotechnology. The aim of this review is to provide a first critical update on the different types of HER-2-targeted nanoparticles that have been proposed in the literature in the last decade for therapeutic purposes. We focus on the different targeting strategies that have been explored, their relative outcomes and current limitations that still need to be improved. Then, we review the nanotools developed as diagnostic kits, focusing on the most recent techniques, which allow accurate quantification of HER-2 levels in tissues, with the aim of promoting more personalized medicinal approaches in patients.
PubMed: 35626028
DOI: 10.3390/cancers14102424 -
Annals of Oncology : Official Journal... Oct 2021
Topics: Antibodies, Monoclonal, Humanized; Breast Neoplasms; Female; Humans; Receptor, ErbB-2; Taxoids; Trastuzumab
PubMed: 34403778
DOI: 10.1016/j.annonc.2021.08.1750 -
Frontiers in Endocrinology 2023Pyrotinib and pertuzumab are effective treatment options for HER2-positive metastatic breast cancer (HER2+ MBC). Our study was to directly compare the efficacy and...
OBJECTIVE
Pyrotinib and pertuzumab are effective treatment options for HER2-positive metastatic breast cancer (HER2+ MBC). Our study was to directly compare the efficacy and safety of pyrotinib plus trastuzumab (PyroH) and pertuzumab plus trastuzumab (HP) in patients with HER2+ MBC.
METHODS
We conducted a retrospective examination of HER2+ MBC patients who received PyroH plus chemotherapy or HP plus chemotherapy between 2017 and 2022 at five institutions in China. Our primary endpoint was progression-free survival (PFS).
RESULTS
This study involved 333 patients, among which 161 received PyroH and 172 received HP. The utilization of PyroH as a first-line therapy for MBC was more prevalent among older patients, those with a shorter duration of disease-free interval, or those who had previously been treated with trastuzumab. Although in the first-line advanced treatment HP cohort showed numerically longer PFS (median PFS: 14.46 vs. 22.90 months, =0.057), in the second-line or later treatments, there was no significant difference in PFS between the PyroH and HP groups (median PFS: 8.67 vs. 7.92 months, =0.286). Despite HP showing a longer PFS in the overall cohort (median PFS: 9.30 vs. 13.01 months, =0.005), it did not serve as an independent predictor of PFS in the multivariate analysis (HR 1.134, 95% CI 0.710-1.811, p=0.598). Without taxane, PyroH demonstrated a longer PFS than HP (median PFS: 10.12 vs. 8.15 months, =0.017). PyroH group displayed a numerically longer median PFS in patients with brain metastases compared to the HP group, though not statistically significant (median PFS: 9.03 vs. 8.15 months, =0.976). PyroH had higher incidence of grade 3/4 diarrhea (34.3% vs. 3.0%) but similar overall adverse events.
CONCLUSION
In conclusion, PyroH is comparable in second-line or later treatment and during brain metastasis, even having superior efficacy without taxane in real-world setting. Toxicities were tolerable in both groups. (ClinicalTrials.gov: NCT05572645).
Topics: Humans; Female; Trastuzumab; Breast Neoplasms; Retrospective Studies; Receptor, ErbB-2; Taxoids
PubMed: 38149099
DOI: 10.3389/fendo.2023.1325540 -
Therapeutic Advances in Medical Oncology 2022Although human epidermal growth factor receptor 2 (HER2)-positive breast cancer was associated with poor prognosis, it has been changed after the development of... (Review)
Review
Although human epidermal growth factor receptor 2 (HER2)-positive breast cancer was associated with poor prognosis, it has been changed after the development of trastuzumab. There has been great progress in perioperative HER2-targeting treatment, and investigations of several novel drugs and their combinations are ongoing. Adjuvant trastuzumab with or without pertuzumab for 1 year in combination with concomitant chemotherapy has become a standard treatment in high-risk node-negative tumors or node-positive HER2-positive early breast cancer patients without residual disease or who have not received neoadjuvant treatment. For low-risk HER2-positive early breast cancer patients, adjuvant paclitaxel and 1-year trastuzumab are possible alternatives. For residual disease after neoadjuvant treatment, adjuvant trastuzumab emtansine (T-DM1) for 14 cycles is a standard treatment. Non-anthracycline chemotherapy with dual anti-HER2 targeting of trastuzumab and pertuzumab represents one of the preferred neoadjuvant regimens to achieve higher pathologic complete response (pCR) rates and better clinical outcomes. Further research is needed to develop and validate potential biomarkers to predict pCR, which could help escalate or de-escalate anti-HER2 therapy. Trials incorporating novel agents such as T-DM1, trastuzumab deruxtecan (T-DXd), and immune checkpoint inhibitors and trying to de-escalate treatments in neoadjuvant setting are ongoing. In the future, tailored treatments such as no adjuvant therapy, various HER2-directed therapies alone with chemotherapy, combinations of various HER2-directed therapies and chemotherapy, addition of immune checkpoint inhibitors, and omission of surgery will be individualized in HER2-positive early breast cancer patients.
PubMed: 35756967
DOI: 10.1177/17588359221106564 -
Journal of Medicine and Life 2019Patients with positive Her-2/neu breast cancer and a high risk of recurrence are known to benefit from the addition of the dual blockade of Her-2/neu with Trastuzumab... (Review)
Review
Patients with positive Her-2/neu breast cancer and a high risk of recurrence are known to benefit from the addition of the dual blockade of Her-2/neu with Trastuzumab and Pertuzumab to the neoadjuvant chemotherapy, a combination which has been demonstrated to give a higher rate of a complete pathologic response in the breast and in the axilla. The purpose of this review is to outline the efficacy of the dual blockade with Trastuzumab and Pertuzumab in the neoadjuvant treatment of high-risk Her-2 positive breast cancer. Electronic databases (Pubmed, Medline, and Cochrane Database of Systematic Reviews) were searched for English- and German-language studies, which were published in the last ten years. The search has been focused on neoadjuvant clinical trials as well as on the data presented in the abstracts published at the San Antonio Breast Cancer Symposium as well as at the annual meeting of the American Society of Clinical Oncology. The results reported in the published clinical trials demonstrated a higher pathologic complete response rate in breast and lymph nodes after using targeted therapy with two anti-Her-2/neu agents - Trastuzumab and Pertuzumab in combination with neoadjuvant chemotherapy for early-stage Her-2/neu positive breast cancers. The pathologic complete response rate is the most important prognostic marker in Her-2/neu positive tumors, a higher pathologic complete response rate being demonstrated to be associated with a better survival outcome in terms of higher overall survival and disease-free survival rates.
Topics: Breast Neoplasms; Disease-Free Survival; Female; Humans; Lymph Nodes; Neoadjuvant Therapy; Neoplasm Staging; Receptor, ErbB-2
PubMed: 32025249
DOI: 10.25122/jml-2019-0115 -
JAMA Cardiology Jul 2023Cancer therapy-related cardiac dysfunction (CTRCD) is a potentially serious cardiotoxicity of treatments for ERBB2-positive breast cancer (formerly HER2). Identifying...
IMPORTANCE
Cancer therapy-related cardiac dysfunction (CTRCD) is a potentially serious cardiotoxicity of treatments for ERBB2-positive breast cancer (formerly HER2). Identifying early biomarkers of cardiotoxicity could facilitate an individualized approach to cardiac surveillance and early pharmacologic intervention. Circulating cell-free DNA (cfDNA) of cardiomyocyte origin is present during acute cardiac injury but has not been established as a biomarker of CTRCD.
OBJECTIVE
To determine whether circulating cardiomyocyte cfDNA is associated with CTRCD in patients with ERBB2-positive breast cancer treated with anthracyclines and ERBB2-targeted therapy.
DESIGN, SETTING, AND PARTICIPANTS
A prospective cohort of 80 patients with ERBB2-positive breast cancer enrolled at an academic cancer center between July 2014 and April 2016 underwent echocardiography and blood collection at baseline, after receiving anthracyclines, and at 3 months and 6 months of ERBB2-targeted therapy. Participants were treated with doxorubicin-based chemotherapy followed by trastuzumab (+/- pertuzumab). The current biomarker study includes participants with sufficient biospecimen available for analysis after anthracycline therapy. Circulating cardiomyocyte-specific cfDNA was quantified by a methylation-specific droplet digital polymerase chain reaction assay. Data for this biomarker study were collected and analyzed from June 2021 through April 2022.
MAIN OUTCOMES AND MEASURES
The outcome of interest was 1-year CTRCD, defined by symptomatic heart failure or an asymptomatic decline in left ventricular ejection fraction (≥10% from baseline to less than lower limit of normal or ≥16%). Values for cardiomyocyte cfDNA and high-sensitivity cardiac troponin I (hs-cTnI) measured after patients completed treatment with anthracyclines were compared between patients who later developed CTRCD vs patients who did not using the Wilcoxon rank sum test, and the association of post-anthracycline cardiomyocyte cfDNA level with CTRCD was estimated using logistic regression.
RESULTS
Of 71 patients included in this study, median (IQR) age was 50 (44-58) years, all were treated with dose-dense doxorubicin, and 48 patients underwent breast radiotherapy. Ten of 71 patients (14%) in this analysis developed CTRCD. The level of cardiomyocyte cfDNA at the post-anthracycline time point was higher in patients who subsequently developed CTRCD (median, 30.5 copies/mL; IQR, 24-46) than those who did not (median, 7 copies/mL; IQR, 2-22; P = .004). Higher cardiomyocyte cfDNA level after completion of anthracycline chemotherapy was associated with risk of CTRCD (hazard ratio, 1.02 per 1-copy/mL increase; 95% CI, 1.00-1.03; P = .046).
CONCLUSIONS AND RELEVANCE
This study found that higher cardiomyocyte cfDNA level after completion of anthracycline chemotherapy was associated with risk of CTRCD. Cardiomyocyte cfDNA quantification shows promise as a predictive biomarker to refine risk stratification for CTRCD among patients with breast cancer receiving cardiotoxic cancer therapy, and its use warrants further validation.
TRIAL REGISTRATION
ClinicalTrials.gov Identifier: NCT02177175.
Topics: Female; Humans; Middle Aged; Anthracyclines; Breast Neoplasms; Cardiotoxicity; Doxorubicin; Heart Diseases; Myocytes, Cardiac; Prospective Studies; Receptor, ErbB-2; Stroke Volume; Ventricular Function, Left; Adult
PubMed: 37256614
DOI: 10.1001/jamacardio.2023.1229 -
Breast Care (Basel, Switzerland) Feb 2023Approximately 20% of all breast cancer cases show overexpression or amplification of the human epidermal growth factor receptor 2 (Her2) [Cancer Epidemiol Biomarkers... (Review)
Review
BACKGROUND
Approximately 20% of all breast cancer cases show overexpression or amplification of the human epidermal growth factor receptor 2 (Her2) [Cancer Epidemiol Biomarkers Prev. 2017;26(4):632-41]. With the introduction of trastuzumab, lapatinib, and pertuzumab to the realm of treatment, a new era of antibody-drug conjugates had only begun. Within the last two decades, survival for patients with this tumor subtype has fundamentally improved.
SUMMARY
Beginning with a taxane plus trastuzumab/pertuzumab followed by trastuzumab deruxtecan, the first- and second-line treatments are set in stone. With the introduction of tucatinib as a newer tyrosine kinase inhibitor in combination with capecitabine and trastuzumab, there is one efficient line of treatment available after trastuzumab deruxtecan or even earlier in selected cases with active brain metastasis. Especially for later stages of disease, several combination strategies are under investigation. There is still a lack of positive results on immune checkpoint inhibition combined with Her2-targeted therapy, but hopefully an extension to the treatment algorithm will be on its way soon.
KEY MESSAGES
With the HER2CLIMB trial, patients with brain metastasis were no longer excluded from bigger trials, and international guidelines implemented its presence or absence in their decision trees [N Engl J Med. 2020;382(7):597-609]. Curing Her2-positive metastatic breast cancer, or at least living a long life with this disease, is increasingly becoming a reality.
PubMed: 36876168
DOI: 10.1159/000528756 -
RSC Advances Jun 2024Monoclonal antibodies (mAbs) are pivotal therapeutic agents for various diseases, and effective treatment hinges on attaining a specific threshold concentration of mAbs...
Monoclonal antibodies (mAbs) are pivotal therapeutic agents for various diseases, and effective treatment hinges on attaining a specific threshold concentration of mAbs in patients. With the rising adoption of combination therapy involving multiple mAbs, there arises a clinical demand for multiplexing assays capable of measuring the concentrations of these mAbs. However, minimizing the complexity of serum samples while achieving rapid and accurate quantification is difficult. In this work, we introduced a novel method termed nano-surface and molecular orientation limited (nSMOL) proteolysis for the fragment of antigen binding (Fab) region-selective proteolysis of co-administered trastuzumab and pertuzumab based on the pore size difference between the protease nanoparticles (∼200 nm) and the resin-captured antibody (∼100 nm). The hydrolyzed peptide fragments were then quantified using liquid chromatography-tandem mass spectrometry (LC-MS/MS). In this process, the digestion time is shortened, and the produced digestive peptides are greatly reduced, thereby minimizing sample complexity and increasing detection accuracy. Assay linearity was confirmed within the ranges of 0.200-200 μg mL for trastuzumab and 0.300-200 μg mL for pertuzumab. The intra- and inter-day precision was within 9.52% and 8.32%, except for 12.5% and 10.8% for the lower limit of quantitation, and the accuracy (bias%) was within 6.3%. Additionally, other validation parameters were evaluated, and all the results met the acceptance criteria of the guiding principles. Our method demonstrated accuracy and selectivity for the simultaneous determination of trastuzumab and pertuzumab in clinical samples, addressing the limitation of ligand binding assays incapable of simultaneously quantifying mAbs targeting the same receptor. This proposed assay provides a promising technical approach for realizing clinical individualized precise treatment, especially for co-administered mAbs.
PubMed: 38895524
DOI: 10.1039/d4ra03060e