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Radiation Recall Reaction Induced by Adjuvant Trastuzumab (Herceptin)
Caroline Chung,David Stuart,Mira Keyes
Case Reports in Medicine , 2009, DOI: 10.1155/2009/307894
Abstract: Although concerns of radiation sensitization have been raised with concurrent trastuzumab (Herceptin) administration, there has been no published case of radiation recall reaction associated with trastuzumab. This case describes a clinical presentation consistent with a radiation recall reaction following administration of adjuvant trastuzumab after neoadjuvant FEC-D chemotherapy and locoregional radiotherapy for HER2-positive, locally advanced breast cancer in a premenopausal woman. Although the mechanism and etiology of radiation recall dermatitis remain unclear, this case raises further hypotheses regarding a possible drug dose-dependence and possible predisposing risk factor for the development of radiation recall reactions.
Plant-Made Trastuzumab (Herceptin) Inhibits HER2/Neu+ Cell Proliferation and Retards Tumor Growth  [PDF]
Tatiana V. Komarova,Vyacheslav S. Kosorukov,Olga Y. Frolova,Igor V. Petrunia,Ksenia A. Skrypnik,Yuri Y. Gleba,Yuri L. Dorokhov
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0017541
Abstract: Plant biotechnology provides a valuable contribution to global health, in part because it can decrease the cost of pharmaceutical products. Breast cancer can now be successfully treated by a humanized monoclonal antibody (mAb), trastuzumab (Herceptin). A course of treatment, however, is expensive and requires repeated administrations of the mAb. Here we used an Agrobacterium-mediated transient expression system to produce trastuzumab in plant cells.
Novel Toll-like receptor-4 deficiency attenuates trastuzumab (Herceptin) induced cardiac injury in mice
Nasser Yousif, Fadhil G Al-amran
BMC Cardiovascular Disorders , 2011, DOI: 10.1186/1471-2261-11-62
Abstract: Seven days after a single injection of herceptin (2 mg/kg; i.p.), left ventricular pressure volume loops were measured in HeN compotent (TLR4+/+) and HeJ mutant (TLR4-/-) treated with trastuzumab and control mice. Immunofluorescent staining for monocyte infiltration and analyses of plasma by (ELISAs) for different chemokines including: MCP-1and tumor necrosis factor-α (TNF-α), Western immunoblotting assay for ICAM-1, and used troponin I for cardiac injury marker.Trastuzumab injection resulted in an impairment of left ventricular function in TLR-4 competent (HeN), in contrast TLR4-/- trastuzumab mice showed improved left ventricular function EF%, CO; p < 0.05, attenuation of mononuclear cell infiltration in TLR4 -/-; p < 0.05 vs.TLR-4 competent (HeN), reduced level of cytokines TNF-α, MCP-1 and ICAM-1 expression in TLR4-/-, marked reduction of myocardial troponin-I levels in TLR4-deficient mice. Data are presented as means ± SE; n = 8 in each group p < 0.05 vs.TLR-4 competent (HeN).Treatment with trastuzumab induces an inflammatory response that contributes to myocardial tissue TLR4 mediates chemokine expression (TNF-α, MCP-1and ICAM-1), so in experimental animals TLR4 deficiency improves left ventricular function and attenuates pathophysiological key mechanisms in trastuzumab induced cardiomyopathy.The human epidermal growth factor receptor (HER) proteins regulate cell growth, survival, adhesion, migration, and differentiation functions that are amplified or weakened in cancer cells. In some cancers, notably some breast cancers, human epidermal growth factor receptor-2 (HER2) is over-expressed, and, among other effects, causes breast cells to reproduce uncontrollably [1]. Trastuzumab is a humanized monoclonal antibody that binds selectively to the HER2 protein. and has become a mainstay in the treatment of women with (HER2) overexpressing breast cancer and in the metastatic and adjuvant settings this increases the survival of people with cancer [2]. One of the signi
Trastuzumab and Gemcitabine in Pretreated HER2 Overexpressing Metastatic Breast Cancer Patients: Retrospective Analysis of Our Series  [PDF]
Vincenzo Di Lauro,Elena Torrisi,Ettore Bidoli,Daniela Quitadamo,Sara Cecco,Andrea Veronesi
Journal of Oncology , 2012, DOI: 10.1155/2012/198412
Abstract: Trastuzumab-based regimes improved clinical outcome in women with overexpressing HER2 metastatic breast cancer, mainly due to the availability of different combination therapies, clinically active and well tolerated. In this study we retrospectively evaluated clinical activity and toxicity of trastuzuamb plus gemcitabine regimen in heavily pretreated HER2 positive metastatic breast cancer patients. Although the observed population was heavily pretreated, the evaluated regimen was notably effective in terms of response rate, time to progression and survival, with very mild toxicity. These data suggest that in over expressing HER2 metastatic breast cancer patients, sequential trastuzumab based chemotherapeutic regimens can achieve good response rate with prolonged TTP in responding patients, even after other target therapy such as lapatinib based combinations. 1. Introduction Human epidermal growth factor receptor 2 (HER2) is a transmembrane tyrosine kinase which is crucial in cell growth and differentiation. The HER2 gene is amplified in 15–20% of human breast cancers, and this feature is a well-known poor prognostic factor [1–3]. Trastuzumab (Herceptin Roche, Basel, Switzerland), a humanised monoclonal antibody with specificity for HER2, changed the natural history of HER2 overexpressing breast cancer, in the adjuvant setting as well as in metastatic disease. After phase II studies, the results of important phase III randomized trial enabled the registration of regimen of weekly paclitaxel plus trastuzumab by Food and Drug Administration (FDA) for HER2-positive metastatic breast cancer (MBC) [4–7]. Although the combination of taxane with trastuzumab is considered the reference regimen for HER2 overexpressing MBC, other combination therapies were evaluated in extensive phase II trials [8]. In patients with progressive disease after first-line trastuzumab-based regimens, a current clinical practice is to continue trastuzumab changing the chemotherapeutic partner. Therefore, the identification of different combinations of trastuzumab-based regimens for sequential use is important. In a previous study, we tested efficacy and tolerability of trastuzumab plus vinorelbine (VNR) regimen in first- and second-line setting for HER2 overexpressing MBC, with value for response rate (RR) of 78%, median time to progression (TTP) of 9 months, and median overall survival (OS) of 28 mounths. Very mild toxicity was observed [9]. Our results were in agreement with those previously published [10–19]. They were recently confirmed in two prospective and randomized trials,
Molecular Mechanisms of Trastuzumab Resistance in HER2 Overexpressing Breast Cancer  [PDF]
Gabriel L. Fiszman,María A. Jasnis
International Journal of Breast Cancer , 2011, DOI: 10.4061/2011/352182
Abstract: The epidermal growth factor receptor 2 (HER2) is a tyrosine kinase overexpressed in nearly 20% to 25% of invasive breast cancers. Trastuzumab is a humanized monoclonal antibody that targets HER2. The majority of patients with metastatic breast cancer initially respond to trastuzumab, however, within 1 year of treatment disease progresses. Several molecular mechanisms have been described as contributing to the development of trastuzumab resistance. They could be grouped as impaired access of trastuzumab to HER2, upregulation of HER2 downstream signaling pathways, signaling of alternative pathways, and impaired immune antitumor mechanisms. However, since many of them have overlapping effects, it would be of great clinical impact to identify the principal signaling pathways involved in drug resistance. Significant efforts are being applied to find other therapeutic modalities besides trastuzumab treatment to be used alone or in combination with current modalities. 1. Introduction Breast cancer is the most common malignancy worldwide and the second leading cause of cancer death in women in USA and the first one in Argentina [1]. In the past decades, the development of strategies for breast cancer treatment focused on understanding the expression, regulation, and function of critical signaling pathways involved in cancer initiation and progression and allowed the identification of breast cancer subsets with different biology [2]. One of the most important targeted therapies has been the use of the antihuman epidermal growth factor receptor 2 (HER2) for tumors overexpressing this receptor [3]. Breast cancer is a heterogeneous disease that can be classified in different subsets with distinct biology and molecular profiles [4], some of which can be associated with enhanced tumor aggressiveness and poor clinical outcome [5]. Breast tumors vary according to the expression of estrogen receptor (ER), progesterone receptor (PR), and amplification of HER2 which is overexpressed in approximately 20% to 25% of invasive breast cancers [6]. The resulting subgroups are important not only for clinical behaviour and prognosis, but also for predictive response to targeted therapies against these receptors and the pathways they activate. The HER2/neu gene encodes a 185-kDA transmembrane tyrosine kinase (TK) receptor that belongs to the EGF receptor (EGFR) family which consists of EGFR/ErbB1 (HER1), ErbB2 (HER2), ErbB3 (HER3), and ErbB4 (HER4). All receptors, with the exception of HER3, contain a cytoplasmatic TK region and all, with the exception of HER2, bind specific
Sustained complete remission of human epidermal growth factor receptor 2-positive metastatic breast cancer in the liver during long-term trastuzumab (Herceptin) maintenance therapy in a woman: a case report
John Syrios, Anna Dokou, Nicolas Tsavaris
Journal of Medical Case Reports , 2010, DOI: 10.1186/1752-1947-4-401
Abstract: We present the case of a 34-year-old Caucasian woman with human epidermal growth factor receptor 2-positive metastatic breast cancer in the liver who achieved prolonged complete remission within six months of receiving trastuzumab (Herceptin) in combination with vinorelbine and gemcitabine. The patient remains in complete remission seven years later and continues to receive trastuzumab as maintenance therapy.Trastuzumab-based therapies have greatly improved the survival rates of patients with human epidermal growth factor receptor 2- positive metastatic breast cancer. Despite such improvements, the safety of trastuzumab administration during pregnancy is yet to be defined.The development of trastuzumab (Herceptin), a humanized human epidermal growth factor receptor 2 (HER2) monoclonal antibody, has changed the natural history of HER2-positive breast cancer, providing superior survival benefits in combination or as monotherapy compared with nontrastuzumab-based therapy [1,2]. However, HER2-positive metastatic breast cancer (MBC) is an aggressive disease, and despite these advances, the majority of patients treated with trastuzumab-based regimens progress within one year, with only very few patients experiencing prolonged remission [3].The case report presented here describes a woman who underwent a mastectomy for invasive ductal carcinoma and subsequently received trastuzumab in combination with chemotherapy as treatment for a single metastatic lesion in the liver. She experienced a complete response, with disappearance of the hepatic lesion, and has been receiving maintenance trastuzumab for seven years. While taking trastuzumab, the patient expressed her intention of starting a family, which raised a number of questions, such as how long maintenance trastuzumab should be administered and whether, in this case, treatment should cease.In February 2001, an otherwise healthy 34-year-old Caucasian woman, with no history of hormone therapy, smoking, drinking, or a family
The importance of antibody dependent cell-mediated cytotoxicity (ADCC) for breast cancer response to trastuzumab - Herceptin
Jurani? Zorica D.,Stanojevi?-Baki? Nevenka,Ne?kovi?-Konstantinovi? Zora,?i?ak ?eljko
Archive of Oncology , 2002, DOI: 10.2298/aoo0203162j
Abstract: In this work we investigated the direct or indirect (through ADCC) cytotoxic action of Herceptin, to two breast carcinoma cell lines: to MDA-MB 361, for HER-2, IHC score (3+) and to MDA-MB 453, IHC score (<2+). Cytotoxic action of Herceptin, of PBMC and of their combination (ADCC) was determined 48h later, indirectly, through the determination of target cell survival by MTT test. Preliminary results indicate that direct cytotoxicity of Herceptin against investigated breast carcinoma cells was very low, probably due to their high duplication time. However, the cytotoxic action of PBMC mediated through Herceptin as ADCC, was noted in investigation of cytotoxicity of some persons' PBMC.
Trastuzumab-DM1: A Review of the Novel Immuno-Conjugate for HER2- Overexpressing Breast Cancer
Myra F. Barginear and Daniel R. Budman
The Open Breast Cancer Journal , 2009, DOI: 10.2174/1876817201002010025]
Abstract: Trastuzumab is a monoclonal antibody targeted against the HER2 tyrosine kinase receptor. Although trastuzumab is a very active agent in HER2-expressing breast cancer, the majority of patients with metastatic HER2 overexpressing breast cancer who initially respond to trastuzumab develop resistance within one year of initiation of treatment, and in the adjuvant setting, progress despite trastuzumab-based therapy. The immuno-conjugate Trastuzumab- DM1 (T-DM1) was designed to combine the biological activity of trastuzumab with the targeted delivery of a highly potent antimicrotubule agent, DM1, a maytansine derivative, to HER2-expressing breast cancer cells. T-DM1 is the first immuno-conjugate with a non-reducible thioether linker in clinical trials. Here, we summarize evidence from pre-clinical studies, analyze clinical data, and discuss the potential clinical implications of T-DM1.
Molecular Mechanisms of Trastuzumab-Based Treatment in HER2-Overexpressing Breast Cancer  [PDF]
Rita Nahta
ISRN Oncology , 2012, DOI: 10.5402/2012/428062
Abstract: The past decade of research into HER2-overexpressing breast cancer has provided significant insight into the mechanisms by which HER2 signaling drives tumor progression, as well as potential mechanisms by which cancer cells escape the anticancer activity of HER2-targeted therapy. Many of these preclinical findings have been translated into clinical development, resulting in novel combinations of HER2-targeted therapies and combinations of trastuzumab plus inhibitors of resistance pathways. In this paper, we will discuss proposed mechanisms of trastuzumab resistance, including epitope masking, cross signaling from other cell surface receptors, hyperactive downstream signaling, and failure to induce antibody-dependent cellular cytotoxicity. In addition, we will discuss the molecular mechanisms of action of dual HER2 inhibition, specifically the combination of trastuzumab plus lapatinib or trastuzumab with pertuzumab. We will also discuss data supporting therapeutic combinations of trastuzumab with agents targeted against molecules implicated in trastuzumab resistance. The roles of insulin-like growth factor-I receptor and the estrogen receptor are discussed in the context of resistance to HER2-targeted therapies. Finally, we will examine the major issues that need to be addressed in order to translate these combinations from the bench to the clinic, including the need to establish relevant biomarkers to select for those patients who are most likely to benefit from a particular drug combination. 1. Introduction The HER2 (erbB2/neu) receptor tyrosine kinase gene is amplified and overexpressed at the protein level in 20–30% of metastatic breast cancers. HER2 overexpression represents an example of oncogene addiction in many of these cancers, as HER2 blockade or kinase inhibition achieves durable responses in many patients with metastatic HER2-overexpressing breast cancer. The first-line treatment for this subtype of breast cancers is the HER2 monoclonal antibody trastuzumab. In combination with cytotoxic chemotherapy, trastuzumab has revolutionized treatment and clinical outcome for patients whose breast tumors express high levels of the HER2 protein. Despite remarkable success, response rates are usually limited in duration, suggesting that the development of resistance is a clinical problem. Research published during the past decade has identified multiple molecular mechanisms contributing to trastuzumab resistance. In addition, recent studies have suggested novel combinations of drugs that will benefit patients who have shown disease progression on prior
Trastuzumab, an appropriate first-line single-agent therapy for HER2-overexpressing metastatic breast cancer
Carlos L Arteaga
Breast Cancer Research , 2002, DOI: 10.1186/bcr574
Abstract: The HER2/Neu proto-oncogene product is a member of the erbB family of transmembrane receptor tyrosine kinases, which also includes the epidermal growth factor receptor (EGFR, HER1, ErbB1), HER3 (ErbB3), and HER4 (ErbB4). Except for HER2, binding of receptor-specific ligands to the extracellular domain of EGFR, HER3, and HER4 results in the formation of homodimeric and heterodimeric phosphorylated, kinase-active complexes into which HER2 is recruited as a preferred partner [1-3]. Even though HER2 is unable to interact directly with HER-activating ligands, it can potentiate signaling by its co-receptors and/or increase the binding affinity of ligands to EGFR and HER3 (reviewed in [1]). Studies with HER2-overexpressing breast cancer cell lines and human tumors have shown constitutive phosphorylation of HER2 [4,5]. The biochemical basis for this activation is not clear but it is consistent with the ability of wild-type Neu, the rat homolog of human HER2, to multimerize and become activated in a ligand-independent fashion when present in cells at high density [6]. Overexpression of HER2 is associated with transformation of mammary epithelial cells [7,8] as well as shorter survival in patients with breast carcinoma [9,10]. The association of HER2 with poor patient prognosis, the ability to measure HER2 levels prospectively in diagnostic tumor tissue, and the lack of an apparent physiological role of HER2 in the adult, initially suggested this receptor as a rational therapeutic target in human breast cancer.One therapeutic approach against HER2-overexpressing breast cancers is the generation of Herceptin (trastuzumab), a humanized IgG1 that binds to residues 529–626 in the HER2 ectodomain [11]. The mouse hybridoma counterpart of Herceptin, 4D5, partly removes HER2 from the plasma membrane [12,13] and/or induces HER2 homodimerization (CL Arteaga, unpublished data), potentially preventing HER2 molecules from interacting with other HER co-receptors and thus impairing the grow
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