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BMC Pharmacology & Toxicology Nov 2023Pertuzumab is widely used for the treatment of HER2 + breast cancer. But its safety in the real world should be continuously monitored. So, we evaluated the safety...
BACKGROUND
Pertuzumab is widely used for the treatment of HER2 + breast cancer. But its safety in the real world should be continuously monitored. So, we evaluated the safety of pertuzumab by pharmacovigilance analyze based on related adverse events (AEs) from the FDA Adverse Event Reporting System (FAERS) and find whether potential or uncertain adverse events were present.
METHODS
In disproportionality analysis, four algorithms were employed to detect the signals of pertuzumab from the FAERS between 2012 and 2022. In addition, we also used MYSQL 8.0, Navicat Premium 15, and Microsoft EXCEL 2019 to analyze the potential and high-ROR (reporting odds ratio) signals of pertuzumab. We also collected the onset times of pertuzumab-associated AEs.
RESULTS
From January 2012 to December 2022, there are 39,190,598 AEs reported from the FAERS database, of which 14,707 AEs listed pertuzumab as the 'primary suspected (PS)' drug. A total of 115 (46 potential) significant disproportionality preferred terms (PTs) conforming to the four algorithms were retained. Finally, we detected that the pertuzumab-induced AEs occurred in 12 organ systems. For pertuzumab, unexpected and significant PTs of AEs were found, including but not limited to below PTs: haematotoxicity, cardiotoxicity, cardiomyopathy, mitral valve incompetence, tachycardia, intestinal perforation, hemorrhoids, erysipelas, dehydration, pneumonitis, skin toxicity, onychomadesis, cyanosis, and circulatory collapse. We found there were 9 strong signals (5 potential safety signals) and 68 medium intensity signals (21 potential safety signals) according to IC (information component). The potential strong signals (IC > 3.0) were myelosuppression, cardiotoxicity, cardiac dysfunction, ejection fraction decreased, interstitial lung disease, and onychomadesis. Excluding unreported or unreasonable onset time reports, a total of 2016 AEs reported onset time and the median onset time was 117 days (4, 96), as median (Q1, Q3). Notably, most of the all AEs (n = 1133, 56%) and cardiac-related events (n = 405, 53%) all occurred within one month after pertuzumab therapy.
CONCLUSION
Analysis of FAERS data identified pertuzumab-associated AEs, and our findings supported continuous clinical monitoring, pharmacovigilance, and further studies of pertuzumab. A significant association was detected between pertuzumab and some potential adverse events which should be regarded with some care. We have to pay attention to the first month after pertuzumab therapy and prepare emergency measures, especially for the elderly and patients with cardiovascular diseases.
Topics: Humans; Aged; Female; Cardiotoxicity; Adverse Drug Reaction Reporting Systems; Antibodies, Monoclonal, Humanized; Pharmacovigilance; Breast Neoplasms
PubMed: 37957717
DOI: 10.1186/s40360-023-00702-w -
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 -
Breast (Edinburgh, Scotland) Dec 2023Inetetamab is a novel recombinant humanized anti-HER2 monoclonal antibody. This study aimed to evaluate the efficacy and safety of inetetamab and predictive factors for...
Exploring the clinical outcomes and safety profile of inetetamab treatment in metastatic breast cancer patients: A multicenter assessment of a Chinese-origin recombinant Anti-HER2 monoclonal antibody.
BACKGROUND
Inetetamab is a novel recombinant humanized anti-HER2 monoclonal antibody. This study aimed to evaluate the efficacy and safety of inetetamab and predictive factors for response in HER2-positive metastatic breast cancer (MBC) patients.
METHODS
A cohort of HER2-positive MBC patients who received inetetamab-based therapy between June 2020 and August 2021 was evaluated. The primary endpoint was progression-free survival (PFS), and the secondary endpoints included objective response rate (ORR) and disease control rate (DCR). Adverse events (AEs) were graded according to the National Cancer Institute Common Toxicity Criteria.
RESULTS
A total of 141 patients were included in the final analysis. The median PFS of the entire cohort was 7.1 months. The median number of treatment lines administered was three. The ORR was 36.9 %, and the DCR was 80.9 %. The most frequently employed treatment strategy was inetetamab + chemotherapy (49/141, 34.8 %), followed by inetetamab + HER2-tyrosine kinase inhibitors (HER2-TKIs) + chemotherapy, inetetamab + pertuzumab + chemotherapy, inetetamab + endocrine treatment and inetetamab + HER2-TKIs. Cox multivariate analysis revealed that PFS was associated with liver metastasis (hazard ratio [HR] 2.112, 95 % confidence interval [CI] 1.334-3.343, p = 0.001), previous HER2-TKI treatment (HR 2.019, 95 % CI 1.133-3.597, p = 0.017) and estrogen receptor positivity (HR 0.587, 95 % CI 0.370-0.934, p = 0.024). The toxicity was tolerable, with neutropenia being the most common treatment-related grade 3/4 AE (14.9 %).
CONCLUSION
Inetetamab demonstrates effectiveness with a manageable safety profile, offering a promising therapeutic option for HER2-positive breast cancer patients who have shown resistance to prior anti-HER2 treatments.
Topics: Female; Humans; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; East Asian People; Receptor, ErbB-2; Trastuzumab; Treatment Outcome; Antibodies, Monoclonal
PubMed: 37944341
DOI: 10.1016/j.breast.2023.103597 -
Breast (Edinburgh, Scotland) Dec 2023The role of regional nodal irradiation (RNI) after preoperative systemic treatment (PST) with targeted therapy for HER2-positive breast cancer remains uncertain. This...
Benefit of postoperative regional nodal irradiation in patients receiving preoperative systemic therapy with docetaxel/carboplatin/trastuzumab/pertuzumab for HER2-positive breast cancer.
AIM
The role of regional nodal irradiation (RNI) after preoperative systemic treatment (PST) with targeted therapy for HER2-positive breast cancer remains uncertain. This study aimed to investigate the impact of RNI on locoregional recurrence (LRR) and disease-free survival (DFS) outcomes after docetaxel/carboplatin/trastuzumab/pertuzumab (TCHP) for PST.
METHODS
We retrospectively analyzed 255 patients who were treated with six cycles of TCHP between 2016 and 2019. The patients were divided into four groups based on clinical nodal involvement: group A, with no nodal disease; group B, with axillary lymph node (AXL) level I; group C, with AXL level I with II/III; and group D, with supraclavicular or internal mammary nodes.
RESULTS
The RNI group had more advanced nodal disease (C/D) than the no RNI group (56.9 % vs. 6.8 %). With a median follow-up of 51.3 months, there were two (0.8 %), three (1.2 %), and 15 (5.9 %) local, regional, and distant metastases, respectively. LRR did not differ significantly according to the RNI (2.6 % vs. 1.0 %, p = 0.651). Group D had the most frequent distant metastases (17.5 %; p = 0.005). The 4-year DFS rate was 92.7 %, and DFS did not improve significantly after RNI (p = 0.074). When stratified by clinical nodal groups and pathological axillary response, RNI had no effect on LRR/DFS outcomes.
CONCLUSION
With a rare incidence of LRR, RNI did not significantly affect LRR or DFS in patients with HER2-positive breast cancer after with PST-TCHP. However, intensive systemic treatment is required for advanced diseases (C/D). Selective de-intensified RNI and intensified systemic treatment should be investigated in future studies.
Topics: Humans; Female; Breast Neoplasms; Carboplatin; Docetaxel; Retrospective Studies; Neoplasm Recurrence, Local; Neoadjuvant Therapy; Trastuzumab
PubMed: 37924622
DOI: 10.1016/j.breast.2023.103594 -
Cancer Medicine Nov 2023About 15%-20% of breast cancer (BC) cases is classified as Human Epidermal growth factor Receptor type 2 (HER2) positive. The Neoadjuvant chemotherapy (NAC) was...
BACKGROUND
About 15%-20% of breast cancer (BC) cases is classified as Human Epidermal growth factor Receptor type 2 (HER2) positive. The Neoadjuvant chemotherapy (NAC) was initially introduced for locally advanced and inflammatory BC patients to allow a less extensive surgical resection, whereas now it represents the current standard for early-stage and operable BC. However, only 20%-40% of patients achieve pathologic complete response (pCR). According to the results of practice-changing clinical trials, the addition of trastuzumab to NAC brings improvements to pCR, and recently, the use of pertuzumab plus trastuzumab has registered further statistically significant and clinically meaningful improvements in terms of pCR. The goal of our work is to propose a machine learning model to predict the pCR to NAC in HER2-positive patients based on a subset of clinical features.
METHOD
First, we evaluated the significant association of clinical features with pCR on the retrospectively collected data referred to 67 patients afferent to Istituto Tumori "Giovanni Paolo II." Then, we performed a feature selection procedure to identify a subset of features to be used for training a machine learning-based classification algorithm. As a result, pCR to NAC was associated with ER status, Pgr status, and HER2 score.
RESULTS
The machine learning model trained on a subgroup of essential features reached an AUC of 73.27% (72.44%-73.66%) and an accuracy of 71.67% (71.64%-73.13%). According to our results, the clinical features alone are not enough to define a support system useful for clinical pathway.
CONCLUSION
Our results seem worthy of further investigation in large validation studies and this work could be the basis of future study that will also involve radiomics analysis of biomedical images.
Topics: Humans; Female; Breast Neoplasms; Prognosis; Neoadjuvant Therapy; Retrospective Studies; Receptor, ErbB-2; Trastuzumab; Machine Learning; Antineoplastic Combined Chemotherapy Protocols
PubMed: 37905688
DOI: 10.1002/cam4.6512 -
Current Oncology (Toronto, Ont.) Oct 2023Anti HER2 therapy and left breast adjuvant radiation therapy (RT) can both result in cardiotoxicity. The aim of this study was to evaluate the influence of radiation...
Correlation of High-Sensitivity Cardiac Troponin I Values and Cardiac Radiation Doses in Patients with Left-Sided Breast Cancer Undergoing Hypofractionated Adjuvant Radiotherapy with Concurrent Anti-HER2 Therapy.
Anti HER2 therapy and left breast adjuvant radiation therapy (RT) can both result in cardiotoxicity. The aim of this study was to evaluate the influence of radiation dose on cardiac structures on the values of the early cardiotoxicity marker high-sensitivity cardiac troponin I (hscTnI) in patients with HER2-positive left breast cancer undergoing adjuvant concomitant antiHER2 therapy and radiotherapy, and to establish a correlation between the hscTnI values and cardiac radiation doses. Sixty-one patients underwent left breast hypofractionated radiotherapy in parallel with anti-HER2 therapy: trastuzumab, combined trastuzumab-pertuzumab or trastuzumab emtansine (T-DM1). The hscTnI values were measured prior to and upon completion of radiotherapy. A significant increase in hscTnI was defined as >30% from baseline, with the second value being 4 ng/L or higher. Dose volume histograms (DVH) were generated for the heart, left ventricle (LV) and left anterior descending artery (LAD). The hscTnI levels were corelated with radiation doses on cardiac structures. An increase in hscTnI values was observed in 17 patients (Group 1). These patients had significantly higher mean radiation doses for the heart ( = 0.02), LV ( = 0.03) and LAD ( = 0.04), and AUC for heart and LV ( = 0.01), than patients without hscTnI increase (Group 2). The patients in Group 1 also had larger volumes of heart and LV receiving 2 Gy ( = 0.01 for both) and 4 Gy ( = 0.02 for both). LAD differences were observed in volumes receiving 2 Gy ( = 0.03), 4 Gy ( = 0.02) and 5 Gy ( = 0.02). The increase in hscTnI observed in patients receiving anti-HER2 therapy after adjuvant RT was positively associated with radiation doses on the heart, LV and LAD.
Topics: Humans; Female; Breast Neoplasms; Unilateral Breast Neoplasms; Radiotherapy, Adjuvant; Troponin I; Cardiotoxicity; Trastuzumab; Radiation Dosage
PubMed: 37887554
DOI: 10.3390/curroncol30100654 -
Current Issues in Molecular Biology Sep 2023The clinically approved human epidermal growth factor receptor 2 (HER2)-targeting monoclonal antibodies (mAbs), trastuzumab, and pertuzumab, target domains IV and II,...
Defucosylated Monoclonal Antibody (HMab-139-mG-f) Exerted Antitumor Activities in Mouse Xenograft Models of Breast Cancers against Human Epidermal Growth Factor Receptor 2.
The clinically approved human epidermal growth factor receptor 2 (HER2)-targeting monoclonal antibodies (mAbs), trastuzumab, and pertuzumab, target domains IV and II, respectively. Trastuzumab is now the standard treatment for HER2-overexpressed breast and gastric cancers, and trastuzumab in combination with pertuzumab showed clinical benefit. However, there still exist patients who do not respond to the therapy. Furthermore, HER2 mutants that cannot be recognized by pertuzumab were found in tumors. Therefore, novel anti-HER2 mAbs and modalities have been desired. In our previous study, we developed a novel anti-HER2 domain I mAb, HMab-139 (mouse IgG, kappa). We herein produced a defucosylated mouse IgG type of mAb against HER2 (HMab-139-mG-f) to enhance antibody-dependent cellular cytotoxicity (ADCC)-mediated antitumor activity. HMab-139-mG-f exhibits a high binding affinity in flow cytometry with the dissociation constant () determined to be 3.9 × 10 M and 7.7 × 10 M against HER2-overexpressed Chinese hamster ovary (CHO)-K1 (CHO/HER2) and HER2-positive BT-474 cells, respectively. Moreover, we showed that HMab-139-mG-f exerted ADCC and complement-dependent cytotoxicity against CHO/HER2 and BT-474 in vitro and exhibited potent antitumor activities in mouse xenograft models. These results indicated that HMab-139-mG-f exerts antitumor effects against HER2-positive human breast cancers and is useful as an antibody treatment for HER2-positive human cancers.
PubMed: 37886932
DOI: 10.3390/cimb45100488 -
Dentistry Journal Sep 2023Salivary duct carcinoma with rhabdoid features (SDC-RF) is a rare form of salivary gland neoplasm that was recently described. We report a case of SDC-RF of the parotid...
Salivary duct carcinoma with rhabdoid features (SDC-RF) is a rare form of salivary gland neoplasm that was recently described. We report a case of SDC-RF of the parotid gland with loss of E-cadherin and decreased β-catenin expression in a 73-year-old male who presented with right facial/neck swelling and intermittent pain. Morphologically, the tumor presented with a discohesive infiltrate of isolated and cords of pleomorphic round cells containing moderate amount of eosinophilic to fine-vacuolated cytoplasm and hyperchromatic nuclei infiltrating through fibroadipose tissue and salivary parenchyma. Immunophenotypically, the tumor was positive for Cytokeratins Oscar and 7, GATA3, GCDFP, HER2, and an androgen receptor but negative for CK20, S100, p40, Melan A, CDX2, TTF1, ER, SATB2, DOG1, synaptophysin, and chromogranin. Due to its diffuse infiltrating pattern, involvement of the parapharyngeal space, supraclavicular fat pad, dermis, and skin without a defined surgical target, the tumor was deemed unresectable. Anti-HER2 therapy (Herceptin and Pertuzumab) was utilized. At the last follow-up, the patient is alive, with complete locoregional control and brain metastases. An electronic search was performed in the following registries for papers published up to June 2023: PubMed, Embase, and Web of Science. For the database searches, the keywords searched were "salivary gland", "salivary duct carcinoma", and "salivary duct carcinoma with rhabdoid features". Our review of the literature identified 30 cases of SDC-RF that reveal there is a predilection for males (83%), parotid gland (72%), and patients older than the 6th decade of life (83%). Immunophenotypically, all SDC-RF cases except one were positive for AR and GCDFP (97%), 81% were positive for HER2, and loss or decreased expression of E-cadherin in 93% of cases. In conclusion, we described a rare case of SDF-RF of the parotid gland with no E-cadherin expression, decreased β-catenin expression, and its immunophenotypic profile.
PubMed: 37886914
DOI: 10.3390/dj11100229 -
JAMA Network Open Oct 2023Targeted therapies directed against ERBB2 are the cornerstone of medical treatment for ERBB2-positive breast cancers but are contraindicated during pregnancy.
IMPORTANCE
Targeted therapies directed against ERBB2 are the cornerstone of medical treatment for ERBB2-positive breast cancers but are contraindicated during pregnancy.
OBJECTIVES
To describe the association of exposure to anti-ERBB2 agents during pregnancy with pregnancy and fetal or newborn outcomes, and to compare the risk and types of adverse outcomes reported more frequently in this context than after exposure to other anticancer agents.
DESIGN, SETTING, AND PARTICIPANTS
For this case-control study, All reports with a pregnancy-related condition and an antineoplastic agent (Anatomical Therapeutic Chemical classification group L01) registered in the World Health Organization international pharmacovigilance database VigiBase up to June 26, 2022, were extracted. All reports with a pregnancy, an antineoplastic treatment during pregnancy, and a cancer were retained. Reports with anticancer agents prescribed for nononcologic purposes were not included.
EXPOSURE
The exposure group was defined as reports that mention anti-ERBB2 agents compared with exposure to other anticancer agents.
MAIN OUTCOME AND MEASURES
The main outcome was the reporting odds ratio (ROR) for maternofetal complications in the group exposed to anti-ERBB2 agents compared with other anticancer agents, as determined using a disproportionality analysis.
RESULTS
A total of 3558 reports (anti-ERBB2 agents, 328; other anticancer agents, 3230) were included in the analysis. In the group exposed to anti-ERBB2 agents, most reports were from the US (159 [48.5%]), the mean (SD) age of participants was 30.8 (10.4) years, and 209 patients (97.7%) were treated for breast cancers. The molecules most frequently involved in cases with anti-ERBB2 agents were trastuzumab (n = 302), pertuzumab (n = 55), trastuzumab-emtansine (n = 20), and lapatinib (n = 18). The outcomes overreported in these cases included oligohydramnios (ROR, 17.68 [95% CI, 12.26-25.52]; P < .001), congenital respiratory tract disorders (ROR, 9.98 [95% CI, 2.88-34.67]; P < .001), and neonatal kidney failure (ROR, 9.15 [95% CI, 4.62-18.12]; P < .001). Sensitivity and multivariable analyses found similar results. Toxic effects were also significantly overreported for trastuzumab-emtansine (cardiovascular malformation: ROR, 4.46 [95% CI, 1.02-19.52]) and lapatinib (intrauterine growth restriction: ROR, 7.68 [95% CI, 3.01-19.59]).
CONCLUSIONS AND RELEVANCE
In this case-control study of 328 individuals exposed to anti-ERBB2 agents during pregnancy, exposure was associated with a severe specific adverse pregnancy and fetal or newborn outcomes compared with exposure to other anticancer treatments.
Topics: Infant, Newborn; Female; Pregnancy; Humans; Adult; Lapatinib; Case-Control Studies; Trastuzumab; Ado-Trastuzumab Emtansine; Breast Neoplasms; Antineoplastic Agents; Receptor, ErbB-2
PubMed: 37883083
DOI: 10.1001/jamanetworkopen.2023.39934 -
Current Treatment Options in Oncology Nov 2023Approximately 15-20% of breast cancers (BC) demonstrate HER2 overexpression/gene amplification. Historically, before the era of HER2-directed therapies, this subtype was... (Review)
Review
Approximately 15-20% of breast cancers (BC) demonstrate HER2 overexpression/gene amplification. Historically, before the era of HER2-directed therapies, this subtype was associated with poor prognosis. Anti-HER2 agents dramatically changed the natural course of disease and significantly prolonged patients' survival. In recent years, a number of new anti-HER2 therapies have been developed, and their approvals offer new therapeutic options for patients with advanced HER2-positive breast cancer. At present, HER2 pathway blocking drugs used in the treatment of metastatic breast cancer worldwide include trastuzumab and pertuzumab in the first-line treatment; trastuzumab deruxtecan and trastuzumab emtansine in the second line; and tucatinib, neratinib, lapatinib, and margetuximab in further lines of treatment of advanced HER2 positive breast cancer. Additionally, there are many clinical trials underway evaluating drugs blocking the HER2 pathway in advanced disease setting. This article presents new treatment options, discussing the most important findings from clinical trials and real-world reports, clinical benefits and risks of treatment, as well as efficacy of re-treatment with trastuzumab in metastatic breast cancer. New data challenge the current standards, and a number of questions arise regarding the optimal sequence of anti-HER2 targeted therapies, the optimal combination, including endocrine agents in luminal HER2 positive tumors and treatment of special patient population such as patients with brain metastases (BM).
Topics: Humans; Female; Breast Neoplasms; Receptor, ErbB-2; Trastuzumab; Ado-Trastuzumab Emtansine; Lapatinib
PubMed: 37878202
DOI: 10.1007/s11864-023-01137-5