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Trastuzumab cardiotoxicity

Tanaya Vaidya, Robert M Straubinger, Sihem Ait-Oudhia
PURPOSE: Trastuzumab combined with Doxorubicin (DOX) demonstrates significant clinical activity in human epidermal growth factor receptor-2 (HER2)-positive breast cancer (BC). However, emergence of treatment resistance and trastuzumab associated cardiotoxicity remain clinical challenges. In an effort to improve patient outcome, we have developed and evaluated novel tri-functional immunoliposomes (TFIL) that target HER2-receptors on BC cells and CD3-receptors on T-lymphocytes, and deliver DOX...
March 13, 2018: Pharmaceutical Research
Diaddin Hamdan, François Darrouzain, Theodora Bejan-Angoulvant, Charles Isorni, Laurent Zelek, Gilles Paintaud, Anne Janin, Guilhem Bousquet
PURPOSE: Trastuzumab is the most widely prescribed anti-HER2 humanized monoclonal antibody. Cardiac toxicity is the only limiting toxicity of trastuzumab and it is of particular concern in patients with complete response, since the drug needs to be stopped, with a risk of disease relapse. To date, no pharmacological data on trastuzumab cardiotoxicity in patients have been made available. Here, we provide proof of concept, demonstrating that it was possible to prevent trastuzumab-induced cardiotoxicity by modifying the drug administration schedule...
March 1, 2018: Cancer Chemotherapy and Pharmacology
Gennaro Riccio, Salvatore Antonucci, Carmela Coppola, Chiara D'Avino, Giovanna Piscopo, Danilo Fiore, Carlo Maurea, Michele Russo, Domenica Rea, Claudio Arra, Gerolama Condorelli, Fabio Di Lisa, Carlo G Tocchetti, Claudia De Lorenzo, Nicola Maurea
The ErbB2 blocker trastuzumab improves survival in oncologic patients, but can cause cardiotoxicity. The late Na+ current inhibitor ranolazine has been shown to counter experimental HF, including doxorubicin cardiotoxicity (a condition characterized by derangements in redox balance), by lowering the levels of reactive oxygen species (ROS). Since ErbB2 can modulate ROS signaling, we tested whether trastuzumab cardiotoxicity could be blunted by ranolazine via redox-mediated mechanisms. Trastuzumab decreased fractional shortening and ejection fraction in mice, but ranolazine prevented heart dysfunction when co-administered with trastuzumab...
2018: Frontiers in Physiology
Ann Banke, Anne Polk, Dorte Nielsen, Lars Videbæk, Ulrik Overgaard, Emil Loldrup Fosbøl, Merete Vaage-Nielsen, Kirsten Melgaard Nielsen, Morten Schou
As the prognoses of both heart and cancer patients have improved along with a longer life expectancy in the general population, the prevalence of both heart- and cancer diseases is increasing. Thus, a larger proportion of cancer patients will have cardiovascular co-morbidity and an increased risk of cardiovascular complications during and after cancer treatment. In this article, the current knowledge on the prevention, monitoring and treatment of cardiotoxicity induced by medical anti-cancer treatment with focus on anthracyclines, trastuzumab and 5-fluorouracil is described...
February 12, 2018: Ugeskrift for Laeger
Jiangsong Jiang, Nishant Mohan, Yukinori Endo, Yi Shen, Wen Jin Wu
Despite heightened risk of cardiotoxicity associated with combination therapy of anthracyclines and trastuzumab in HER2-positive breast cancer patients, little research effort has been invested in exploring the molecular mechanisms of cardiotoxicity induced by this combination therapy. In this study, we demonstrate that trastuzumab downregulates both gene and protein expressions of type IIB DNA topoisomerase/DNA topoisomerase IIB (TOP2B), a major intracellular target mediating doxorubicin-induced cardiotoxicity, in human primary cardiomyocytes...
January 19, 2018: Oncotarget
M Wesley Milks, Michael R Velez, Nishaki Mehta, Abiodun Ishola, Thomas Van Houten, Vedat O Yildiz, Raquel Reinbolt, Maryam Lustberg, Sakima A Smith, David A Orsinelli
The prediction of cancer therapeutics-related cardiac dysfunction (CTRCD) is an essential aspect of care for individuals who receive potentially cardiotoxic oncologic treatments. Certain clinical risk factors have been described for incident CTRCD, and measurement of left ventricular (LV) longitudinal strain by speckle tracking 2-dimensional echocardiography (2DE) is the best-validated myocardial mechanical imaging assessment to detect subtle changes in LV function during cancer treatment. However, the direct integration of clinical and imaging risk factors to predict CTRCD has not yet been extensively examined...
January 12, 2018: American Journal of Cardiology
Aurelia H M de Vries Schultink, Annelies H Boekhout, Jourik A Gietema, Artur M Burylo, Thomas P C Dorlo, J G Coen van Hasselt, Jan H M Schellens, Alwin D R Huitema
Trastuzumab is associated with cardiotoxicity, manifesting as a decrease of the left-ventricular ejection fraction (LVEF). Administration of anthracyclines prior to trastuzumab increases risk of cardiotoxicity. High-sensitive troponin T and N-terminal-pro-brain natriuretic peptide (NT-proBNP) are molecular markers that may allow earlier detection of drug-induced cardiotoxicity. In this analysis we aimed to quantify the kinetics and exposure-response relationships of LVEF, troponin T and NT-proBNP measurements, in patients receiving anthracycline and trastuzumab...
February 10, 2018: Journal of Pharmacokinetics and Pharmacodynamics
Anya Litvak, Bhavina Batukbhai, Stuart D Russell, Hua-Ling Tsai, Gary L Rosner, Stacie C Jeter, Deborah Armstrong, Leisha A Emens, John Fetting, Antonio C Wolff, Raquel Silhy, Vered Stearns, Roisin M Connolly
BACKGROUND: Human epidermal growth factor receptor 2 (HER2)-targeted therapies are highly effective at preventing breast cancer recurrence but are associated with cardiotoxicity in some patients, and minimal data are available regarding racial disparities in the incidence of this toxicity. The authors conducted a retrospective study to analyze the association of black or white race with treatment-induced cardiotoxicity and incomplete therapy among patients with HER2-positive early breast cancer...
January 30, 2018: Cancer
Takaaki Fujii, Jun Horiguchi, Yasuhiro Yanagita, Yukio Koibuchi, Fumihiro Ikeda, Nobuyuki Uchida, Morihiko Kimura
AIM: Treatment strategies for patients with human epidermal growth factor 2 (HER2)-positive metastatic breast cancer (MBC) have significantly progressed. The use of trastuzumab, a monoclonal antibody targeting the HER2 (human epidermal growth factor 2) protein, in combination with chemotherapy improves survival in patients with HER2-positive breast cancer. S-1, an oral combination of fluorouracil derivatives, is widely used in Japan and is more convenient than intravenous drugs. However, little is known about the combination of S-1 and trastuzumab in patients with HER2-positive MBC...
February 2018: Anticancer Research
Hiroshi Akazawa
Recent progress in cancer chemotherapy has improved the long-term outcome for cancer patients. Under such circumstances, it is increasingly of clinical importance to manage the cardiovascular complications, which are related to both cancer itself and adverse effects of cancer therapies. Among the most concerning as cardiovascular complications of cancer therapies is chemotherapy-induced cardiotoxicity or chemotherapy-related cardiac dysfunction(CTRCD). CTRCD has been intuitively classified according to the extent of structural abnormalities and degree of reversibility; type 1 is irreversible and dose-dependent with structural abnormalities, and type 2 is reversible after cessation of treatment and dose-independent without structural abnormalities...
December 2017: Gan to Kagaku Ryoho. Cancer & Chemotherapy
Yosuke K Kurokawa, Michael R Shang, Rose T Yin, Steven C George
Trastuzumab (Herceptin®), a monoclonal antibody against the ErbB2 (HER2) receptor, has significantly improved clinical outcomes for HER2+ breast cancer patients. However, the drug also has known cardiotoxic side effects through mechanisms that are not fully understood. Here we utilized human induced pluripotent stem cell-derived cardiomyocytes (iPS-CMs) to model trastuzumab-related cardiotoxicity in vitro. We demonstrate that cardiotoxic effects of ErbB2 inhibition by trastuzumab can be recapitulated only when the cardioprotective effects of ErbB2/4 signaling is observed...
January 2, 2018: Toxicology Letters
Noam Ponde, Ian Bradbury, Matteo Lambertini, Michael Ewer, Christine Campbell, Helene Ameels, Dimitrios Zardavas, Serena Di Cosimo, José Baselga, Jens Huober, Miguel Izquierdo, Debora Fumagalli, Ivana Bozovic-Spasojevic, Marion Maetens, Nadia Harbeck, Lajos Pusztai, Michael Berghorn, Young-Hyuck Im, Manuel Ruiz Borrego, Dar-Ren Chen, Richard Rodeheffer, Martine Piccart, Thomas Suter, Evandro de Azambuja
BACKGROUND: Biomarkers of cardiac damages, such as troponin T (TnT) and the amino-terminal fragment of brain natriuretic peptide (NT-proBNP), may be useful as early predictors of cardiac dysfunction. The role of these biomarkers in patients receiving lapatinib and/or trastuzumab before anthracyclines is unknown. This study explores TnT and NT-proBNP as predictors of early cardiac toxicity in neoadjuvant breast cancer patients. METHODS: This sub-study of the NEOALTTO trial tested if changes in the levels of TnT and NT-proBNP occurred after 2 weeks of anti-HER2 therapy (lapatinib, trastuzumab or their combination) alone and/or after 18 weeks of anti-HER2 therapy plus weekly paclitaxel...
December 27, 2017: Breast Cancer Research and Treatment
Chihiro Udagawa, Hiromi Nakamura, Hiroshi Ohnishi, Kenji Tamura, Tatsunori Shimoi, Masayuki Yoshida, Teruhiko Yoshida, Yasushi Totoki, Tatsuhiro Shibata, Hitoshi Zembutsu
Although trastuzumab-induced cardiotoxicity is an important determinant to limit the use of this drug, the molecular mechanism of risk for this toxicity is not well understood. To identify genetic variants determining the risk of trastuzumab-induced cardiotoxicity, we performed whole exome sequencing of germline DNA samples from 9 patients with trastuzumab-induced cardiotoxicity, and conducted a case-control association study of 2,258 genetic variants between 9 cases (with trastuzumab-induced cardiotoxicity) and general Japanese population controls registered in Human Genetic Variation Database (HGVD)...
December 16, 2017: Cancer Science
Rebecca Madden, Sam Kosari, Gregory M Peterson, Nasser Bagheri, Jackson Thomas
OBJECTIVE: Human epidermal growth factor receptor 2 (HER2)-positive breast cancer, which accounts for 20 - 25% of cases of breast cancers, is highly aggressive. Due to cardiotoxicity and increasing resistance associated with trastuzumab, the first-line treatment, there is a need for effective second-line therapies in treating HER2-positive breast cancer. In this context, there has been increasing interest in the combination of lapatinib plus capecitabine. The aim of this systematic review was to assess the efficacy of lapatinib plus capecitabine for HER2-positive breast cancer after progression with trastuzumab therapy, in comparison with capecitabine monotherapy and other agents such as vinorelbine and trastuzumab emtansine...
February 2018: International Journal of Clinical Pharmacology and Therapeutics
Somaira Nowsheen, Paul V Viscuse, Ciara C O'Sullivan, Nicole P Sandhu, Tufia C Haddad, Anne Blaes, Jennifer Klemp, Lara Nhola, Joerg Herrmann, Kathryn J Ruddy
Purpose of review: Treatment with trastuzumab is a cornerstone of human epidermal growth factor receptor 2 (HER2)-overexpressing breast cancer treatment, but carries an unfortunate risk of toxicity to the cardiovascular system. Here we review recent findings on trastuzumab-associated cardiotoxicity, focusing on its incidence, diagnosis, and treatment. Recent findings: Screening with multigated acquisition scan (MUGA) or echocardiogram (ECHO) is recommended to assess cardiac function prior to and during trastuzumab therapy...
September 2017: Current Breast Cancer Reports
A Tiwari, A Gogia, Svs Deo, N K Shukla, S Mathur, D N Sharma
BACKGROUND: The neoadjuvant chemotherapy in HER2-positive breast cancer consists of a chemotherapy backbone and HER2-directed therapy. The increase in cardiotoxicity by the use of trastuzumab with an anthracycline-based regimen has led to the use of nonanthracycline-based alternative regimens. The docetaxel, carboplatin, and trastuzumab (TCH) are one such regimen. The efficacy and toxicity of this regimen have not been widely studied in Indian patients. AIMS: This retrospective study aims to evaluate the efficacy and toxicity of neoadjuvant TCH regimen in locally advanced and oligometastatic HER2-positive breast cancer in Indian patients...
January 2017: Indian Journal of Cancer
Jie An, M Saeed Sheikh
Trastuzumab is a humanized monoclonal antibody that is approved for the treatment of breast and gastric malignancies. Although it has shown promise as a biotherapeutic, its cardiotoxicity remains a major concern. Genotoxic anticancer anthracyclines such as doxorubicin and epirubicin are also known for their cardiotoxic effects. However, trastuzumab and anthracyclines are suggested to mediate cardiotoxicity via different pathways. The available lines of evidence suggest that trastuzumab can exacerbate the cardiotoxic effects of anthracyclines and thus, prior exposure to anthracyclines is a regarded as one of the risk factors for trastuzumab-induced cardiotoxcity...
November 29, 2017: Current Cancer Drug Targets
Mi Hyung Lee, Jeong Yee, Young Ju Kim, Jin Young Moon, Joo Hee Kim, Sandy Jeong Rhie, Hye Sun Gwak
Trastuzumab is a drug used for the treatment of metastatic breast cancer patients. Due to blockage of the human epidermal growth factor receptor 2 signaling in cardiac myocytes, cardiotoxicity has been observed. There are many studies that investigated risk factors for trastuzumab-induced cardiotoxicity, but no study has been published for factors on the time to cardiotoxicity. This study aimed to investigate the factors for the time to occur trastuzumab-induced cardiotoxicity. From January 2014 to December 2015, a retrospective study was performed with breast cancer patients who were treated with trastuzumab...
November 21, 2017: Medical Oncology
Santino Minichillo, Ilaria Gallelli, Elena Barbieri, Marta Cubelli, Daniela Rubino, Sara Quercia, Massimo Dall'Olio, Claudio Rapezzi, Claudio Zamagni
BACKGROUND: Trastuzumab-related cardiotoxicity has been reported in patients receiving trastuzumab concurrently with other agents, especially with anthracyclines. Cardiac function damage is generally rare, precox and mild with trastuzumab alone. CASE PRESENTATION: We report the case of a 49 year-old woman affected by metastatic breast cancer who developed trastuzumab-related cardiogenic shock due to pump failure (with LVEF of about 15%) after three months of treatment...
November 7, 2017: BMC Cancer
Hai-Yan Wang, Bei-Bei Yin, Dan-Yan Jia, Ying-Long Hou
Purpose: Trastuzumab can improve the prognosis for patients with breast cancer, but its related cardiac toxicity is concerning. This study aimed to identify the risk factors associated with trastuzumab-related cardiac toxicity in elderly patients with HER2-positive breast cancer. Patients and methods: A total of 133 elderly (≥ 65 years) patients who were diagnosed with breast cancer between June 1, 2007, and January 31, 2016, and received trastuzumab treatment were retrospectively reviewed...
October 3, 2017: Oncotarget
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