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Her2 Positive Breast Cancer

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HER2 Positive Breast Cancer

HER2 Positive Breast Cancer Book
Author : Sara Hurvitz,Kelly McCann
Publisher : Elsevier Health Sciences
Release : 2018-07-26
ISBN : 0323581234
Language : En, Es, Fr & De

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Book Description :

Get a quick, expert overview of clinically-focused topics and guidelines that are relevant to testing for HER2, which contributes to approximately 25% of breast cancers today. This concise resource by Drs. Sara Hurvitz, and Kelly McCann consolidates today’s available information on this growing topic into one convenient resource, making it an ideal, easy-to-digest reference for practicing and trainee oncologists.

Mechanisms of Resistance to T DM1 in HER2 positive Breast Cancer

Mechanisms of Resistance to T DM1 in HER2 positive Breast Cancer Book
Author : Junjie Zhang
Publisher :
Release : 2018
ISBN : 9788449080326
Language : En, Es, Fr & De

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Book Description :

El cáncer de mama HER2-positivo representa alrededor del 15-30% del total de pacientes con cáncer de mama. Este subtipo tiene un mal pronóstico, seguido del subtipo Triple-negativo (TNBC), que lo tiene aún peor. Actualmente, varios medicamentos están aprobados para las pacientes HER2-positivo, como Trastuzumab, Lapatinib y T-DM1. Sin embargo, a menudo éstas adquieren resistencia a estas terapias en un período de 1 a 2 años. El objetivo principal de este estudio es definir los mecanismos de resistencia a T-DM1. Durante mi tesis, generé líneas celulares resistentes a T-DM1 y exploré diferentes posibilidades in vitro que pudieran explicar cómo estas células escapan de la terapia contra HER2. Obtuve células resistentes a T-DM1 usando una línea celular derivada de un tumor primario de una paciente (PDX, Patient-derived xenograft) tratándolas con dosis crecientes de T-DM1. Comprobé los niveles de HER2 por mRNA y proteína, número de copias, efectores de señalización, analicé la región citotóxica de T-DM1 y su actividad lisosómica diferencial comparando la línea parental y las células resistentes. Esta tesis describe punto por punto todos los posibles mecanismos de resistencia que investigamos y cuales resultaron ser los responsables de la resistencia a T-DM1.

Immunotherapy Against HER2 positive Breast Cancers

Immunotherapy Against HER2 positive Breast Cancers Book
Author : Rocío Vicario
Publisher :
Release : 2016
ISBN : 9788449068768
Language : En, Es, Fr & De

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Book Description :

El 20% de los tumores mamarios sobre expresan el receptor de tirosina quinasa HER2, debido a su amplificación génica, tanto dentro de los cromosomas (HSR) como fuera ellos (DM). Se sabe muy poco acerca de la respuesta clínica o el rol en resistencia a terapias de estos patrones de amplificación. Por otro lado, un porcentaje de pacientes HER2+ expresa fragmentos carboxyl-terminales de HER2, p95HER2. Mas de la mitad de pacientes HER2+ no responde a las terapias disponibles. Hasta el momento, se desconoce si p95HER2 puede ser un blanco terapéutico. En este trabajo estudiaremos resistencias a terapias anti-HER2 y desarrollaremos nuevas terapias para el tratamiento de tumores p95HER2/HER2+. En esta tesis, evaluamos si el patrón de amplificación tiene impacto en la respuesta terapéutica. Mostramos que el ̃30% de los tumores HER2+ tienen amplificación en DM pero responden a la terapia de la misma manera que los HSR. El número de DM se mantiene cuando se desarrolla resistencia a la terapia, incluso si se pierde expresión proteica de HER2. Por lo tanto, la perdida de DM no parece ser un mecanismo de resistencia a terapias anti-HER2. Por otro lado, también evaluamos si p95HER2 puede ser un blanco para inmunoterapia. Presentamos un anticuerpo bi-especifico de células T (p95-TCB) que se une a p95HER2 en la célula tumoral y a CD3e, miembro del receptor de células T, presente en linfocitos T. La unión simultanea a la célula tumoral y a la célula T induce la activación de la célula T, la secreción de gránulos citotóxicos y la lisis de la célula tumoral. En modelos pre-clínicos, mostramos que p95-TCB aumenta la infiltración de células T y promueve la regresión tumoral. Comparado con HER2-TCB, p95-TCB tiene la ventaja de discriminar las células normales con baja expresión de HER2 previniendo efectos colaterales. En resumen, este trabajo descarta a los DMs como predictores de respuesta a terapias anti-HER2, y describe un nuevo anticuerpo bi-especifico que recluta y active células inmunes a los tumores p95HER2/HER2+ y como consecuencia la regresión de los mismos.

DNA Methylome in HER2 positive Resistant Breast Cancer

DNA Methylome in HER2 positive Resistant Breast Cancer Book
Author : Sònia Palomeras
Publisher :
Release : 2019
ISBN :
Language : En, Es, Fr & De

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Book Description :

The major clinical problem for HER2+ breast cancer target therapies is the acquisition of resistance. The DNA methylation status of the promoter gene region has been described as a common epigenetic alteration for transcriptional repression in human malignancies as breast cancer. The purpose of this thesis was to evaluate how the DNA methylation was involved in trastuzumab and lapatinib resistance in HER2+ breast cancer. We identify the epigenetic silencing of the TGFBI gene in trastuzumab resistance HER2+ breast cancer cell model and in post-treatment samples of patients treated with neoadjuvant anthracycline-taxane-based chemotherapy plus trastuzumab. Furthermore, the in vitro analysis revealed that the TGFBI reexpression induced greater sensitivity to trastuzumab in our resistant model, probably through its integrin-binding domains (EPDIM, NKDIL, YH and RGD). These results provide a basis for further studies to validate the hypermethylation status of TGFBI gene as monitoring biomarkers of trastuzumab resistance in HER2 breast cancer patients.

The Human Epidermal Growth Factor Receptor 2 HER2 in the Breast Cancer

The Human Epidermal Growth Factor Receptor 2  HER2  in the Breast Cancer Book
Author : Daniela Furrer
Publisher :
Release : 2017
ISBN :
Language : En, Es, Fr & De

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Book Description :

The overexpression of the human epidermal growth factor receptor 2 (HER2) and/or HER2 gene amplification are predictive factors in breast cancer. Following the HER2-targeted treatment with trastuzumab, the reliable evaluation of HER2 has become essential. Unfortunately, up to 50% of HER2-positive breast cancer patients develop resistance towards this drug. The objectives were: 1). To determine the most reliable and economical method to evaluate HER2 status (cohort of 521 consecutive breast cancer cases); 2). To examine the association between tobacco and alcohol consumption, and two HER2 polymorphisms (Ile655Val and Ala1170Pro), and the response to trastuzumab (cohort of 236 HER2-positive breast cancer patients treated with trastuzumab). Moreover, in a pilot study, we explored the association between genome-wide DNA methylation patterns in breast cancer tissues and the response to trastuzumab (cohort of 12 breast cancer patients treated with trastuzumab). HER2 status was evaluated by immunohistochemistry (IHC), fluorescence in situ hybridization (FISH), and TaqMan assay. We compared HER2 status determined by FISH on whole tissue (WT, one tissue per slide) section and tissue microarray (TMA, 60 tissues per slide) section, and HER2 status evaluated by IHC and FISH on the block used for diagnostic (diagnostic block) and on a randomly chosen additional block (random block). Clinicopathological information were assessed by review of medical records, tobacco and alcohol consumption by an administered validated questionnaire. DNA methylation patterns were evaluated using the Illumina Infinium HumanMethylation450 BeadChip. Overall concordance between HER2 status determined by FISH on WT and TMA sections was 98.2% and that between diagnostic and random blocks was 98.0% for FISH and 93.6% for IHC. Tobacco consumption and the Val allele were associated with a worse response, whereas alcohol consumption was associated with a better response. Methylation pattern in tumor tissues of HER2-positive breast cancer patients who acquired resistance to trastuzumab treatment differed from that of HER2-positive breast cancer patients who responded to trastuzumab treatment. However, this observation seemed to depend upon the method of bioinformatics analysis used. We conclude that FISH performed on TMA section represents a reliable and economical method for the evaluation of HER2. Results obtained by FISH, but not those obtained by IHC, fulfill the recommendations of the College of American Pathologists of concordance greater than 95% between the reference method and the new method. Tobacco use, alcohol consumption and Ile655Val HER2 polymorphism might influence the response to trastuzumab treatment.

Adjuvant Therapy for Breast Cancer

Adjuvant Therapy for Breast Cancer Book
Author : Monica Castiglione,Martine J. Piccart
Publisher : Springer Science & Business Media
Release : 2009-07-11
ISBN : 9780387751153
Language : En, Es, Fr & De

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Book Description :

Adjuvant treatment is administered prior to or as follow up to surgical procedures for breast cancer. Proven success in using medical therapies allowing for breast conserving procedures or reducing risk of occurrence. Although there has been much progress towards a cure, including the introduction of new targeted therapies, metastasizing cancer remains highly incurable.

Handbook of HER2 targeted agents in breast cancer

Handbook of HER2 targeted agents in breast cancer Book
Author : Ricardo H Alvarez,Javier Cortés,Leticia Mattos-Arruda,Mary Falzon,Angelica Fasolo,Michael Gandy,Luca Gianni,Nadia Harbeck,Martine Piccart,Stefania Zambelli,Dimitrios Zardavas
Publisher : Springer
Release : 2014-05-28
ISBN : 1907673946
Language : En, Es, Fr & De

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Book Description :

​Breast cancer is the most frequently diagnosed cancer and the leading cause of cancer death in women worldwide, accounting for nearly a quarter of the total new cancer cases each year. Of these cases, approximately 15–25% overexpress HER2, a transmembrane RTK kinase that is associated with aggressive tumor growth and poor outcomes. However, in the past decade, survival rates of patients with HER-positive breast cancer have significantly improved due to increased screening, HER2 testing, and breakthrough HER2-targeted drug therapies. Handbook of HER2-Targeted Agents in Breast Cancer provides oncologists, primary care physicians, trainees and other healthcare providers with a concise, accessible, and up-to-date survey of the field, including a review of our current understanding of the biology of the HER2 pathway and the rationale for targeting it in early-stage and advanced breast cancer, an overview of HER2-testing, and evidence-based discussions of available HER2-targeted regimens in the adjuvant and metastatic settings.

Analysis of Organotropic Metastasis in Relation to Herceptin Response of HER2 Positive Breast Cancer Cells

Analysis of Organotropic Metastasis in Relation to Herceptin Response of HER2 Positive Breast Cancer Cells Book
Author : Justin Molnar
Publisher :
Release : 2017
ISBN :
Language : En, Es, Fr & De

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Book Description :

HER2 (Epidermal Growth Factor Receptor Type 2) positive breast cancer accounts for 20-30 percent of cases and is associated with increased tumor cell proliferation, resistance to hormonal therapies and decreased patient survival. Trastuzumab (Herceptin®, Genentech-Roche) induces cytotoxicity in HER2+ breast cancer, significantly increases patient survival and is one of only a few targeted therapies approved for this aggressive malignancy. However, the majority of patients that qualify for this line of therapy exhibit innate or acquired resistance and must stop treatment. Herceptin resistance is associated with increased incidence of local invasion and systemic metastasis, and there is a need for in vivo methods to study the metastatic potential of Herceptin resistant and sensitive HER2+ breast cancer cells. Here, we have used the chicken (Gallus gallus) embryo chorioallantoic membrane (CAM) to establish an in vivo model of spontaneous metastasis for evaluating organotropism in Herceptin sensitive (SKBR3 and BT474) and resistant (AU565/innate and BT474-HR6/acquired) HER2+ breast cancer cells. Importantly, we demonstrate for the first time that Herceptin resistant cells are significantly more metastatic than their sensitive counterparts. We confirmed these results in vitro using 4D confocal microscopy and demonstrate that Herceptin resistant cells are also more invasive. Most notably, we report significant differences in the organotropisms for HER2+ breast cancer cells with innate versus acquired Herceptin resistance. Innately resistant cells exhibit significant increases in pulmotropic and hepatotropic metastases consistent with their increased expression of KRT81 and ID1. Alternatively, cells with acquired resistance exhibit significant increases in neurotropic metastasis consistent with their increased expression of HBEGF. Interestingly, cancer-associated fibroblasts (CAFs) derived from HER2+ breast cancer patients have been previously reported to also express elevated levels of HBEGF, suggesting that HER2+ CAFs may potentiate Herceptin resistance and neurotropic metastasis. To evaluate the role of stromal fibroblasts on HER2+ breast cancer cell organotropism, we first co-xenografted embryonic fibroblasts together with HER2+ breast cancer cells into the CAM model - we observed selective prometastatic effects of these stromal fibroblasts only on Herceptin resistant cells. We propose that this novel co-xenografting in vivo model can be used to evaluate the regulatory effects of patient-derived CAFs on organotropism of HER2+ breast cancer cells in relation to their Herceptin responsiveness. Findings from these studies will illuminate the cellular and molecular mechanisms that drive organotropism in aggressive and therapy-refractory breast cancers.

Drugs for HER 2 positive Breast Cancer

Drugs for HER 2 positive Breast Cancer Book
Author : Maria Sibilia,Christoph C. Zielinski,Rupert Bartsch,Thomas W. Grunt
Publisher : Springer Science & Business Media
Release : 2011-01-06
ISBN : 9783034600941
Language : En, Es, Fr & De

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Book Description :

Growth factor receptors have long been known to drive malignant transformation and cancer progression. The epidermal growth factor receptor (EGFR, ErbB, HER) system is likely the best described membrane receptor tyrosine kinase family in malignant tumors. With implementation of the growth-inhibitory anti-HER-2 antibody trastuzumab (Herceptin) for the treatment of HER-2-positive advanced metastatic breast cancer, a new era has dawned in the therapy of this malignant disease. Unfortunately, trastuzumab-sensitive cancers invariably develop resistance to the antibody after some time. Recent clinical studies have revealed that these refractory tumors are still responsive to inhibition of the HER receptor family using dual HER-1/-2 inhibitors such as lapatinib (Tykerb/Tyverb). Moreover, a multiplicity of novel, improved irreversibly acting small molecular HER tyrosine kinase inhibitors are in the pipeline of many drug developing companies and are being evaluated in the clinical setting.

Cardiac Toxicity of HER2 Directed Therapy in Women with Breast Cancer Epidemiology Etiology Risk Factors and Management

Cardiac Toxicity of HER2 Directed Therapy in Women with Breast Cancer  Epidemiology  Etiology  Risk Factors  and Management Book
Author : Shahid Ahmed
Publisher :
Release : 2017
ISBN :
Language : En, Es, Fr & De

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Book Description :

The HER2-targeted therapy have profoundly changed the outcomes of women with HER2-positive breast cancers. Trastuzumab and pertuzumab, HER2-targeting monoclonal antibodies, lapatinib and Neratinib, small molecule inhibitors of HER2 and the epidermal growth factor receptor, and ado-trastuzumab emtansine, a HER2-positive directed antibody drug conjugate, are approved for the treatment of HER2-positive breast cancer.

Breast Cancer ECT V1 I 3

Breast Cancer  ECT V1 I 3 Book
Author : N.A
Publisher : Demos Medical Publishing
Release : 2010-12-16
ISBN : 1617050431
Language : En, Es, Fr & De

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Book Description :

Breast Cancer: Breast cancer is second only to lung cancer as the leading cancer cause of death in women. In 2010 207,000 women will be diagnosed with breast cancer and over 39,000 are expected to die from breast cancer. Nevertheless, ongoing research and recent advances in both diagnostic and therapeutic modalities continue to make breast cancer management a rapidly evolving area in which the practitioner will want to be fully updated on current developments. Breast Cancer offers a comprehensive and in-depth review of the current literature of breast cancer. Chapters examine risk factors and prevention strategies, trends and developments in imaging, surgical management, radiotherapy advances, adjuvant endocrine and chemotherapies, targeted metastatic therapy, and the role of bisphosphonates and novel bone agents in breast cancer. With this volume the oncology practitioner will have a full and current overview of all significant current trends in this important area of oncology. About the Series: Emerging Cancer Therapeutics is an invited review publication providing a through analysis of key clinical research related to cancer therapeutics, including a discussion and assessment of current evidence, current clinical best practice, and likely near future developments. There is an emphasis throughout on multidisciplinary approaches to the specialty, as well as on quality and outcomes analysis. Published three times a year Emerging Cancer Therapeutics provides authoritative, thorough assessments of advances in therapeutics in all major areas of oncology, both solid and hematologic malignancies, with a focus on advances in medical and biological therapies with emerging clinical impact and encompassing new technologies with implications for management such as molecular imaging. Features of Emerging Cancer Therapeutics include: Editorial board of nationally recognized experts across the spectrum of Cancer Therapeutics In-depth, up-to-date expert reviews and analysis of major new developments in all areas of Cancer Therapeutics Issues edited by an authority in specific subject area Focuses on major topics in Cancer Therapeutics with in-depth articles covering advances in clinical and translational research developments, as well as clinical applications and experience Emphasizes multidisciplinary approaches to research and practice

Quantifying Tumor Evolutionary Dynamics and Predictors of Response in HER2 positive Breast Cancer Treated with Targeted Therapy

Quantifying Tumor Evolutionary Dynamics and Predictors of Response in HER2 positive Breast Cancer Treated with Targeted Therapy Book
Author : Katherine Lee McNamara
Publisher :
Release : 2020
ISBN :
Language : En, Es, Fr & De

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Book Description :

Evolution during treatment is a significant clinical problem that leads to treatment failure, resistance, and disease progression in many solid tumors, including breast cancer. Through analysis of clinical tissue samples and using a combination of established genomic techniques, computational modeling, and novel molecular profiling methods, this dissertation explores how HER2-positive breast tumors evolve under systemic therapy and characterizes predictors of treatment response. First using multi-region genomic sequencing and computational modeling, we show that the mutational landscape of a tumor can shift dramatically over a few months of combination chemotherapy and HER2-targeted therapy (termed "clonal replacement"). We then utilized tissue from a neoadjuvant HER2-positive breast cancer clinical trial to explore tumor-associated and immune-associated predictors of treatment response. We demonstrate the utility of spatial proteomic analysis of on-treatment biopsies to define biomarkers that stratify sensitive tumors early during neoadjuvant HER2-targeted therapy with implications for tailoring subsequent therapy. Taken together, our results shed light on the roles of heterogeneity, the frequency of resistance-causing aberrations, and the immune microenvironment in response to HER2-targeted therapy. In addition, our results also provide insights into the design of clinical trials that have a molecular analysis component.

Disparities of Trastuzumab Use in Resource Limited Or Resource Abundant Regions and Its Survival Benefit on HER2 Positive Breast Cancer A Real World Study from China

Disparities of Trastuzumab Use in Resource   Limited Or Resource   Abundant Regions and Its Survival Benefit on HER2 Positive Breast Cancer  A Real   World Study from China Book
Author : N.A
Publisher :
Release : 2017
ISBN :
Language : En, Es, Fr & De

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Book Description :

Abstract: Background: Trastuzumab is a key component of therapy for human epidermal growth receptor 2 (HER2) positive breast cancer. Because real‐world data are lacking, the present research was conducted to evaluate the actual use of and the effectiveness of trastuzumab in the real world in China. Methods: Inpatients with HER2 positive invasive breast cancer from 13 hospitals in Eastern China (2010–2015, n = 1, 139) were included in this study. We aimed to assess the actual use of trastuzumab and to evaluate potential efficacy from trastuzumab in real‐world research. Results: Of 1, 017 patients with early stage breast cancer (EBC), 40.5% (412/1, 017) received trastuzumab therapy. Patients with EBC in resource‐abundant regions (gross domestic product per capita >$15, 000 and trastuzumab included in Medicare) are more likely to receive trastuzumab than those in resource‐limited regions (37.3% vs. 13.0%, p

Systemic Treatment of HER2 positive Metastatic Breast Cancer A Systematic Review

Systemic Treatment of HER2   positive Metastatic Breast Cancer  A Systematic Review Book
Author : N.A
Publisher :
Release : 2014
ISBN :
Language : En, Es, Fr & De

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Book Description :

Abstract: Aim: We aimed to systematically review and summarize data from the available clinical trials that examined the treatment of HER2‐positive metastatic breast cancer. Methods: We reviewed phase 2 and 3 studies in which an anti‐HER2 agent was used in one or both arms of the study. While formal meta‐analysis was not possible for such a heterogeneous group of trials, resulting forest plots outline some generalizable findings. Results: There is strong evidence that the addition of an anti‐HER2 agent to standard chemo‐ or endocrine therapy improves clinically relevant measurable outcomes. There is also consistent evidence that initial treatment with trastuzumab alone (and subsequent use of a cytotoxic) is inferior to the initial combination of trastuzumab plus chemotherapy, and that either T‐DM1 or dual anti‐HER2 agents are superior to single anti‐HER2 agent regimens. There is no strong evidence that the use of more than one cytotoxic agent together with an anti‐HER2 agent confers any benefit over a single cytotoxic, anti‐HER2 combination. Conclusion: This review provides a strong evidence base for current clinical practice with a discussion of treatment in the Australian setting.

Targeted Therapies in Breast Cancer

Targeted Therapies in Breast Cancer Book
Author : Harold J. Burstein
Publisher : Oxford University Press, USA
Release : 2011
ISBN : 0199735670
Language : En, Es, Fr & De

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Book Description :

The development of monoclonal antibodies and other inhibitors of specific molecules, fully utilizing the insights learned from molecular techniques such as comparative microarrays and protein expression patterns, has led to the development and FDA approval of several agents for the treatment of breast cancer, such as trastuzamab (Herceptin, targeting HER-2 positive tumors) and lapatinib (Tykerb, targeting tumors with mutated/overexpressed EGFR 1 and 2). Other agents specifically targeting the estrogen receptor, the aromatose pathway and microtubule dynamics, fulvestrant (Faslodex, targeting the ER specifically in breast cancer cells), and letrozole (Femara, targeting the aromatose pathway), raloxifene (Evista, a selective estrogen receptor modulator), ixabepilone (Ixempra, a ?-tubulin inhibitor) have also been approved for various stages and specific settings in breast cancer treatment. The current challenges in the field include further targeting of these agents as part of specific strategies for each patient (biomarker testing, pharmacogenetics, etc.), as well as follow-up and management of adverse events. Part of the Oxford American Pocket Notes series, this volume provides clinicians with the ultra-concise, evidence-based, current information and insight on implementing the latest treatment strategies, including targeted agents, into clinical practice. This portable volume is intended to provide quick, easily accessible guidance for the practicing oncologist, oncology care staff (including nurses and PAs) as well as the primary care practitioner, on the mechanism of action, dosing and administration and adverse effects of the approved targeted agents.