scholarly journals Trastuzumab-Modified Gold Nanoparticles Labeled with 211At as a Prospective Tool for Local Treatment of HER2-Positive Breast Cancer

Nanomaterials ◽  
2019 ◽  
Vol 9 (4) ◽  
pp. 632 ◽  
Author(s):  
Łucja Dziawer ◽  
Agnieszka Majkowska-Pilip ◽  
Damian Gaweł ◽  
Marlena Godlewska ◽  
Marek Pruszyński ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Gold Nanoparticles ◽  
Local Treatment ◽  
Growth Factor Receptor ◽  
Dark Field ◽  
Her2 Positive ◽  
Her2 Positive Breast Cancer ◽  
Biological Studies ◽  
Positive Breast Cancer

Highly localized radiotherapy with radionuclides is a commonly used treatment modality for patients with unresectable solid tumors. Herein, we propose a novel α-nanobrachytherapy approach for selective therapy of human epidermal growth factor receptor 2 (HER2)-positive breast cancer. This uses local intratumoral injection of 5-nm-diameter gold nanoparticles (AuNPs) labeled with an α-emitter (211At), modified with polyethylene glycol (PEG) chains and attached to HER2-specific monoclonal antibody (trastuzumab). The size, shape, morphology, and zeta potential of the 5 nm synthesized AuNPs were characterized by TEM (Transmission Electron Microscopy) and DLS (Dynamic Light Scattering) techniques. The gold nanoparticle surface was modified by PEG and subsequently used for antibody immobilization. Utilizing the high affinity of gold for heavy halogens, the bioconjugate was labelled with 211At obtained by α irradiation of the bismuth target. The labeling yield of 211At was greater than 99%. 211At bioconjugates were stable in human serum. Additionally, in vitro biological studies indicated that 211At-AuNP-PEG-trastuzumab exhibited higher affinity and cytotoxicity towards the HER2-overexpressing human ovarian SKOV-3 cell line than unmodified nanoparticles. Confocal and dark field microscopy studies revealed that 211At-AuNP-PEG-trastuzumab was effectively internalized and deposited near the nucleus. These findings show promising potential for the 211At-AuNP-PEG-trastuzumab radiobioconjugate as a perspective therapeutic agent in the treatment of unresectable solid cancers expressing HER2 receptors.

scholarly journals Anthracycline-containing versus carboplatin-containing neoadjuvant chemotherapy in combination with trastuzumab for HER2-positive breast cancer: the neoCARH phase II randomized clinical trial

2021 ◽  
Vol 13 ◽  
pp. 175883592110090
Author(s):  
Hong-Fei Gao ◽  
Zhiyong Wu ◽  
Ying Lin ◽  
Xiang-Yang Song ◽  
Yin Cao ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Neoadjuvant Chemotherapy ◽  
Primary Endpoint ◽  
Growth Factor Receptor ◽  
Group Versus ◽  
Complete Response ◽  
Her2 Positive ◽  
Her2 Positive Breast Cancer ◽  
Epidermal Growth ◽  
Positive Breast Cancer

Background: Although dual blockade HER2-based neoadjuvant chemotherapy is associated with excellent outcomes for human epidermal growth factor receptor 2 (HER2)-positive breast cancer, pertuzumab is not available to all patients due to cost. The optimal neoadjuvant chemotherapy for HER2-positive breast cancer in the presence of a single HER2 blockade is unknown. This study aimed to compare the efficacy and safety of epirubicin/cyclophosphamide followed by docetaxel/trastuzumab (EC-TH) with docetaxel/carboplatin/trastuzumab (TCH) neoadjuvant setting for HER2-positive breast cancer under the single HER2 blockade. Methods: Patients with stage II-IIIC HER2-positive breast cancer were randomly assigned to either eight cycles of EC-TH every 3 weeks during all chemotherapy cycles, or six cycles of TCH every 3 weeks. The primary endpoint was pathological complete response (pCR) (defined as the absence of invasive tumor cells in breast and axilla, ypT0/is ypN0). Results: From May 2017 to November 2019, 140 patients were randomly assigned, and 135 patients were ultimately found evaluable for the primary endpoint. The pCR was recorded in 25 of 67 patients [37.3%; 95% confidence interval (CI), 25.8–50.0] in the EC-TH group and in 38 of 68 patients (55.9%, 95% CI, 43.3–67.9) in the TCH group ( p = 0.032). The most common adverse events (AEs) were neutropenia in 24 of 67 (35.8%) patients in the EC-TH group versus 27 of 68 (39.7%) in the TCH group ( p = 0.642), anemia in 33 of 67 (49.3%) patients in the EC-TH group versus 34 of 68 (50.0%) in the TCH group ( p = 0.931), and thrombocytopenia in five of 67 (7.5%) patients in the EC-TH group versus 17 of 68 (25.0%) in the TCH group ( p = 0.006). Conclusion: For patients receiving the single HER2 blockade trastuzumab for HER2-positive breast cancer, TCH regimen might be a preferred neoadjuvant therapy. Trial registration: This trial was registered with ClinicalTrials.gov identifier: NCT03140553) on 2 May 2017.

scholarly journals Oleanolic Acid’s Semisynthetic Derivatives HIMOXOL and Br-HIMOLID Show Proautophagic Potential and Inhibit Migration of HER2-Positive Breast Cancer Cells In Vitro

2021 ◽  
Vol 22 (20) ◽  
pp. 11273
Author(s):  
Natalia Magdalena Lisiak ◽  
Izabela Lewicka ◽  
Mariusz Kaczmarek ◽  
Jacek Kujawski ◽  
Barbara Bednarczyk-Cwynar ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Biological Activity ◽  
Cancer Cells ◽  
Oleanolic Acid ◽  
Breast Cancer Cells ◽  
Breast Cancer Patients ◽  
Her2 Positive ◽  
Her2 Positive Breast Cancer ◽  
Positive Breast Cancer

Approximately 20–30% of the diagnosed breast cancers overexpress the human epidermal growth factor receptor 2 (HER2). This type of cancer is associated with a more aggressive phenotype; thus, there is a need for the discovery of new compounds that would improve the survival in HER2-positive breast cancer patients. It seems that one of the most promising therapeutic cancer strategies could be based on the biological activity of pentacyclic triterpenes’ derivatives and the best-known representative of this group, oleanolic acid (OA). The biological activity of oleanolic acid and its two semisynthetic derivatives, methyl 3-hydroxyimino-11-oxoolean-12-en-28-oate (HIMOXOL) and 12α-bromo-3-hydroxyimonoolean-28→13-olide (Br-HIMOLID), was assessed in SK-BR-3 breast cancer cells (HER2-positive). Viability tests, cell cycle assessment, evaluation of apoptosis, autophagy, and adhesion/migration processes were performed using MTT, clonogenic, cytofluorometry, Western blot, and qPCR. Both derivatives revealed higher cytotoxicity in studied breast cancer cells than the maternal compound, OA. They also decreased cell viability, induced autophagy, and (when applied in sub-cytotoxic concentrations) decreased the migration of SK-BR-3 cells.This study is the first to report the cytostatic, proautophagic (mTOR/LC3/SQSTM/BECN1 pathway), and anti-migratory (integrin β1/FAK/paxillin pathway) activities of HIMOXOL and Br-HIMOLID in HER2-positive breast cancer cells.

scholarly journals A Novel Small Molecular Antibody, HER2-Nanobody, Inhibits Tumor Proliferation in HER2-Positive Breast Cancer Cells In Vitro and In Vivo

2021 ◽  
Vol 11 ◽  
Author(s):  
Yan Yan ◽  
Xiao Cheng ◽  
Lin Li ◽  
Rumeng Zhang ◽  
Yong Zhu ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Suppressive Effect ◽  
Her2 Positive ◽  
Her2 Positive Breast Cancer ◽  
Large Molecular Weight ◽  
Positive Breast Cancer

Breast cancer is the most common malignant cancer in women worldwide, especially in developing countries. Herceptin is a monoclonal antibody with an antitumor effect in HER2-positive breast cancer. However, the large molecular weight of Herceptin limited its employment. In this study, we constructed and screened HER2-nanobody and verified its tumor-suppressive effect in HER2-positive breast cancer cells. HER2-nanobody was established, filtrated, purified, and was demonstrated to inhibit cell total number, viability, colony formation and mitosis, and promote cell apoptosis in HER2-positive breast cancer cells in vitro. Treated with HER2-nanobody, tumor growth was significantly inhibited by both intratumor injection and tail intravenous injection in vivo. The phosphorylation of ERK and AKT was restrained by HER2-nanobody in HER2-positive breast cancer cells. RAS-RAF-MAPK and PI3K-AKT-mTOR are two important pathways involved in HER2. It was credible for HER2-nanobody to play the tumor suppressive role by inhibiting the phosphorylation of ERK and AKT. Therefore, HER2-nanobody could be employed as a small molecular antibody to suppress HER2-positive breast cancer.

scholarly journals Dual anti-HER2 blockade in late-line treatment of metastatic HER2-positive breast cancer

2021 ◽  
pp. 156-159
Author(s):  
M. A. Frolova ◽  
M. B. Stenina
Keyword(s):  
Breast Cancer ◽  
Treatment Options ◽  
Migration And Invasion ◽  
Line Treatment ◽  
Her2 Positive ◽  
Her2 Positive Breast Cancer ◽  
Wide Range ◽  
Positive Breast Cancer

In recent years, there has been a wide range of treatment options for patients with metastatic HER2-positive breast cancer, resulting in  the  highest life expectancy for  these patients among all subtypes. The  addition of  pertuzumab to trastuzumab and docetaxel has been shown to increase overall survival and is therefore recognized as the standard first-line treatment. The most optimal second-line treatment option is trastuzumab emtansine. In  addition, various combinations of  cytostatics and anti HER2 targeting agents can be used. The choice of treatment options in heavily pretreated patients is of great interest. If they have not previously received pertuzumab, is it worth to use it and which combination is the best? One possible option is the combination of eribulin with the dual anti-HER2 blockade with trastuzumab and pertuzumab. Eribulin is an anti-microtubule agent that irreversibly blocks mitosis. In addition, it has non-mitotic effects – in vivo and in vitro experiments demonstrated its ability to restore normal tumor vascularization, reduce the area of hypoxia and, as a consequence, decrease tumor cells migration and invasion. This article represents a clinical case of the use of eribulin with double anti-HER2 blockade in the 6th line of treatment in a patient with metastatic HER2-positive breast cancer. Long-term control of the disease (within 2 years) with a satisfactory quality of life has been demonstrated. 

scholarly journals A Case of Multiple Liver Metastases after Surgery in Elderly HER2-Positive Breast Cancer in Which Anastrozole + Trastuzumab Was Ineffective but T-DM1 Was Effective

2021 ◽  
pp. 1632-1637
Author(s):  
Tomohiro Shidahara ◽  
Shozo Ohsumi ◽  
Yuichiro Miyoshi ◽  
Mina Takahashi ◽  
Seiki Takashima ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Liver Metastases ◽  
Growth Factor Receptor ◽  
Complete Response ◽  
Lymph Node Biopsy ◽  
Her2 Positive ◽  
Her2 Positive Breast Cancer ◽  
Pathological Result ◽  
Multiple Liver Metastases ◽  
Positive Breast Cancer

Chemotherapy is often difficult to treat human epidermal growth factor receptor 2 (HER2)-positive metastatic recurrent breast cancer in the elderly, and no standard treatment has been established at this point. We experienced a case in which trastuzumab (Tmab) + anastrozole (ANA) was ineffective (progressive disease; PD) in elderly HER2-positive breast cancer with postoperative multiple liver metastases, but T-DM1 was significantly effective (complete response; CR), and treatment could be continued safely. An 82-year-old woman was referred to our department with a right breast mass. A close examination revealed right breast cancer cT1bN0M0 cStage I, and total mastectomy and sentinel lymph node biopsy were performed. The postoperative pathological result was pT1bN0M0 pStage I (luminal HER2 type). The patient was elderly and had no adjuvant treatment after the operation. Approximately 2 years after the operation, multiple liver metastases were observed, and treatment with ANA and Tmab was started. Four months later, MRI showed that the number of multiple liver metastases increased. The patient was diagnosed with PD, and the anti-HER2 drug was changed from trastuzumab to trastuzumab emtansine (T-DM1). The dose was reduced due to vomiting (grade 3). Two months later, MRI showed that the multiple liver metastases shrank and became obscure after 5 months. After that, T-DM1 was continued, and the disease did not worsen. In elderly people with difficulty in administering chemotherapy, T-DM1 may have a safe and sufficient therapeutic effect by adjusting the dose and managing side effects appropriately.

scholarly journals Translational Breast Cancer Research Consortium (TBCRC) 022: A Phase II Trial of Neratinib for Patients With Human Epidermal Growth Factor Receptor 2–Positive Breast Cancer and Brain Metastases

2016 ◽  
Vol 34 (9) ◽  
pp. 945-952 ◽  
Author(s):  
Rachel A. Freedman ◽  
Rebecca S. Gelman ◽  
Jeffrey S. Wefel ◽  
Michelle E. Melisko ◽  
Kenneth R. Hess ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Brain Metastases ◽  
Objective Response ◽  
Growth Factor Receptor ◽  
Whole Brain Radiotherapy ◽  
Her2 Positive ◽  
Her2 Positive Breast Cancer ◽  
Brain Radiotherapy ◽  
Epidermal Growth ◽  
Positive Breast Cancer

Purpose Evidence-based treatments for metastatic, human epidermal growth factor receptor 2 (HER2)–positive breast cancer in the CNS are limited. Neratinib is an irreversible inhibitor of erbB1, HER2, and erbB4, with promising activity in HER2-positive breast cancer; however, its activity in the CNS is unknown. We evaluated the efficacy of treatment with neratinib in patients with HER2-positive breast cancer brain metastases in a multicenter, phase II open-label trial. Patients and Methods Eligible patients were those with HER2-positive brain metastases (≥ 1 cm in longest dimension) who experienced progression in the CNS after one or more line of CNS-directed therapy, such as whole-brain radiotherapy, stereotactic radiosurgery, and/or surgical resection. Patients received neratinib 240 mg orally once per day, and tumors were assessed every two cycles. The primary endpoint was composite CNS objective response rate (ORR), requiring all of the following: ≥50% reduction in volumetric sum of target CNS lesions and no progression of non-target lesions, new lesions, escalating corticosteroids, progressive neurologic signs/symptoms, or non-CNS progression—the threshold for success was five of 40 responders. Results Forty patients were enrolled between February 2012 and June 2013; 78% of patients had previous whole-brain radiotherapy. Three women achieved a partial response (CNS objective response rate, 8%; 95% CI, 2% to 22%). The median number of cycles received was two (range, one to seven cycles), with a median progression-free survival of 1.9 months. Five women received six or more cycles. The most common grade ≥ 3 event was diarrhea (occurring in 21% of patients taking prespecified loperamide prophylaxis and 28% of those without prophylaxis). Patients in the study experienced a decreased quality of life over time. Conclusion Although neratinib had low activity and did not meet our threshold for success, 12.5% of patients received six or more cycles. Studies combining neratinib with chemotherapy in patients with CNS disease are ongoing.

scholarly journals Temozolomide in secondary prevention of HER2-positive breast cancer brain metastases

2020 ◽  
Vol 16 (14) ◽  
pp. 899-909 ◽  
Author(s):  
Alexandra S Zimmer ◽  
Seth M Steinberg ◽  
Dee Dee Smart ◽  
Mark R Gilbert ◽  
Terri S Armstrong ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Secondary Prevention ◽  
Brain Metastases ◽  
Local Treatment ◽  
Breast Cancer Patients ◽  
Her2 Positive ◽  
Her2 Positive Breast Cancer ◽  
Prevention Clinical Trial ◽  
Breast Cancer Brain Metastases ◽  
Positive Breast Cancer

Brain metastases occur in up to 25–55% of patients with metastatic HER2-positive breast cancer. Standard treatment has high rates of recurrence or progression, limiting survival and quality of life in most patients. Temozolomide (TMZ) is known to penetrate the blood–brain barrier and is US FDA approved for treatment of glioblastoma. Our group has demonstrated that low doses of TMZ administered in a prophylactic, metronomic fashion can significantly prevent development of brain metastases in murine models of breast cancer. Based on these findings, we initiated a secondary-prevention clinical trial with oral TMZ given to HER2-positive breast cancer patients with brain metastases after recent local treatment in combination with T-DM1 for systemic control of disease. Primary end point is freedom from new brain metastases at 1 year. (NCT03190967).

Local Radiation Treatment of HER2-Positive Breast Cancer Using Trastuzumab-Modified Gold Nanoparticles Labeled with 177Lu

2016 ◽  
Vol 34 (3) ◽  
pp. 579-590 ◽  
Author(s):  
Zhongli Cai ◽  
Simmyung Yook ◽  
Yijie Lu ◽  
Dane Bergstrom ◽  
Mitchell A. Winnik ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Gold Nanoparticles ◽  
Radiation Treatment ◽  
Her2 Positive ◽  
Her2 Positive Breast Cancer ◽  
Local Radiation ◽  
Positive Breast Cancer
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