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Cancer Therapies and Cardiac Dysfunction
Published in Andreas P. Kalogeropoulos, Hal A. Skopicki, Javed Butler, Heart Failure, 2023
Victoria Shklar, Katherine Godfrey, Michelle E. Bloom
The blockade of the human epidermal growth factor receptor 2 (HER2) signaling pathway alters cancer progression in multiple malignancies, but particularly in breast tumors which frequently overexpress HER2.44,45 HER2, a tyrosine kinase transmembrane receptor encoded by the ErbB2 gene, is expressed in various tissues, including the heart.46 HER2 is a key regulator of cardiomyocyte growth and proliferation and plays a key role in cardiac response to oxygenic stress.47–49 Trastuzumab and pertuzumab are recombinant humanized monoclonal antibodies that target different subdomains of HER2. They inhibit HER2 activation and signaling in the heart, thereby compromising cardioprotective mechanisms (Figure 29.1). Combination of anthracyclines with trastuzumab therapy induces a “two-hit” phenomenon in which anthracyclines are a “first hit” causing oxidative stress, and trastuzumab lowers cardiac protective mechanisms.50
Antibody-Based Therapies
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
Human Epidermal Growth Factor Receptor 2 (HER2) is a target that has been validated by over 15 years of therapeutic use of trastuzumab (HerceptinTM) in HER2-positive (HER2+) breast cancer patients. HER signaling pathways play a critical role in cancer biology, and dysregulation of these pathways facilitates the growth and spread of cancer cells. The HER family consists of four structurally related receptors: HER1 (EGFR), HER2, HER3, and HER4. Inappropriate signaling may occur as a result of receptor overexpression or dysregulation of receptor activation, which may lead to increased/uncontrolled cell proliferation and enhanced cancer cell motility, resistance to apoptosis (programmed cell death), and angiogenesis. Trastuzumab (HerceptinTM), which targets HER signaling, was approved for use in HER2+ve breast cancer in 1998 and is described below in more detail. It was one of the first Ab-based agents to require a pharmacogenetic test (i.e., the HerceptTM test) to select patients suitable for treatment with the agent.
Hormone Receptors and Endocrine Therapy in Breast Cancer
Published in Sherry X. Yang, Janet E. Dancey, Handbook of Therapeutic Biomarkers in Cancer, 2021
Sherry X. Yang, Nancy E. Davidson
As mentioned earlier, HR+ and HER2-breast cancers represent the most common subtype of breast cancer. Nearly 80% of patients with advanced breast cancer have HER2-disease. Endocrine therapy is thus the cornerstone of treatment for advanced HR+ breast cancer. There are 4 classes of ER-targeted agents to choose from for the treatment of HR+ recurrent or metastatic breast cancer. These are SERMs (tamoxifen and toremifene), and estrogen-deprivation approaches including AIs (letrozole, anastrozole and exemestane), SERDs (fulvestrant) and LHRH agonists (goserelin).
High-throughput optofluidic screening of single B cells identifies novel cross-reactive antibodies as inhibitors of uPAR with antibody-dependent effector functions
Published in mAbs, 2023
André Luiz Lourenço, Shih-Wei Chuo, Markus F. Bohn, Byron Hann, Shireen Khan, Neha Yevalekar, Nitin Patel, Teddy Yang, Lina Xu, Dandan Lv, Robert Drakas, Sarah Lively, Charles S. Craik
Effective tumor-targeting antibodies induce direct and indirect effects on tumor cells, mediated by their Fab variable and Fc constant domains, respectively.49 The targeted therapies for HER2-positive breast cancer in clinical use (i.e., trastuzumab (Herceptin®) and pertuzumab (Perjeta®)) involve ADCC by targeting HER2 and recruiting immune effector cells through the Fc domain as part of their mechanism for killing tumors.50 To confer the ADCC activity to the mouse antibodies identified from the Beacon platform, we fused their Fab variable domains to the trastuzumab constant domains for expressing antibodies in a mouse/human chimeric format. Interestingly, different amplitudes of ADCC were observed in the presence of NK-92 cells, suggesting the epitope recognition of antibodies is critical to modulate ADCC activity. These findings corroborated previous studies that antigen binding altered an IgG conformation and affected the recognition of the Fc region by the FcγRIIIa and FcγRIIIb receptors on the surface of NK cells and PBMCs.51–53 In addition, the angle of its Fc domain relative to the target cell surface could govern the accessibility of the Fc region for the interaction with effector cells to induce ADCC.54,55
Delta NT-proBNP predicts cardiotoxicity in HER2-positive breast cancer patients treated with trastuzumab
Published in Acta Oncologica, 2021
Anton E. Andersson, Barbro Linderholm, Daniel Giglio
All patients with HER2-positive breast cancer where the physician judged the patient to be eligible to trastuzumab treatment were offered to participate in the study. After informed consent, 137 patients diagnosed with HER2-positive breast cancer were recruited at the Department of Oncology, Sahlgrenska University Hospital, Gothenburg, Sweden, between 2013 to 2018. One patient accepted to participate in the study but did not undergo trastuzumab therapy due to personal reasons. For the statistical analyses we therefore have included 136 patients. The majority of patients were treated with trastuzumab (Herceptin®) subcutaneously (600 mg) or intravenously (6 mg/kg, start dose 8 mg/kg) in the adjuvant setting (85%), while a small number of patients were treated in the neoadjuvant or the palliative settings. The majority (113 patients) were treated with the subcutaneous form of Herceptin®, five patients with the intravenous form of Herceptin® and 17 patients shifted from the intravenous to the subcutaneous form of Herceptin® during the 12 months of adjuvant HER2 blockade due to changes in treatment recommendations at the clinic.
Trastuzumab-deruxtecan: an investigational agent for the treatment of HER2-positive breast cancer
Published in Expert Opinion on Investigational Drugs, 2020
Breast cancer is the most common malignant disease in women worldwide [1]. The term breast cancer encompasses a heterogeneous group of malignancies differentiated by underlying biology, clinical behavior, and treatment strategies [2,3]. Approximately two-thirds of all breast cancers belong to the luminal subtype as defined by the expression of hormone receptors (estrogen and/or progesterone receptor), making antihormonal interventions the mainstay of treatment [4–7]. HER2-positive breast cancer is defined by the overexpression of the transmembrane HER2 (Human-EGFR-Related 2) receptor as defined by immunohistochemistry or by the amplification of the HER2/neu gene located on chromosome 17. HER2/neu was first described in 1984 and as early as 1987, Slamon et al. identified HER2-positive breast cancer as a high-risk disease subtype [8,9]. The prognosis of these patients has dramatically changed with the introduction of HER2-directed targeted therapies [10,11]. Finally, breast tumors lacking expression of the hormone receptors and HER2 overexpression or HER2/neu gene-amplification are summarized by the term triple-negative breast cancer (TNBC) which is, however, a heterogeneous group of malignancies in itself [12–14].