Proteomics Analysis of Trastuzumab Toxicity in the H9c2 Cardiomyoblast Cell Line and its Inhibition by Carvedilol

2020 ◽  
Vol 21 (13) ◽  
pp. 1377-1385
Author(s):  
Elham Beiranvand ◽  
Fatemeh Torkashvand ◽  
Seyed N. Ostad ◽  
Mehdi Mirzaie ◽  
Esmat M. Ardakani ◽  
...  
Keyword(s):  
Growth Factor Receptor ◽  
Breast Cancers ◽  
Her2 Positive ◽  
Proteomics Analysis ◽  
H9c2 Cardiomyoblasts ◽  
Epidermal Growth ◽  
Proteome Changes ◽  
Partial Reversion ◽  
New Strategies ◽  
Differentially Abundant Proteins

Objective: Heart dysfunctions are the major complications of trastuzumab in patients with Human Epidermal growth factor Receptor-2 (HER2)-positive breast cancers. Methods: In this study, the cytotoxicity of trastuzumab on H9c2 cardiomyoblasts was demonstrated, and the proteome changes of cells were investigated by a tandem mass tagging quantitative approach. The Differentially Abundant Proteins (DAPs) were identified and functionally enriched. Results: We determined that carvedilol, a non-selective beta-blocker, could effectively inhibit trastuzumab toxicity when administrated in a proper dose and at the same time. The proteomics analysis of carvedilol co-treated cardiomyoblasts showed complete or partial reversion in expressional levels of trastuzumab-induced DAPs. Conclusion: Downregulation of proteins involved in the translation biological process is one of the most important changes induced by trastuzumab and reversed by carvedilol. These findings provide novel insights to develop new strategies for the cardiotoxicity of trastuzumab.

scholarly journals CDK4/6 inhibitors in breast cancer: beyond hormone receptor-positive HER2-negative disease

2018 ◽  
Vol 10 ◽  
pp. 175883591881834 ◽  
Author(s):  
Adriana Matutino ◽  
Carla Amaro ◽  
Sunil Verma
Keyword(s):  
Breast Cancer ◽  
Hormone Receptor ◽  
Growth Factor Receptor ◽  
Metastatic Breast ◽  
Progression Free Survival ◽  
Breast Cancers ◽  
Cyclin Dependent Kinase ◽  
Her2 Positive ◽  
Hormone Receptor Positive ◽  
Epidermal Growth

The development of cyclin-dependent kinase (CDK) 4/6 inhibitors has been more prominent in hormone receptor (HR)-positive human epidermal growth factor receptor 2 (HER2)-negative breast cancers, with a significant improvement in progression-free survival (PFS) in first and later lines of metastatic breast cancer (MBC) therapy. Preclinical evidence suggests that there is activity of CDK4/6 inhibitors in nonluminal cell lines. Here, we present a review of the current preclinical and clinical data on the use of CDK inhibitors in HER2-positive and triple-negative breast cancer (TNBC).

scholarly journals Human Epidermal Growth Factor Receptor 2 (HER2) in Cancers: Overexpression and Therapeutic Implications

2014 ◽  
Vol 2014 ◽  
pp. 1-9 ◽  
Author(s):  
Nida Iqbal ◽  
Naveed Iqbal
Keyword(s):  
Epidermal Growth Factor Receptor ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Growth Factor Receptor ◽  
Her2 Overexpression ◽  
Breast Cancers ◽  
Her2 Positive ◽  
Therapeutic Implications ◽  
Human Epidermal Growth Factor ◽  
Epidermal Growth

Human epidermal growth factor receptor 2 (HER2) is a member of the epidermal growth factor receptor family having tyrosine kinase activity. Dimerization of the receptor results in the autophosphorylation of tyrosine residues within the cytoplasmic domain of the receptors and initiates a variety of signaling pathways leading to cell proliferation and tumorigenesis. Amplification or overexpression of HER2 occurs in approximately 15–30% of breast cancers and 10–30% of gastric/gastroesophageal cancers and serves as a prognostic and predictive biomarker. HER2 overexpression has also been seen in other cancers like ovary, endometrium, bladder, lung, colon, and head and neck. The introduction of HER2 directed therapies has dramatically influenced the outcome of patients with HER2 positive breast and gastric/gastroesophageal cancers; however, the results have been proved disappointing in other HER2 overexpressing cancers. This review discusses the role of HER2 in various cancers and therapeutic modalities available targeting HER2.

Selection of Optimal Adjuvant Chemotherapy Regimens for Human Epidermal Growth Factor Receptor 2 (HER2) –Negative and Adjuvant Targeted Therapy for HER2-Positive Breast Cancers: An American Society of Clinical Oncology Guideline Adaptation of the Cancer Care Ontario Clinical Practice Guideline

2016 ◽  
Vol 34 (20) ◽  
pp. 2416-2427 ◽  
Author(s):  
Neelima Denduluri ◽  
Mark R. Somerfield ◽  
Andrea Eisen ◽  
Jamie N. Holloway ◽  
Arti Hurria ◽  
...  
Keyword(s):  
Epidermal Growth Factor Receptor ◽  
Clinical Practice ◽  
Targeted Therapy ◽  
Adjuvant Chemotherapy ◽  
Growth Factor Receptor ◽  
Breast Cancers ◽  
Her2 Positive ◽  
Epidermal Growth ◽  
American Society ◽  
Selection Of

Purpose A Cancer Care Ontario (CCO) guideline on the selection of optimal adjuvant chemotherapy regimens for early breast cancer including adjuvant targeted therapy for human epidermal growth factor receptor 2 (HER2)–positive breast cancers was identified for adaptation. Methods The American Society of Clinical Oncology (ASCO) has a policy and set of procedures for adapting clinical practice guidelines developed by other organizations. The CCO guideline was reviewed for developmental rigor and content applicability. Results On the basis of the content review of the CCO guideline, the ASCO Panel agreed that, in general, the recommendations were clear and thorough and were based on the most relevant scientific evidence, and they presented options that will be acceptable to patients. However, for some topics addressed in the CCO guideline, the ASCO Panel formulated a set of adapted recommendations on the basis of local context and practice beliefs of the Panel members. Recommendations Decisions regarding adjuvant chemotherapy regimens should take into account baseline recurrence risk, toxicities, likelihood of benefit, and host factors such as comorbidities. In high-risk HER2-negative populations with excellent performance status, anthracycline- and taxane-containing regimens are the standard of care. Docetaxel and cyclophosphamide for four cycles is an acceptable non-anthracycline regimen. In high-risk HER2-positive disease, sequential anthracycline and taxanes administered concurrently with trastuzumab or docetaxel, carboplatin, and trastuzumab for six cycles are recommended. An alternative regimen in a lower-risk, node-negative, HER2-positive population is paclitaxel and trastuzumab once per week for 12 cycles. Trastuzumab should be given for 1 year. Platinum salts should not be routinely administered in the adjuvant triple-negative population until survival efficacy data become available.

Human Epidermal Growth Factor Receptor 2 Overexpression As a Prognostic Factor in a Large Tissue Microarray Series of Node-Negative Breast Cancers

2008 ◽  
Vol 26 (35) ◽  
pp. 5697-5704 ◽  
Author(s):  
Stephen Chia ◽  
Brian Norris ◽  
Caroline Speers ◽  
Maggie Cheang ◽  
Blake Gilks ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Epidermal Growth Factor Receptor ◽  
Prognostic Factor ◽  
Growth Factor Receptor ◽  
Her2 Overexpression ◽  
Prognostic Impact ◽  
Breast Cancers ◽  
Her2 Positive ◽  
Node Negative ◽  
Epidermal Growth

Purpose Human epidermal growth factor receptor 2 gene (HER2) is associated with a poorer outcome in node-positive breast cancer, but the results are conflicting in node-negative disease. This study assessed the prognostic impact of HER2 overexpression/amplification in a large series of node-negative breast cancers. Patients and Methods A tissue microarray (TMA) series was constructed consisting of 4,444 invasive breast cancers diagnosed in British Columbia from 1986 to 1992. Within this series, 2,026 patients were node negative, of whom 70% did not receive adjuvant systemic therapy. The TMA series was assessed for estrogen receptor (ER) and HER2. Logistic regression modeling was used to estimate odds ratios at the 10-year follow-up. Results HER2 was positive in 10.2% of the node-negative cohort. In this cohort, an inferior outcome was seen in patients with HER2-positive tumors compared with HER2-negative tumors for 10-year relapse-free survival (RFS; 65.9% v 75.5%, respectively; P = .01), distant RFS (71.2% v 81.8%, respectively; P = .004), and breast cancer–specific survival (BCSS; 75.5% v 86.3%, respectively; P = .001). A trend for a worse overall survival was also seen (P = .06). HER2 was an independent poor prognostic factor for RFS and BCSS at 10 years, with odds ratios of 1.71 (P = .01) and 2.03 (P = .003), respectively. The number of HER2-positive tumors that were ≤ 1 cm was small, but there was a trend for a worse outcome in T1b tumors. Conclusion HER2 overexpression/amplification is correlated with a poorer outcome in node-negative breast cancer. Larger studies are needed to more clearly define the prognostic impact of HER2 in tumors ≤ 1 cm, particularly within the separate hormone receptor subgroups.

Reagent-saving immunohistochemistry for HER2 using non-contact alternating current electric field mixing

2018 ◽  
Vol 72 (1) ◽  
pp. 25-30 ◽  
Author(s):  
Iku Hoshino ◽  
Kazuhiro Imai ◽  
Hiroshi Nanjo ◽  
Ryuta Nakamura ◽  
Yoshitaro Saito ◽  
...  
Keyword(s):  
Electric Field ◽  
Growth Factor Receptor ◽  
Alternating Current ◽  
Her2 Status ◽  
Breast Cancers ◽  
Clinical Tool ◽  
Her2 Positive ◽  
Specific Staining ◽  
Epidermal Growth ◽  
Current Electric Field

AimsHuman epidermal growth factor receptor 2 (HER2)-targeted agents are an effective approach to treating patients with HER2-positive breast cancer. However, the lack of survival benefit in HER2-negative patients, as well as the toxic effects and high cost of the drugs, highlight the need for accurate and prompt assessment of HER2 status. Our aim was to evaluate the clinical utility of a novel reagent-saving immunohistochemistry method (AC-IHC) that saves HER2 antibody by taking advantage of the non-contact mixing effect in microdroplets subjected to an alternating current electric field.MethodsNinety-five specimens were used from patients diagnosed with primary breast cancers identified immunohistochemically as HER2 0/1+, 2+ or 3+ using ASCO/CAP guideline-certified standard IHC. The specimens were all tested using the conventional IHC method (1:50 antibody dilution) as well as AC-IHC (1:50 dilution) and reagent-saving AC-IHC (1:100 dilution).ResultsThe reagent-saving AC-IHC produced stable results with less non-specific staining using smaller amounts of labelled antibody. Moreover, the staining and accuracy of HER2 status evaluated with the reagent-saving AC-IHC method was equal to that achieved with standard IHC.ConclusionsThese results suggest reagent-saving AC-IHC could be used as a clinical tool for accurate and stable HER2 IHC, even when reagent concentrations vary.

scholarly journals Nanotechnology approaches to addressing HER2-positive breast cancer

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Bryan E. White ◽  
Molly K. White ◽  
Het Adhvaryu ◽  
Issam Makhoul ◽  
Zeid A. Nima ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Growth Factor Receptor ◽  
The United States ◽  
Breast Cancers ◽  
Specific Design ◽  
Her2 Positive ◽  
Her2 Positive Breast Cancer ◽  
Epidermal Growth ◽  
Growth Promoting ◽  
Positive Breast Cancer

Abstract Breast cancer is a major cause of cancer-associated deaths in the United States. It was estimated that 12% of women in the U.S. will develop invasive breast cancer in their lifetime. The human epidermal growth factor receptor (HER2/neu) is a growth-promoting protein that is overexpressed in 15–20% of breast cancers (HER2-positive breast cancer). HER2-positive breast cancer generally grows and spreads more quickly than other breast cancers, but it can be targeted therapeutically. Targeting drugs have been developed with a specific design to stop the growth and even the spread of cancer. These drugs include trastuzumab (Herceptin), pertuzumab (Perjeta), ado-trastuzumab emtansine (Kadcyla, or TDM-1), fam-trastuzumab deruxtecan, lapatinib, neratinib and tucatinib. However, the need for better targeted therapy and efficacy still exists. Nanotechnology could have major advantages in terms of detection, targeting, drug delivery, and destruction of cancer cells and tumors. Although a great deal of progress has been accomplished major challenges still need to be addressed. In this review, we examine the major areas of research in the area of nanotechnology and HER2-positive breast cancer.

scholarly journals Testing for HER2 in Breast Cancer: A Continuing Evolution

2011 ◽  
Vol 2011 ◽  
pp. 1-16 ◽  
Author(s):  
Sejal Shah ◽  
Beiyun Chen
Keyword(s):  
Breast Cancer ◽  
Growth Factor Receptor ◽  
Disease Free Survival ◽  
Breast Cancers ◽  
Her2 Positive ◽  
Free Survival ◽  
Humanized Monoclonal Antibody ◽  
Epidermal Growth ◽  
Invasive Breast Carcinomas ◽  
Disease Free

Human epidermal growth factor receptor 2 (HER2) is an important prognostic and predictive factor in breast cancer. HER2 is overexpressed in approximately 15%–20% of invasive breast carcinomas and is associated with earlier recurrence, shortened disease free survival, and poor prognosis. Trastuzumab (Herceptin) a “humanized” monoclonal antibody targets the extracellular domain of HER2 and is widely used in the management of HER2 positive breast cancers. Accurate assessment of HER2 is thus critical in the management of breast cancer. The aim of this paper is to present a comprehensive review of HER2 with reference to its discovery and biology, clinical significance, prognostic value, targeted therapy, current and new testing modalities, and the interpretation guidelines and pitfalls.

scholarly journals High Risk of Recurrence for Patients With Breast Cancer Who Have Human Epidermal Growth Factor Receptor 2–Positive, Node-Negative Tumors 1 cm or Smaller

2009 ◽  
Vol 27 (34) ◽  
pp. 5700-5706 ◽  
Author(s):  
Ana M. Gonzalez-Angulo ◽  
Jennifer K. Litton ◽  
Kristine R. Broglio ◽  
Funda Meric-Bernstam ◽  
Ronjay Rakkhit ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Epidermal Growth Factor Receptor ◽  
Growth Factor Receptor ◽  
Distant Recurrence ◽  
Recurrence Free Survival ◽  
Breast Cancers ◽  
Her2 Positive ◽  
Free Survival ◽  
Node Negative ◽  
Epidermal Growth

Purpose To evaluate the risk of recurrence in women diagnosed with T1a and T1b, node-negative, human epidermal growth factor receptor 2 (HER2) –positive breast cancer. Methods We reviewed 965 T1a,bN0M0 breast cancers diagnosed at our institution between 1990 and 2002. Dedicated breast pathologists confirmed HER2 positivity if 3+ by immunohistochemistry or if it had a ratio of 2.0 or greater by fluorescence in situ hybridization (FISH). Patients who received adjuvant chemotherapy or trastuzumab were excluded. Kaplan-Meier product was used to calculate recurrence-free survival (RFS) and distant recurrence–free survival (DRFS). Cox proportional hazard models were fit to determine associations between HER2 status and survival after adjustment for patient and disease characteristics. Additionally, 350 breast cancers from two other institutions were used for validation. Results Ten percent of patients had HER2-positive tumors. At a median follow-up of 74 months, there were 72 recurrences. The 5-year RFS rates were 77.1% and 93.7% in patients with HER2-positive and HER2-negative tumors, respectively (P < .001). The 5-year DRFS rates were 86.4% and 97.2% in patients with HER2-positive and HER2-negative tumors, respectively (P < .001). In multivariate analysis, patients with HER2-positive tumors had higher risks of recurrence (hazard ratio [HR], 2.68; 95% CI, 1.44 to 5.0; P = .002) and distant recurrence (HR, 5.3; 95% CI, 2.23 to 12.62; P < .001) than those with HER2-negative tumors. Patients with HER2-positive tumors had 5.09 times (95% CI, 2.56 to 10.14; P < .0001) the rate of recurrences and 7.81 times (95% CI, 3.17 to 19.22; P < .0001) the rate of distant recurrences at 5 years compared with patients who had hormone receptor–positive tumors. Conclusion Patients with HER2-positive T1abN0M0 tumors have a significant risk of relapse and should be considered for systemic, anti-HER2, adjuvant therapy.

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